From 1d30e09e4cdd9d2c87bfd7c37582c93a099aad1f Mon Sep 17 00:00:00 2001 From: github-actions <41898282+github-actions[bot]@users.noreply.github.com> Date: Sat, 13 Apr 2024 00:54:27 +0000 Subject: [PATCH] [automated] update transfemscience --- ... in Male to Female Transgender Patients.pdf | Bin 0 -> 52144 bytes ... in Male to Female Transgender Patients.pdf | Bin 0 -> 50970 bytes .... (USPATH 2023, abstract no. SAT-B2-T2).pdf | Bin 0 -> 133645 bytes .../articles/bica-adoption/index.html | 2 +- .../progestogens-breast-dev/index.html | 2 +- .../articles/spiro-testosterone/index.html | 2 +- .../articles/transfem-intro/index.html | 2 +- transfemscience.org/feed-posts.xml | 2 +- transfemscience.org/feed.xml | 16 ++++++++-------- 9 files changed, 13 insertions(+), 13 deletions(-) create mode 100644 files.transfemscience.org/pdfs/Igo & Visram (2021) - Progesterone Therapy Use and Safety in Male to Female Transgender Patients.pdf create mode 100644 files.transfemscience.org/pdfs/Igo & Visram (2021) - Testosterone Suppression With Injectable Estrogen Therapy Alone in Male to Female Transgender Patients.pdf create mode 100644 files.transfemscience.org/pdfs/Krishnamurthy et al. (2023) - Not all transfeminine individuals on estradiol can reach both target testosterone and target estradiol levels... (USPATH 2023, abstract no. 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Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy

By Aly | First published July 1, 2020 | Last modified April 2, 2024

Abstract / TL;DR

Bicalutamide is an antiandrogen which was introduced for the treatment of prostate cancer many years ago. Cost precluded its widespread use for other indications for many years. However, its cost has since come down and bicalutamide is now seeing significant adoption for use in transfeminine hormone therapy as well as for treatment of androgen-dependent conditions in other populations like cisgender women. Bicalutamide has risks of certain rare adverse effects like liver toxicity which have generated concerns about its safety and have limited its use in transfeminine people. However, while still significant, these risks are low with appropriate monitoring and clinical management. Prominent researchers in transgender medicine have recently shown openness to bicalutamide for potential use in transfeminine people and have written positively about it. Bicalutamide could eventually come to be regarded as acceptably safe for use in transfeminine hormone therapy, similarly to other antiandrogens with rare risks like spironolactone and cyproterone acetate. However, more studies and characterization of bicalutamide in transfeminine people will likely be needed before it could see wider adoption in transgender medicine.

History of Bicalutamide for Transfeminine People

Bicalutamide (Casodex) is a nonsteroidal antiandrogen and selective antagonist of the androgen receptor which was originally introduced for the treatment of prostate cancer in cisgender men in 1995. Prostate cancer is an androgen-dependent disease, so antiandrogens are effective in treating it. Bicalutamide has major advantages over other antiandrogens such as spironolactone (Aldactone) and cyproterone acetate (Androcur) in terms of antiandrogenic potency, clinical effectiveness, pharmacological selectivity, and tolerability. It also has improved potency, pharmacokinetic properties, and tolerability, as well as far better safety, compared to the older nonsteroidal antiandrogens flutamide (Eulexin) and nilutamide (Anandron, Nilandron). However, use of bicalutamide as an antiandrogen in transfeminine hormone therapy is very recent. The employment of bicalutamide for transfeminine people was largely precluded for many years by the fact that bicalutamide had pharmaceutical patent protection and was very expensive. However, this changed with the availability of generic versions of bicalutamide starting in 2007 to 2009. In addition, newer and more effective antiandrogens like abiraterone acetate (Zytiga) in 2011 and enzalutamide (Xtandi) in 2012 were introduced and superseded bicalutamide as the standard-of-care antiandrogen for the treatment of prostate cancer. These developments have greatly reduced the cost of bicalutamide and it has gradually become much more affordable in the last decade.

Before 2015, there were only a few mentions in the literature of bicalutamide for transfeminine people and a handful of anecdotal reports online of transfeminine people using it. The earliest clear mention of bicalutamide in the literature in the context of transfeminine hormone therapy was by Louis Gooren in 2011 (Gooren, 2011). Gooren is a major longtime researcher in the field of transgender medicine and is one of the coauthors of the Endocrine Society’s transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017). He and his colleagues at the Center of Expertise on Gender Dysphoria of the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands had conducted studies on nilutamide (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (de Voogt et al., 1987a; de Voogt et al., 1987b; Gooren et al., 1987; Johannes et al., 1987; Rao et al., 1988; Asscheman, Gooren, & Peereboom-Wynia, 1989; van Kemenade et al., 1989; Wiki). However, they seem to have abandoned it—probably due to its high incidence of lung toxicity and other off-target side effects. Nonetheless, Gooren began including nonsteroidal antiandrogens like flutamide and nilutamide in his publications as potential treatment options for transfeminine hormone therapy starting in the 1990s (Asscheman & Gooren, 1992; Gooren, 1999). Subsequently, flutamide was included in transgender health guidelines and other publications, though not necessarily favorably (e.g., Israel & Tarver, 1997; Levy, Crown, & Reid, 2003; Dahl et al., 2006a; Dahl et al., 2006b; Hembree et al., 2009; Moreno-Pérez et al., 2012). As a researcher interested in nonsteroidal antiandrogens for transfeminine people, bicalutamide—with its far better safety profile than flutamide and nilutamide—may have been appealing to Gooren. However, Gooren and his colleagues didn’t conduct clinical studies on bicalutamide for transfeminine people and never went beyond brief mention of it for such uses in their publications. Nor did any other academics.

Besides transfeminine people and men with prostate cancer, bicalutamide has been studied for use in the treatment of androgen-dependent conditions in other populations. For example, it has been used in the treatment of hirsutism (excessive facial/body hair growth) in cisgender women with and without polycystic ovary syndrome (PCOS) (Müderris, Bayram, & Güven, 1999; Müderris et al., 2002; Bahceci et al., 2004; Müderris & Öner, 2009; Moretti et al., 2016; Moretti et al., 2018; Wiki). Bicalutamide has also been studied in combination with anastrozole (Arimidex), an aromatase inhibitor, for the treatment of gonadotropin-independent precocious puberty in cisgender boys (Kreher et al., 2006; Lewis et al., 2009; Mitre & Lteif, 2009; Stenger et al., 2009; Lenz et al., 2010; Reiter et al., 2010; Tessaris et al., 2012; Özcabı et al., 2015; Kor, 2018; Arya & Davies, 2019; Nabhan & Eugster, 2019; Finkle et al., 2020; Gurnurkar, DiLillo, & Carakushansky, 2021; Wiki). This is a rare form of precocious puberty in which gonadotropin-releasing hormone modulators are not effective. A phase 2 clinical trial was completed and a New Drug Application (NDA) was submitted in the United States for treatment of the condition with bicalutamide and anastrozole, but the application was not approved due to inadequate evidence of effectiveness on the primary efficacy endpoint of limiting height (AstraZeneca, 2008). However, bicalutamide is still used off-label for this indication, and information on bicalutamide for this use is provided in the the Casodex Food and Drug Administration (FDA) label (FDA, 2017).

Although there was little discussion or use of bicalutamide in transfeminine people prior to 2015, this started to change in mid-2015. At that time, the Wikipedia content for bicalutamide was greatly expanded, which made information about bicalutamide more accessible. In addition, certain transfeminine people, noting its advantages over existing options and its excellent potential for use in transfeminine hormone therapy, began advocating for use of bicalutamide in transfeminine people in online circles. A number of open-minded clinicians started adopting bicalutamide in transfeminine people around this time and thereafter as well. The first clinical study of bicalutamide in transfeminine people, which began in 2013, was published as an abstract in 2017 and as a full paper in 2019 (Neyman, Fuqua, & Eugster, 2017; Neyman, Fuqua, & Eugster, 2019). It was a small retrospective chart review of bicalutamide alone as a second-line puberty blocker in adolescent transgender girls for whom gonadotropin-releasing hormone analogues were denied by insurance. As of present, it remains the only published clinical data on bicalutamide in transfeminine people. It’s not exactly great data by any means, but it’s a study at least. The researchers who conducted the study had previously published on bicalutamide as a puberty blocker in boys with gonadotropin-independent precocious puberty (e.g., Lenz et al., 2010; Haddad & Eugster, 2012). While limited in its findings, Neyman, Fuqua, and Eugster (2019) helped to generate significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.

In any case, due to the recent nature of bicalutamide as an option for use in transfeminine hormone therapy, as well as the lack of studies and characterization of bicalutamide in transfeminine people and concerns about its safety (see next section), bicalutamide isn’t widely used in transfeminine people at this time. In fact, transgender hormone therapy guidelines largely don’t even mention it still. At present, the use of bicalutamide in transfeminine people is mostly limited to a number of more flexible clinicians and to people in the transgender do-it-yourself (DIY) hormone therapy community.

Concerns About Bicalutamide Limiting its Use

The transgender medical community has been reluctant to endorse the use of bicalutamide in transfeminine people to date. This is because of the lack of clinical studies and characterization of bicalutamide in transfeminine people, most importantly in terms of safety. There have been concerns about rare instances of liver failure that have occurred with bicalutamide in men with prostate cancer (Wiki). The reported cases of liver toxicity with bicalutamide have generally been sudden-onset and severe. Rare liver toxicity is an acceptable risk in men with prostate cancer because the risk–benefit ratio of bicalutamide therapy is very favorable, with the benefit of treating prostate cancer vastly outweighing the harm of the very rare instances of liver problems. But transfeminine people are typically young and healthy, and bicalutamide isn’t treating a terminal illness when it’s used in us. If a transfeminine person develops liver failure and dies because of bicalutamide, that’s unnecessary harm and a life needlessly lost. Accordingly, the University of California San Francisco (UCSF) transgender care guidelines warn against use of bicalutamide in transfeminine people currently due to potential liver risks (Deutsch, 2016). Aside from risks, there is also a lack of data to guide appropriate dosing of bicalutamide in transfeminine people at this time. A typical bicalutamide dosage of 50 mg/day is being used and recommended, but this has been arbitrarily chosen with little basis to support it.

To date, there are 10 published case reports of serious liver toxicity in association with bicalutamide (Table). All of these cases were in men with prostate cancer and all occurred within 6 months of initiation of bicalutamide therapy, with two of the cases resulting in death. While this is not a lot of cases and may seem reassuring, it must be noted that quantity of published case reports tends to vastly underestimate the true incidence of rare adverse reactions. As an example, there are around 50 published case reports of meningioma with cyproterone acetate (Table), but a recent large study by the French government found that there were more than 500 operated instances of meningioma in association with high-dose cyproterone acetate over an 8-year period in France alone (Aly, 2020). Accordingly, as of writing there are 40 reports of liver failure, including 25 consequent deaths, in association with bicalutamide in the U.S. FDA’s international MedWatch/FAERS database. (As well as 240 cases of interstitial lung disease associated with bicalutamide notably—relative to only 14 published case reports; Table.) Even with this database however, fewer than 10% of serious adverse reactions are estimated to be reported (Graham, Ahmad, & Piazza-Hepp, 2002). Hence, the true numbers may be much greater. These instances are merely co-occurrences, and causality in terms of bicalutamide and liver toxicity has not been established. But they are concerning nonetheless. There is additionally an unpublished case anecdote of death in a young transfeminine person associated with bicalutamide that’s been making its rounds through the transgender medical community. Per certain very credible people in the field of transgender medicine (e.g., Asa Radix and Zil Goldstein), she is said to have been a 20-year-old transgender girl in Texas taking bicalutamide with rapid-onset liver failure and no warning signs. This case has given clinicians and researchers who are aware of it reservations about the use of bicalutamide in hormone therapy for transfeminine people. Another case of liver failure and death in a transgender person over 60 years of age who was treated with bicalutamide has also been informally reported (QueerDoc).

In any case, the reported cases of serious liver toxicity with bicalutamide in transgender people have not been published nor properly confirmed. In addition, the absolute incidence of liver toxicity with bicalutamide is likely to be very low. For instance, the incidence of abnormal liver function tests (i.e., elevated liver enzymes on blood work) was only 3.4% with high-dose (150 mg/day) bicalutamide monotherapy relative to 1.9% for placebo (a 1.5% difference attributable to bicalutamide) at 3.0 years of follow-up in the Early Prostate Cancer (EPC) clinical programme, a series of three phase 3 randomized controlled trials consisting of over 8,000 patients in which bicalutamide was evaluated for treatment of early prostate cancer (Anderson, 2003; Iversen et al., 2004; Wiki; Wiki). Moreover, there were no cases of serious liver toxicity or liver failure with bicalutamide in the initial clinical development programme of bicalutamide for advanced prostate cancer, in which almost 4,000 men were treated with bicalutamide (Blackledge, 1996; Kolvenbag & Blackledge, 1996; McLeod, 1997; Anderson, 2003; Iversen et al., 2004; Wiki). However, it should be noted that this was with careful monitoring of liver function in patients and with prompt discontinuation of bicalutamide upon detection of clinically concerning hepatic abnormalities. About 0.5 to 1.5% of men taking 50 to 150 mg/day bicalutamide in the major clinical programmes of bicalutamide for prostate cancer developed liver changes sufficiently marked that they required discontinuation (Blackledge, 1996; See et al., 2002; Wiki). Hence, regular liver monitoring is essential with bicalutamide to ensure that the possibility of severe liver toxicity is avoided.

Bicalutamide has a much lower risk of liver toxicity than its analogue flutamide (Kolvenbag & Blackledge, 1996; Schellhammer et al., 1997; Thole et al., 2004; Manso et al., 2006; Table). However, it retains a small risk of liver toxicity of its own—one with the potential for serious consequences. Hence, caution is warranted with its use, and careful liver monitoring is a necessity for anyone taking it.

Recent Developments and the Future

Bicalutamide is currently being adopted and characterized for use in the treatment androgen-dependent skin and hair conditions in cisgender women. For instance, a rigorous Italian phase 3 randomized controlled trial of bicalutamide for hirsutism was recently published (Moretti et al., 2018). Retrospective chart reviews of bicalutamide for scalp hair loss in cisgender women have also been published recently (Fernandez-Nieto et al., 2019; Ismail et al., 2020; Fernandez-Nieto et al., 2020; Moussa et al., 2021). The hair loss studies have observed low though significant rates of liver changes with bicalutamide.

Certain transgender medical researchers are showing interest in bicalutamide as well. Perhaps most notably, Wylie Hembree—the lead author of the Endocrine Society’s 2009 and 2017 transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017)—wrote positively about bicalutamide for transfeminine people in a recent review (Fishman, Paliou, Poretsky, & Hembree, 2019). He and his colleagues cited the recent phase 3 trial of bicalutamide for hirsutism in cisgender women and the study of bicalutamide as a puberty blocker in transgender girls in support of potential use of bicalutamide for transfeminine people. Guy T’Sjoen—another major researcher in transgender medicine and co-author of the Endocrine Society guidelines (Hembree et al., 2017; Mitchell, 2020)—seemed to show openness to bicalutamide with his colleagues in a recent review as well (Iwamoto et al., 2019). Researchers outside of the United States in particular may be more open to bicalutamide, owing to accumulating health concerns with cyproterone acetate—the most commonly used antiandrogen outside of the United States (Aly, 2020). John Randolph, a researcher at the University of Michigan, has also written positively about bicalutamide (Randolph, 2018), though he may have since changed his mind on it (Michigan Medicine, 2020). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (e.g., Hamidi & Davidge-Pitts, 2019; Cocchetti et al., 2020).

The small risks of bicalutamide with appropriate monitoring may prove to be acceptable to the transgender medical community. This would perhaps be analogous to the rare incidences of serious adverse effects with say spironolactone (e.g., hyperkalemia) or cyproterone acetate (e.g., benign brain tumors, blood clots, breast cancer, liver toxicity). It’s possible that bicalutamide may not ultimately be recommended as a first-line therapy due to its risks. However, it could still be allowed as a second-line option when other antiandrogens are less feasible or not possible due to being for instance inadequately effective, poorly tolerated, contraindicated, or unavailable. The transgender medical community isn’t there at this time though. More developments—namely studies and characterization of bicalutamide in actual transfeminine people—are likely to be needed before bicalutamide could become more accepted for use in transfeminine people or recommended in transgender hormone therapy guidelines.

Updates

Update 1: Thompson et al. (2021) [Fenway Health Guidelines]

In March 2021, the Fenway Health transgender health clinical practice guidelines were updated from the last version (October 2015) to the following latest edition (Aly, 2020):

  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]

This update is notable as these guidelines included bicalutamide as an antiandrogen option for transfeminine people. While they did not recommend bicalutamide as a first-line agent due to its limited characterization in transfeminine people and its known small risk of liver toxicity, they were cautiously permissive of its use in transfeminine hormone therapy:

Bicalutamide can be used for [gender-affirming hormone therapy], but there are very few studies examining its use and the relative risk/benefit for this purpose. Because of reported cases of fulminant hepatitis, consensus is that its use in gender affirming hormonal regimen should be carefully considered, used only after alternative options have been trialed or offered, and an in-depth discussion of these potential risks have been had.

These are the first transgender care guidelines to allow the use of bicalutamide, and only the second guidelines to include bicalutamide. Previously, only the UCSF guidelines mentioned bicalutamide, but they were not permissive of its use in transfeminine people.

Update 2: Tomson et al. (2021) [SAHCS Guidelines]

In September 2021, the Southern African HIV Clinicians Society (SAHCS) published clinical guidelines for transgender care for the first time:

  • Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]

Surprisingly, these guidelines not only included bicalutamide but recommended it as the preferred antiandrogen over spironolactone and cyproterone acetate. The reason stated for this was “less risk of neurosteroid depletion (does not cross blood-brain-barrier readily).” However, this supposed effect isn’t a known concern with antiandrogens besides 5α-reductase inhibitors, and bicalutamide actually does appear to be centrally permeable in humans (Wiki). Also surprisingly, no mention of liver toxicity or liver enzyme monitoring with bicalutamide was made in these guidelines. Considering these apparent oversights and others, these guidelines’s recommendations should probably be interpreted with caution.

Update 3: Coleman et al. (2022) [WPATH SOC8 Guidelines]

In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published (Coleman et al., 2022). The WPATH SOC8 are among the most important if not the most important transgender care guidelines that exist and that are consulted by health care professionals. These guidelines briefly discussed bicalutamide including in the following two instances:

Bicalutamide is an antiandrogen that has been used in the treatment of prostate cancer. It competitively binds to the androgen receptor to block the binding of androgens. Data on the use of bicalutamide in trans feminine populations is very sparse and safety data is lacking. One small study looked at the use of bicalutamide 50 mg daily as a puberty blocker in 23 trans feminine adolescents who could not obtain treatment with a GnRH analogue (Neyman et al., 2019). All adolescents experienced breast development which is also commonly seen in men with prostate cancer who are treated with bicalutamide. Although rare, fulminant hepatotoxicity resulting in death has been described with bicalutamide (O’Bryant et al., 2008). Given that bicalutamide has not been adequately studied in trans feminine populations, we do not recommend its routine use.

When selecting a medication, we advise using those which have been studied in multiple transgender populations (i.e., estrogen, cyproterone acetate, GnRH agonists) rather than medications with little to no peer-reviewed scientific studies (i.e., bicalutamide, rectal progesterone, etc.) (Angus et al., 2021; Butler et al., 2017; Efstathiou et al., 2019; Tosun et al., 2019).

As can be seen, the WPATH SOC8 did not recommend the routine use of bicalutamide in transfeminine people owing to the lack of studies of it in this population and its potential risks. As touched on in the present article, it is likely that more studies of bicalutamide in transfeminine people will be needed before bicalutamide could become endorsed by major transgender care guidelines.

Update 4: Jamie Reed 2023 Bicalutamide Liver Toxicity Case

In February 2023, Jamie Reed, a former case manager at the The Washington University Transgender Center at St. Louis Children’s Hospital in St. Louis, Missouri, published the op-ed “I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle.” in a conservative online news outlet called The Free Press. In this article, Reed expressed that she had become disillusioned with the medical care of transgender youth and layed out her grievances. In addition however, she briefly described an additional case of liver toxicity with bicalutamide in a transfeminine person that had allegedly occurred at her center. This individual was said to be 15 years of age and was given bicalutamide as a puberty blocker by Dr. Christopher Lewis, one of the co-founders of the center. She was said to have subsequently developed liver toxicity and was taken off of bicalutamide. In an electronic message to the center, her mother said that they were “lucky her family was not the type to sue”. This instance, and Reed’s op-ed in general, were subsequently widely reported on in conservative news media, for instance on Fox News and in the Daily Mail (Google). In addition to her op-ed, Reed provided a sworn affidavit to the office of Republican Missouri attorney general Andrew Bailey, who proceeded to launch an investigation of the clinic (Missouri Government, 2023a). The following further information was released in the affidavit:

One doctor at the Center, Dr. Chris Lewis, is giving patients a drug called Bicalutamide. The drug has a legitimate use for treating pancreatic cancer [sic], but it has a side effect of causing breasts to grow, and it can poison the liver. There are no clinical studies for using this drug for gender transitions, and there are no established standards of care for using this drug.

Because of these risks and the lack of scientific studies, other centers that do gender transitions will not use Bicalutamide. The adult center affiliated with Washington University will not use this medication for this reason. But the Center treating children does.

I know of at least one patient at the Center who was advised by the renal department to stop taking Bicalutamide because the child was experiencing liver damage. The child’s parent reported this to the Center through the patient’s online self-reporting medical chart (MyChart). The parent said they were not the type to sue, but “this could be a huge PR problem for you.”

While unpublished and unverified like the earlier reports of liver toxicity with bicalutamide in transfeminine people, this case represents yet another report, and is notably by far the best-documented one. No other clinical details on the case were provided, and it is unclear whether it involved serious liver toxicity, merely asymptomatic liver function test abnormalities, or a clinical situation somewhere in-between these extremes. In any case, it does seem clear that this instance is not likely to have a positive influence on the further adoption of bicalutamide in transfeminine hormone therapy.

Subsequent to the investigation of the clinic being launched, in April 2023, Missouri greatly restricted gender-affirming care for transgender youth and adults, with some of the most severe limits that have been enacted in the United States (Associated Press, 2023a; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments. The new state law restricting gender-affirming care took effect August 28, 2023, and Washington University announced that it would stop prescribing puberty blockers and hormone therapy to transgender youth shortly thereafter (Associated Press, 2023b).

A New York Times article with additional information on the case was also subsequently published (Ghorayshi, 2023 [Excerpts]). It was noted that the adolescent had been on bicalutamide for 1 year and definitely experienced hepatotoxicity. However, she also had a complicated medical history, including being immunocompromised, having recently had COVID-19, and having taken another drug known to be associated with hepatotoxicity. As such, the hepatotoxicity cannot be definitively attributed to bicalutamide, but it simultaneously cannot be ruled out that bicalutamide was involved or causative.

Subsequent Burgener et al. (2023, 2024) Findings

Following the preceding case, Lewis and colleagues went on to publish a conference abstract and preprint of a study of bicalutamide in transfeminine youth and young adults in which they stated that it does not increase liver enzymes in this population (Burgener et al., 2023; Burgener et al., 2024). However, a closer look at their data show that bicalutamide did statistically significantly elevate certain liver parameters relative to other antiandrogens, namely rates of elevated aspartate aminotransferase (AST) (upper limit of normal 10.7% vs. 1.5%, P = 0.02) (Burgener et al., 2024). Likewise, rates of elevated alanine aminotransferase (ALT) appeared to trend in the direction of being increased, though this was not statistically significant (upper limit of normal 16.7% vs. 11.6%, P = 0.37) (Burgener et al., 2024). In any case, rates of clinically significant elevations in liver enzymes with bicalutamide, defined as greater than three times the upper limit of normal, were not significantly increased in the study.

On the basis of the relevant research in men with prostate cancer (Wiki), Lewis and colleagues’ study, with a bicalutamide-group sample size of only 84 transfeminine individuals, was clearly greatly underpowered for evaluating liver function changes. Per the Early Prostate Cancer trial of high-dose bicalutamide monotherapy in men with prostate cancer, elevated liver enzymes appear to occur with bicalutamide at a rate of only about 1.5% more than placebo, or roughly an additional 1 in every 66 people (Wiki). Based on power analysis, this would require a far larger sample size to have adequate statistical power and actually have a chance of achieving statistical significance.

As such, it seems to the present author premature to conclude that bicalutamide does not elevate liver enzymes in transfeminine people.

Lewis and colleagues didn’t mention in their study paper the transfeminine adolescent liver toxicity case reported by Jamie Reed that was said to have occurred at their clinic nor have they published a case report about this instance. Instead, only the following is stated:

One case report published in 2024 described a transgender female adolescent prescribed bicalutamide 50 mg daily who presented to a hospital with liver toxicity that resolved after stopping bicalutamide (Wilde et al., 2024). This appears to be the first documented case of bicalutamide-induced hepatoxicity in a transgender female.

While this case was, coincidentally, also a 17-year-old transfeminine adolescent (Wilde et al., 2024), this instance, per the medical histories and reporting authors/institutions, appears to be distinct from Dr. Lewis’s that was reported by Jamie Reed.

However, Lewis and colleagues did note the following in their paper, which plausibly might have been the Jamie Reed case:

There was one individual in whom bicalutamide was stopped after the follow-up period designated for the study. This individual developed ALT and AST >2x ULN after an episode of COVID and had a thorough hepatology evaluation. As ALT and AST were never > 3x ULN, it was not recommended that bicalutamide be stopped; however, ultimately a clinical decision was made to stop the medication and ALT and AST normalized.

Another concern with Lewis and colleagues’ paper pertains to the following statements:

Whereas bicalutamide doses for prostate cancer reach 150 mg daily, doses used in the care of AMAB transfeminine individuals are much lower (25-50 mg daily).

Bicalutamide doses used in prostate cancer are up to 150 mg daily. Due to these concerns of liver toxicity, bicalutamide has not been routinely used as an anti-androgen in AMAB transfeminine individuals, despite the much lower doses needed in this population (∼25-50 mg daily).

In actuality, bicalutamide is most widely used in prostate cancer, in the form of combined androgen blockade with surgical or medical castration, at a dosage of 50 mg/day, whereas the 150 mg/day dosage is used less commonly, in the form of monotherapy (Wiki). Moreover, only the 50 mg/day dosage is used in the United States, where monotherapy is not approved. Among the published case reports of hepatotoxicity with bicalutamide in men with prostate cancer, half have been at a dose of 50 mg/day and the other half have been at a dose of 80 to 150 mg/day (Wiki). The two instances of death due to hepatotoxicity with bicalutamide were both at 50 mg/day. There is currently no evidence that the hepatotoxicity of bicalutamide is dose-dependent across its clinically used dosage range (Wiki), although employment of the lowest effective dose in transfeminine people nonetheless seems prudent just in case. Hence, in contrast to Lewis and colleague’s claims, a bicalutamide dosage of 50 mg/day is not less than that generally used in prostate cancer, and clearly retains substantial hepatotoxic potential.

Update 5: New Bicalutamide Publications in 2022 Through 2024

  • Angus, L., Nolan, B., Zajac, J., & Cheung, A. (November 2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (November 2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
  • Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
  • Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (May 2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]), 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
  • Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
  • Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
  • Vierregger, K. S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Warus, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
  • Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
  • Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
  • Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. Journal of Adolescent Health, 74(1), 5–6. [DOI:10.1016/j.jadohealth.2023.10.010]

Update 6: Original Bicalutamide Liver and Lung Toxicity Analysis by Sam

A few years ago back in 2021, Transfeminine Science author Sam conducted an original analysis of the incidence of liver and lung toxicity with bicalutamide in the published clinical trial literature. This project was never finished or made publicly available. However, with bicalutamide being increasingly studied and adopted for use in transfeminine people, it seems quite valuable and relevant today. As such, we have opted to now publish Sam’s analysis in this section.

Sam’s analysis can be found in the provided document here. In terms of methodology, she searched PubMed for all clinical trials of bicalutamide, collated all of the relevant results into a table, and then calculated the incidences of serious liver toxicity and lung toxicity from those data. In clinical trials, adverse events are rated in terms of grades of severity, with a Grade 3 adverse event defined as “severe”, Grade 4 as “life-threatening”, and Grade 5 as “death” (Wiki).

Of 229 results, 33 trials were found to be relevant and were included. Most of the trials were in men with prostate cancer, but a few were in women with cancer and boys with precocious puberty. Sam found that of a total of 7,703 evaluable participants, there were 2 instances of serious liver toxicity and 2 instances of serious lung toxicity with bicalutamide. This resulted in the same incidence rate of 0.026% (95% CI: 0.003% to 0.094%) or approximately 1 in 3,846 individuals for both liver toxicity and lung toxicity. Combining these toxicities resulted in a total incidence of serious liver or serious lung toxicity with bicalutamide of 0.052% (95% CI: 0.014% to 0.133%) or approximately 1 in 1,923 individuals. All of the observed toxicity events were rated as Grade 3 or 4. It should be noted that clinical trials of bicalutamide typically employ careful laboratory monitoring and assessment of clinical adverse events as well as prompt medication discontinuation upon unfavorable laboratory changes.

While the confidence intervals (CIs) in Sam’s analysis were wide and hence the estimates are very rough, they provide an idea of the potential real-world risk of serious toxicity with bicalutamide in transfeminine people based on high-quality clinical data. Notably, they do not suffer from the problem of under-reporting of adverse events that occurs with published case reports, pharmacovigilance databases, and certain types of observational studies. However, limitations of Sam’s analysis include (1) toxicity incidence rates for non-bicalutamide-treated controls not being assessed and (2) most of the patients having cancer and being of older age, and hence the generalizability of the findings to healthy transfeminine people not being fully clear. In any case, I was surprised by how high the incidence rates were when I first saw her analysis, and I suspect that others may be as well.

References

  • Anderson, J. (2003). The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU International, 91(5), 455–461. [DOI:10.1046/j.1464-410X.2003.04026.x]
  • Angus, L., Nolan, B., Zajac, J., & Cheung, A. (2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
  • Arya, V. B., & Davies, J. H. (2019). Idiopathic gonadotropin-independent precocious puberty - is regular surveillance required? Journal of Pediatric Endocrinology & Metabolism: JPEM, 32(4), 403–407. [DOI:10.1515/jpem-2018-0419]
  • Asscheman, H., Gooren, L. J., & Peereboom-Wynia, J. D. (1989). Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals—experiences with a novel androgen receptor blocker. Clinical and Experimental Dermatology, 14(5), 361–363. [DOI:10.1111/j.1365-2230.1989.tb02585.x]
  • Asscheman, H., & Gooren, L. J. (1992). Hormone Treatment in Transsexuals. In Bocking, W. O., Coleman, E. (Eds). Gender Dysphoria: Interdisciplinary Approaches in Clinical Management (pp. 39–54). Binghamton: Haworth Press. / Journal of Psychology & Human Sexuality, 5(4), 39–54. [Google Scholar] [Google Books] [DOI:10.1300/J056v05n04_03]
  • AstraZeneca. (2008). Clinical Review. NDA. 22-310/S-001. Casodex (bicalutamide) for Testotoxicosis. Food and Drug Administration/AstraZeneca Pharmaceuticals. [URL] [PDF]
  • Bahceci, M., Tuzcu, A., Canoruc, N., Tuzun, Y., Kidir, V., & Aslan, C. (2004). Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance. Hormone Research in Paediatrics, 62(6), 283–287. [DOI:10.1159/000081973]
  • Bailey, A. (2023 February 9). Missouri Attorney General Andrew Bailey Confirms Launch of Multi-Agency Investigation into St. Louis Transgender Center for Harming Hundreds of Children. Attorney General Andrew Bailey, Missouri Government. [URL] [Affadavit of Jamie Reed]
  • Bailey, A. (2023 April 13). Missouri Attorney General Andrew Bailey Promulgates Emergency Regulation Targeting Gender Transition Procedures for Minors. Attorney General Andrew Bailey, Missouri Government. [URL] [Emergency Regulation PDF]
  • Ballentine, S., & Hollingsworth, H. (2023 April 13). Missouri to limit gender-affirming care for minors, adults. Associated Press. [URL]
  • Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
  • Blackledge, G. R. P. (1996). Clinical progress with a new antiandrogen, Casodex™ (bicalutamide). European Urology, 29(Suppl 2), 96–104. [DOI:10.1159/000473847]
  • Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]), 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
  • Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
  • Cocchetti, C., Ristori, J., Romani, A., Maggi, M., & Fisher, A. D. (2020). Hormonal Treatment Strategies Tailored to Non-Binary Transgender Individuals. Journal of Clinical Medicine, 9(6), 1609. [DOI:10.3390/jcm9061609]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Dahl, M., Feldman, J. L., Goldberg, J. M., & Jaberi, A. (2006). Physical aspects of transgender endocrine therapy. International Journal of Transgenderism, 9(3–4), 111–134. [DOI:10.1300/J485v09n03_06]
  • Dahl, M., Feldman, J. L., Goldberg, J., & Jaberi, A. (2006). Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines. Physical Aspects of Transgender Endocrine Therapy. Vancouver: Vancouver Coastal Health. [Google Scholar] [PDF]
  • de Voogt, H. J., Rao, B. R., Gooren, L. J. G., Geldof, A. A., & Bouman, F. G. (1987). Considerations About the Use of Anti-Androgenic Drugs in Male-to-Female Transsexuals. Tenth International Symposium on Gender Dysphoria, Diagnosis and Treatment of Transsexualism, Vrije Universiteit Amsterdam, The Netherlands, June 9–12, 1987. Harry Benjamin International Gender Dysphoria Association. [PDF]
  • de Voogt, H. J., Rao, B. R., Geldof, A. A., Gooren, L. J. G., & Bouman, F. G. (1987). Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate. The Prostate, 11(4), 305–311. [DOI:10.1002/pros.2990110403]
  • Deutsch, M. B. (2016). Overview of feminizing hormone therapy. In Deutsch, M. B. (Ed.). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition (pp. 26–48). San Francisco: University of California, San Francisco/UCSF Transgender Care. [URL] [PDF]
  • Fernandez-Nieto, D., Saceda-Corralo, D., Rodrigues-Barata, R., Hermosa-Gelbard, A., Moreno-Arrones, O., Jimenez-Cauhe, J., Ortega-Quijano, D., & Vano-Galvan, S. (2019). Oral bicalutamide for female pattern hair loss: A pilot study. Dermatologic Therapy, 32(6), e13096. [DOI:10.1111/dth.13096]
  • Fernandez-Nieto, D., Saceda-Corralo, D., Jimenez-Cauhe, J., Moreno-Arrones, O. M., Rodrigues-Barata, R., Hermosa-Gelbard, A., & Vano-Galvan, S. (2020). Bicalutamide: A potential new oral antiandrogenic drug for female pattern hair loss. Journal of the American Academy of Dermatology, 83(5), e355–e356. [DOI:10.1016/j.jaad.2020.04.054]
  • Finkle, A., Zavertnik, S., Myers, S., Cormier, D., Heithaus, J., & Augustyn, M. (2020). Growing Up Fast: Managing Autism Spectrum Disorder and Precocious Puberty. Journal of Developmental and Behavioral Pediatrics: JDBP, 41(9), 740–742. [DOI:10.1097/DBP.0000000000000865]
  • Fishman, S. L., Paliou, M., Poretsky, L., & Hembree, W. C. (2019). Endocrine Care of Transgender Adults. In Poretsky, L., & Hembree, W. C. (Eds.). Transgender Medicine (pp. 143–163). Cham: Humana Press. [DOI:10.1007/978-3-030-05683-4_8]
  • Food and Drug Administration (FDA). (2017). CASODEX (bicalutamide) tablet, for oral use. [URL] [PDF]
  • Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
  • Ghorayshi, A. (2023 August 29). How a Small Gender Clinic Landed in a Political Storm. The New York Times. [URL]
  • Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
  • Gooren, L., Spinder, T., Spijkstra, J. J., Van Kessel, H., Smals, A., Rao, B. R., & Hoogslag, M. (1987). Sex steroids and pulsatile luteinizing hormone release in men. Studies in estrogen-treated agonadal subjects and eugonadal subjects treated with a novel nonsteroidal antiandrogen. The Journal of Clinical Endocrinology & Metabolism, 64(4), 763–770. [DOI:10.1210/jcem-64-4-763]
  • Gooren, L. J. G. (1999). Hormonal Sex Reassignment. International Journal of Transgenderism, 3(3), 1–7. [Google Scholar] [URL] [Alt]
  • Gooren, L. J. (2011). Care of transsexual persons. New England Journal of Medicine, 364(13), 1251–1257. [DOI:10.1056/NEJMcp1008161]
  • Graham, D. J., Ahmad, S. R., & Piazza‐Hepp, T. (2002). Spontaneous Reporting—USA. In Mann, R. D., & Andrews, E. B. (Eds.). Pharmacovigilance (pp. 219–227). Chichester: John Wiley & Sons. [DOI:10.1002/0470853093.ch17]
  • Gurnurkar, S., DiLillo, E., & Carakushansky, M. (2021). A Case of Familial Male-limited Precocious Puberty with a Novel Mutation. Journal of Clinical Research in Pediatric Endocrinology, 13(2), 239–244. [DOI:10.4274/jcrpe.galenos.2020.2020.0067]
  • Haddad, N. G., & Eugster, E. A. (2012). Peripheral Precocious Puberty: Interventions to Improve Growth. In Preedy, V. R. (Ed.). Handbook of Growth and Growth Monitoring in Health and Disease (pp. 1199–1212). New York: Springer. [DOI:10.1007/978-1-4419-1795-9_71]
  • Hamidi, O., & Davidge-Pitts, C. J. (2019). Transfeminine Hormone Therapy. Endocrinology and Metabolism Clinics, 48(2), 341–355. [DOI:10.1016/j.ecl.2019.02.001]
  • Hembree, W. C., Cohen-Kettenis, P., Delemarre-Van De Waal, H. A., Gooren, L. J., Meyer III, W. J., Spack, N. P., Tangpricha, V., & Montori, V. M. (2009). Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 94(9), 3132–3154. [DOI:10.1210/jc.2009-0345]
  • Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., Rosenthal, S. M., Safer, J. D., Tangpricha, V., & T’Sjoen, G. G. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism, 102(11), 3869–3903. [DOI:10.1210/jc.2017-01658] [PDF]
  • Ismail, F. F., Meah, N., de Carvalho, L. T., Bhoyrul, B., Wall, D., & Sinclair, R. (2020). Safety of oral bicalutamide in female pattern hair loss: A retrospective review of 316 patients. Journal of the American Academy of Dermatology, 83(5), 1478–1479. [DOI:10.1016/j.jaad.2020.03.034]
  • Israel, G. E., & Tarver, D. E. (1997). Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts (p. 66). Philadelphia: Temple University Press. [Google Scholar] [Google Books]
  • Iversen, P., Johansson, J. E., Lodding, P., Lukkarinen, O., Lundmo, P., Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T., Carroll, K., & Scandinavian Prostatic Cancer Group. (2004). Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. The Journal of Urology, 172(5 Part 1), 1871–1876. [DOI:10.1097/01.ju.0000139719.99825.54]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 2042018819871166. [DOI:10.1177/2042018819871166]
  • Johannes, F. L. M., van Kemenade, M. A., Cohen-Kettenis, P. T., Cohen, L., & Gooren, L. J. G. (1987). Effects of RU 23.903 (Anandron) on Lateralization and Spatial Ability in Male-to-Female-Transsexuals. Tenth International Symposium on Gender Dysphoria, Diagnosis and Treatment of Transsexualism, Vrije Universiteit Amsterdam, The Netherlands, June 9–12, 1987. Harry Benjamin International Gender Dysphoria Association. [PDF]
  • Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
  • Kolvenbag, G. J., & Blackledge, G. R. (1996). Worldwide activity and safety of bicalutamide: a summary review. Urology, 47(1), 70–79. [DOI:10.1016/S0090-4295(96)80012-4]
  • Kor, Y. (2018). Central precocious puberty in a case of late-diagnosed familial testotoxicosis and long-term treatment monitoring. Hormones, 17(2), 275–278. [DOI:10.1007/s42000-018-0029-1]
  • Kreher, N. C., Pescovitz, O. H., Delameter, P., Tiulpakov, A., & Hochberg, Z. E. (2006). Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole. The Journal of Pediatrics, 149(3), 416–420. [DOI:10.1016/j.jpeds.2006.04.027]
  • Lenz, A. M., Shulman, D., Eugster, E. A., Rahhal, S., Fuqua, J. S., Pescovitz, O. H., & Lewis, K. A. (2010). Bicalutamide and third-generation aromatase inhibitors in testotoxicosis. Pediatrics, 126(3), e728–e733. [DOI:10.1542/peds.2010-0596]
  • Levy, A., Crown, A., & Reid, R. (2003). Endocrine intervention for transsexuals. Clinical Endocrinology, 59(4), 409–418. [DOI:10.1046/j.1365-2265.2003.01821.x]
  • Lewis, K. A., Lenz, A., Eugster, E. A., Fuqua, J. S., Pescovitz, O. H., Rahhal, S., & Shulman, D. (2009). Long term bicalutamide and 3rd generation aromatase inhibitor therapy in two boys with testotoxicosis. Hormone Research [in Paediatrics], 72(Suppl 3), 266–267 (PO2-189). [Google Scholar] [DOI:10.1159/000239668]
  • Manso, G., Thole, Z., Salgueiro, E., Revuelta, P., & Hidalgo, A. (2006). Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiology and Drug Safety, 15(4), 253–259. [DOI:10.1002/pds.1168]
  • McLeod, D. G. (1997). Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer. The Oncologist, 2(1), 18–27. [DOI:10.1634/theoncologist.2-1-18]
  • Michigan Medicine. (2020). Feminizing Gender-Affirming Hormone Care: The Michigan Medicine Approach. Ann Arbor: Michigan Medicine/University of Michigan. [URL] [PDF]
  • Mitchell, F. (2020). Guy T’Sjoen: collaborating to improve transgender wellbeing. The Lancet Diabetes & Endocrinology, 8(7), 568–568. [DOI:10.1016/S2213-8587(20)30192-3]
  • Mitre, N., & Lteif, A. (2009). Treatment of familial male-limited precocious puberty (testotoxicosis) with anastrozole and bicalutamide in a boy with a novel mutation in the luteinizing hormone receptor. Journal of Pediatric Endocrinology and Metabolism, 22(12), 1163–1168. [DOI:10.1515/JPEM.2009.22.12.1163]
  • Moreno-Pérez, Ó., De Antonio, I. E., & Grupo de Identidad y Diferenciación Sexual de la SEEN (GIDSEEN. (2012). Clinical practice guidelines for assessment and treatment of transsexualism. SEEN Identity and Sexual Differentiation Group (GIDSEEN). Endocrinología y Nutrición (English Edition), 59(6), 367–382. [DOI:10.1016/j.endoen.2012.07.004]
  • Moretti, C. G., Guccione, L., Di Giacinto, P., Cannuccia, A., Meleca, C., Lanzolla, G., Andreadi, A., & Lauro, D. (2016). Efficacy and Safety of Myo-Inositol Supplementation in the Treatment of Obese Hirsute PCOS Women: Comparative Evaluation with OCP+Bicalutamide Therapy. Endocrine Reviews, 37(2 Suppl 1), ?–? (abstract no. SUN-153). [URL] [DOI:10.1093/edrv/37.supp.1]
  • Moretti, C., Guccione, L., Di Giacinto, P., Simonelli, I., Exacoustos, C., Toscano, V., Motta, C., De Leo, V., Petraglia, F., & Lenzi, A. (2018). Combined oral contraception and bicalutamide in polycystic ovary syndrome and severe hirsutism: a double-blind randomized controlled trial. The Journal of Clinical Endocrinology & Metabolism, 103(3), 824–838. [DOI:10.1210/jc.2017-01186]
  • Moussa, A., Kazmi, A., Bokhari, L., & Sinclair, R. D. (2022). Bicalutamide improves minoxidil-induced hypertrichosis in female pattern hair loss: A retrospective review of 35 patients. Journal of the American Academy of Dermatology, 87(2), 488–490. [DOI:10.1016/j.jaad.2021.10.048]
  • Muderris, I. I., Bayram, F., & Guven, M. (1999). Bicalutamide 25 mg/day in the treatment of hirsutism. Human Reproduction, 14(Suppl 3), 366–366 (R-196). [DOI:10.1093/humrep/14.Suppl_3.366-a]
  • Müderris, I. I., Bayram, F., Özçelik, B., & Güven, M. (2002). New alternative treatment in hirsutism: bicalutamide 25 mg/day. Gynecological Endocrinology, 16(1), 63–66. [DOI:10.1080/gye.16.1.63.66]
  • Müderris, İ. İ., & Öner, G. (2009). Hirsutizm Tedavisinde Flutamid ve Bikalutamid Kullanımı. [Flutamide and Bicalutamide Treatment in Hirsutism.] Türkiye Klinikleri Endokrinoloji-Özel Dergisi, 2(2), 110–112. [ISSN:1308-0954] [URL] [PDF] [Translation]
  • Nabhan, Z. M., & Eugster, E. A. (2019). Testotoxicosis with an episodic course: an unusual case within a series. AACE Clinical Case Reports, 5(1), e50–e53. [DOI:10.4158/ACCR-2018-0246]
  • Neyman, A., Fuqua, J. S., & Eugster, E. A. (2017). Bicalutamide as an Androgen Blocker with Secondary Effect of Promoting Feminization in Male to Female (MTF) Transgender Adolescents. Hormone Research in Paediatrics, 88(Suppl 1 [10th Individual Abstracts for International Meeting of Pediatric Endocrinology: Free Communication and Poster Sessions, Abstracts]), 477–477 (abstract no. P3-605). [DOI:10.1159/000481424] [PDF]
  • Neyman, A., Fuqua, J. S., & Eugster, E. A. (2019). Bicalutamide as an androgen blocker with secondary effect of promoting feminization in male-to-female transgender adolescents. Journal of Adolescent Health, 64(4), 544–546. [DOI:10.1016/j.jadohealth.2018.10.296]
  • Özcabı, B., Ceylaner, S., Özcan, R., Büyükünal, C., Ercan, O., Tüysüz, B., & Evliyaoğlu, O. (2015). Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene. Journal of Clinical Research in Pediatric Endocrinology, 7(3), 242–248. [DOI:10.4274/jcrpe.2067]
  • Randolph Jr, J. F. (2018). Gender-Affirming Hormone Therapy for Transgender Females. Clinical Obstetrics and Gynecology, 61(4), 705–721. [DOI:10.1097/GRF.0000000000000396] [URL]
  • Rao, B. R., De Voogt, H. J., Geldof, A. A., Gooren, L. J. G., & Bouman, F. G. (1988). Merits and considerations in the use of anti-androgen. Journal of Steroid Biochemistry, 31(4), 731–737. [DOI:10.1016/0022-4731(88)90024-6]
  • Reed, J. (2023 February 9). I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle. The Free Press. [URL]
  • Reiter, E. O., Mauras, N., McCormick, K., Kulshreshtha, B., Amrhein, J., De Luca, F., O’Brien, S., Armstrong, J., & Melezinkova, H. (2010). Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT). Journal of Pediatric Endocrinology & Metabolism: JPEM, 23(10), 999–1009. [DOI:10.1515/jpem.2010.161]
  • Salter, J., & Ballentine, S. (2023 September 12). Missouri clinics halt transgender care for minors in wake of new state law. Associated Press. [URL]
  • Schellhammer, P. F., Sharifi, R., Block, N. L., Soloway, M. S., Venner, P. M., Patterson, A. L., Sarosdy, M. F., Vogelzang, N. J., Schellenger, J. J., Kolvenbag, G. J., & Casodex Combination Study Group. (1997). Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology, 50(3), 330–336. [DOI:10.1016/s0090-4295(97)00279-3]
  • Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. Journal of Adolescent Health, 74(1), 5–6. [DOI:10.1016/j.jadohealth.2023.10.010]
  • See, W. A., Wirth, M. P., McLeod, D. G., Iversen, P., Klimberg, I., Gleason, D., Chodak, G., Montie, J., Tyrrell, C., Wallace, D. M., Delaere, K. P., Vaage, S., Tammela, T. L., Lukkarinen, O., Persson, B. E., Carroll, K., Kolvenbag, G. J., & Casodex Early Prostate Cancer Trialist Group. (2002). Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. The Journal of Urology, 168(2), 429–435. [DOI:10.1016/S0022-5347(05)64652-6]
  • Stenger, P. J., Wagner, L., Egelhoff, J., & Rose, S. R. (2009). Bicalutamide and letrozole treatment of precocious puberty due to elevated levels of human chorionic gonadotropin (hCG). Hormone Research [in Paediatrics], 72(Suppl 3), 391–391 (PO3-149). [Google Scholar] [DOI:10.1159/000239668]
  • Tessaris, D., Matarazzo, P., Mussa, A., Tuli, G., Verna, F., Fiore, L., & Lala, R. (2012). Combined treatment with bicalutamide and anastrozole in a young boy with peripheral precocious puberty due to McCune-Albright Syndrome. Endocrine Journal, 59(2), 111–117. [DOI:10.1507/endocrj.ej11-0214]
  • Thole, Z., Manso, G., Salgueiro, E., Revuelta, P., & Hidalgo, A. (2004). Hepatotoxicity induced by antiandrogens: a review of the literature. Urologia Internationalis, 73(4), 289–295. [DOI:10.1159/000081585]
  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
  • Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
  • van Kemenade, J. F., Cohen-Kettenis, P. T., Cohen, L., & Gooren, L. J. (1989). Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals. Archives of Sexual Behavior, 18(3), 217–228. [DOI:10.1007/BF01543196]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
  • Vierregger, K. S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Warus, J. (2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
\ No newline at end of file +Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy - Transfeminine Science Link

Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy

By Aly | First published July 1, 2020 | Last modified April 6, 2024

Abstract / TL;DR

Bicalutamide is an antiandrogen which was introduced for the treatment of prostate cancer many years ago. Cost precluded its widespread use for other indications for many years. However, its cost has since come down and bicalutamide is now seeing significant adoption for use in transfeminine hormone therapy as well as for treatment of androgen-dependent conditions in other populations like cisgender women. Bicalutamide has risks of certain rare adverse effects like liver toxicity which have generated concerns about its safety and have limited its use in transfeminine people. However, while still significant, these risks are low with appropriate monitoring and clinical management. Prominent researchers in transgender medicine have recently shown openness to bicalutamide for potential use in transfeminine people and have written positively about it. Bicalutamide could eventually come to be regarded as acceptably safe for use in transfeminine hormone therapy, similarly to other antiandrogens with rare risks like spironolactone and cyproterone acetate. However, more studies and characterization of bicalutamide in transfeminine people will likely be needed before it could see wider adoption in transgender medicine.

History of Bicalutamide for Transfeminine People

Bicalutamide (Casodex) is a nonsteroidal antiandrogen and selective antagonist of the androgen receptor which was originally introduced for the treatment of prostate cancer in cisgender men in 1995. Prostate cancer is an androgen-dependent disease, so antiandrogens are effective in treating it. Bicalutamide has major advantages over other antiandrogens such as spironolactone (Aldactone) and cyproterone acetate (Androcur) in terms of antiandrogenic potency, clinical effectiveness, pharmacological selectivity, and tolerability. It also has improved potency, pharmacokinetic properties, and tolerability, as well as far better safety, compared to the older nonsteroidal antiandrogens flutamide (Eulexin) and nilutamide (Anandron, Nilandron). However, use of bicalutamide as an antiandrogen in transfeminine hormone therapy is very recent. The employment of bicalutamide for transfeminine people was largely precluded for many years by the fact that bicalutamide had pharmaceutical patent protection and was very expensive. However, this changed with the availability of generic versions of bicalutamide starting in 2007 to 2009. In addition, newer and more effective antiandrogens like abiraterone acetate (Zytiga) in 2011 and enzalutamide (Xtandi) in 2012 were introduced and superseded bicalutamide as the standard-of-care antiandrogen for the treatment of prostate cancer. These developments have greatly reduced the cost of bicalutamide and it has gradually become much more affordable in the last decade.

Before 2015, there were only a few mentions in the literature of bicalutamide for transfeminine people and a handful of anecdotal reports online of transfeminine people using it. The earliest clear mention of bicalutamide in the literature in the context of transfeminine hormone therapy was by Louis Gooren in 2011 (Gooren, 2011). Gooren is a major longtime researcher in the field of transgender medicine and is one of the coauthors of the Endocrine Society’s transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017). He and his colleagues at the Center of Expertise on Gender Dysphoria of the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands had conducted studies on nilutamide (Anandron, Nilandron) as an antiandrogen for transfeminine people in the late 1980s and early 1990s (de Voogt et al., 1987a; de Voogt et al., 1987b; Gooren et al., 1987; Johannes et al., 1987; Rao et al., 1988; Asscheman, Gooren, & Peereboom-Wynia, 1989; van Kemenade et al., 1989; Wiki). However, they seem to have abandoned it—probably due to its high incidence of lung toxicity and other off-target side effects. Nonetheless, Gooren began including nonsteroidal antiandrogens like flutamide and nilutamide in his publications as potential treatment options for transfeminine hormone therapy starting in the 1990s (Asscheman & Gooren, 1992; Gooren, 1999). Subsequently, flutamide was included in transgender health guidelines and other publications, though not necessarily favorably (e.g., Israel & Tarver, 1997; Levy, Crown, & Reid, 2003; Dahl et al., 2006a; Dahl et al., 2006b; Hembree et al., 2009; Moreno-Pérez et al., 2012). As a researcher interested in nonsteroidal antiandrogens for transfeminine people, bicalutamide—with its far better safety profile than flutamide and nilutamide—may have been appealing to Gooren. However, Gooren and his colleagues didn’t conduct clinical studies on bicalutamide for transfeminine people and never went beyond brief mention of it for such uses in their publications. Nor did any other academics.

Besides transfeminine people and men with prostate cancer, bicalutamide has been studied for use in the treatment of androgen-dependent conditions in other populations. For example, it has been used in the treatment of hirsutism (excessive facial/body hair growth) in cisgender women with and without polycystic ovary syndrome (PCOS) (Müderris, Bayram, & Güven, 1999; Müderris et al., 2002; Bahceci et al., 2004; Müderris & Öner, 2009; Moretti et al., 2016; Moretti et al., 2018; Wiki). Bicalutamide has also been studied in combination with anastrozole (Arimidex), an aromatase inhibitor, for the treatment of gonadotropin-independent precocious puberty in cisgender boys (Kreher et al., 2006; Lewis et al., 2009; Mitre & Lteif, 2009; Stenger et al., 2009; Lenz et al., 2010; Reiter et al., 2010; Tessaris et al., 2012; Özcabı et al., 2015; Kor, 2018; Arya & Davies, 2019; Nabhan & Eugster, 2019; Finkle et al., 2020; Gurnurkar, DiLillo, & Carakushansky, 2021; Wiki). This is a rare form of precocious puberty in which gonadotropin-releasing hormone modulators are not effective. A phase 2 clinical trial was completed and a New Drug Application (NDA) was submitted in the United States for treatment of the condition with bicalutamide and anastrozole, but the application was not approved due to inadequate evidence of effectiveness on the primary efficacy endpoint of limiting height (AstraZeneca, 2008). However, bicalutamide is still used off-label for this indication, and information on bicalutamide for this use is provided in the the Casodex Food and Drug Administration (FDA) label (FDA, 2017).

Although there was little discussion or use of bicalutamide in transfeminine people prior to 2015, this started to change in mid-2015. At that time, the Wikipedia content for bicalutamide was greatly expanded, which made information about bicalutamide more accessible. In addition, certain transfeminine people, noting its advantages over existing options and its excellent potential for use in transfeminine hormone therapy, began advocating for use of bicalutamide in transfeminine people in online circles. A number of open-minded clinicians started adopting bicalutamide in transfeminine people around this time and thereafter as well. The first clinical study of bicalutamide in transfeminine people, which began in 2013, was published as an abstract in 2017 and as a full paper in 2019 (Neyman, Fuqua, & Eugster, 2017; Neyman, Fuqua, & Eugster, 2019). It was a small retrospective chart review of bicalutamide alone as a second-line puberty blocker in adolescent transgender girls for whom gonadotropin-releasing hormone analogues were denied by insurance. As of present, it remains the only published clinical data on bicalutamide in transfeminine people. It’s not exactly great data by any means, but it’s a study at least. The researchers who conducted the study had previously published on bicalutamide as a puberty blocker in boys with gonadotropin-independent precocious puberty (e.g., Lenz et al., 2010; Haddad & Eugster, 2012). While limited in its findings, Neyman, Fuqua, and Eugster (2019) helped to generate significant interest among clinicians and researchers in bicalutamide for use in transfeminine hormone therapy.

In any case, due to the recent nature of bicalutamide as an option for use in transfeminine hormone therapy, as well as the lack of studies and characterization of bicalutamide in transfeminine people and concerns about its safety (see next section), bicalutamide isn’t widely used in transfeminine people at this time. In fact, transgender hormone therapy guidelines largely don’t even mention it still. At present, the use of bicalutamide in transfeminine people is mostly limited to a number of more flexible clinicians and to people in the transgender do-it-yourself (DIY) hormone therapy community.

Concerns About Bicalutamide Limiting its Use

The transgender medical community has been reluctant to endorse the use of bicalutamide in transfeminine people to date. This is because of the lack of clinical studies and characterization of bicalutamide in transfeminine people, most importantly in terms of safety. There have been concerns about rare instances of liver failure that have occurred with bicalutamide in men with prostate cancer (Wiki). The reported cases of liver toxicity with bicalutamide have generally been sudden-onset and severe. Rare liver toxicity is an acceptable risk in men with prostate cancer because the risk–benefit ratio of bicalutamide therapy is very favorable, with the benefit of treating prostate cancer vastly outweighing the harm of the very rare instances of liver problems. But transfeminine people are typically young and healthy, and bicalutamide isn’t treating a terminal illness when it’s used in us. If a transfeminine person develops liver failure and dies because of bicalutamide, that’s unnecessary harm and a life needlessly lost. Accordingly, the University of California San Francisco (UCSF) transgender care guidelines warn against use of bicalutamide in transfeminine people currently due to potential liver risks (Deutsch, 2016). Aside from risks, there is also a lack of data to guide appropriate dosing of bicalutamide in transfeminine people at this time. A typical bicalutamide dosage of 50 mg/day is being used and recommended, but this has been arbitrarily chosen with little basis to support it.

To date, there are 10 published case reports of serious liver toxicity in association with bicalutamide (Table). All of these cases were in men with prostate cancer and all occurred within 6 months of initiation of bicalutamide therapy, with two of the cases resulting in death. While this is not a lot of cases and may seem reassuring, it must be noted that quantity of published case reports tends to vastly underestimate the true incidence of rare adverse reactions. As an example, there are around 50 published case reports of meningioma with cyproterone acetate (Table), but a recent large study by the French government found that there were more than 500 operated instances of meningioma in association with high-dose cyproterone acetate over an 8-year period in France alone (Aly, 2020). Accordingly, as of writing there are 40 reports of liver failure, including 25 consequent deaths, in association with bicalutamide in the U.S. FDA’s international MedWatch/FAERS database. (As well as 240 cases of interstitial lung disease associated with bicalutamide notably—relative to only 14 published case reports; Table.) Even with this database however, fewer than 10% of serious adverse reactions are estimated to be reported (Graham, Ahmad, & Piazza-Hepp, 2002). Hence, the true numbers may be much greater. These instances are merely co-occurrences, and causality in terms of bicalutamide and liver toxicity has not been established. But they are concerning nonetheless. There is additionally an unpublished case anecdote of death in a young transfeminine person associated with bicalutamide that’s been making its rounds through the transgender medical community. Per certain very credible people in the field of transgender medicine (e.g., Asa Radix and Zil Goldstein), she is said to have been a 20-year-old transgender girl in Texas taking bicalutamide with rapid-onset liver failure and no warning signs. This case has given clinicians and researchers who are aware of it reservations about the use of bicalutamide in hormone therapy for transfeminine people. Another case of liver failure and death in a transgender person over 60 years of age who was treated with bicalutamide has also been informally reported (QueerDoc).

In any case, the reported cases of serious liver toxicity with bicalutamide in transgender people have not been published nor properly confirmed. In addition, the absolute incidence of liver toxicity with bicalutamide is likely to be very low. For instance, the incidence of abnormal liver function tests (i.e., elevated liver enzymes on blood work) was only 3.4% with high-dose (150 mg/day) bicalutamide monotherapy relative to 1.9% for placebo (a 1.5% difference attributable to bicalutamide) at 3.0 years of follow-up in the Early Prostate Cancer (EPC) clinical programme, a series of three phase 3 randomized controlled trials consisting of over 8,000 patients in which bicalutamide was evaluated for treatment of early prostate cancer (Anderson, 2003; Iversen et al., 2004; Wiki; Wiki). Moreover, there were no cases of serious liver toxicity or liver failure with bicalutamide in the initial clinical development programme of bicalutamide for advanced prostate cancer, in which almost 4,000 men were treated with bicalutamide (Blackledge, 1996; Kolvenbag & Blackledge, 1996; McLeod, 1997; Anderson, 2003; Iversen et al., 2004; Wiki). However, it should be noted that this was with careful monitoring of liver function in patients and with prompt discontinuation of bicalutamide upon detection of clinically concerning hepatic abnormalities. About 0.5 to 1.5% of men taking 50 to 150 mg/day bicalutamide in the major clinical programmes of bicalutamide for prostate cancer developed liver changes sufficiently marked that they required discontinuation (Blackledge, 1996; See et al., 2002; Wiki). Hence, regular liver monitoring is essential with bicalutamide to ensure that the possibility of severe liver toxicity is avoided.

Bicalutamide has a much lower risk of liver toxicity than its analogue flutamide (Kolvenbag & Blackledge, 1996; Schellhammer et al., 1997; Thole et al., 2004; Manso et al., 2006; Table). However, it retains a small risk of liver toxicity of its own—one with the potential for serious consequences. Hence, caution is warranted with its use, and careful liver monitoring is a necessity for anyone taking it.

Recent Developments and the Future

Bicalutamide is currently being adopted and characterized for use in the treatment androgen-dependent skin and hair conditions in cisgender women. For instance, a rigorous Italian phase 3 randomized controlled trial of bicalutamide for hirsutism was recently published (Moretti et al., 2018). Retrospective chart reviews of bicalutamide for scalp hair loss in cisgender women have also been published recently (Fernandez-Nieto et al., 2019; Ismail et al., 2020; Fernandez-Nieto et al., 2020; Moussa et al., 2021). The hair loss studies have observed low though significant rates of liver changes with bicalutamide.

Certain transgender medical researchers are showing interest in bicalutamide as well. Perhaps most notably, Wylie Hembree—the lead author of the Endocrine Society’s 2009 and 2017 transgender hormone therapy guidelines (Hembree et al., 2009; Hembree et al., 2017)—wrote positively about bicalutamide for transfeminine people in a recent review (Fishman, Paliou, Poretsky, & Hembree, 2019). He and his colleagues cited the recent phase 3 trial of bicalutamide for hirsutism in cisgender women and the study of bicalutamide as a puberty blocker in transgender girls in support of potential use of bicalutamide for transfeminine people. Guy T’Sjoen—another major researcher in transgender medicine and co-author of the Endocrine Society guidelines (Hembree et al., 2017; Mitchell, 2020)—seemed to show openness to bicalutamide with his colleagues in a recent review as well (Iwamoto et al., 2019). Researchers outside of the United States in particular may be more open to bicalutamide, owing to accumulating health concerns with cyproterone acetate—the most commonly used antiandrogen outside of the United States (Aly, 2020). John Randolph, a researcher at the University of Michigan, has also written positively about bicalutamide (Randolph, 2018), though he may have since changed his mind on it (Michigan Medicine, 2020). On the other hand, other authors have not been as welcoming of bicalutamide for transfeminine people (e.g., Hamidi & Davidge-Pitts, 2019; Cocchetti et al., 2020).

The small risks of bicalutamide with appropriate monitoring may prove to be acceptable to the transgender medical community. This would perhaps be analogous to the rare incidences of serious adverse effects with say spironolactone (e.g., hyperkalemia) or cyproterone acetate (e.g., benign brain tumors, blood clots, breast cancer, liver toxicity). It’s possible that bicalutamide may not ultimately be recommended as a first-line therapy due to its risks. However, it could still be allowed as a second-line option when other antiandrogens are less feasible or not possible due to being for instance inadequately effective, poorly tolerated, contraindicated, or unavailable. The transgender medical community isn’t there at this time though. More developments—namely studies and characterization of bicalutamide in actual transfeminine people—are likely to be needed before bicalutamide could become more accepted for use in transfeminine people or recommended in transgender hormone therapy guidelines.

Updates

Update 1: Thompson et al. (2021) [Fenway Health Guidelines]

In March 2021, the Fenway Health transgender health clinical practice guidelines were updated from the last version (October 2015) to the following latest edition (Aly, 2020):

  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]

This update is notable as these guidelines included bicalutamide as an antiandrogen option for transfeminine people. While they did not recommend bicalutamide as a first-line agent due to its limited characterization in transfeminine people and its known small risk of liver toxicity, they were cautiously permissive of its use in transfeminine hormone therapy:

Bicalutamide can be used for [gender-affirming hormone therapy], but there are very few studies examining its use and the relative risk/benefit for this purpose. Because of reported cases of fulminant hepatitis, consensus is that its use in gender affirming hormonal regimen should be carefully considered, used only after alternative options have been trialed or offered, and an in-depth discussion of these potential risks have been had.

These are the first transgender care guidelines to allow the use of bicalutamide, and only the second guidelines to include bicalutamide. Previously, only the UCSF guidelines mentioned bicalutamide, but they were not permissive of its use in transfeminine people.

Update 2: Tomson et al. (2021) [SAHCS Guidelines]

In September 2021, the Southern African HIV Clinicians Society (SAHCS) published clinical guidelines for transgender care for the first time:

  • Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]

Surprisingly, these guidelines not only included bicalutamide but recommended it as the preferred antiandrogen over spironolactone and cyproterone acetate. The reason stated for this was “less risk of neurosteroid depletion (does not cross blood-brain-barrier readily).” However, this supposed effect isn’t a known concern with antiandrogens besides 5α-reductase inhibitors, and bicalutamide actually does appear to be centrally permeable in humans (Wiki). Also surprisingly, no mention of liver toxicity or liver enzyme monitoring with bicalutamide was made in these guidelines. Considering these apparent oversights and others, these guidelines’s recommendations should probably be interpreted with caution.

Update 3: Coleman et al. (2022) [WPATH SOC8 Guidelines]

In September 2022, the World Professional Association for Transgender Health (WPATH) Standards of Care for the Health of Transgender and Gender Diverse People Version 8 (SOC8) were published (Coleman et al., 2022). The WPATH SOC8 are among the most important if not the most important transgender care guidelines that exist and that are consulted by health care professionals. These guidelines briefly discussed bicalutamide including in the following two instances:

Bicalutamide is an antiandrogen that has been used in the treatment of prostate cancer. It competitively binds to the androgen receptor to block the binding of androgens. Data on the use of bicalutamide in trans feminine populations is very sparse and safety data is lacking. One small study looked at the use of bicalutamide 50 mg daily as a puberty blocker in 23 trans feminine adolescents who could not obtain treatment with a GnRH analogue (Neyman et al., 2019). All adolescents experienced breast development which is also commonly seen in men with prostate cancer who are treated with bicalutamide. Although rare, fulminant hepatotoxicity resulting in death has been described with bicalutamide (O’Bryant et al., 2008). Given that bicalutamide has not been adequately studied in trans feminine populations, we do not recommend its routine use.

When selecting a medication, we advise using those which have been studied in multiple transgender populations (i.e., estrogen, cyproterone acetate, GnRH agonists) rather than medications with little to no peer-reviewed scientific studies (i.e., bicalutamide, rectal progesterone, etc.) (Angus et al., 2021; Butler et al., 2017; Efstathiou et al., 2019; Tosun et al., 2019).

As can be seen, the WPATH SOC8 did not recommend the routine use of bicalutamide in transfeminine people owing to the lack of studies of it in this population and its potential risks. As touched on in the present article, it is likely that more studies of bicalutamide in transfeminine people will be needed before bicalutamide could become endorsed by major transgender care guidelines.

Update 4: Jamie Reed 2023 Bicalutamide Liver Toxicity Case

In February 2023, Jamie Reed, a former case manager at the The Washington University Transgender Center at St. Louis Children’s Hospital in St. Louis, Missouri, published the op-ed “I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle.” in a conservative online news outlet called The Free Press. In this article, Reed expressed that she had become disillusioned with the medical care of transgender youth and layed out her grievances. In addition however, she briefly described an additional case of liver toxicity with bicalutamide in a transfeminine person that had allegedly occurred at her center. This individual was said to be 15 years of age and was given bicalutamide as a puberty blocker by Dr. Christopher Lewis, one of the co-founders of the center. She was said to have subsequently developed liver toxicity and was taken off of bicalutamide. In an electronic message to the center, her mother said that they were “lucky her family was not the type to sue”. This instance, and Reed’s op-ed in general, were subsequently widely reported on in conservative news media, for instance on Fox News and in the Daily Mail (Google). In addition to her op-ed, Reed provided a sworn affidavit to the office of Republican Missouri attorney general Andrew Bailey, who proceeded to launch an investigation of the clinic (Missouri Government, 2023a). The following further information was released in the affidavit:

One doctor at the Center, Dr. Chris Lewis, is giving patients a drug called Bicalutamide. The drug has a legitimate use for treating pancreatic cancer [sic], but it has a side effect of causing breasts to grow, and it can poison the liver. There are no clinical studies for using this drug for gender transitions, and there are no established standards of care for using this drug.

Because of these risks and the lack of scientific studies, other centers that do gender transitions will not use Bicalutamide. The adult center affiliated with Washington University will not use this medication for this reason. But the Center treating children does.

I know of at least one patient at the Center who was advised by the renal department to stop taking Bicalutamide because the child was experiencing liver damage. The child’s parent reported this to the Center through the patient’s online self-reporting medical chart (MyChart). The parent said they were not the type to sue, but “this could be a huge PR problem for you.”

While unpublished and unverified like the earlier reports of liver toxicity with bicalutamide in transfeminine people, this case represents yet another report, and is notably by far the best-documented one. No other clinical details on the case were provided, and it is unclear whether it involved serious liver toxicity, merely asymptomatic liver function test abnormalities, or a clinical situation somewhere in-between these extremes. In any case, it does seem clear that this instance is not likely to have a positive influence on the further adoption of bicalutamide in transfeminine hormone therapy.

Subsequent to the investigation of the clinic being launched, in April 2023, Missouri greatly restricted gender-affirming care for transgender youth and adults, with some of the most severe limits that have been enacted in the United States (Associated Press, 2023a; Missouri Government, 2023b). Bicalutamide and the liver toxicity instance were not further described with these developments. The new state law restricting gender-affirming care took effect August 28, 2023, and Washington University announced that it would stop prescribing puberty blockers and hormone therapy to transgender youth shortly thereafter (Associated Press, 2023b).

A New York Times article with additional information on the case was also subsequently published (Ghorayshi, 2023 [Excerpts]). It was noted that the adolescent had been on bicalutamide for 1 year and definitely experienced hepatotoxicity. However, she also had a complicated medical history, including being immunocompromised, having recently had COVID-19, and having taken another drug known to be associated with hepatotoxicity. As such, the hepatotoxicity cannot be definitively attributed to bicalutamide, but it simultaneously cannot be ruled out that bicalutamide was involved or causative.

Subsequent Burgener et al. (2023, 2024) Findings

Following the preceding case, Lewis and colleagues went on to publish a conference abstract and preprint of a study of bicalutamide in transfeminine youth and young adults in which they stated that it does not increase liver enzymes in this population (Burgener et al., 2023; Burgener et al., 2024). However, a closer look at their data show that bicalutamide did statistically significantly elevate certain liver parameters relative to other antiandrogens, namely rates of elevated aspartate aminotransferase (AST) (upper limit of normal 10.7% vs. 1.5%, P = 0.02) (Burgener et al., 2024). Likewise, rates of elevated alanine aminotransferase (ALT) appeared to trend in the direction of being increased, though this was not statistically significant (upper limit of normal 16.7% vs. 11.6%, P = 0.37) (Burgener et al., 2024). In any case, rates of clinically significant elevations in liver enzymes with bicalutamide, defined as greater than three times the upper limit of normal, were not significantly increased in the study.

On the basis of the relevant research in men with prostate cancer (Wiki), Lewis and colleagues’ study, with a bicalutamide-group sample size of only 84 transfeminine individuals, was clearly greatly underpowered for evaluating liver function changes. Per the Early Prostate Cancer trial of high-dose bicalutamide monotherapy in men with prostate cancer, elevated liver enzymes appear to occur with bicalutamide at a rate of only about 1.5% more than placebo, or roughly an additional 1 in every 66 people (Wiki). Based on power analysis, this would require a far larger sample size to have adequate statistical power and actually have a chance of achieving statistical significance.

As such, it seems to the present author premature to conclude that bicalutamide does not elevate liver enzymes in transfeminine people.

Lewis and colleagues didn’t mention in their study paper the transfeminine adolescent liver toxicity case reported by Jamie Reed that was said to have occurred at their clinic nor have they published a case report about this instance. Instead, only the following is stated:

One case report published in 2024 described a transgender female adolescent prescribed bicalutamide 50 mg daily who presented to a hospital with liver toxicity that resolved after stopping bicalutamide (Wilde et al., 2024). This appears to be the first documented case of bicalutamide-induced hepatoxicity in a transgender female.

While this case was, coincidentally, also a 17-year-old transfeminine adolescent (Wilde et al., 2024), this instance, per the medical histories and reporting authors/institutions, appears to be distinct from Dr. Lewis’s that was reported by Jamie Reed.

However, Lewis and colleagues did note the following in their paper, which plausibly might have been the Jamie Reed case:

There was one individual in whom bicalutamide was stopped after the follow-up period designated for the study. This individual developed ALT and AST >2x ULN after an episode of COVID and had a thorough hepatology evaluation. As ALT and AST were never > 3x ULN, it was not recommended that bicalutamide be stopped; however, ultimately a clinical decision was made to stop the medication and ALT and AST normalized.

Another concern with Lewis and colleagues’ paper pertains to the following statements:

Whereas bicalutamide doses for prostate cancer reach 150 mg daily, doses used in the care of AMAB transfeminine individuals are much lower (25-50 mg daily).

Bicalutamide doses used in prostate cancer are up to 150 mg daily. Due to these concerns of liver toxicity, bicalutamide has not been routinely used as an anti-androgen in AMAB transfeminine individuals, despite the much lower doses needed in this population (∼25-50 mg daily).

In actuality, bicalutamide is most widely used in prostate cancer, in the form of combined androgen blockade with surgical or medical castration, at a dosage of 50 mg/day, whereas the 150 mg/day dosage is used less commonly, in the form of monotherapy (Wiki). Moreover, only the 50 mg/day dosage is used in the United States, where monotherapy is not approved. Among the published case reports of hepatotoxicity with bicalutamide in men with prostate cancer, half have been at a dose of 50 mg/day and the other half have been at a dose of 80 to 150 mg/day (Wiki). The two instances of death due to hepatotoxicity with bicalutamide were both at 50 mg/day. There is currently no evidence that the hepatotoxicity of bicalutamide is dose-dependent across its clinically used dosage range (Wiki), although employment of the lowest effective dose in transfeminine people nonetheless seems prudent just in case. Hence, in contrast to Lewis and colleague’s claims, a bicalutamide dosage of 50 mg/day is not less than that generally used in prostate cancer, and clearly retains substantial hepatotoxic potential.

Update 5: New Bicalutamide Publications in 2022 Through 2024

  • Angus, L., Nolan, B., Zajac, J., & Cheung, A. (November 2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (November 2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
  • Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
  • Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (May 2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]), 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
  • Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
  • Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
  • Vierregger, K., Tetzlaf, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Warus, J., Rincon, M. G., Salvetti, B., & Olson-Kennedy, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
  • Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
  • Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
  • Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. Journal of Adolescent Health, 74(1), 5–6. [DOI:10.1016/j.jadohealth.2023.10.010]

Update 6: Original Bicalutamide Liver and Lung Toxicity Analysis by Sam

A few years ago back in 2021, Transfeminine Science author Sam conducted an original analysis of the incidence of liver and lung toxicity with bicalutamide in the published clinical trial literature. This project was never finished or made publicly available. However, with bicalutamide being increasingly studied and adopted for use in transfeminine people, it seems quite valuable and relevant today. As such, we have opted to now publish Sam’s analysis in this section.

Sam’s analysis can be found in the provided document here. In terms of methodology, she searched PubMed for all clinical trials of bicalutamide, collated all of the relevant results into a table, and then calculated the incidences of serious liver toxicity and lung toxicity from those data. In clinical trials, adverse events are rated in terms of grades of severity, with a Grade 3 adverse event defined as “severe”, Grade 4 as “life-threatening”, and Grade 5 as “death” (Wiki).

Of 229 results, 33 trials were found to be relevant and were included. Most of the trials were in men with prostate cancer, but a few were in women with cancer and boys with precocious puberty. Sam found that of a total of 7,703 evaluable participants, there were 2 instances of serious liver toxicity and 2 instances of serious lung toxicity with bicalutamide. This resulted in the same incidence rate of 0.026% (95% CI: 0.003% to 0.094%) or approximately 1 in 3,846 individuals for both liver toxicity and lung toxicity. Combining these toxicities resulted in a total incidence of serious liver or serious lung toxicity with bicalutamide of 0.052% (95% CI: 0.014% to 0.133%) or approximately 1 in 1,923 individuals. All of the observed toxicity events were rated as Grade 3 or 4. It should be noted that clinical trials of bicalutamide typically employ careful laboratory monitoring and assessment of clinical adverse events as well as prompt medication discontinuation upon unfavorable laboratory changes.

While the confidence intervals (CIs) in Sam’s analysis were wide and hence the estimates are very rough, they provide an idea of the potential real-world risk of serious toxicity with bicalutamide in transfeminine people based on high-quality clinical data. Notably, they do not suffer from the problem of under-reporting of adverse events that occurs with published case reports, pharmacovigilance databases, and certain types of observational studies. However, limitations of Sam’s analysis include (1) toxicity incidence rates for non-bicalutamide-treated controls not being assessed and (2) most of the patients having cancer and being of older age, and hence the generalizability of the findings to healthy transfeminine people not being fully clear. In any case, I was surprised by how high the incidence rates were when I first saw her analysis, and I suspect that others may be as well.

References

  • Anderson, J. (2003). The role of antiandrogen monotherapy in the treatment of prostate cancer. BJU International, 91(5), 455–461. [DOI:10.1046/j.1464-410X.2003.04026.x]
  • Angus, L., Nolan, B., Zajac, J., & Cheung, A. (2022). Use of bicalutamide as an androgen receptor antagonist in transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 280). [URL] [PDF] [Full Abstract Book]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2023). Bicalutamide as an anti-androgen in trans people: a cross-sectional study. AusPATH 2023 Symposium. [URL] [PDF] [Slides] [Trans Health Research Blog Post]
  • Arya, V. B., & Davies, J. H. (2019). Idiopathic gonadotropin-independent precocious puberty - is regular surveillance required? Journal of Pediatric Endocrinology & Metabolism: JPEM, 32(4), 403–407. [DOI:10.1515/jpem-2018-0419]
  • Asscheman, H., Gooren, L. J., & Peereboom-Wynia, J. D. (1989). Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals—experiences with a novel androgen receptor blocker. Clinical and Experimental Dermatology, 14(5), 361–363. [DOI:10.1111/j.1365-2230.1989.tb02585.x]
  • Asscheman, H., & Gooren, L. J. (1992). Hormone Treatment in Transsexuals. In Bocking, W. O., Coleman, E. (Eds). Gender Dysphoria: Interdisciplinary Approaches in Clinical Management (pp. 39–54). Binghamton: Haworth Press. / Journal of Psychology & Human Sexuality, 5(4), 39–54. [Google Scholar] [Google Books] [DOI:10.1300/J056v05n04_03]
  • AstraZeneca. (2008). Clinical Review. NDA. 22-310/S-001. Casodex (bicalutamide) for Testotoxicosis. Food and Drug Administration/AstraZeneca Pharmaceuticals. [URL] [PDF]
  • Bahceci, M., Tuzcu, A., Canoruc, N., Tuzun, Y., Kidir, V., & Aslan, C. (2004). Serum C-reactive protein (CRP) levels and insulin resistance in non-obese women with polycystic ovarian syndrome, and effect of bicalutamide on hirsutism, CRP levels and insulin resistance. Hormone Research in Paediatrics, 62(6), 283–287. [DOI:10.1159/000081973]
  • Bailey, A. (2023 February 9). Missouri Attorney General Andrew Bailey Confirms Launch of Multi-Agency Investigation into St. Louis Transgender Center for Harming Hundreds of Children. Attorney General Andrew Bailey, Missouri Government. [URL] [Affadavit of Jamie Reed]
  • Bailey, A. (2023 April 13). Missouri Attorney General Andrew Bailey Promulgates Emergency Regulation Targeting Gender Transition Procedures for Minors. Attorney General Andrew Bailey, Missouri Government. [URL] [Emergency Regulation PDF]
  • Ballentine, S., & Hollingsworth, H. (2023 April 13). Missouri to limit gender-affirming care for minors, adults. Associated Press. [URL]
  • Bambilla, A., Beal, C., & Vigil, P. (2023). Improving Access to Bicalutamide in Gender Affirming Medical Care. [Unpubished/pending publication] [QueerCME Blog Post]
  • Blackledge, G. R. P. (1996). Clinical progress with a new antiandrogen, Casodex™ (bicalutamide). European Urology, 29(Suppl 2), 96–104. [DOI:10.1159/000473847]
  • Burgener, K., DeBosch, B., Lewis, C., Wallendorf, M., & Herrick, C. (2023). Assessment of Liver Function and Toxicity in Transgender Female Adolescents Prescribed Bicalutamide. Hormone Research in Paediatrics, 96(Suppl 3 [Abstracts of the 2023 Pediatric Endocrine Society (PES) Annual Meeting’ to Hormone Research in Paediatrics]), 377–378 (abstract no. 6232). [DOI:10.1159/000531602] [PDF]
  • Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
  • Cocchetti, C., Ristori, J., Romani, A., Maggi, M., & Fisher, A. D. (2020). Hormonal Treatment Strategies Tailored to Non-Binary Transgender Individuals. Journal of Clinical Medicine, 9(6), 1609. [DOI:10.3390/jcm9061609]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Dahl, M., Feldman, J. L., Goldberg, J. M., & Jaberi, A. (2006). Physical aspects of transgender endocrine therapy. International Journal of Transgenderism, 9(3–4), 111–134. [DOI:10.1300/J485v09n03_06]
  • Dahl, M., Feldman, J. L., Goldberg, J., & Jaberi, A. (2006). Endocrine Therapy for Transgender Adults in British Columbia: Suggested Guidelines. Physical Aspects of Transgender Endocrine Therapy. Vancouver: Vancouver Coastal Health. [Google Scholar] [PDF]
  • de Voogt, H. J., Rao, B. R., Gooren, L. J. G., Geldof, A. A., & Bouman, F. G. (1987). Considerations About the Use of Anti-Androgenic Drugs in Male-to-Female Transsexuals. Tenth International Symposium on Gender Dysphoria, Diagnosis and Treatment of Transsexualism, Vrije Universiteit Amsterdam, The Netherlands, June 9–12, 1987. Harry Benjamin International Gender Dysphoria Association. [PDF]
  • de Voogt, H. J., Rao, B. R., Geldof, A. A., Gooren, L. J. G., & Bouman, F. G. (1987). Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate. The Prostate, 11(4), 305–311. [DOI:10.1002/pros.2990110403]
  • Deutsch, M. B. (2016). Overview of feminizing hormone therapy. In Deutsch, M. B. (Ed.). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition (pp. 26–48). San Francisco: University of California, San Francisco/UCSF Transgender Care. [URL] [PDF]
  • Fernandez-Nieto, D., Saceda-Corralo, D., Rodrigues-Barata, R., Hermosa-Gelbard, A., Moreno-Arrones, O., Jimenez-Cauhe, J., Ortega-Quijano, D., & Vano-Galvan, S. (2019). Oral bicalutamide for female pattern hair loss: A pilot study. Dermatologic Therapy, 32(6), e13096. [DOI:10.1111/dth.13096]
  • Fernandez-Nieto, D., Saceda-Corralo, D., Jimenez-Cauhe, J., Moreno-Arrones, O. M., Rodrigues-Barata, R., Hermosa-Gelbard, A., & Vano-Galvan, S. (2020). Bicalutamide: A potential new oral antiandrogenic drug for female pattern hair loss. Journal of the American Academy of Dermatology, 83(5), e355–e356. [DOI:10.1016/j.jaad.2020.04.054]
  • Finkle, A., Zavertnik, S., Myers, S., Cormier, D., Heithaus, J., & Augustyn, M. (2020). Growing Up Fast: Managing Autism Spectrum Disorder and Precocious Puberty. Journal of Developmental and Behavioral Pediatrics: JDBP, 41(9), 740–742. [DOI:10.1097/DBP.0000000000000865]
  • Fishman, S. L., Paliou, M., Poretsky, L., & Hembree, W. C. (2019). Endocrine Care of Transgender Adults. In Poretsky, L., & Hembree, W. C. (Eds.). Transgender Medicine (pp. 143–163). Cham: Humana Press. [DOI:10.1007/978-3-030-05683-4_8]
  • Food and Drug Administration (FDA). (2017). CASODEX (bicalutamide) tablet, for oral use. [URL] [PDF]
  • Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
  • Ghorayshi, A. (2023 August 29). How a Small Gender Clinic Landed in a Political Storm. The New York Times. [URL]
  • Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
  • Gooren, L., Spinder, T., Spijkstra, J. J., Van Kessel, H., Smals, A., Rao, B. R., & Hoogslag, M. (1987). Sex steroids and pulsatile luteinizing hormone release in men. Studies in estrogen-treated agonadal subjects and eugonadal subjects treated with a novel nonsteroidal antiandrogen. The Journal of Clinical Endocrinology & Metabolism, 64(4), 763–770. [DOI:10.1210/jcem-64-4-763]
  • Gooren, L. J. G. (1999). Hormonal Sex Reassignment. International Journal of Transgenderism, 3(3), 1–7. [Google Scholar] [URL] [Alt]
  • Gooren, L. J. (2011). Care of transsexual persons. New England Journal of Medicine, 364(13), 1251–1257. [DOI:10.1056/NEJMcp1008161]
  • Graham, D. J., Ahmad, S. R., & Piazza‐Hepp, T. (2002). Spontaneous Reporting—USA. In Mann, R. D., & Andrews, E. B. (Eds.). Pharmacovigilance (pp. 219–227). Chichester: John Wiley & Sons. [DOI:10.1002/0470853093.ch17]
  • Gurnurkar, S., DiLillo, E., & Carakushansky, M. (2021). A Case of Familial Male-limited Precocious Puberty with a Novel Mutation. Journal of Clinical Research in Pediatric Endocrinology, 13(2), 239–244. [DOI:10.4274/jcrpe.galenos.2020.2020.0067]
  • Haddad, N. G., & Eugster, E. A. (2012). Peripheral Precocious Puberty: Interventions to Improve Growth. In Preedy, V. R. (Ed.). Handbook of Growth and Growth Monitoring in Health and Disease (pp. 1199–1212). New York: Springer. [DOI:10.1007/978-1-4419-1795-9_71]
  • Hamidi, O., & Davidge-Pitts, C. J. (2019). Transfeminine Hormone Therapy. Endocrinology and Metabolism Clinics, 48(2), 341–355. [DOI:10.1016/j.ecl.2019.02.001]
  • Hembree, W. C., Cohen-Kettenis, P., Delemarre-Van De Waal, H. A., Gooren, L. J., Meyer III, W. J., Spack, N. P., Tangpricha, V., & Montori, V. M. (2009). Endocrine treatment of transsexual persons: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 94(9), 3132–3154. [DOI:10.1210/jc.2009-0345]
  • Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., Rosenthal, S. M., Safer, J. D., Tangpricha, V., & T’Sjoen, G. G. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism, 102(11), 3869–3903. [DOI:10.1210/jc.2017-01658] [PDF]
  • Ismail, F. F., Meah, N., de Carvalho, L. T., Bhoyrul, B., Wall, D., & Sinclair, R. (2020). Safety of oral bicalutamide in female pattern hair loss: A retrospective review of 316 patients. Journal of the American Academy of Dermatology, 83(5), 1478–1479. [DOI:10.1016/j.jaad.2020.03.034]
  • Israel, G. E., & Tarver, D. E. (1997). Transgender Care: Recommended Guidelines, Practical Information, and Personal Accounts (p. 66). Philadelphia: Temple University Press. [Google Scholar] [Google Books]
  • Iversen, P., Johansson, J. E., Lodding, P., Lukkarinen, O., Lundmo, P., Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T., Carroll, K., & Scandinavian Prostatic Cancer Group. (2004). Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. The Journal of Urology, 172(5 Part 1), 1871–1876. [DOI:10.1097/01.ju.0000139719.99825.54]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 2042018819871166. [DOI:10.1177/2042018819871166]
  • Johannes, F. L. M., van Kemenade, M. A., Cohen-Kettenis, P. T., Cohen, L., & Gooren, L. J. G. (1987). Effects of RU 23.903 (Anandron) on Lateralization and Spatial Ability in Male-to-Female-Transsexuals. Tenth International Symposium on Gender Dysphoria, Diagnosis and Treatment of Transsexualism, Vrije Universiteit Amsterdam, The Netherlands, June 9–12, 1987. Harry Benjamin International Gender Dysphoria Association. [PDF]
  • Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
  • Kolvenbag, G. J., & Blackledge, G. R. (1996). Worldwide activity and safety of bicalutamide: a summary review. Urology, 47(1), 70–79. [DOI:10.1016/S0090-4295(96)80012-4]
  • Kor, Y. (2018). Central precocious puberty in a case of late-diagnosed familial testotoxicosis and long-term treatment monitoring. Hormones, 17(2), 275–278. [DOI:10.1007/s42000-018-0029-1]
  • Kreher, N. C., Pescovitz, O. H., Delameter, P., Tiulpakov, A., & Hochberg, Z. E. (2006). Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole. The Journal of Pediatrics, 149(3), 416–420. [DOI:10.1016/j.jpeds.2006.04.027]
  • Lenz, A. M., Shulman, D., Eugster, E. A., Rahhal, S., Fuqua, J. S., Pescovitz, O. H., & Lewis, K. A. (2010). Bicalutamide and third-generation aromatase inhibitors in testotoxicosis. Pediatrics, 126(3), e728–e733. [DOI:10.1542/peds.2010-0596]
  • Levy, A., Crown, A., & Reid, R. (2003). Endocrine intervention for transsexuals. Clinical Endocrinology, 59(4), 409–418. [DOI:10.1046/j.1365-2265.2003.01821.x]
  • Lewis, K. A., Lenz, A., Eugster, E. A., Fuqua, J. S., Pescovitz, O. H., Rahhal, S., & Shulman, D. (2009). Long term bicalutamide and 3rd generation aromatase inhibitor therapy in two boys with testotoxicosis. Hormone Research [in Paediatrics], 72(Suppl 3), 266–267 (PO2-189). [Google Scholar] [DOI:10.1159/000239668]
  • Manso, G., Thole, Z., Salgueiro, E., Revuelta, P., & Hidalgo, A. (2006). Spontaneous reporting of hepatotoxicity associated with antiandrogens: data from the Spanish pharmacovigilance system. Pharmacoepidemiology and Drug Safety, 15(4), 253–259. [DOI:10.1002/pds.1168]
  • McLeod, D. G. (1997). Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer. The Oncologist, 2(1), 18–27. [DOI:10.1634/theoncologist.2-1-18]
  • Michigan Medicine. (2020). Feminizing Gender-Affirming Hormone Care: The Michigan Medicine Approach. Ann Arbor: Michigan Medicine/University of Michigan. [URL] [PDF]
  • Mitchell, F. (2020). Guy T’Sjoen: collaborating to improve transgender wellbeing. The Lancet Diabetes & Endocrinology, 8(7), 568–568. [DOI:10.1016/S2213-8587(20)30192-3]
  • Mitre, N., & Lteif, A. (2009). Treatment of familial male-limited precocious puberty (testotoxicosis) with anastrozole and bicalutamide in a boy with a novel mutation in the luteinizing hormone receptor. Journal of Pediatric Endocrinology and Metabolism, 22(12), 1163–1168. [DOI:10.1515/JPEM.2009.22.12.1163]
  • Moreno-Pérez, Ó., De Antonio, I. E., & Grupo de Identidad y Diferenciación Sexual de la SEEN (GIDSEEN. (2012). Clinical practice guidelines for assessment and treatment of transsexualism. SEEN Identity and Sexual Differentiation Group (GIDSEEN). Endocrinología y Nutrición (English Edition), 59(6), 367–382. [DOI:10.1016/j.endoen.2012.07.004]
  • Moretti, C. G., Guccione, L., Di Giacinto, P., Cannuccia, A., Meleca, C., Lanzolla, G., Andreadi, A., & Lauro, D. (2016). Efficacy and Safety of Myo-Inositol Supplementation in the Treatment of Obese Hirsute PCOS Women: Comparative Evaluation with OCP+Bicalutamide Therapy. Endocrine Reviews, 37(2 Suppl 1), ?–? (abstract no. SUN-153). [URL] [DOI:10.1093/edrv/37.supp.1]
  • Moretti, C., Guccione, L., Di Giacinto, P., Simonelli, I., Exacoustos, C., Toscano, V., Motta, C., De Leo, V., Petraglia, F., & Lenzi, A. (2018). Combined oral contraception and bicalutamide in polycystic ovary syndrome and severe hirsutism: a double-blind randomized controlled trial. The Journal of Clinical Endocrinology & Metabolism, 103(3), 824–838. [DOI:10.1210/jc.2017-01186]
  • Moussa, A., Kazmi, A., Bokhari, L., & Sinclair, R. D. (2022). Bicalutamide improves minoxidil-induced hypertrichosis in female pattern hair loss: A retrospective review of 35 patients. Journal of the American Academy of Dermatology, 87(2), 488–490. [DOI:10.1016/j.jaad.2021.10.048]
  • Muderris, I. I., Bayram, F., & Guven, M. (1999). Bicalutamide 25 mg/day in the treatment of hirsutism. Human Reproduction, 14(Suppl 3), 366–366 (R-196). [DOI:10.1093/humrep/14.Suppl_3.366-a]
  • Müderris, I. I., Bayram, F., Özçelik, B., & Güven, M. (2002). New alternative treatment in hirsutism: bicalutamide 25 mg/day. Gynecological Endocrinology, 16(1), 63–66. [DOI:10.1080/gye.16.1.63.66]
  • Müderris, İ. İ., & Öner, G. (2009). Hirsutizm Tedavisinde Flutamid ve Bikalutamid Kullanımı. [Flutamide and Bicalutamide Treatment in Hirsutism.] Türkiye Klinikleri Endokrinoloji-Özel Dergisi, 2(2), 110–112. [ISSN:1308-0954] [URL] [PDF] [Translation]
  • Nabhan, Z. M., & Eugster, E. A. (2019). Testotoxicosis with an episodic course: an unusual case within a series. AACE Clinical Case Reports, 5(1), e50–e53. [DOI:10.4158/ACCR-2018-0246]
  • Neyman, A., Fuqua, J. S., & Eugster, E. A. (2017). Bicalutamide as an Androgen Blocker with Secondary Effect of Promoting Feminization in Male to Female (MTF) Transgender Adolescents. Hormone Research in Paediatrics, 88(Suppl 1 [10th Individual Abstracts for International Meeting of Pediatric Endocrinology: Free Communication and Poster Sessions, Abstracts]), 477–477 (abstract no. P3-605). [DOI:10.1159/000481424] [PDF]
  • Neyman, A., Fuqua, J. S., & Eugster, E. A. (2019). Bicalutamide as an androgen blocker with secondary effect of promoting feminization in male-to-female transgender adolescents. Journal of Adolescent Health, 64(4), 544–546. [DOI:10.1016/j.jadohealth.2018.10.296]
  • Özcabı, B., Ceylaner, S., Özcan, R., Büyükünal, C., Ercan, O., Tüysüz, B., & Evliyaoğlu, O. (2015). Testotoxicosis: Report of Two Cases, One with a Novel Mutation in LHCGR Gene. Journal of Clinical Research in Pediatric Endocrinology, 7(3), 242–248. [DOI:10.4274/jcrpe.2067]
  • Randolph Jr, J. F. (2018). Gender-Affirming Hormone Therapy for Transgender Females. Clinical Obstetrics and Gynecology, 61(4), 705–721. [DOI:10.1097/GRF.0000000000000396] [URL]
  • Rao, B. R., De Voogt, H. J., Geldof, A. A., Gooren, L. J. G., & Bouman, F. G. (1988). Merits and considerations in the use of anti-androgen. Journal of Steroid Biochemistry, 31(4), 731–737. [DOI:10.1016/0022-4731(88)90024-6]
  • Reed, J. (2023 February 9). I Thought I Was Saving Trans Kids. Now I’m Blowing the Whistle. The Free Press. [URL]
  • Reiter, E. O., Mauras, N., McCormick, K., Kulshreshtha, B., Amrhein, J., De Luca, F., O’Brien, S., Armstrong, J., & Melezinkova, H. (2010). Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT). Journal of Pediatric Endocrinology & Metabolism: JPEM, 23(10), 999–1009. [DOI:10.1515/jpem.2010.161]
  • Salter, J., & Ballentine, S. (2023 September 12). Missouri clinics halt transgender care for minors in wake of new state law. Associated Press. [URL]
  • Schellhammer, P. F., Sharifi, R., Block, N. L., Soloway, M. S., Venner, P. M., Patterson, A. L., Sarosdy, M. F., Vogelzang, N. J., Schellenger, J. J., Kolvenbag, G. J., & Casodex Combination Study Group. (1997). Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Urology, 50(3), 330–336. [DOI:10.1016/s0090-4295(97)00279-3]
  • Shumer, D., & Roberts, S. A. (2024). Placing a Report of Bicalutamide-Induced Hepatotoxicity in the Context of Current Standards of Care for Transgender Adolescents. Journal of Adolescent Health, 74(1), 5–6. [DOI:10.1016/j.jadohealth.2023.10.010]
  • See, W. A., Wirth, M. P., McLeod, D. G., Iversen, P., Klimberg, I., Gleason, D., Chodak, G., Montie, J., Tyrrell, C., Wallace, D. M., Delaere, K. P., Vaage, S., Tammela, T. L., Lukkarinen, O., Persson, B. E., Carroll, K., Kolvenbag, G. J., & Casodex Early Prostate Cancer Trialist Group. (2002). Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program. The Journal of Urology, 168(2), 429–435. [DOI:10.1016/S0022-5347(05)64652-6]
  • Stenger, P. J., Wagner, L., Egelhoff, J., & Rose, S. R. (2009). Bicalutamide and letrozole treatment of precocious puberty due to elevated levels of human chorionic gonadotropin (hCG). Hormone Research [in Paediatrics], 72(Suppl 3), 391–391 (PO3-149). [Google Scholar] [DOI:10.1159/000239668]
  • Tessaris, D., Matarazzo, P., Mussa, A., Tuli, G., Verna, F., Fiore, L., & Lala, R. (2012). Combined treatment with bicalutamide and anastrozole in a young boy with peripheral precocious puberty due to McCune-Albright Syndrome. Endocrine Journal, 59(2), 111–117. [DOI:10.1507/endocrj.ej11-0214]
  • Thole, Z., Manso, G., Salgueiro, E., Revuelta, P., & Hidalgo, A. (2004). Hepatotoxicity induced by antiandrogens: a review of the literature. Urologia Internationalis, 73(4), 289–295. [DOI:10.1159/000081585]
  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
  • Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
  • van Kemenade, J. F., Cohen-Kettenis, P. T., Cohen, L., & Gooren, L. J. (1989). Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals. Archives of Sexual Behavior, 18(3), 217–228. [DOI:10.1007/BF01543196]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
  • Vierregger, K., Tetzlaf, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Warus, J., Rincon, M. G., Salvetti, B., & Olson-Kennedy, J. (2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
\ No newline at end of file diff --git a/transfemscience.org/articles/progestogens-breast-dev/index.html b/transfemscience.org/articles/progestogens-breast-dev/index.html index e1a3244c6..81ef3fe35 100644 --- a/transfemscience.org/articles/progestogens-breast-dev/index.html +++ b/transfemscience.org/articles/progestogens-breast-dev/index.html @@ -1 +1 @@ -A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People - Transfeminine Science Link

A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People

By Aly | First published February 14, 2020 | Last modified April 1, 2024

Abstract / TL;DR

The major female sex hormones are estrogen and progesterone. Both of these hormones are known to be importantly involved in the development of the breasts at different stages of life. Speculation, use, and anecdotes of progestogens for enhancing breast development in transfeminine people date back to at least the 1960s. A limited number of clinical studies have assessed breast development with progestogens in transfeminine people, but current evidence on progestogens for improving breast development is of very low quality and is inconclusive. Studies of progestogens and breast development in cisgender girls and women are similarly limited. In any case, more studies evaluating progestogens and breast development are currently underway. The possible role of progestogens in enhancing breast development can also be informed by indirect and circumstantial evidence, including notably findings on progesterone and breast changes during normal puberty, the menstrual cycle, and pregnancy in humans and animals. Available evidence overall is not suggestive of an essential role for progesterone in breast growth during puberty, but progesterone does have a clear and key role in lobuloalveolar development of the breasts during pregnancy. However, breast changes in pregnancy revert following cessation of lactation and breastfeeding. Progesterone may additionally contribute to reversible breast enlargement during the luteal phase of the menstrual cycle. There are some findings to suggest that progestogens may have antiestrogenic effects in the breasts and may have a stunting influence on breast development if introduced too early following initiation of hormone therapy. However, more research is needed to assess this possibility. In any case, if progestogens are used, it may be advisable to delay their introduction until most or all estrogen-mediated breast development is complete. Options for progestogen therapy in transfeminine people include bioidentical progesterone and progestins. However, oral progesterone has major bioavailability problems and does not achieve satisfactory progesterone levels. Progestogens, including progesterone, have been variously linked to significant health risks, which is an important consideration in terms of their use in transfeminine people. Overall, based on current knowledge, progestogens do not seem to be promising for lastingly improving breast development in transfeminine people, but more research and data are still needed for clear conclusions.

Introduction

Breast development in terms of size and shape is often less than desired in transfeminine people, and there is a need for therapeutic approaches that improve breast growth in this population. There are two major types of female hormones, estrogens and progestogens. Estrogens are almost universally employed in transfeminine hormone therapy, while progestogens are used in a subset of transfeminine people. Progestogens that have been commonly employed in transfeminine people include bioidentical progesterone, the progestin (synthetic progestogen) medroxyprogesterone acetate (MPA), and the strongly progestogenic antiandrogen cyproterone acetate (CPA). Estrogens are the major mediators of feminization and breast development in females. However, progestogens also have physiological effects on the breasts, and in relation to this, may or may not provide benefits to breast development as well.

The topic of progestogens and breast development has been discussed for many years in the transgender community and is a controversial subject (Coleman et al., 2012). Use of progestogens to improve breast development in transfeminine people goes back at least as far as Harry Benjamin and Christian Hamburger in the 1960s (Benjamin, 1966; Benjamin, 1967; Hamburger & Benjamin, 1969; Wiki). Arguments have been made both for (e.g., Bevan, 2012; Bellwether, 2019; Bevan, 2019) and against (e.g., Curtis, 2009) a possible role of progestogens in terms of breast development. It is often claimed that progestogens can enhance breast development or are even required for full breast development in cisgender females and transfeminine people. With respect to the latter, it is sometimes said that progestogens are necessary for people to move from Tanner stage 4 to Tanner stage 5 pubertal breast development and that progestogens help to fill and round out the breasts (e.g., Vorherr, 1974a; Basson & Prior, 1998; Kaiser & Ho, 2015; Prior, 2011; Prior, 2019a; Prior, 2020). It has even been claimed by some that without progestogens, the breasts will remain conical and “pointy” like they are in the earlier Tanner stages. On the other extreme, certain critics have claimed that there are “no biologically significant progesterone receptor sites for biological males” and that progesterone is not produced during normal female puberty until after breast development has been fully completed (Barrett, 2009; Seal, 2017; Coxon & Seal, 2018; Price, McManus, & Barrett, 2019; Richards & Barrett, 2020). In turn, these particular authors have argued against the use of progestogens in transfeminine people in various of their publications (Google Scholar). In general, the use of progestogens in transfeminine people has longstandingly been controversial, with positions both for and against (Sam, 2020).

The purpose of this article is to review the available direct and circumstantial evidence on the topic of progestogens and breast development in order to help inform whether progestogen therapy may be able to enhance breast development in transfeminine people. Aside from an involvement in breast development, progestogens are not otherwise currently thought to be or known to be involved in physical feminization (e.g., Coleman et al., 2012; Gooren, 2016). In relation to this, the present article will limit its discussion to breast development with progestogens, and will not explore feminization in general.

Progestogen Therapy and Breast Development in Humans

Progestogens and Breast Development in Transfeminine People

At present, only a limited number of studies have assessed breast development with progestogen therapy in transfeminine people. These studies have employed either bioidentical progesterone or a progestin like MPA or CPA. The subject of and the available data on progestogens and breast development in transfeminine people has also been partly reviewed in papers including Wierckx, Gooren, & T’Sjoen (2014), Reisman, Goldstein, & Safer (2019), Patel et al. (2020), Patel et al. (2022), Milionis, Ilias, & Koukkou (2022), Coleman et al. (2022), and Berliere et al. (2023).

Orentreich & Durr (1974) was one of the earliest studies on breast development in transfeminine people. They employed combinations of estrogens and progestogens as well as gonadectomy to produce feminization and breast development in a case series of 5 transfeminine people. The employed estrogens were estradiol valerate 30 mg/2 weeks by intramuscular injection and oral conjugated estrogens 1.25–5.0 mg/day and the used progestogens were “60 mg medroxyprogesterone caproate” every 2 weeks by intramuscular injection and oral medroxyprogesterone acetate 0–10 mg/day. Medroxyprogesterone caproate (MPC) has never been used pharmaceutically, so this was likely a typo and the actual progestogen employed was likely either MPA or hydroxyprogesterone caproate (OHPC). The authors reported that estrogen and progestogen therapy produced modest to significant breast development in the transfeminine people that was not strictly dose-related and included clinical photographs of the breasts. They concluded that the breast development was comparable to that of adult cisgender women. Orentreich and colleagues also discussed the topic of lobuloalveolar maturation of the breasts, which was known to be progestogen-dependent, but noted that they had not done histological assessment and that the degree of lobuloalveolar development of the breasts does not necessarily correlate with clinical breast size per findings in cisgender women. The findings of Orentreich and colleagues are limited by methodological problems like lack of objective measurements, lack of estrogen-only controls, and the small sample size of only 5 transfeminine people, and hence the study is of limited value in terms of assessing the involvement of progestogens in breast development.

Meyer et al. (1986) assessed the effects of progestogens added to estrogen therapy on breast development and other clinical parameters in transfeminine people. Of the 60 transfeminine people in the study, 15 (25%) received an oral progestogen, usually MPA at a dosage of 10 mg/day, for “at least for a short time”, and with only 8 (13.3%) receiving progestogen therapy for the full treatment period. In an earlier report of the study, it was noted that in 90% of observation periods the dose was 10 mg/day and for the remainder it was 20 mg/day (Meyer et al., 1981). A dosage of 10 mg/day MPA is roughly comparable to luteal-phase progesterone exposure in terms of progestogenic potency (Wiki). Breast development was measured in the study via breast hemicircumference (Diagram). Progestogen therapy was reported to not modify estrogen-induced changes, including laboratory measurements, hormone levels, and physical parameters like weight and breast growth. The lack of apparent changes in hormone levels is unexpected, as MPA in higher-quality studies has shown clear testosterone suppression (e.g., Jain, Kwan, & Forcier, 2019; Wiki). Meyer and colleagues concluded that adding progestogens to estrogen does not seem to enhance breast development in transfeminine people. However, they noted that the number of individuals who received progestogens was small and further studies were needed.

Prior et al. (1986) and Prior, Vigna, & Watson (1989) studied estrogen, high-dose spironolactone (100–600 mg/day), and MPA (10–20 mg/day cylically or continuously) in transfeminine people who were either pre-hormone therapy or had previously been on higher doses of estrogens (and/or progestogens) without spironolactone prior to the study. The researchers reported that following 12 months of treatment with the study’s hormone therapy regimen, there was increased breast size and increased nipple development. Most individuals reached an A cup size, or approximately 8 to 14 cm in diameter of breast tissue, by the end of the study. Breast development was measured in part with photographic documentation. Although breast development reportedly improved, the researchers themselves noted that it was difficult to determine whether the enhanced breast development could be attributed to spironolactone or to MPA. Moreover, testosterone suppression was inadequate before the study and improved with the study’s hormone therapy regimen, which may have helped to improve breast development regardless of any potential direct progestogenic action of MPA on the breasts. Finally, it is possible that breast development with estrogen may not yet have been complete, and that the improved breast development may have simply been continued progression due to estrogen alone. In other publications, Jerilynn Prior, the lead study author, has claimed that progesterone enhances breast development, and has cited the preceding studies by her in support of this claim (Prior, 2011; Prior, 2019a; Prior, 2019b; Prior, 2020). However, her claim is not well-supported due to the study limitations discussed.

Dittrich et al. (2005) reported that the combination of oral estradiol valerate and a gonadotropin-releasing hormone (GnRH) agonist for 2 years in transfeminine people resulted in self-reported breast cup sizes of C cup or greater in 5%, B cup in 30%, A cup in 35%, and less than A cup in 30%. They noted however that 70% of the individuals were unsatisfied with their breast development and wished to undergo breast augmentation surgery. The researchers claimed that the regimen had similar effectiveness in terms of feminization, including increases in breast size, compared to prior reported treatment regimens of ethinylestradiol and CPA. No other details or specifics were given. The claim about similar breast development to regimens containing CPA is relevant as CPA is a very strong progestogen at the doses used historically in transfeminine people (Aly, 2019). It should be cautioned however that this study did not actually employ or study progestogen therapy itself. In addition, self-reported breast cup size is a subjective and low-quality means of measuring breast development and size. As such, the findings of this study are of questionable value in terms of understanding progestogens and breast development.

Estrogen is primarily involved in ductal development of the breasts, whereas progesterone is mainly involved in lobuloalveolar development. Kanhai et al. (2000) compared internal histological breast tissue changes with estrogen and CPA 100 mg/day (i.e. very-high-dose progestogen) therapy in 14 transfeminine people versus nonsteroidal antiandrogen monotherapy with flutamide or bicalutamide in 2 cisgender men with prostate cancer. Both types of treatments block androgens, increase estrogen levels, and are known to induce breast development or gynecomastia at similarly high rates. However, nonsteroidal antiandrogen monotherapy differs from combined estrogen and progestogen therapy in that it lacks any progestogenic effects. In the transfeminine people, full lobuloalveolar formation was apparent in the biopsied breast tissue, whereas in the men with prostate cancer, only “moderate” and incomplete lobuloalveolar maturation was found. It was also noted that lobuloalveolar formation tended to regress upon discontinuation of CPA following gonadectomy in transfeminine people. The researchers concluded that progestogenic exposure is needed for the breasts to fully develop on a histological level and for the breast tissue of transfeminine people to completely mimic the histology of the mature female breast. While the findings of this study are interesting, they only concern tissue characteristics and do not actually provide any information about breast development in terms of physical form or appearance. With regard to this, tissue-level differences may or may not translate to relevant differences in for instance breast size or shape. As such, the study is of limited value in understanding whether progestogens improve breast development in transfeminine people in the ways that are actually valued.

Seal and colleagues conducted a retrospective chart review assessing clinical predictors for surgical breast augmentation in transfeminine people (Seal et al., 2012). In the transfeminine people who underwent breast augmentation, significantly more of them were taking spironolactone than were those who did not undergo breast augmentation. Conversely, the differential rates of use of specific antiandrogens were not significantly discordant between those who did and did not undergo breast augmentation in the case of the other prescribed antiandrogens, including cyproterone acetate, the 5α-reductase inhibitors, and GnRH analogues. However, this study had many methodological limitations, including the use of almost three dozen t-tests with no adjustment for multiple comparisons (and hence risk of false positives and concerns about p-hacking), small sample sizes for individual antiandrogens, use of undergoing breast augmentation as a surrogate for breast development with no actual physical measurement of the breasts or breast sizes, and a correlational design with lack of control for potential confounding variables. As such, the study does not show that different antiandrogens result in differences in breast development, and its findings must be considered with due caution.

Jain, Kwan, & Forcier (2019) studied sublingual estradiol and spironolactone with and without MPA in 92 transfeminine people. MPA was given at a dose of 5 to 10 mg/day sublingually or at a dose of 150 mg once every 3 months by intramuscular injection. Of 39 transfeminine people who received MPA, 26 (67%) self-reported improved breast development. No further details were provided, but measurement of breast development was presumably subjective and anecdotal. Igo & Visram (2021) studied addition of progesterone to hormone therapy in transfeminine people. Progesterone was provided as 100 mg micronized progesterone (probably oral) and was prescribed when progesterone was specifically requested by the patient or when the patient expressed dissatisfaction with feminization and/or breast development. Of 190 individuals, 51 (26.8%) received progesterone therapy. Treatment with progesterone on average began after 12.7 months of estradiol therapy, and the mean total follow-up time was 14.3 months of hormone therapy. Of those who received progesterone, only 6 (11.8%) reported benefit to breast development. No further details were provided, but as with other studies, breast development was likely quantified anecdotally via self-report. As breast development does not appear to have been objectively measured or compared to a control group in either Jain, Kwan, & Forcier (2019) or Igo & Visram (2021), the findings of these studies are limitedly informative.

Nolan and colleagues assessed the short-term effects of low-dose oral micronized progesterone on breast development in transfeminine people on stable hormone therapy in a prospective controlled study (Nolan et al., 2022a; Nolan et al., 2022b). Progesterone was given at a dose of 100 mg/day for 3 months to 23 transfeminine people and findings were compared to those of a control group of 19 transfeminine people. Breast development was measured using self-reported Tanner stage, with participants provided photographs of different Tanner stages to self-select from. At the end of the 3 months, Tanner stage was not significantly different between groups (mean 3.5, 95% CI 3.2–3.7 for progesterone vs. mean 3.6, 95% CI 3.3–3.9 for controls; p = 0.42). A limitation of this study is that oral progesterone has very low bioavailability and 100 mg/day oral progesterone achieves very low progesterone levels that are well below normal luteal-phase progesterone levels (Aly, 2018a; Wiki). As such, progestogenic exposure in this study, and notably also in Igo & Visram (2021) and other studies, is likely to have been inadequate. Besides the issue of progestogenic strength, the very short duration of the study (3 months) and the reliance on self-reported subjective Tanner stages (as opposed to more objective physical breast measurements) are also major limitations. In any case, this study is of higher quality than previous studies, and is notably likely to continue and report further follow-up at later points in the future.

Bahr et al. (2024) conducted a retrospective chart review at their clinic and compared 29 transfeminine people who had received progestogens versus 59 transfeminine people who had not. The form of progestogen used was oral or rectal progesterone in 93% of cases and MPA by intramuscular injection in the remaining 7% of cases. Of those who took progesterone, 25 (93%) used it orally and 2 (7%) used oral progesterone capsules rectally. Progestogen doses were not reported, except that 100 mg progesterone capsules were employed. Most of those in the progestogen-treated group (59%) had started it 1 to 6 months following initiation of standard hormone therapy. The researchers found that progestogen-treated group had significantly better self-reported breast development satisfaction (rated as satisfied, neutral, or unsatisfied) compared to the group that did not receive progestogens at 6 months (satisfied: 53.8% vs. 19.6%; p = 0.004) and 9 months (satisfied: 71.4% vs. 20.8%; p = 0.003) of hormone therapy. Limitations of this study include the lack of objective measurement of breast development, the restrospective nature of the study, and the lack of randomization of treatment, among others.

Aside from the above studies, a variety of other studies have also reported breast development with estrogen and CPA in transfeminine people. These studies have often employed objective physical measurements of breast development (e.g., breast volume, breast–chest difference, breast cup size, breast hemicircumference). However, they have lacked comparison groups, thereby precluding comparison of progestogenic versus non-progestogenic hormone therapy. In addition, CPA is unusual among progestogens in that it is employed at very high doses in transfeminine people (Aly, 2019), which may result in different and potentially stunted outcomes in terms of breast development than more physiological progestogenic exposure. As such, most studies of breast development with estrogen and CPA in transfeminine people have not been discussed in the present section and are instead discussed elsewhere in this article (see the section below). In any case, to briefly summarize the findings, breast development in transfeminine people with estrogen and CPA has generally been poor in these studies. The outcomes have included incomplete maturation in terms of Tanner staging (stage 2–4), small cup sizes, small breast volumes, and breasts much smaller in size than those in cisgender women.

The findings from the preceding studies in transfeminine people are of very low-quality due to methodological limitations, including lack of control groups, lack of randomization, reliance on poor measures of breast development (e.g., subjective and self-report) rather than objective physical measurements (Wiki), short treatment durations, and small sample sizes, among others. This may explain the conflicting results of the studies. More research is still needed to assess the influence of progestogens on breast development in transfeminine people. There is specifically a need for randomized controlled trials (RCTs) of feminizing hormone therapy with versus without progestogen therapy that employ objective measures of breast development, have adequate sample sizes, and have sufficient follow-up durations. Additional variables like progestogen type, route, dose, and timing of introduction would also be of value to explore. A 2014 review on hormone therapy in transfeminine people summarizes the state of research on progestogens and breast development in transfeminine people, with their conclusions still holding true today (Wierckx, Gooren, & T’Sjoen, 2014):

Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in trans women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in trans women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.

Accordingly, reviews and guidelines have concluded that there is currently no reliable evidence that progestogens included in hormone therapy are of benefit or are not of benefit for breast development in transfeminine people (Wierckx, Gooren, & T’Sjoen, 2014; Reisman, Goldstein, & Safer, 2019; Patel et al., 2022; Milionis, Ilias, & Koukkou, 2022; Coleman et al., 2022; Berliere et al., 2023).

Future Studies Currently Underway

Several studies of progesterone and other progestogens in transfeminine people are currently underway. These studies include (1) an RCT of oral progesterone added to hormone therapy by Sandeep Dhindsa and colleagues in St. Louis, Missouri in the United States (ClinicalTrials.gov; MediFind; ICH GCP); (2) a prospective observational study and/or RCT of addition of oral progesterone to hormone therapy by Ada Cheung and colleagues in Melbourne, Australia (University of Melbourne; University of Melbourne); (3) an RCT of estradiol plus spironolactone versus estradiol plus CPA also by Ada Cheung and colleagues (update: see below) (ANZCTR; WHO ICTRP; Trans Health Research [Flyer] [Poster]; University of Melbourne); and (4) a large RCT of oral progesterone at different doses added to hormone therapy by Martin den Heijer and colleagues at the Vrije Universiteit University Medical Center (VUMC) in Amsterdam, the Netherlands (Dijkman et al., 2023a; General Info/Links; Info Sheet Dutch; Info Sheet English Translated). Unfortunately however, all of the studies using progesterone employ oral progesterone, which has major bioavailability and potency problems (Aly, 2018a; Wiki). In any case, it was said that the VUMC researchers may follow their trial up with studies of other progesterone routes (General Info/Links). The preceding studies may provide more insight on the question of whether progestogen therapy is of therapeutic benefit to breast development in transfeminine people.

Progestogens and Breast Development in Cisgender Females

To date, there appear to be no useful studies on breast development with progesterone or other progestogens in cisgender females. There seem to mostly only be a few brief and conflicting anecdotal clinical statements in this area that are scattered throughout the literature. These include the following literature excerpts, which are specifically in the context of progestogens as part of puberty induction in cisgender girls and women with delayed or absent puberty due to hypogonadism:

I […] performed studies on three women lacking mammary development and exhibiting signs of marked hypogonadism. […] Corpus luteum extract, 5 international units daily for a period of thirty days, when given alone produced no detectable change in the breasts. This is in accord with the experimental observations on animals of Turner,2 Corner 3 and others. When, however, patients were given alternate daily injections of 1 international unit of progesterone and from 20,000 to 50,000 international units of estrone or of estradiol benzoate, breast growth was more rapid than that produced by the estrogenic hormones alone. The simultaneous use of the corpus luteum and estrogenic therapy definitely produced a much firmer breast growth, which was distinctly lobular to palpation, whereas the growth produced by the estrogenic hormones alone was smooth and the borders of the glandular tissue were difficult to define. Rapid regression in the size of the breasts followed the omission of the hormone injections, but the regression was less rapid when the combined therapy had been used. [MacBryde (1939)]

There are authorities who consider that breast growth is better if a progestogen is combined with oestrogen for the latter part of the cycle of treatment (Capraro, 1971). Shearman (1971) employs sequential therapy in his cases. Huffman (1971) however, does not believe that there is any improvement with the addition of progestogens. [Dewhurst (1971a)]

The effects of progesterone on the human breast remain obscure. Although widely stated to cause glandular development, the evidence for this is slender (Benson et al 1959). [Shearman (1972a)]

Many people use oestrogens alone, but the addition of a progestin for 6 or 10 days each month gives much better cycle control and appears to cause better breast development. [Shearman (1972b)]

Some authorities consider that breast growth is better if a progestogen is given for the latter part of each course of treatment. [Capraro & Dewhurst (1975)]

It has been suggested that progestins be added during the last week of each cycle of estrogen therapy in order to develop more rounded breasts rather than the conical breasts many of these patients develop, but we have been unable to detect any difference in breast contour with or without progestins. [Davajan & Kletzky (1979)]

I have been satisfied that the addition of a progestogen was necessary to get a good breast response to hormone treatment although the progestogen, as I have said, is required after the first year if the uterus is present. [Dewhurst (1982)]

In addition to the preceding instances, Werner (1935) and Geschickter (1945) assessed the effects of progesterone on the breasts in cisgender women. Werner (1935) attempted to induce lactation in 8 surgically gonadectomized cisgender women with combinations of estrogen, progesterone, and prolactin, all in the form of crude extracts by injection. In two women who were given progesterone, he claimed that a marked increase in the size of the breasts beyond that with estrogen alone was observed. Additionally, he claimed that the breasts were more firm, the glandular tissue “more tortuous and nodular”, and the nipples more prominent. He was not successful in inducing lactation in the women in this study. The doses of hormones used were unclear as they were in the form of extracts, and were likely supraphysiological, potentially pregnancy-like due to the nature of the experiment. Werner’s study was also briefly discussed by Nelson (1936), among other citations. Geschickter (1945) observed lobuloalveolar growth on histological examination with administration of progesterone for 6 weeks to 2 months in one woman but not in another woman. However, the exterior physical changes of the breasts were not assessed or reported by this author and hence his findings are limitedly informative.

Surprisingly, there have been few analogous studies of the effects of progestogens on the breasts in cisgender girls and women following the preceding reports and anecdotes. Although there are very little data on progestogens and breast growth in cisgender females, clinical studies are finally starting to look more closely at the specifics of hormonal medications, including progestogens, in terms of breast development in girls undergoing puberty induction (e.g., Rodari et al., 2023). As such, future studies may provide more insight on the subject of progestogens and breast development in cisgender females.

Progesterone and its Physiological Role in Breast Development in Humans

Progesterone and Breast Development in Puberty

The role of progesterone in breast development and its possible usefulness for helping with breast development in transfeminine hormone therapy can be informed by the normal biological circumstances of puberty in cisgender females. Puberty in cisgender girls usually starts around age 11 (range 8–13 years) and completes around age 15 years (range 12–19 years), taking on average 3 to 4 years (but with a range of about 1.5–6 years in most cases) (Schauffler, 1942; Marshall & Tanner, 1969; Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986). Progesterone essentially does not appear during puberty until ovulatory menstrual cycles begin. Menarche, the onset of menstruation and hence of menstrual cycling, occurs on average at Tanner breast stage 4 or about 13 years of age, although it occurs at Tanner breast stage 3 or Tanner breast stage 5 in significant subsets of girls (26% for Tanner stage 3, 62% for Tanner stage 4, and 10% for Tanner stage 5) (Marshall & Tanner, 1969; Marshall, 1978; Drife, 1986; Hillard, 2007). Hence, the appearance of progesterone in normal female puberty is a relatively late event (Scott et al., 1950; Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986), and most breast development appears to be complete by menarche and thus by the time that progesterone is first produced (Huffman, Dewhurst, & Capraro, 1981; Drife, 1982). Moreover, a small but significant subset of girls reaches Tanner breast stage 5 and hence fully developed breasts before menarche (Edmonds, 1989), which suggests that progesterone may not be essential for complete pubertal breast development.

The reproductive axis in pubertal and adolescent cisgender girls is immature (Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019; Sun et al., 2019). In the first 1 to 2 years postmenarche, most menstrual cycles are anovulatory (i.e., ovulation does not occur) (Döring, 1963 [Table]; Apter, 1980; Lemarchand-Béraud et al., 1982; Talbert et al., 1985; Venturoli et al., 1987; Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019). Without ovulation, the corpus luteum doesn’t form from a ruptured ovarian follicle and progesterone production doesn’t commence. Only about half of menstrual cycles are ovulatory by Tanner breast stage 5 (Talbert et al., 1985). In addition, menstrual cycles are unusually long for some time after menarche (e.g., 50 days vs. 28 days for adult cycles) and thus there are fewer menstrual cycles per reproductive year (Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019). Luteal-phase progesterone levels are also lower in postmenarche adolescents than in adulthood even when ovulation does occur (McArthur, 1966 [Figure]; Lemarchand-Béraud et al., 1982; Apter et al., 1987; Venturoli et al., 1987; Venturoli et al., 1989; Sun et al., 2019). Consequently, progesterone exposure is sporadic and relatively limited even during late female puberty. Moreover, this is the case not only by the time of Tanner stage 5, but for many years after it as well. It takes more than 6 years after menarche for menstrual cycling to become fully mature and consistently ovulatory (Lemarchand-Béraud et al., 1982; Venturoli et al., 1987; Carlson & Shaw, 2019). Over this period of time, the rate of ovulatory cycles increases progressively until it reaches approximately 100% (Lemarchand-Béraud et al., 1982; Venturoli et al., 1987; Carlson & Shaw, 2019). Only then is full adult-level exposure to progesterone finally achieved (Lemarchand-Béraud et al., 1982; Venturoli et al., 1987).

Only a handful of studies and sources have reported progesterone levels during puberty across Tanner stages or by age in cisgender girls (e.g., Sizonenko, 1978 [Graph]; Kühnel, 2000; Lee, 2001 [Table]; Aly, 2020a). They corroborate the above findings with regard to limited progesterone exposure during puberty. The “A Girl’s First Period Study” is an ambitious research project announced in 2022 that aims to better characterize reproductive hormone levels in pubertal and adolescent girls and may shed more light on the physiological role of progesterone during puberty (Lucien et al., 2022). The researchers have specifically highlighted the possible role of progesterone in breast development as part of their interests:

Does exposure to low levels of [progesterone (P4)], as occurs before menarche, during anovulatory cycles with some degree of follicle luteinization, and during early, immature ovulatory cycles play an important role in normal breast development during puberty? This question has important clinical implications as hormone replacement during puberty does not typically include low-dose P4; rather, it is conducted using a staggered approach of estrogen-only therapy followed by the addition of full adult doses of exogenous P4 only after 2 years or when breakthrough bleeding occurs.27 This is done to avoid development of tubular breasts, although there are limited data linking early P4 exposure to suboptimal breast development.28

Taken together, production of progesterone is a late event in normal female puberty, and even once it does begin, exposure to progesterone is low and sporadic until well after puberty has completed. Moreover, a subset of girls complete breast development before progesterone production starts. These facts call into some question the role of progesterone in breast development in female puberty, as most breast development appears to be complete prior to the appearance of progesterone. However, more research is still needed on the role of progesterone in breast development during normal puberty.

On the basis of normal female puberty, it seems it may be advisable that if progestogens are introduced in an attempt to enhance breast development in transfeminine people, their introduction be delayed until after 2 or 3 years of hormone therapy, so as to mimic the normal progestogenic exposure of puberty.

Progesterone and Breast Development in Pregnancy

During pregnancy, under the influence of ovarian hyperstimulation and placental formation, there are profound changes in hormonal profiles, including of hormones like estrogen, progesterone, and prolactin, among many others (Table 1). Comparing hormone levels during the menstrual cycle to those during the third trimester of pregnancy, estradiol levels increase on the order of 100-fold, progesterone levels increase on the order of 10- to 20-fold, and prolactin levels increase by around 10-fold (Table 1). Levels of numerous other hormones also change considerably during pregnancy, for instance other estrogens besides estradiol, androgens, gonadotropins (e.g., human choronic gonadotropin or hCG), human placental lactogen (hPL), relaxin, adrenocorticotropic hormone (ACTH), cortisol, aldosterone, growth hormone (GH), and insulin-like growth factor 1 (IGF-1), among others (Goodman, 2009 [Figure]; Mesiano, 2019). These hormones are variously produced by the ovaries, the placenta, and the pituitary gland, among other glands. In response to the myriad hormonal changes during pregnancy, there are dramatic changes to the breasts, which prepare the mother for postpartum lactation and breastfeeding.

Table 1: Changes in hormone levels (estradiol, progesterone, and prolactin) during normal pregnancy:

HormoneNon-PregnantFirst TrimesterSecond TrimesterThird Trimester
Estradiol100 (~5–750) pg/mL1,000–5,000 pg/mL5,000–15,000 pg/mL10,000–40,000 pg/mL
Progesterone8.9 (1.0–24) ng/mLa22 (5–75 ng/mL)35 (15–85) ng/mL102 (25–280) ng/mL
Prolactin13.0 (4.6–37) ng/mL16 (3.2–43 ng/mL)49 (13–166) ng/mL113 (13–318) ng/mL

Note: Values are median (range) or range. Footnotes: a Specifically during the luteal phase of the menstrual cycle. Sources: estradiol (Aly, 2018b; Wiki; Wiki); progesterone (Kühnel, 2000; Aly, 2020a; Wiki; Wiki); and prolactin (Kühnel, 2000; Wiki).

Prior to pregnancy, there is significant although fairly minimal lobuloalveolar development of the breasts with each menstrual-cycle luteal phase (Scott et al., 1950; Drife, 1984; Drife, 1989; Drife, 1990; Pocock, Richards, & Richards, 2013; Johnson & Cutler, 2016; Alekseev, 2021). During pregnancy however, the breasts undergo much more considerable lobuloalveolar development and achieve full maturity. This allows for milk production and lactation following childbirth. During pregnancy, the breasts progressively and considerably increase in size (Hytten, 1954a; Hytten, 1954b; Baird, Hytten, & Thomson,1958; Hytten & Thomson, 1965; Hytten & Leitch, 1971a; Hytten & Leitch, 1971b; Hytten, 1976; Thoresen & Wesche, 1988; Cox et al., 1994; Whiteley, 1994; Cox et al., 1999; Cregan & Hartmann, 1999; Kent et al., 1999; Galbarczyk, 2011; Abduljalil et al., 2012; Bayer et al., 2014; Lawrence & Lawrence, 2015; Żelaźniewicz & Pawłowski, 2015; Dallman et al., 2017; Drąsutis, 2017; Żelaźniewicz & Pawłowski, 2019). Quantitative clinical studies have found the breasts to increase on average by about 100 to 300 mL (range -20 to 880 mL) in volume, or by about 200 to 400 g in mass, going from early pregnancy to late pregnancy or early postpartum (Hytten & Thomson, 1965; Hytten & Thomson, 1968; Hytten & Leitch, 1971a; Hytten & Leitch, 1971b; Hytten, 1976; Thoresen & Wesche, 1988; Whiteley, 1994; Hartmann et al., 1996; Cox et al., 1999; Cregan & Hartmann, 1999; Kent et al., 1999; Wright, 2015; Bayer et al., 2014; Żelaźniewicz & Pawłowski, 2015; Drąsutis, 2017; Żelaźniewicz & Pawłowski, 2019). The breasts can reportedly increase as much two to three times in size in some women (Greydanus et al., 2010). There is marked variation between individuals in the breast size increases during pregnancy (Hytten & Thomson, 1965; Hytten & Leitch, 1971a; Hassiotou & Geddes, 2013; Bayer et al., 2014). Increases in breast size are inversely associated with age, with considerably greater increases in younger women than in older women (e.g., +234–258 mL in <20 years vs. +79–131 mL in >30 years) (Hytten & Baird, 1958; Hytten & Leitch, 1971a [Excerpt]; Hytten, 1976). In addition to overall breast size, the nipples and areolae increase in size during pregnancy (Hytten & Baird, 1958; Hytten & Leitch, 1971a; Rohn, 1989; Cox et al., 1999; Hassiotou & Geddes, 2013; Thanaboonyawat et al., 2013; Park et al., 2014). They also become more darkly pigmented, reaching a dark brown or even black color (Dickson & Hewer, 1950; Thody & Smith, 1977; Wade, Wade, & Jones, 1978; Wong & Ellis, 1984; Elling & Powell, 1997; Muzaffar, Hussain, & Haroon, 1998; Muallem & Rubeiz, 2006; Nussbaum & Benedetto, 2006; Olanrewaju et al., 2017). The breasts become capable of lactation by 3 to 4 months of pregnancy (Walker, Baker, & Lamb, 2013; Pipkin, 2019; Pocock, Richards, & Richards, 2013; Wright, 2015; Lawrence & Lawrence, 2015). However, maturation of the breasts for lactation does not appear to be complete until at least about 6.5 months of pregnancy (Hassiotou & Geddes, 2013). Photographic timelines of women throughout pregnancy provide a visual impression of the breast changes that occur during this time (caution—NSFW: Reddit; More).

There are large and dramatic changes in levels of numerous hormones during pregnancy, and the exact hormones responsible for the breast changes during pregnancy are not known (Hytten & Leitch, 1971a; Hytten, 1976). However, it is considered likely, on the basis of animal studies, that a variety of hormones, including estrogen, progesterone, prolactin, placental lactogen, glucocorticoids, and growth hormone, are all importantly involved in different aspects of the maturation (Hytten & Leitch, 1971a; Hytten, 1976; Cox et al., 1999). Moreover, in a quantitative clinical study of breast changes during pregnancy, increases in breast volume and areola size were positively correlated with levels of hPL, while increases in nipple size were positively correlated with levels of prolactin (Cox et al., 1999). Progesterone and prolactin have specifically been implicated in the lobuloalveolar development of the breasts during pregnancy (Bässler, 1970; Lee & Ormandy, 2012; Obr & Edwards, 2012). Both hormones appear to be independently essential in normal lobuloalveolar growth per animal studies (Obr & Edwards, 2012; McNally & Stein, 2017; Hannan et al., 2023). Prolactin likewise appears to be essential in humans, based on case reports of lactation failure in women with isolated prolactin deficiency (Buhimschi, 2004). Conversely, hPL may not be essential for lactation based on case reports of normal lactation in women with very low levels of hPL during pregnancy (Gaede, Trolle, & Pedersen, 1978; Hannan et al., 2023).

Following childbirth and lactation, the breasts undergo a process known as post-lactational involution and return to a pre-pregnancy-like state (Dickson & Hewer, 1950; Ingleby, Moore, & Gershon-Cohen, 1957; Harley, 1969; Gershon-Cohen, 1970; Petrakis, 1978; Huffman, Dewhurst, & Capraro, 1981; Drife, 1986; Caro, 1987; Tanos & Brisken, 2008; Radisky & Hartmann, 2009; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; Hassiotou & Geddes, 2013; Sun et al., 2018; Alex, Bhandary, & McGuire, 2020). This involves massive cell death and regression of the lobuloalveolar development and other breast changes that occurred during pregnancy (Radisky & Hartmann, 2009; Alex, Bhandary, & McGuire, 2020). With involution, there is, on the basis of quantitative clinical studies, a complete reversion to pre-pregnancy breast size, or even to a slightly smaller breast size (Kent et al., 1999 [Figure]; Jernström et al., 2005; Dorgan et al., 2013; Lim et al., 2018). The same reversion has also been observed in gestational macromastia (breast hypertrophy of pregnancy), with striking and complete or near-complete regressions in breast size reported—although often with concomitant sagging and deformity that necessitates surgical intervention (Moss, 1968; van der Meulen, 1974 [Figure]; Swelstad et al., 2006; Naik et al., 2015). Following involution, it is also impossible to reliably distinguish between nulliparous and parous breasts even with internal histological examination (Drife, 1986). However, the parous breasts are not exactly the same as they were before pregnancy—the breasts remain more complex on a histological level (Dickson & Hewer, 1950; Gershon-Cohen, 1970; Hytten, 1976; Drife, 1986; Drife, 1989; Jeruss, 2006; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; Hassiotou & Geddes, 2013; Lewin, 2016; Sun et al., 2019), tend to be looser, more flaccid, and more pendulous due to stretching of skin and ligaments (Begley, Firth, & Hoult, 1980; Duncan, 2010; Rauh et al., 2013; Lewin, 2016), and the nipples and areolae remain more maturely developed and pigmented (Dickson & Hewer, 1950; Hytten & Baird, 1958; Hytten, 1976; Nussbaum & Benedetto, 2006; Sanuki, Fukuma, & Uchida, 2009; Thanaboonyawat et al., 2013; Park et al., 2014). In terms of subjective perceptions, some women perceive their breasts to be larger following pregnancy, whereas others perceive them to be smaller (Rauh et al., 2013; Lewin, 2016). Pregnancy can temporarily improve breast size in women with small breasts (Capraro & Dewhurst, 1975; Petrakis, 1978; Huffman, Dewhurst, & Capraro, 1981), but it has been said that the subsequent regressions in breast size after pregnancy can be “disturbing” (Capraro & Dewhurst, 1975). Following the first pregnancy and post-lactational involution, the breasts undergo the same cycle of expansion and regression with each subsequent pregnancy (Hassiotou & Geddes, 2013).

On the basis of the preceding, in spite of rather extreme hormonal stimulation, the breast changes of pregnancy, although quite dramatic, are essentially temporary and fully reversible, remaining only as long as continuous hormonal exposure is maintained. This hormonal stimulation includes exposure to extremely high levels of progesterone. It would seem, based on pregnancy, that once pubertal breast development is completed, the breasts are rather unamenable to permanent further growth, whether that involves exposure to progestogens or to a variety of other hormones known to act on the breasts.

Breast Composition and Lobuloalveolar Tissue Proportion

The breasts are made up of two main types of tissue: (1) epithelial tissue, the actual functional internal mammary glandular tissue, including ducts and alveoli or lobules; and (2) stromal tissue, a mixture of connective tissue and adipose (fat) tissue. Lobuloalveolar development refers to growth and maturation of the alveoli and lobules, and hence is a form of epithelial or glandular development. Progestogens are involved primarily in lobuloalveolar development of the breasts, which is the type of breast development that is necessary for lactation and breastfeeding and that occurs mainly during pregnancy.

In women who are not pregnant or lactating, studies have found that only about 5 to 20% of the volume of the breasts is composed of epithelial tissue on average, while the remaining 80 to 95% is composed of stromal tissue (Hutson, Cowen, & Bird, 1985; Drife, 1986; Drife, 1989; Bryant et al., 1998; Gertig et al., 1999; Howard & Gusterson, 2000; Cline & Wood, 2006; Lorincz & Sukumar, 2006; Wilson et al., 2006; Xu et al., 2010; Pandya & Moore, 2011; Hagisawa, Shimura, & Arisaka, 2012; Sandhu et al., 2016; Rosenfield, Cooke, & Radovick, 2021; Wiki). More specifically, one major study in in reproductive-age women found that the breasts are about 10 to 20% epithelial tissue, 10 to 35% fat tissue, and 60 to 80% connective tissue (Hutson, Cowen, & Bird, 1985; Wilson et al., 2006). Conflictingly however, a couple of studies that employed mammography have reported higher breast glandular proportions ranging from 35 to 48% (Klein et al., 1997; Jamal et al., 2004; Duncan, 2010). Aside from glandular tissue, other studies have found breast fat percentages of mean 26 to 48% (range 2 to 78%) (Lejour, 1994; Lejour, 1997; Vandeweyer & Hertens, 2002). Similarly to the findings of most studies of women’s breasts in general, only a small proportion of the breasts is glandular tissue (e.g., 1–7%) in women who have macromastia (breast hypertrophy, or extremely large breasts) (Bames, 1948; Cruz-Korchin et al., 2001).

During pregnancy and lactation in humans, the breasts undergo dramatic changes, and epithelial tissue comes to make up a much greater proportion of the breasts (Ramsay et al., 2005; Bland, Copeland, & Klimberg, 2018). In fact, sources state that glandular tissue comprises a majority of the breast during pregnancy and lactation, with one study of lactating women finding that the breasts were composed 63% (range 46–83%) of glandular tissue (Ramsay et al., 2005). This is not merely due to lobuloalveolar development and glandular growth, but is also due to a marked reversible reduction in mammary adipose tissue (Wang & Scherer, 2019; Alex, Bhandary, & McGuire, 2020). In any case, under more normal physiological circumstances and progesterone exposure, the contribution of lobuloalveolar tissue to the size of the breasts would appear to be quite small. In relation to this, outside of pregnancy levels of progesterone, the significance of progestogen-mediated breast lobuloalveolar growth in terms of breast size is unclear but seemingly questionable (Orentreich & Durr, 1974; Wierkcx, Gooren, & T’Sjoen, 2014).

Breast Development in Cisgender Women with Complete Androgen Insensitivity Syndrome and Consequent Absence of Progesterone

It has been claimed that progesterone helps to move transfeminine people and cisgender females from Tanner stage 4 to 5 breast development and that it helps to round out the breasts (e.g., Vorherr, 1974a; Prior, 2011; Prior, 2019a; Prior, 2020). It has also sometimes been claimed in the online transgender community that cisgender women with complete androgen insensitivity syndrome (CAIS), an experiment of nature of women who lack progesterone, are stuck at Tanner stage 4 breast growth and have “cone-shaped” breasts due to their absence of progesterone. In actuality however, there is no good evidence at this time that progesterone is required for normal pubertal breast development, that progesterone is needed to reach Tanner stage 5, or that it helps to round out the breasts. Such claims are contradicted by extensive available literature and evidence, including notably the literature on CAIS women themselves.

Women with CAIS are individuals who have a 46,XY karyotype (i.e., are genetically “male”), testes, and who would otherwise have physically developed as males, but did not because they have a mutation in the gene encoding the androgen receptor that makes them completely insensitive to the effects of androgens. There are also incomplete forms of the syndrome, like partial androgen insensitivity syndrome (PAIS) and mild androgen insensitivity syndrome (MAIS). CAIS women have a male-typical hormonal profile, generated by their testes, including high male-range levels of testosterone, low female-range estradiol levels, and negligible progesterone levels (Wiki; Table). Instead of developing physically as males however, CAIS women are perfectly phenotypically female, with a normal female body, vagina, and breasts (Wiki; Photo). Their testosterone has been unable to masculinize them, while their estradiol, unopposed by androgens, is able to fully feminize them. The internal reproductive system in CAIS women is essentially that of an underdeveloped male, with testes instead of ovaries, and no uterus. The vagina is often short and is blind-ending with no cervix, which is related to their lack of a uterus. CAIS women are also described as feminine in terms of behavior, gender, and sexuality.

Women with CAIS have breast development that is described throughout the literature as “good”, “excellent”, “normal”, “full”, “complete”, “well-developed”, “overdeveloped”, “generous”, “enhanced”, “typically above-average”, “large”, and even “voluptuous” (Morris, 1953; Simmer, Pion, & Dignam, 1965; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971b; Perez-Palacios & Jaffe, 1972; Glenn, 1976; Dewhurst & Spence, 1977; Rutgers & Scully, 1991; Patterson, McPhaul, & Hughes, 1994; Quigley et al., 1995; McPhaul, 2002; Galani et al., 2008; Oakes et al., 2008; Tiefenbacher & Daxenbichler, 2008; Barbieri, 2019). John McLean Morris, the gynecologist who reviewed and summarized all of the existing scientific literature on CAIS women in 1953 (including 82 cases) and gave their condition the now-abandoned name “testicular feminization”, described their breasts as “unusually large” and “jumbo-sized” (Morris, 1953; Quigley et al., 1995). He additionally said in his famous 1953 review that they had “normal female breasts, often with a tendency to be overdeveloped” (Morris, 1953). Per another author, “Probably under no other circumstance does breast development in the [‘male’] reach the florid degree seen in testicular feminization” (Wilson, 1968).

Despite claims that CAIS women have generous breast sizes however, in actuality, some CAIS women have large breasts, while some have small breasts, with one study finding a wide range of breast size measurements of 16×14 cm to 41×31 cm (Wisniewski et al., 2000). Moreover, the breasts of CAIS women have never been directly compared to those of normal women. Hence, there are no clear data at this time that the breasts of CAIS women are actually larger than average for women. The variation in breast growth in CAIS women parallels the same large variation in breast size between individuals that is seen in cisgender women in general. Here is a collection of photos of CAIS women and their breast development from published case reports and reviews throughout the literature. As can be seen from these photos, breast development in CAIS women is normal and often excellent, although subject to considerable variation between individuals in terms of breast size and shape as in women generally.

If CAIS women truly do have enhanced breast development and breast sizes compared to normal women, it may be that their androgen insensitivity, and hence lack of inhibition of estrogen-mediated breast development by androgens, is responsible for this (Wilson, 1968; Sobrinho, Kase, & Grunt, 1971; Andler & Zachmann, 1979; Zachmann et al., 1986; Patterson, McPhaul, & Hughes, 1994; Barbieri, 2019). Another theoretical possibility is that the high testosterone levels may be aromatized into greater amounts of estradiol locally within the breasts and other tissues in CAIS women and that this may somehow allow for enhanced breast development (Ladjouze & Donaldson, 2019).

Baron evaluated a total of 41 people with androgen insensitivity syndrome (AIS) and found that 97% of CAIS women had normal breast development while 63% of individuals with “incomplete AIS” (likely PAIS) had normal breast development (Baron, 1993; Baron, 1994a; Baron, 1994b). In another earlier published study of 50 CAIS females, by Sir Christopher John Dewhurst, 76% were rated as having full breast development, 14% as having moderate breast development, 10% as having “mild” breast development, and 0% as having absent breast development (Dewhurst, 1971b). Hence, based on findings in large samples of CAIS females, most to almost all have normal or full breast development. That a minority of CAIS females have had less breast growth may be due to factors like low and inadequate estradiol levels in some individuals, young age at time of assessment by which breast development has not fully completed, and/or a small subset of women in general having underdeveloped or small breasts.

CAIS women have never been described in the literature as having “cone-shaped”, “pointy”, or otherwise abnormal breasts. The only exception is that they are often said to have nipples and areolas that are described as “juvenile”, “infantile”, “small”, “pale”, and “non-pigmented” (e.g., Photo) (e.g., Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; Dewhurst, 1967; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977). This has been said to be the case regardless of breast size or maturation (Khoo & Mackay, 1972). A possible reason for this phenomenon is that estradiol levels in CAIS women are relatively low, only about 35 pg/mL (130 pmol/L) on average (Wiki; Table). This is relevant as estrogens are known to concentration-dependently produce nipple and areolar pigmentation and enlargement (Davis et al., 1945; Kennedy & Nathanson, 1953). In contrast to estrogens, progestogens have not been implicated in nipple or areolar pigmentation. Hence, it seems that higher estrogen levels may be necessary for full adult-like nipple and areolar maturation.

CAIS women are able to reach Tanner stage 5 breast development and hence full maturation of the breasts similarly to normal women (Quigley, 1988; Quigley et al., 1995; Gordon & Laufer, 2005; Finkenzeller & Loveless, 2007; Cheikhelard et al., 2008; Ramos et al., 2018; Arya et al., 2021; Zhang et al., 2021). One gynecologist, Robert Rebar, has claimed in his publications over several decades, including in reviews and book chapters, that CAIS women usually only reach Tanner stage 3 breast development (Kustin & Rebar, 1987; Rebar, 1988; Rebar, 1990; Simpson & Rebar, 1990; Rebar, 1993; Rebar, 1996; Wellons & Rebar, 2013; Wellons, Weeber, & Rebar, 2017). However, this claim conflicts with the statements of other researchers and with studies and case reports of CAIS women. In one book chapter, Rebar said that CAIS females undergo breast development and feminization and that the breasts contain normal ductal and glandular tissue, but stated that “the areolae are pale and poorly developed (Tanner stage 3)” (Rebar, 1993). This suggests that he may have been meant Tanner stage 3 in terms of nipple and areolar maturation rather than breast growth as a whole (Rebar, 1993). Aside from CAIS females, even individuals with PAIS often have substantial breast growth and female-like breasts (e.g., Saito et al., 2014; Lee et al., 2015). Additionally, PAIS females treated with estrogen therapy have similarly been reported to reach Tanner breast stage 5 (Guaragna-Filho et al., 2023).

Despite their often large breasts, CAIS women are said to have relatively little breast glandular tissue, as opposed to fat and connective tissue, and to have minimal breast lobuloalveolar development (Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982). This is in accordance with the lack of progesterone in CAIS women, since progesterone is important in mediating lobuloalveolar growth. The retained breast sizes of CAIS women despite reduced glandular and lobuloalveolar structures is consistent with the fact that the breasts are composed mostly of stromal adipose and connective tissue. Hence, as touched on previously in this article, greater glandular or lobuloalveolar formation in the breasts may not necessarily translate to greater breast size, which seems readily apparent in CAIS women.

The normal and excellent breast development of CAIS women is notable because these individuals, owing to their testes and hence absence of significant gonadal progesterone production, have very low and negligible levels of progesterone (Wiki; Table; Barbieri, 2019). CAIS womens’ normal breast development, often large breasts, and ability to reach complete breast maturation, as measured by the Tanner scale, are collectively suggestive that progesterone is not required for normal or complete pubertal breast development (Barbieri, 2019). In any case, it must be noted and cautioned again that the breasts of CAIS women have never been directly compared to those in normal women. In addition, quantitative studies of the breasts of CAIS women are very scarce, and much of our knowledge in this area is based on anecdotal clinical experience and subjective breast evaluation. This is in large part due to the rarity of CAIS women and the difficulty in obtaining decent samples of them for study. Furthermore, CAIS women also have other differences from regular women besides their lack of progesterone, for instance their relatively low circulating estradiol levels, high testosterone levels (which can be aromatized into estradiol within tissues like the breasts), androgen insensitivity, and XY karyotype, among others. Hence, the insights into breast development provided by CAIS women come with a variety of caveats.

Interestingly, in spite of their well-developed breasts, breast cancer has never been reported in CAIS women, and would appear to be very rare in these individuals (Aly, 2020b; Aly, 2020c). This may be related to factors like the lack of progesterone and lobuloalveolar maturation in CAIS women and/or their absence of a second X chromosome (Aly, 2020b; Aly, 2020c). CAIS women suggest that breast cancer is not an inherent eventual consequence of excellent breast development.

Menstrual Cycles and Temporary Cyclic Breast Enlargement

The breasts fluctuate in size across the menstrual cycle, with significant enlargement apparent during the luteal phase of each cycle (Shuttleworth, 1938 [Figure]; Ingleby, 1949; Scott et al., 1950; Milligan, Drife, & Short, 1975; Drife, 1982; Malini, Smith, & Goldzieher, 1985; Drife, 1989; Fowler et al., 1990; Graham et al., 1995; Jemström & Olsson, 1997; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Wang et al., 2019; Rix et al., 2023). This is experienced by women as a sense of fullness, as well as tingling sensations and tenderness (Shuttleworth, 1938 [Figure]; Milligan, Drife, & Short, 1975; Laessle et al., 1990; Jemström & Olsson, 1997). The change in the volume of the breasts has been reported to be approximately 75 to 100 mL on average, with volume falling to as low as 90% of mean volume during the follicular phase or at ovulation and increasing to up to 110% of average volume during the luteal phase (or about 15 to 20% mean total change from smallest to largest volume) (Milligan, Drife, & Short, 1975; Malini et al., 1985; Drife, 1989; Fowler et al., 1990; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Rix et al., 2023). However, more recent studies using better measurement methods of breast volume suggest more modest changes, like a decrease in breast volume of 4 to 10% during the follicular phase and an increase in breast volume of 3 to 21% during the luteal phase (Rix et al., 2023). The changes in breast size have also been described as an increase of one-third of a bra cup size (37 mL or 35 g) on average and up to one bra cup size in some (Rix et al., 2023). There is substantial variation between individuals in the changes in breast volume across the menstrual cycle, ranging from no change to up to a 40 to 45% increase in the most extreme cases (Ingleby, 1949; Malini, Smith, & Goldzieher, 1985; Fowler et al., 1990; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Rix et al., 2023).

The enlargement of the breasts during the luteal phase of the menstrual cycle is believed to be due to temporary glandular and stromal tissue growth, luminal dilation of the ducts and alveoli, fluid retention in the glandular and stromal structures, and increased vascularization and blood flow (Scott et al., 1950; Drife, 1989; Fowler et al., 1990; Hussain et al., 1999; Alekseev, 2021; Biswas et al., 2022). However, studies suggest that most of the changes are merely due to water fluctuations and that change in breast glandular volume change is relatively small (Rix et al., 2023). The breast changes during the menstrual cycle have been positively correlated with increased levels of estradiol and progesterone during the luteal phase (Jemström & Olsson, 1997; Clendenen et al., 2013; Rix et al., 2023). In addition, estrogen therapy has been found to reversibly increase breast size (e.g., Hartmann et al., 1998) and estradiol levels are positively associated with breast tenderness (e.g., de Lignières & Mauvais-Jarvis, 1981; Sitruk-Ware et al., 1984). Both estradiol and progesterone can promote water retention via distinct hormonal mechanisms as well as mediate breast glandular growth and changes (Rix et al., 2023). As such, the breast changes during the menstrual cycle are assumed to be due to changing levels of estradiol and progesterone, though it is noteworthy that progesterone has been particularly implicated owing to the breast volume increase occurring during the luteal phase (Lawrence & Lawrence, 2015; Rix et al., 2023). There is a delay in breast volume increases following the peaks of estradiol and progesterone levels during the menstrual cycle and hence the changes are not instantaneous (Rix et al., 2023).

Combined oral contraceptives, which are estrogen–progestogen preparations, as well as menopausal estrogen–progestogen hormone therapy, may produce temporary breast enlargement and feelings of breast fullness analogous to those that occur during the luteal phase of the menstrual cycle (Milligan, Drife, & Short, 1975; Dennerstein et al., 1980 [Figure]; Malini, Smith, & Goldzieher, 1985; Jemström & Olsson, 1997; Jernström et al., 2005). In one study, breast volume was around 100 mL greater (~30% higher) in women who were currently taking oral contraceptives relative to those who had not taken or had previously taken oral contraceptives (Jemström & Olsson, 1997). In some women, the increase in breast size with oral contraceptives was subjectively reported to be up to a single bra cup size in volume (Jemström & Olsson, 1997). However, in another study by the same group of researchers that had a much larger sample size (n=258 vs. n=65), breast volumes were not significantly different between current hormonal contraceptive users and non-users (Jernström et al., 2005). Additionally, another study found no significant differences in breast volume in women between different estrogen–progestogen oral contraceptives that had 6.25-fold variation in dose of the same progestin (0.4 to 2.5 mg/day norethisterone) as well as non-users (Malini, Smith, & Goldzieher, 1985). However, this study was underpowered due to small sample sizes (n=5 to n=15 per group) (Malini, Smith, & Goldzieher, 1985).

Engman et al. (2008) conducted an RCT of treatment with mifepristone, a selective progesterone receptor modulator (SPRM) with predominantly antiprogestogenic effects, versus placebo for 3 months in normally cycling premenopausal cisgender women, and evaluated the effects of this progesterone receptor blockade on the breasts. They found that mifepristone significantly reduced Ki-67 index, a measure of cellular proliferation in the breasts, and reduced subjectively rated symptom scores on the Breast Symptom Index (BSI). More specifically, breast soreness, breast swelling, sense of increased breast volume, and the total breast symptoms score were all significantly reduced on the BSI. However, breast volume was not objectively measured in this study. A major limitation of this study is that mifepristone inhibits ovulation and modifies levels of estradiol and other hormones (Spitz et al., 1989; Spitz et al., 1994; Engman et al., 2008, Spitz, 2010). As such, it is unclear whether the effects observed by Engman and colleagues were specifically due to progesterone receptor antagonism in the breasts or due to disruption of the hypothalamic–pituitary–gonadal (HPG) axis, for instance lowered estradiol levels.

An interesting case report of an adult woman with CAIS documented a significant increase in breast volume with combined estrogen–progestogen therapy relative to estrogen monotherapy (Dijkman et al., 2023b). The woman was started on cyclic oral estradiol 2 mg/day and dydrogesterone 10 mg/day and subjectively experienced breast pain and fluctuations in breast volume of about one cup size while on this regimen. Subsequently, she was switched to oral estradiol valerate 3 mg/day monotherapy and the fluctuations in breast volume ceased. However, her overall breast volume was reduced as well, and the woman decided to resume combined estradiol and dydrogesterone therapy. Her clinicians proceeded to measure her breast volume using 3D body scanning. Her left breast was 758 mL and right breast was 673 mL with estrogen monotherapy, and her breasts increased to respective volumes of 875 mL and 784 mL during combined estrogen–progestogen therapy, giving net volume increases of 117 mL (+16%) and 111 mL (+17%). These differences in volume corresponded to an almost one bra cup difference in size. The researchers noted that estradiol and progesterone are associated with cyclical breast changes, and hypothesized that the changes in their patient were due to increased fluid retention in the breasts. Taken together, the case report demonstrates that progestogens can cause rapid and considerable reversible breast enlargement in some women analogous to that during the normal menstrual cycle.

Progesterone and Mammary Development in Animals

Progesterone and Pubertal Mammary Development in Animals

Knockout of the progesterone receptor (PR) in female mice results in complete infertility and severely compromised ovarian and uterine functions (Lydon et al., 1995; Ismail et al., 2003). On the other hand, pubertal mammary development in progesterone-receptor knockout mice is normal and morphologically indistinguishable from that of regular mice (Soyal et al., 2002; Ismail et al., 2003; Fernandez-Valdivia et al., 2005). This is in contrast to the case of estrogen receptor alpha (ERα) knockout mice, in which pubertal mammary development is abolished (Ismail et al., 2003; Fernandez-Valdivia et al., 2005; Wiki; Wiki). However, subsequent studies revealed that mammary ductal development during puberty, while eventually normal, is delayed in female mice that have loss of progesterone production, loss of the progesterone receptor, or progesterone receptor antagonism with mifepristone (Shi, Lydon, & Zhang, 2004). In other words, progesterone stimulates and accelerates ductal development during puberty, and hence appears to have a significant physiological role in early mammary development during puberty. The stimulation of ductal development by progesterone appears to be mediated by induction of the expression of amphiregulin in mammary ducts and terminal end buds (Kariagina et al., 2010; Aupperlee et al., 2013). This growth factor is an agonist of the epidermal growth factor receptor (EGFR), and is also notably the major growth factor that estrogen induces the expression of to mediate mammary gland development during puberty (Ciarloni, Mallepell, & Brisken, 2007; LaMarca & Rosen, 2007; McBryan et al., 2008). In any case, as mammary ductal development during puberty without progesterone is delayed, but eventually normal, it has been concluded that progesterone is dispensable for pubertal mammary gland development in mice (Soyal et al., 2002; Ismail et al., 2003; Fernandez-Valdivia et al., 2005).

Although progesterone does not seem to be essential in normal pubertal mammary development in mice, studies have interestingly found that it is able to substitute for estrogen in mediating pubertal ductal mammary development in this species. Ruan, Monaco, & Kleinberg (2005) studied the effects of various combinations of exogenous estradiol, progesterone, and IGF-1 on mammary development in oophorectomized female IGF-1-knockout mice. In terms of stimulation of ductal development to occupy the mammary gland fat pad, the combination of progesterone and IGF-1 produced 92% occupation, estradiol and IGF-1 resulted in 92% occupation, estradiol, progesterone, and IGF-1 achieved 96% occupation, and IGF-1 alone resulted in only 28% occupation (Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008). In terms of gross anatomical appearance, the ductal tree with progesterone and IGF-1 was said to resemble that of a normal fully developed pubertal mammary gland (Ruan, Monaco, & Kleinberg, 2005). However, differences in mammary development between the combination of estradiol and IGF-1 and the combination of progesterone and IGF-1 were apparent, with estradiol and IGF-1 having greater effect on terminal end bud formation, ductal decorations, and slight alveolar maturation, and progesterone and IGF-1 having more effect on ductal formation, extension, and branching (Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008). The effects of progesterone on mammary development were reversed by the progesterone receptor antagonist mifepristone (Ruan, Monaco, & Kleinberg, 2005). Only the combination of estradiol, progesterone, and IGF-1 produced mammary development that resembled that during mid-pregnancy, with full maturation of secretory alveolar structures (Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008).

Aside from the preceding studies, a number of other studies have also found increased ductal branching of mammary glands during puberty with exogenous progesterone administration in mice (Atwood et al., 2000; Hovey et al., 2001; Satoh et al., 2007; Aupperlee et al., 2013).

A limitation of studies that have used exogenous progesterone to stimulate pubertal ductal mammary development in mice is that the doses of progesterone employed, in conjunction with other hormones like estradiol, have been sufficient to mediate mammary growth to a level typical of pregnancy, with robust maturation of mammary lobuloalveolar structures (e.g., Škarda, Fremrová, & Bezecný, 1989; Ruan, Monaco, & Kleinberg, 2005). Pregnancy is a time when hormone levels are much higher than usual. Hence, the progesterone exposure in these studies may have been supraphysiological relative to normal puberty, and may have produced effects on mammary growth that would not otherwise occur during this time. Accordingly, Škarda, Fremrová, & Bezecný (1989) found that whereas untreated normal female mice naturally grew to a mammary gland area of 26.4 mm2 and normal female mice treated with exogenous estradiol grew to a mammary gland area of 25.3 mm2, normal female mice treated with exogenous estradiol and progesterone grew to a mammary gland area of 43.5 mm2 and with exogenous progesterone alone to a mammary gland area of 64.6 mm2. The untreated control mice did not show alveolar buds, whereas the progesterone-treated groups did have alveolar maturation, indicating supraphysiological and pregnancy-like development compared to non-pregnant mice (Škarda, Fremrová, & Bezecný, 1989). In any case, one study employed low doses of progesterone (0.1 mg/day), one-tenth of that used in most other studies (1 mg/day), and found that progesterone still stimulated significant ductal development in mice at these doses (Aupperlee et al., 2013; Berryhill, Trott, & Hovey, 2016). Hence, progesterone is still able to stimulate some level of ductal growth in mice even at lower levels.

Although progestogens by themselves can apparently stimulate normal pubertal mammary development in lieu of estrogen exposure in mice, it is not clear that they do so similarly in humans. It is well-known that progestogens alone, without concomitant estrogenic activity, do not generally produce breast development in humans. As an example, progestogens, for instance MPA and CPA, have been used as puberty blockers in boys and girls at very high doses, and do not produce breast development in this context, instead causing arrest and regression of breast development via gonadal suppression (Lyon, De Bruyn, & Grant, 1985; Fuqua & Eugster, 2022). Cases of gynecomastia in boys have occurred with CPA, but only in a minority and with this easily attributable to other causes than progestogenic activity, for instance the antiandrogenic activity of CPA and disruption of the HPG axis (Kauli et al., 1984; Laron & Kauli, 2000). Similarly, progestogens like MPA and CPA have been used at very high doses in men to treat prostate conditions and sexual disorders, and likewise do not usually produce gynecomastia under these circumstances. Rates of gynecomastia with CPA used in the treatment of prostate cancer are low and are not noticeably different from the rates with surgical or medical castration (~10%) (Fourcade & McLeod, 2004; Di Lorenzo et al., 2005). This is in major contrast to the high rates of gynecomastia with estrogens and nonsteroidal antiandrogens (up to 70–80%) (Fourcade & McLeod, 2004; Di Lorenzo et al., 2005; Deepinder & Braunstein, 2012). Species differences may be present such that progestogens can produce robust pubertal mammary development in mice but do not do so in humans.

Progesterone and Gestational Mammary Development in Animals

As in humans, pregnancy results in increased levels of estrogen, progesterone, prolactin, and many other hormones in various animal species like rodents and non-human primates (Hasan, 1974; Cowie, Forsyth, & Hart, 1980; Pasqualini & Kincl, 1985; Günzel et al., 1987; Seibert & Günzel, 1994). Along with this, there are dramatic changes in the mammary glands (Cowie, Forsyth, & Hart, 1980; Richert et al., 2000; Cline & Wood, 2008; McNally & Stein, 2017). This includes extensive lobuloalveolar maturation of the mammary glands in preparation of lactation and nursing (Cowie, Forsyth, & Hart, 1980; Richert et al., 2000; Cline & Wood, 2008; McNally & Stein, 2017). Permanently enlarged breasts, mainly due to accumulation of abundant adipose tissue during puberty, is unique to humans, and in animal species, although there is significant growth with puberty (e.g., Geschickter, 1945 [Figure]), the exterior mammae enlarge considerably only with pregnancy (Pawłowski & Żelaźniewicz, 2021). In the case of macaques, there is a roughly 10- to 20-fold increase in the glandular tissue during pregnancy (Cline & Wood, 2008).

Administration of exogenous estradiol and progesterone in specific amounts to virgin adult females of various animal species, including rodents, results in mammary development that is very similar to that which occurs normally during pregnancy (Nelson, 1936; Turner, 1939; Folley, 1940; Folley, 1947; Folley & Malpress, 1948; Folley, 1950; Folley, 1952; Folley, 1956; Lyons, 1958; Lyons, Li, & Johnson, 1958; Cowie & Folley, 1961; Jacbosohn, 1961; Cole & Hopkins, 1962; Lloyd & Leathem, 1964; Meites, 1966; Bässler, 1970; Ceriani, 1974; Vorherr, 1974b; Cowie, Forsyth, & Hart, 1980; Tucker, 2000; Kleinberg, 2006; Kleinberg & Ruan, 2008; Kleinberg et al., 2009; Kleinberg & Barcellos-Hoff, 2011). High levels of prolactin also occur in this context, as estrogen and progesterone induce production and secretion of prolactin from the pituitary gland (Ceriani, 1974; Bethea, Kohama, & Pecins-Thompson, 1997; Camilletti et al., 2019). Although estradiol and progesterone alone seem to be adequate for producing full pregnancy-type mammary development in many species, the combination of estradiol, progesterone, and placental lactogen in rhesus monkeys produced considerably less lactational activity than occurs during normal pregnancy in this species (Beck, 1972; Cowie, Forsyth, & Hart, 1980). In relation to this, placental lactogen and/or additional hormonal factors may also be necessary for complete pregnancy-like mammary gland maturation in primates (Beck, 1972; Cowie, Forsyth, & Hart, 1980).

As with humans, following cessation of lactation and nursing, the mammary glands are well-known to undergo post-lactational involution and to return to a pre-pregnancy-like state in animals, including in rodents and monkeys (Richert et al., 2000; Cline & Wood, 2006; Cline & Wood, 2008; Fridriksdottir, Petersen, & Rnnov-Jessen, 2011; McNally & Stein, 2017).

Breast Changes with Therapeutic Pseudopregnancy

Therapeutic or pharmacological pseudopregnancy is a type of hormone therapy that attempts to replicate the hormonal mileu of pregnancy for certain medical indications in cisgender females by administering exogenous hormones. In practice, this has involved the administration of very high doses of estrogens and progestogens, with most other pregnancy hormones not included. Therapeutic pseudopregnancy was first developed in the 1950s and is largely no longer used in medicine today (Kaiser, 1993).

The effects of therapeutic pseudopregnancy on the breasts are of interest due to the breast changes that occur during pregnancy, for instance lobuloalveolar development and substantial reversible breast enlargement. In the 1980s, Lauritzen and colleagues conducted a study of therapeutic pseudopregnancy for treatment of breast hypoplasia (small/underdeveloped breasts) in cisgender women (Lauritzen, 1980; Lauritzen, 1982; Lauritzen, 1989; Göretzlehner & Lauritzen, 1992). They employed the estrogen estradiol valerate 40 mg/week and the progestogen hydroxyprogesterone caproate (OHPC) 250 to 500 mg/week both by intramuscular injection for 4 to 5 months. The estradiol valerate dosage employed was very high, with other studies by the same authors reporting that this dosage of estradiol valerate resulted in first-trimester pregnancy levels of estradiol in women (~3,000 pg/mL [~11,000 pmol/L]) (Ulrich, Pfeifer, & Lauritzen, 1994; Ulrich et al., 1995). These estradiol levels are roughly 30 times the normal concentrations outside of pregnancy (Aly, 2018b). Similarly, the OHPC doses were very high, with 250 to 500 mg per month being similar in strength to luteal-phase progestogenic exposure (Wiki). Hence, as the same OHPC doses were used weekly in the study, the doses were roughly around 4.5 times luteal-phase exposure and thus were analogously similar to first- or second-trimester progesterone levels in terms of strength (Aly, 2020d). The authors noted that they had initially tried lower hormone doses, similar to those originally used in the 1950s, but did not achieve significant breast growth with these doses, and so increased the dosage. Breast changes were measured in the study with a tape measure (applied horizontally and vertically to the breast area), photographs, breast imaging using mammography and sonography, and, later in the study, plasticine impressions/molds with determination of the filling volume.

Lauritzen and colleagues reported the study findings in four different publications with different follow-up times and growing sample sizes. In the final follow-up, a total of 221 women had been treated. In the second follow-up, when 78 women had been treated, it was noted that 29 of the cases (37%) were less than 18 years old. However, in the final follow-up of 221 women, the age range was listed as 18 to 42 years. The researchers found that breast volume increased by 10 to 30% above baseline in 65% of the women. This was also accompanied by breast tenderness in almost all of the women, though the breast tenderness progressively declined during the treatment period. Other breast-related side effects like pigmentation and stretch marks were rarely observed. Prolactin levels slightly increased to 14 to 28 pg/mL by the end of treatment. Breast imaging showed an increase in the density of breast glandular tissue. The researchers claimed that the increase in breast size in their study was due to increased adipose tissue, water retention, and moderate hypertrophy of the glandular tissue.

Following treatment discontinuation, the increases in breast volume gradually and partially regressed in 40% of the women, to an increase of 10 to 20% above baseline. However, the authors claimed that the regression in breast volume could be reduced with adequate-dose combined estrogen–progestogen birth control pills or with topical estrogen and progestogen therapy applied to the breasts. In addition, they noted that therapeutic pseudopregnancy could be repeated to increase breast volume again. This was performed in a subset of the women, with treatment repeated 1 to 2 times after 6 months. In the second follow-up, which had 78 women, it was noted that 12 women (15%) had undergone multiple treatments. Aside from Lauritzen and colleagues, many other researchers have also reported substantial or full regression in breast size following estrogen and/or progestogen therapy to increase breast size in cisgender women (e.g., Cernea, 1944; Müller, 1953; Anderson, 1962; Bruck & Müller, 1967; Keller, 1984; Kaiser & Leidenberger, 1991; Keller, 1995; Hartmann et al., 1998).

The findings of Lauritzen and colleagues were reported very informally, in the form of non-peer-reviewed book chapters, conference papers, and medical magazines, and were never published in a peer-reviewed journal article. In relation to this, the methodology and results of the study were only briefly and imprecisely described. There are also additional concerns related to study design, such as lack of controls, randomization, and the quality of the breast measurement methods. As a result of the preceding issues, it is difficult to fully interpret the results of the study and to have complete confidence in its findings. In any case, Lauritzen and colleages’ results suggest that treatment with high-dose combined estrogen–progestogen therapy, achieving earlier-pregnancy estrogenic and progestogenic exposure, may be able to produce a significant temporary increase in breast size and a smaller long-term increase. The findings of a permanent increase in breast size conflict with those of other researchers who have reported complete regression in breast changes following treatment discontinuation. Moreover, the results are contradicted by findings in pregnant women, who, as described previously, show complete reversion to pre-pregnancy breast size or to even slightly smaller breasts following cessation of lactation.

It is difficult to evaluate the relative roles of the estrogen and the progestogen in the findings of Lauritzen and colleagues, as there were no comparison groups employing estrogen or progestogen therapy alone in the study. Both estrogens and progestogens have been implicated in causing breast enlargement and plausibly could have contributed to the breast changes. As such, it is unclear to what extent the breast changes were specifically due to progestogenic exposure rather than to estrogenic exposure.

The breast size increases observed by Lauritzen and colleagues were seemingly more modest relative to those that occur normally during pregnancy. They also lacked certain characteristics of pregnancy-related breast changes, like nipple and areolar pigmentation. The reasons for this are not fully clear. The subject populations between these studies were different, for instance in terms of factors like initial breast size and age, which may be contributing reasons. Another possible contributing factor is that only estrogen and progestogen levels increased in the study, whereas levels of other pregnancy hormones, besides the slight increase in prolactin levels, did not increase. These other pregnancy hormones, for instance hPL and IGF-1, may also be involved in breast development during pregnancy. Finally, the treatment duration was only 4 to 5 months, and the estrogen and progestogen exposure was only similar to that during early-to-mid pregnancy, whereas normal pregnancy lasts 9 months and involves continued dramatic increases in estrogen and progesterone levels through to childbirth.

It should be noted that, owing to the highly supraphysiological estrogen and progestogen levels required, which can cause serious health complications like blood clots and cardiovascular problems (Aly, 2020e), as well as the small to negligible lasting increase in breast volume, therapeutic pseudopregnancy is inadvisable for transfeminine people and should not be pursued or employed. Nonetheless, the historical findings of therapeutic pseudopregnancy for increasing breast size in cisgender females are of significant theoretical interest in exploring the roles of estrogens and progestogens in breast growth.

Early Progestogen Exposure and the Possibility of Suboptimal Breast Development

While progestogens are typically sought after by transfeminine people for their potential in improving breast development, there have also been various suggestions in the literature that early or premature exposure to progestogens may result in suboptimal breast development and that progestogens may suppress or reduce estrogen-mediated breast development. These suggestions include progestogens having known antiestrogenic effects in the breasts, animal studies finding stunted mammary development with high doses of progestogens, clinical publications cautioning against premature introduction of progestogens in female puberty induction due to concerns about possibly stunted breast growth, clinical use of progestogens to treat macromastia in cisgender females, poor breast development with estrogen therapy in cisgender girls with a disorder of sexual development that results in high progesterone exposure, and breast development with estrogen and CPA (a very strong progestogen) typically being poor in transfeminine people. As with the question of whether progestogens can enhance breast development, it is currently unknown whether progestogens could worsen breast development. It is also unknown what dosage level and timing of introduction would be required for such an effect. In any case, for informational purposes, the preceding topics will each be discussed in the subsequent sections.

Antiestrogenic Effects of Progestogens in the Breasts

Progestogens are well-known to have potent functional antiestrogenic effects in tissues such as the uterus, vagina, and cervix (Wiki). The antiestrogenic effects of progestogens in the uterus are in fact the reason that they are used in menopausal hormone therapy—to prevent the risks of endometrial hyperplasia and endometrial cancer that unopposed estrogen therapy otherwise produces (Wiki). Progestogens also appear to have antiestrogenic effects in the breasts (Mauvais-Jarvis, Kuttenn, & Gompel, 1986a; Mauvais-Jarvis, Kuttenn, & Gompel, 1986b; Mauvais-Jarvis, Kuttenn, & Gompel, 1987; Mauvais-Jarvis et al., 1987; Kuttenn et al., 1994; Wren & Eden, 1996; Plu-Bureau, Touraine, & Mauvais-Jarvis, 1999; Wiki). This may include by inhibiting estrogen synthesis and enhancing estrogen inactivation in the breasts (Pasqualini, 2007; Pasqualini, 2009) and by reducing expression of the estrogen receptors in the breasts (Mauvais-Jarvis, Kuttenn, & Gompel, 1986b; Malet et al., 1991; Kuttenn et al., 1994; Wren & Eden, 1996; Graham & Clarke, 1997; Plu-Bureau, Touraine, & Mauvais-Jarvis, 1999). Clinical studies have found that direct application of topical progesterone to the breasts suppresses estradiol-mediated breast cell proliferation, although this may be due to the delivery of supraphysiological levels of progesterone in the breasts (Barrat et al., 1990; Chang et al., 1995; Foidart et al., 1996; Spicer, Ursin, & Pike, 1996; Foidart et al., 1998; de Lignières, 2002; Gompel & Plu-Bureau, 2018; Trabert et al., 2020). In accordance with their antiestrogenic effects in the breasts, progestogens are considered to be useful in treating estrogen-dependent benign breast disorders such as breast pain, nodularity, and fibrocystic breast disease (Mauvais-Jarvis, Sitruk-Ware, & Kuttenn, 1981; Winkler et al., 2001; Schindler, 2011; Wiki; Wiki; Wiki). Progestogens have also been reported to antagonize nipple and areolar hyperpigmentation induced by high-dose estrogen therapy (Crowley & Macdonald, 1965). In contrast to the preceding findings however, the addition of a progestogen to an estrogen in menopausal hormone therapy has been shown to significantly increase the risk of breast cancer (Aly, 2020a; Wiki). In any case, the antiestrogenic effects of progestogens in the breasts provide a plausible potential mechanism by which they might limit estrogen-mediated breast development. However, an alternative possible mechanism is that such actions may be related to simultaneous induction of ductal development and lobuloalveolar maturation, the latter of which is notably not normal for puberty (Randolph, 2018).

Stunted Mammary Growth with Progestogens in Animal Studies

Animal studies using progestogens including bioidentical progesterone and chlormadinone acetate (CMA), a progestin closely related to CPA, have found that high doses of these progestogens substantially stunt mammary gland development in rabbits, whereas lower doses do not do so (Lyons & McGinty, 1941; Beyer, Cruz, & Martinez-Manautou, 1970). See here for relevant literature excerpts as well as figures from these studies. Lyons & McGinty (1941) [Figure] found that estrogen alone induced ductal mammary development and estrogen plus progesterone 0.25 to 1 mg/day produced ductal development and slight to “fair” lobuloalveolar development. Conversely, estrogen plus progesterone 4 to 8 mg/day, which were 4- to 8-fold higher doses of progesterone than the most optimal dose, produced stunted mammary development with inhibited ductal development, only slight lobuloalveolar development, and, at the highest dosage, resulted in a much smaller mammary gland in terms of size than in the ≤1 mg/day groups. They concluded that high doses of progesterone are inhibitory and result in relatively poor mammary development. In the paper, doses of progesterone in international units (IU) were reported, but a citing review, Pfeiffer (1943), indicated that 1 IU progesterone is equal to 1 mg progesterone. As such, the milligram doses are listed above instead. Beyer, Cruz, & Martinez-Manautou (1970) [Figure] found that estrogen alone produced good ductal development without lobuloalveolar growth (mean mammary area = 376 mm2) and both estrogen plus CMA 0.5 mg/day and estrogen plus progesterone 2.5 mg/day produced optimal ductal and lobuloalveolar development (mean mammary area = 765 mm2 and mean mammary area = 688 mm2, respectively). Conversely, estrogen plus CMA 2.5 mg/day, a 5-fold higher dose of CMA than the optimal dose, resulted in dramatically reduced ductal development and mammary gland size albeit with significant lobuloalveolar growth (mean mammary area = 284 mm2). The authors concluded that moderate doses of progestogens stimulate mammary gland growth whereas large doses inhibit mammary gland development.

While these animal studies are suggestive that high doses of progestogens may be able to stunt breast development in humans, this is far from a certainty. There are species differences in hormone-mediated mammary development such that findings in one species, such as rabbits, may not translate to another species, like humans, or sometimes even to closely related species, like rats or guinea pigs (Bässler, 1970). As far as the present author is aware, stunted mammary development with high doses of progestogens has not been studied or reported in other animal species, for instance other rodent species or monkeys. It is also unclear that the doses employed in these animal studies are necessarily relevant to progestogen therapy in humans. This is because pregnancy levels of progesterone, which are much higher than luteal-phase progesterone levels, are necessary for substantial mammary lobuloalveolar development, and the doses of progestogens used in these studies were above that magnitude of progestogenic exposure. Hence, the doses may have corresponded to what in humans would be extremely high doses. However, such doses could still be relevant in the case of CPA used as an antiandrogen in humans, as CPA is used in this context at very high doses (see section below). The present author is unaware of any animal studies finding that physiological non-pregnancy levels of progesterone have any stunting or other adverse influence on mammary development, suggesting that only high doses of progestogens may have such effects. Finally, it seems notable that the estrogen and progestogen were initiated simultaneously in these animal studies and yet produced optimal pregnancy-like mammary development at the right doses. This suggests that early or immediate progestogen exposure might not be unfavorable in terms of breast development in humans. However, once again species differences may be present and confirmatory clinical studies are needed in humans.

Clinical Publications Cautioning Against Premature Introduction of Progestogens Due to Possibly Stunted Breast Development

A large number of clinical publications largely in the pediatric endocrinology literature have warned that premature exposure to progestogens during for instance puberty induction may result in suboptimal breast development in cisgender girls and/or transfeminine people (Zacharin, 2000; Bondy et al., 2007; Colvin, Devineni, & Ashraf, 2014; Wierckx, Gooren, & T’Sjoen, 2014; Kaiser & Ho, 2015; Bauman, Novello, & Kreitzer, 2016; Gawlik et al., 2016; Randolph, 2018; Donaldson et al., 2019; Heath & Wynne, 2019a; Heath & Wynne, 2019b; Iwamoto et al., 2019; Crowley & Pitteloud, 2020; Naseem, Lokman, & Fitzgerald, 2021; Federici et al., 2022; Lucien et al., 2022; Rothman & Iwamoto, 2022). The full relevant excerpts from these sources can be found here. In relation to these claims, and in order to mimic normal female puberty, a progestogen is not typically added to estrogen therapy during puberty induction in cisgender girls with delayed puberty until after about 2 to 3 years of treatment, by which point breast growth is generally considered complete. Additionally, progestogens are generally never added as part of puberty induction in transfeminine adolescents. Despite the preceding widespread literature statements and accepted clinical practices in the field of puberty induction however, it is important to note that the claims that premature introduction of progestogens might stunt breast development in this context are currently not based on any actual reliable clinical evidence and hence remain unsubstantiated. It is not even clear that these statements are based on anecdotal clinical experience as opposed to simple conjecture. The absence of data in this area may finally change in the future as more clinical studies of progestogens in puberty induction in cisgender girls are conducted (e.g., Rodari et al., 2023).

Rodari and colleagues studied optimization of puberty induction with estrogen therapy followed by eventual introduction of progestogen therapy in 49 cisgender girls with hypogonadism (e.g., Rodari et al., 2022; Rodari, 2022; Rodari et al., 2023). The researchers employed incrementally titrated low-dose transdermal estradiol to mimic the low and gradually increasing estradiol levels during normal puberty and added a progestogen only once menstrual bleeding began. The total duration of treatment was mean 2.65 ± 1 years, the time of first menstrual bleeding occurrence was 2.3 ± 1 years, and the time of progestogen introduction was median 2.22 years (IQR 1.56–2.87 years). Of the girls, 90% reached Tanner breast stage 4, but only 41% reached Tanner breast stage 5. Reaching the final Tanner breast stage was significantly associated with the number of estradiol dose increases (i.e., gradual estradiol dose titration) and the estradiol dose at progestogen introduction. The researchers interpreted the latter finding as progestogen exposure potentially hampering breast development. They questioned introducing progestogen therapy in the presence of incompletely developed breasts and suggested that instead of adding a progestogen upon onset of menstrual bleeding, clinicians should consider slightly reducing the estradiol dosage to delay progestogen introduction until the breasts complete maturation. While interesting, it must be noted that the findings of Rodari and colleagues are merely correlational, are open to multiple interpretations, and do not causally show that progestogens impair breast maturation.

Progestogens in the Treatment of Breast Hypertrophy

Low progesterone levels have been suggested as a possible contributing factor in the development of pubertal macromastia (breast hypertrophy) (Sun et al., 2018). A number of case reports and series of progestogens in the treatment of pubertal macromastia have been published (Sperling & Gold, 1973; Boyce, Hoffman, & Mathes, 1984; Ryan & Pernoll, 1985; Aritaki et al., 1992; Gliosci & Presutti, 1993; Sridhar & Jaya Sinha, 1995; Baker et al., 2001; Dancey et al., 2008; Bland, Howard, Romrell, 2009; Hoppe et al., 2011; Sun et al., 2018). Progestogens such as dydrogesterone, MPA, and CPA were used for this purpose in an attempt to stop or slow the growth of the breasts under the assumption that they are functionally antiestrogenic in breast tissue. Clinical success in these limited cases was mixed. Due to the self-resolving nature of pubertal macromastia (i.e., breast development stops on its own eventually) and other methodological limitations, such as very small numbers of individuals and lack of untreated control groups, it is difficult to draw any reliable conclusions about effectiveness from these reports.

More recently, a couple of studies, both by the same group of researchers, assessed the impact of different types of hormonal contraception on macromastia in adolescent cisgender females with macromastia (Nuzzi et al., 2021; Nuzzi et al., 2022). They found that use of progestin-only contraceptives were associated with significantly more breast tissue removed upon surgical breast reduction (959.9 g/m2 vs. 735.9 g/m2 [+30%]; p = 0.04) and worse clinical symptoms (e.g., breast pain—odds ratio, 4.94, p = 0.005) relative to non-users of hormonal contraception (Nuzzi et al., 2021). Conversely, use of combined oral contraceptives, which are estrogen–progestogen preparations, were associated with significantly less breast tissue removed with breast reduction (639.5 g/m2 vs. 735.9 g/m2 [−13%]; p = 0.003), though not with any differences in clinical symptoms, relative to those naive to hormonal contraception (Nuzzi et al., 2022). It should be noted that progestin-only contraceptives suppress the HPG axis and result in low estradiol levels, whereas combined oral contraceptives suppress the HPG axis and lower estradiol production but simultaneously supplement estrogen signaling by delivering exogenous estrogen. This difference may somehow be responsible for the opposite influence of estrogen–progestogen therapy versus progestogen-alone therapy on macromastia severity. While the findings of Nuzzi and colleagues are interesting, it is noteworthy that the methodology and findings of their research were criticized on various grounds in a letter to the editor concerning one of the articles (Karp, 2022).

Santen et al. (2024), in a case series of cisgender girls with juvenile gigantomastia, noted that breast growth continues for only a number of years following onset and hence there must be some form of stop signal that is activated and that prevents further breast growth. They speculated that this signal may be related to apoptosis (programmed cell death). Santen and colleagues noted that in adult cisgender women, proliferation of breast cells is increased during the follicular phase of the menstrual cycle, whereas apoptosis in breast cells is increased during the luteal phase of the cycle. They hypothesized that the apoptosis during the luteal phase may block further breast development. Since progesterone is produced during the luteal phase and may mediate said apoptosis, this would substantiate the use of progestogens in the treatment of breast hypertrophy. However, the researchers noted that no data exist on apoptosis in the breasts of girls with juvenile gigantomastia. Moreover, an important point against the authors’ hypothesis is that breast growth gradually ceases in people without luteal phases or progestogenic exposure, for instance CAIS women, transfeminine people, and other examples.

Poor Breast Development in 17α-Hydroxylase/17,20-Lyase Deficiency

Poor breast development with exogenous estrogen therapy has been reported in cisgender girls with 17α-hydroxylase/17,20-lyase deficiency, and prior exposure to high progesterone levels consequent to the condition has been hypothesized to be responsible for this (Turan et al., 2009; Athanasoulia et al., 2013; Deeb et al., 2015; Çamtosun et al., 2017; Fernández-Cancio et al., 2017; Kardelen et al., 2018). However, this is only speculation, and at this time, there is no causal evidence or other substantiation that progesterone specifically is responsible for the observations of poor breast growth.

Non-Comparative Clinical Studies of Breast Development with Estrogen and Cyproterone Acetate in Transfeminine People

The possibility of suboptimal breast development with premature exposure to progestogens is of particular relevance in the case of CPA used as an antiandrogen in transfeminine people. This is because CPA is a potent progestogen in addition to antiandrogen, starts to be taken at the initiation of hormone therapy, and happens to be used in transfeminine people at doses that result in very strong to profound progestogenic exposure (Aly, 2019). In terms of progestogenic strength, CPA at a dosage of 2 mg/day is comparable to the progesterone exposure during the luteal phase of the menstrual cycle (Aly, 2019; Wiki). For comparison, CPA has been used in transfeminine people at doses ranging from 10 to 100 mg/day (Aly, 2019). This would mean that CPA provides roughly 6.25 times the progestogenic impact of luteal-phase progesterone exposure at a dosage of 12.5 mg/day, 12.5 times the impact at 25 mg/day, 25 times the impact at 50 mg/day, and 50 times the impact at 100 mg/day. Moreover, this does not consider the fact that progesterone is only produced during the luteal phase, or half of the menstrual cycle, whereas CPA is taken continuously every day of the month. The preceding magnitudes of progestogenic exposure with CPA are on par with and even beyond those during pregnancy. Only recently have lower doses of CPA (e.g., ≤12.5 mg/day) started to be used in transfeminine hormone therapy.

Studies in pubertal and adolescent transfeminine people given GnRH agonists to block puberty plus estrogen therapy have reported good breast development in these individuals as assessed by subjective clinical impression or Tanner staging (de Vries et al., 2010; Hannema et al., 2017). However, quality objective measures of breast development were not employed in these studies. Conversely, non-comparative studies using estrogen plus CPA in adult transfeminine people have commonly reported modest breast development, including incomplete breast development only to Tanner stage 2 to 4, small breast cup sizes, and small breast volumes (Kanhai et al., 1999; Sosa et al., 2003; Sosa et al., 2004; Wierckx et al., 2014; Fisher et al., 2016; Tack et al., 2017; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019; Meyer et al., 2020; de Blok et al., 2021). Additionally, breast sizes smaller than those in cisgender women have been reported (Asscheman & Gooren, 1992; Kanhai et al., 1999). In one study, breast development with estrogen plus CPA was also poor in late-adolescent transfeminine people (Tack et al., 2017). However, in this particular study, the estrogen dose used was likely too low and resulted in inadequate estradiol levels, as noted by the authors themselves, and this is a potential confounding factor in their findings (Tack et al., 2017). In any case, breast growth with estrogen plus CPA in transfeminine people would seem to consistently be poor. In contrast to the regimen of estrogen and CPA, breast development with other hormone therapy regimens, for instance estrogen with non-progestogenic antiandrogens like spironolactone, bicalutamide, and GnRH modulators, has not been nearly as well-studied in comparison, and hence comparisons of outcomes between regimens is difficult.

In one of the highest quality studies of estrogen and CPA and breast development in adult transfeminine people, breast volume measured with 3D body scanning (Vectra XT) was approximately mean 100 mL (95% CI ~75–125 mL; range up to ~750 mL), equating to less than an A cup size on average, after 3 years of hormone therapy with estrogen and CPA in 69 transfeminine people (de Blok et al., 2021 [Figure]). In this study, breast changes over time had clearly plateaued, suggesting that breast development was either complete or was nearly so (de Blok et al., 2021 [Figure]). Although most of the transfeminine people in this study had less than an A cup breast size (71%), a minority had cup sizes ranging from an A cup (9%), B cup (16%), C cup (3%), to E cup (1%) (de Blok et al., 2021 [Figure]). For comparison, a study of normative data on breast volumes in cisgender women, using a different 3D body scanning device (Artec Eva 3D), found breast volumes of median ~515 mL and mean ~650 mL (IQR ~310–850 mL; range ~50–3,100 mL) in 378 cisgender women (Coltman, Steele, & McGhee, 2017). As such, adult transfeminine people treated with estrogen and CPA would appear to have substantially smaller breasts than cisgender women. However, it must be emphasized that the preceding data come from separate clinical studies and hence are not directly comparative. It is noteworthy in this regard that breast volumes can vary considerably between different studies even using similar measurement methods (e.g., magnetic resonance imaging) (Sindi et al., 2019 [Table]). Hence, there is a need for studies directly comparing breast volumes in transfeminine people to those in cisgender women using the same measurement method in order to comparatively evaluate breast development.

Regardless of the preceding, transfeminine people could simply have poor breast development in general without this necessarily being related to CPA or progestogenic exposure. Indeed, a more recent study in transfeminine people who underwent pubertal suppression in adolescence, presumably with GnRH agonists and then estrogen therapy, found similarly poor breast development as has been reported in adults (Boogers et al., 2022; c.f. de Blok et al., 2021). This study used breast volume via 3D body scanning to measure breast development and found a mean breast volume of 114 mL (IQR 58–203 mL), equating to less than an A cup size, after 4.2 years of hormone therapy (Boogers et al., 2022). It was notably conducted by the same group of researchers who did the earlier higher-quality study in adult transfeminine people, and hence likely used the same 3D scanning method (de Blok et al., 2021).

No directly comparative studies of breast development with CPA versus other antiandrogens in transfeminine people are currently available. Hence, it’s not fully known whether the findings are specific to CPA or also generalize to other antiandrogens that are not also strongly progestogenic. The RCT of estradiol and spironolactone versus estradiol and CPA in transfeminine people by Ada Cheung and colleagues that is currently underway in Australia may provide more insight on this issue, as spironolactone is only a weakly or clinically non-progestogenic antiandrogen (Aly, 2018b; Wiki).

Additional Considerations for Progestogen Therapy and Breast Development in Transfeminine People

Anecdotes About Progestogens and Breast Development

Many transfeminine people who have taken progestogens as part of hormone therapy have anedotally reported that the progestogens improved their breast development. At the same time, many other transfeminine people have anecdotally reported no benefit of progestogens to breast development. It must be cautioned in general that anecdotal reports are unreliable and represent a very low form of medical evidence. This is because subjective observations and attributions are often erroneous. Perceptions can be faulty and inaccurate, especially with slowly developing physical changes, and true physical changes can be due to coincidence and unrelated confounding factors rather than due to a person’s causal attributions. A couple notable examples of potential confounding factors with regard to progestogens and breast development include: (1) continued breast development from estrogen acting on its own; and (2) temporary breast enlargement due to local fluid retention, increased blood flow, and reversible lobuloalveolar growth caused by progestogens. Such factors have the potential to mislead, and may contribute significantly to anecdotal reports of enhanced breast development with progestogens in transfeminine people. Clinical studies that are well-designed, controlled, and employ reliable objective measures, with long-term follow-up and eventual discontinuation of the progestogen to control for reversible effects, are needed to properly evaluate the effects of progestogens on breast development.

Therapeutic Limitations of Oral Progesterone

Oral progesterone producles very low progesterone levels and has only weak progestogenic effects even at high doses (Aly, 2018a; Wiki). These low progesterone levels are likely to be inadequate in terms of desired physiological progestogenic effects, for instance in the breasts. Oral progesterone also uniquely has potent neurosteroid actions via active metabolites like allopregnanolone, which can result in prominent side effects such as alcohol-like central nervous system inhibition as well as mood swings (Aly, 2018b; Wiki; Wiki). These neurosteroid effects are dose-dependent and are more severe at high doses. Non-oral progesterone forms like rectal or injectable progesterone or progestins, which do not have the preceding problems, can be used instead to avoid such concerns (Aly, 2018a; Aly, 2018b).

Tolerability and Safety Considerations for Progestogens

Progestogens have a variety of tolerability issues and safety risks (Aly, 2018b). Examples of such risks variously include adverse mood changes, breast cancer, blood clots, cardiovascular complications, benign brain tumors including prolactinomas and meningiomas, and off-target actions with undesirable effects (e.g., androgenic or glucocorticoid activity), among others (Aly, 2018b). CPA at high doses also uniquely has a significant risk of serious liver toxicity (Aly, 2018b). The risks of progestogens vary depending on the specific progestogen and dosage, but all progestogens, including even bioidentical progesterone, have significant known risks. The risks of progestogens, along with lack of evidence of beneficial effects in terms of feminization, well-being, and health, in transfeminine people, are why there are concerns about and restrictions on their use in transfeminine people (Aly, 2018b). However, cisgender women naturally have progesterone in their bodies, and the absolute risks of progestogens are low (Aly, 2018b). The risks of progestogens can be minimized by use for a limited duration of time (e.g., a few years), by using the lowest dosages expected to be effective in terms of desired effects, and by selection of progestogens with more favorable pharmacological profiles (Aly, 2018a; Aly, 2018b).

Updates

Update 1: Angus et al. (2023–2024)

It was previously reported in this article that an RCT assessing breast development with estradiol plus spironolactone versus estradiol plus CPA in transfeminine people was being conducted by Ada Cheung and colleagues. This study could provide more insight into breast development with progestogens, as CPA is a very potent progestogen whereas spironolactone is not meaningfully progestogenic. Cheung and colleagues’ study, led by Lachlan Angus, has now been published in the form of the following two conference abstracts, with a journal article also currently in the process of being published:

  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]

The study assessed estradiol plus spironolactone 100 mg/day versus estradiol plus CPA 12.5 mg/day in 55 transfeminine people, with 27 in the spironolactone group and 28 in the CPA group. Hormone therapy duration, at least at this follow-up point in the study, was 6 months. The measures of breast development included breast–chest difference (primary) and estimated breast volume (secondary).

Breast development, measured by breast–chest difference (mean ± SD), was 8.3 ± 2.7 cm with spironolactone and 9.2 ± 3.0 cm with CPA, with the differences between groups not statistically significant (p = 0.27). In addition, breast development, measured by estimated breast volume (mean ± SD), was 158 ± 112 mL with spironolactone and 190 ± 159 mL with CPA, with the differences between groups not statistically significant (p = 0.39). There was variability between individuals in estimated breast volume, with breast volume measurements ranging from 20 to 788 mL. Besides breast growth, the researchers found that CPA also resulted in a greater increase in body fat percentage and gynoid fat compared to spironolactone. Estradiol levels were comparable between antiandrogen groups, whereas total testosterone levels were (mean ± SD) 4.29 ± 5.44 nmol/L (124 ± 157 ng/dL) with spironolactone and 1.48 ± 3.45 nmol/L (43 ± 99 ng/dL) with CPA, a difference that was statistically significant (p = 0.04).

The researchers concluded that there was no difference in breast development with spironolactone versus CPA in their study and that antiandrogen choice should be individualized based on patient and clinician preference as well as consideration of associated side effects. Moreover, they concluded that further research is needed to optimize breast development in transfeminine people.

The measure of breast volume in the study was the BreastIdea Volume Estimator, a freely available web app that employs 2D photography to provide an estimate of breast volume (Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019; Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020). This breast volume measure has been validated in both cisgender women and cisgender men (Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019; Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020). Additionally, Cheung and Angus, along with other colleagues, notably including some of the original developers of the BreastIdea Volume Estimator, validated the BreastIdea Volume Estimator in cisgender men and transfeminine people in the following 2022 conference abstract study:

  • Angus, L., Mikolajczyk, M., Cheung, A., Zajac, J., Antoszewski, B., & Kasielska-Trojan, A. (2022). Estimation of breast volume in transgender women using 2D photography: validation of the BreastIdea Volume Estimator in men and transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 279). [URL] [PDF] [Full Abstract Book]

In studies by the developers of the BreastIdea Volume Estimator, they reported breast volumes measured with the tool in cisgender women. These estimated breast volumes can provide comparison to the breast-volume findings in transfeminine people by Cheung and Angus and colleagues. The developers of the BreastIdea Volume Estimator reported that breast volume (mean ± SD) in cisgender women with normal breasts (n=30) was 283 ± 144 mL and in cisgender women with macromastia or gigantomastia (n=35) was 888 ± 277 mL (Kasielska-Trojan, Zawadzki, & Antoszewski, 2022). In another study, they reported that breast volume (mean ± SD) in cisgender women was 272 ± 150 mL, with a range of 99 to 694 mL (Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020).

Although the BreastIdea Volume Estimator is an interesting and promising tool for quantifying breast development, it has notable limitations, such as its resolution and accuracy being much less than that with 3D scanners like the Artec Eva and Vectra XT (Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019). Vectra and Artec 3D scanners have been and are being employed to measure breast development with hormone therapy in other studies in transfeminine people (de Blok et al., 2021; Boogers et al., 2022; Dijkman et al., 2023a; Dijkman et al., 2023b; Lopez et al., 2023). The accuracy limitations of the BreastIdea Volume Estimator may explain why the breast volume findings with it in transfeminine people and cisgender women were different from those seen in other studies that employed more advanced 3D scanning methods. Aside from the breast volume measurement, breast–chest difference also has limitations as a measure of breast development in transfeminine people, for instance failing to identify continued breast growth that can be detected with breast volume measurement (de Blok et al., 2021).

Besides the employed measurement methods for breast development, limitations of Lachlan Angus and colleagues’ RCT of breast development with spironolactone and CPA in transfeminine people include its limited duration of follow-up of only 6 months, the fact that testosterone levels were non-equivalent between the spironolactone and CPA groups, and its limited sample size. The incompletely suppressed testosterone levels with spironolactone are notable as androgens oppose estrogen-mediated breast development and could have reduced breast development in the spironolactone group. The limited sample size of the study was responsible for the numeric difference in breast measurements between antiandrogen groups not being statistically significant. In any case, Angus and colleagues’ findings are suggestive that CPA, which is highly progestogenic, neither enhances nor stunts breast development, at least relative to non-progestogenic spironolactone for up to 6 months of hormone therapy. It seems likely that the RCT will continue to longer follow-up times and durations of hormone therapy in the future.

Update 2: Flamant, Vervalcke, & T’Sjoen (2023) and Yang et al. (2024)

The following two recent studies provide additional information on the topic of breast development with progestogen exposure—specifically with CPA—in transfeminine people:

  • Flamant, T., Vervalcke, J., & T’Sjoen, G. (November 2023). Dose Reduction of Cyproterone Acetate in Trans Women and the Effect on Patient-reported Outcomes: Results from the ENIGI Study. Endocrine Abstracts, 97 [Belgian Endocrine Society 2023], 5–5 (abstract no. 007). [URL] [PDF]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]

In the first study, Flamant, Vervalcke, & T’Sjoen (2023), clinical outcomes in transfeminine people at the University of Ghent, Belgium clinic were compared in 72 people taking CPA at low doses (10–12.5 mg/day) or high doses (25–50 mg/day). Testosterone suppression was equivalent between the two dose groups. Breast development satisfaction, measured with the Body Image Scale, was not significantly different with low-dose CPA versus high-dose CPA following 1 year of hormone therapy (p = 0.078). However, the p-value indicates that there was almost a statistically significant difference between groups, though it was not stated which group was numerically higher in terms of satisfaction. In any case, the researchers stated that breast development satisfaction was “non-inferior” with low-dose CPA compared to high-dose CPA, which seems suggestive that satisfaction may have been higher in the high-dose CPA group. These findings suggest that higher doses of CPA may not stunt breast development relative to doses of CPA that are lower, although still quite high in terms of progestogenic activity.

In the second study, Yang et al. (2024), clinical outcomes in transfeminine people at the Peking University Third Hospital in China with estradiol plus spironolactone (n=43) versus estradiol plus CPA (n=53) were retrospectively compared. Testosterone levels were much higher in the spironolactone group relative to the CPA group (374 ng/dL [13.0 nmol/L] vs. 20 ng/dL [0.7 nmol/L]; p < 0.001) and duration of hormone therapy was shorter in the spironolactone group than in the CPA group (median 12 months vs. 18 months). Breast development satisfaction, measured with a visual analogue scale (VAS), was median 6.0 (IQR 4.0–7.0) with spironolactone and 6.0 (IQR 4.0–7.0) with CPA, and was not statistically different. On the other hand, the CPA group outperformed the spironolactone group in terms of several other VAS-based clinical-outcome measures, including figure feminization, testicular atrophy, decreased penile erections, and in terms of a composite overall satifaction score. These findings suggest, as with the RCT by Lachlan Angus and colleagues, that spironolactone and CPA result in similar breast development in transfeminine people despite differences in testosterone levels and other clinical outcomes.

A major limitation of both Flamant, Vervalcke, & T’Sjoen (2023) and Yang et al. (2024) is the use of subjective self-report measures of breast development as opposed to objective physical measurements.

References

  • Abduljalil, K., Furness, P., Johnson, T. N., Rostami-Hodjegan, A., & Soltani, H. (2012). Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy. Clinical Pharmacokinetics, 51(6), 365–396. [DOI:10.2165/11597440-000000000-00000]
  • Adams, R. D., Kliman, B., Federman, D. D., Ulfelder, H. S., & Holmes, L. B. (1970). Syndromes of Testicular Feminization. Clinical Pediatrics, 9(3), 165–178. [DOI:10.1177/000992287000900312]
  • Alekseev, N. P. (2021). Origin and Development of the Mammary Glands. In Alekseev, N. P. Physiology of Human Female Lactation (pp. 11–66). Cham: Springer. [DOI:10.1007/978-3-030-66364-3_2]
  • Alex, A., Bhandary, E., & McGuire, K. P. (2020). Anatomy and Physiology of the Breast during Pregnancy and Lactation. In Alipour, S., & Omranipour, R. (Eds.). Diseases of the Breast during Pregnancy and Lactation (Advances in Experimental Medicine and Biology, Volume 1252) (pp. 3–7). Cham: Springer. [DOI:10.1007/978-3-030-41596-9]
  • Anderson, W. A. (1962). Experimental stimulation of breast development in the teen-age female. The Journal of the Medical Society of New Jersey, 59, 541–543. [Google Scholar] [PubMed] [PDF]
  • Andler, W., & Zachmann, M. (1979). Spontaneous breast development in an adolescent girl with testicular feminization after castration in early childhood. The Journal of Pediatrics, 94(2), 304–305. [DOI:10.1016/s0022-3476(79)80852-5]
  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
  • Angus, L., Mikolajczyk, M., Cheung, A., Zajac, J., Antoszewski, B., & Kasielska-Trojan, A. (2022). Estimation of breast volume in transgender women using 2D photography: validation of the BreastIdea Volume Estimator in men and transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 279). [URL] [PDF] [Full Abstract Book]
  • Apter, D. (1980). Serum steroids and pituitary hormones in female puberty: a partly longitudinal study. Clinical Endocrinology, 12(2), 107–120. [DOI:10.1111/j.1365-2265.1980.tb02125.x]
  • Apter, D., Räisänen, I., Ylöstalo, P., & Vihko, R. (1987). Follicular growth in relation to serum hormonal patterns in adolescent compared with adult menstrual cycles. Fertility and Sterility, 47(1), 82–88. [DOI:10.1016/s0015-0282(16)49940-1]
  • Aritaki, S., Miyazawa, H., Ogihara, M., Ushio, M., & Izumizawa, A. (1992). An Endocrinological Study of Persistent Pubertal Macromastia. The Tohoku Journal of Experimental Medicine, 167(3), 189–196. [DOI:10.1620/tjem.167.189]
  • Arya, S., Barnabas, R., Lila, A. R., Sarathi, V., Memon, S. S., Bhandare, V. V., Thakkar, K., Patil, V., Shah, N. S., Kunwar, A., & Bandgar, T. (2021). Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India. Sexual Development, 15(4), 253–261. [DOI:10.1159/000517763]
  • Asscheman, H., & Gooren, L. J. (1992). Hormone Treatment in Transsexuals. In Bocking, W. O., Coleman, E. (Eds). Gender Dysphoria: Interdisciplinary Approaches in Clinical Management (pp. 39–54). Binghamton: Haworth Press. / Journal of Psychology & Human Sexuality, 5(4), 39–54. [Google Scholar] [Google Books] [DOI:10.1300/J056v05n04_03]
  • Athanasoulia, A., Auer, M., Riepe, F., & Stalla, G. (2013). Rare Missense P450c17 (CYP17A1) Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness’ despite Adequate Estradiol Substitution. Sexual Development, 7(4), 212–215. [DOI:10.1159/000348301]
  • Atwood, C., Hovey, R., Glover, J., Chepko, G., Ginsburg, E., Robison, W., & Vonderhaar, B. (2000). Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. Journal of Endocrinology, 167(1), 39–52. [DOI:10.1677/joe.0.1670039]
  • Aupperlee, M. D., Leipprandt, J. R., Bennett, J. M., Schwartz, R. C., & Haslam, S. Z. (2013). Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Research, 15(3), R44. [DOI:10.1186/bcr3431]
  • Bahr, C., Ewald, J., Dragovich, R., & Gothard, M. D. (2024). Effects of progesterone on gender affirmation outcomes as part of feminizing hormone therapy. Journal of the American Pharmacists Association, 64(1), 268–272. [DOI:10.1016/j.japh.2023.08.001]
  • Baird, D., Hytten, F. E., & Thomson, A. M. (1958). Age and Human Reproduction. BJOG, 65(6), 865–876. [DOI:10.1111/j.1471-0528.1958.tb08582.x]
  • Baker, S. B., Burkey, B. A., Thornton, P., & LaRossa, D. (2001). Juvenile Gigantomastia: Presentation of Four Cases and Review of the Literature. Annals of Plastic Surgery, 46(5), 517–526. [DOI:10.1097/00000637-200105000-00011]
  • Bames, H. O. (1948). Reduction of massive breast hypertrophy. Plastic and Reconstructive Surgery, 3(5), 560–569. [DOI:10.1097/00006534-194809000-00006]
  • Barbieri, R. L. (2019). Breast. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 248–255.e3). Philadelphia: Elsevier. [Google Books] [DOI:10.1016/B978-0-323-47912-7.00010-X]
  • Baron, J. (1993). Zespół braku wrazliwości na androgeny. Studium kliniczne i endokrynologiczne 40 osobników [Androgen insensitivity syndrome. Clinical and endocrinologic study of 40 cases]. Endokrynologia Polska, 44(2), 175–186. [Google Scholar] [PubMed]
  • Baron, J. (1994). Klasyczne i niepełne zespoły braku wrazliwości na androgeny [Classical and incomplete androgen insensitivity syndromes]. Ginekologia Polska, 65(7), 377–386. [Google Scholar] [PubMed]
  • Baron, J. (1994). Niepełny lub cześciowy zespół braku wrazliwości na androgeny [Partial androgen insensitivity syndrome]. Ginekologia Polska, 65(6), 319–325. [Google Scholar] [PubMed]
  • Barrat, J., de Lignières, B., Marpeau, L., Larue, L., Fournier, S., Nahoul, K., Linares, G., Giorgi, H., & Contesso, G. (1990). Effet in vivo de l’administration locale de progestérone sur l’activité mitotique des galactophores humains. Résultat d’une étude pilote. [The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot study.] Journal de Gynecologie, Obstetrique et Biologie de la Reproduction, 19(3), 269–274. [Google Scholar 1] [Google Scholar 2] [PubMed]
  • Barrett, J. (2009). The clinical risks associated with the diagnosis and management of disorders of gender identity. Clinical Risk, 15(4), 131–134. [DOI:10.1258/cr.2008.080069]
  • Bässler, R. (1970). The Morphology of Hormone Induced Structural Changes in the Female Breast. In Altmann, H.-W., et al. (Eds.). Current Topics in Pathology: Ergebnisse der Pathology, Volume 53 (pp. 1–89). Heidelberg: Springer Berlin. [DOI:10.1007/978-3-662-30514-0_1] [PDF]
  • Basson, R., & Prior, J. C. (1998). Hormonal Therapy of Gender Dysphoria: The Male-to-Female Transsexual. In Denny, D. (Ed.). Concepts in Transgender Identity (Garland Gay and Lesbian Studies, Volume 11) (pp. 277–296). New York: Garland Publishing Inc. [Google Scholar] [Google Books] [DOI:10.4324/9780203775134-19] [PDF]
  • Bauman, A., Novello, L., & Kreitzer, P. (2016). Endocrine Disorders and Delayed Puberty. In Appelbaum, H. (Ed.). Abnormal Female Puberty: A Clinical Casebook (pp. 87–107). Cham: Springer. [DOI:10.1007/978-3-319-27225-2_5]
  • Bayer, C. M., Bani, M. R., Schneider, M., Dammer, U., Raabe, E., Haeberle, L., Faschingbauer, F., Schneeberger, S., Renner, S. P., Fischer, D., Schulz-Wendtland, R., Fasching, P. A., Beckmann, M. W., & Jud, S. M. (2014). Assessment of breast volume changes during human pregnancy using a three-dimensional surface assessment technique in the prospective CGATE study. European Journal of Cancer Prevention, 23(3), 151–157. [DOI:10.1097/cej.0b013e3283651ccb]
  • Beck, P. (1972). Lactogenic Activity of Human Chorionic Somatomammotropin in Rhesus Monkeys. Experimental Biology and Medicine, 140(1), 183–187. [DOI:10.3181/00379727-140-36422]
  • Begley, D. J., Firth, J. A., & Hoult, J. R. (1980). The Breast and Lactation. In Begley, D. J., Firth, J. A., & Hoult, J. R. Human Reproduction and Developmental Biology (pp. 204–219). London: Macmillan Education UK. [DOI:10.1007/978-1-349-16260-4_14]
  • Bellwether, C. J. (2020). Why Should a Transfeminine Person Consider Progesterone? Google Docs. [URL]
  • Benjamin, H. (1966). Nonsurgical Management of Transsexualism. In Benjamin, H. The Transsexual Phenomenon (pp. 86–99). New York: Julian Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Benjamin, H. (1967). Transvestism and Transsexualism in the male and female. Journal of Sex Research, 3(2), 107–127. [DOI:10.1080/00224496709550519]
  • Berliere, M., Coche, M., Lacroix, C., Riggi, J., Coyette, M., Coulie, J., Galant, C., Fellah, L., Leconte, I., Maiter, D., Duhoux, F. P., & François, A. (2022). Effects of Hormones on Breast Development and Breast Cancer Risk in Transgender Women. Cancers, 15(1), 245. [DOI:10.3390/cancers15010245]
  • Berryhill, G. E., Trott, J. F., & Hovey, R. C. (2016). Mammary gland development—It’s not just about estrogen. Journal of Dairy Science, 99(1), 875–883. [DOI:10.3168/jds.2015-10105]
  • Bethea, C. L., Kohama, S. G., & Pecins-Thompson, M. (1997). Pituitary and Brain Actions of Estrogen and Progesterone in the Regulation of Primate Prolactin Secretion. In Pavlik, E. J. (Ed.). Estrogens, Progestins, and Their Antagonists: Functions and Mechanisms of Action (pp. 3–46). Boston: Birkhäuser. [DOI:10.1007/978-1-4612-2004-6_1]
  • Bevan, D. J. (2012). Progesterone for Breast Development? / Should Male-to-Female Transsexuals Take Progesterone as part of Hormone Therapy (HT) for Better Breast Development? Biopsychology of TSTG / Transgender Forum. [URL 1] [URL 2]
  • Bevan, D. J. (2019). Grow Your Own : Breast Development Update. Transgender Forum. [URL]
  • Beyer, C., Cruz, M. L., & Martinez-Manautou, J. (1970). Effect of Chlormadinone Acetate on Mammary Development and Lactation in the Rabbit. Endocrinology, 86(5), 1172–1174. [DOI:10.1210/endo-86-5-1172]
  • Biswas, S. K., Banerjee, S., Baker, G. W., Kuo, C., & Chowdhury, I. (2022). The Mammary Gland: Basic Structure and Molecular Signaling during Development. International Journal of Molecular Sciences, 23(7), 3883. [DOI:10.3390/ijms23073883]
  • Bland, K. I., Copeland, E. M., & Klimberg, V. S. (2018). Anatomy of the Breast, Axilla, Chest Wall, and Related Metastatic Sites. In Bland, K. I., Copeland, E. M., Klimberg, V. S., Gradishar, W. J., White, J., & Korourian, S. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 5th Edition (pp. 20–36.e2). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-35955-9.00002-7]
  • Bland, K. I., Harrison Howard, J., & Romrell, L. J. (2009). Congenital and Acquired Disturbances of Breast Development and Growth. In Bland, K. I., & Copeland, E. M. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th Edition (pp. 189–207). Philadelphia: Saunders/Elsevier. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Bondy, C. A., & Turner Syndrome Consensus Study Group. (2007). Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. The Journal of Clinical Endocrinology & Metabolism, 92(1), 10–25. [DOI:10.1210/jc.2006-1374]
  • Boogers, L., Infirri, S. S., Bouchareb, A., de Blok, C., Liberton, N., van Trotsenburg, P., Dreijerink, K., den Heijer, M., Wiepjes, C., & Hannema, S. (2022). The effect of timing of puberty suppression on breast development in trans girls; a cross-sectional study. Hormone Research in Paediatrics, 95(Suppl 2) [60th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE), Rome, Italy, September 15–17, 2022], 390–391 (abstract no. P1-379). [Google Scholar] [DOI:10.1159/000525606] [URL] [PDF 1] [PDF 2]
  • Boyce, S. W., Hoffman, P. G., & Mathes, S. J. (1984). Recurrent Macromastia after Subcutaneous Mastectomy. Annals of Plastic Surgery, 13(6), 511–518. [DOI:10.1097/00000637-198412000-00008]
  • Bruck, H. G., & Müller, G. (1967). Zur Hormontherapie der Hypoplastischen Weiblichen Brust. [On Hormonal Therapy of the Hypoplastic Female Breast.] Ästhetische Medizin [Ästhetische Medizin : Kongreß-Organ der Deutschen Gesellschaft für die Ästhetische Medizin und ihre Grenzgebiete], 16(12), 365–366. [ISSN:0400-6755] [Google Scholar] [PubMed] [WorldCat] [PDF] [Translation]
  • Bryant, R., Underwood, A., Robinson, A., Stephenson, T., & Underwood, J. (1998). Determination of breast tissue composition for improved accuracy in estimating radiation doses and risks in mammographic screening. The Breast, 7(2), 95–98. [DOI:10.1016/s0960-9776(98)90064-9]
  • Buhimschi, C. S. (2004). Endocrinology of lactation. Obstetrics and Gynecology Clinics of North America, 31(4), 963–979. [DOI:10.1016/j.ogc.2004.08.002]
  • Camilletti, M. A., Abeledo-Machado, A., Faraoni, E. Y., Thomas, P., & Díaz-Torga, G. (2019). New insights into progesterone actions on prolactin secretion and prolactinoma development. Steroids, 152, 108496. [DOI:10.1016/j.steroids.2019.108496]
  • Çamtosun, E., Şıklar, Z., Ceylaner, S., Kocaay, P., & Berberoğlu, M. (2017). Delayed Diagnosis of a 17-Hydroxylase/17,20-Lyase Deficient Patient Presenting as a 46,XY Female: A Low Normal Potassium Level Can Be an Alerting Diagnostic Sign. Journal of Clinical Research in Pediatric Endocrinology, 9(2), 163–167. [DOI:10.4274/jcrpe.3839]
  • Capraro, V. J., & Dewhurst, C. J. (1975). Breast Disorders in Childhood and Adolescence. Clinical Obstetrics and Gynecology, 18(2), 25–50. [DOI:10.1097/00003081-197506000-00003]
  • Carlson, L. J., & Shaw, N. D. (2019). Development of Ovulatory Menstrual Cycles in Adolescent Girls. Journal of Pediatric and Adolescent Gynecology, 32(3), 249–253. [DOI:10.1016/j.jpag.2019.02.119]
  • Caro, T. M. (1987). Human breasts: Unsupported hypotheses reviewed. Human Evolution, 2(3), 271–282. [DOI:10.1007/bf03016112]
  • Ceriani, R. L. (1974). Hormones and Other Factors Controlling Growth in the Mammary Gland: A Review. Journal of Investigative Dermatology, 63(1), 93–108. [DOI:10.1111/1523-1747.ep12678104]
  • Cernea, R. (1944). Lokale Hormonbehandlung bei Mammaatrophie und Unterentwicklung. [Local Hormone Treatment in Mammary Atrophy and Underdevelopment.] Medizinische Klinik, 40(11/12), 169–170. [Google Scholar] [PDF] [Translation]
  • Chang, K., Lee, T. T., Linares-Cruz, G., Fournier, S., & de Ligniéres, B. (1995). Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility, 63(4), 785–791. [DOI:10.1016/s0015-0282(16)57482-2]
  • Cheikhelard, A., Morel, Y., Thibaud, E., Lortat-Jacob, S., Jaubert, F., Polak, M., & Nihoul-Fekete, C. (2008). Long-Term Followup and Comparison Between Genotype and Phenotype in 29 Cases of Complete Androgen Insensitivity Syndrome. Journal of Urology, 180(4), 1496–1501. [DOI:10.1016/j.juro.2008.06.045]
  • Ciarloni, L., Mallepell, S., & Brisken, C. (2007). Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proceedings of the National Academy of Sciences, 104(13), 5455–5460. [DOI:10.1073/pnas.0611647104]
  • Clendenen, T. V., Kim, S., Moy, L., Wan, L., Rusinek, H., Stanczyk, F. Z., Pike, M. C., & Zeleniuch-Jacquotte, A. (2013). Magnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women. Magnetic Resonance Imaging, 31(1), 1–9. [DOI:10.1016/j.mri.2012.06.022]
  • Cline, J. M., & Wood, C. E. (2006). Hormonal Effects on the Mammary Gland of Postmenopausal Nonhuman Primates. Breast Disease, 24(1), 59–70. [DOI:10.3233/bd-2006-24105]
  • Cline, J. M., & Wood, C. E. (2008). The Mammary Glands of Macaques. Toxicologic Pathology, 36(7 Suppl), 130S–141S. [DOI:10.1177/0192623308327411]
  • Cole, R. D., & Hopkins, T. R. (1962). A Biochemical Test of Artificial Mammogenesis and Lactogenesis As Models of the Natural Processes. Endocrinology, 70(3), 375–380. [DOI:10.1210/endo-70-3-375]
  • Coleman, E., Bockting, W., Botzer, M., Cohen-Kettenis, P., DeCuypere, G., Feldman, J., Fraser, L., Green, J., Knudson, G., Meyer, W. J., Monstrey, S., Adler, R. K., Brown, G. R., Devor, A. H., Ehrbar, R., Ettner, R., Eyler, E., Garofalo, R., Karasic, D. H., Lev, A. I., Mayer, G., Meyer-Bahlburg, H., Hall, B. P., Pfaefflin, F., Rachlin, K., Robinson, B., Schechter, L. S., Tangpricha, V., van Trotsenburg, M., Vitale, A., Winter, S., Whittle, S., Wylie, K. R., & Zucker, K. (2012). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. International Journal of Transgenderism, 13(4), 165–232. [DOI:10.1080/15532739.2011.700873] [URL] [PDF]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Coltman, C. E., Steele, J. R., & McGhee, D. E. (2017). Breast volume is affected by body mass index but not age. Ergonomics, 60(11), 1576–1585. [DOI:10.1080/00140139.2017.1330968]
  • Colvin, C., Devineni, G., & Ashraf, A. P. (2014). Delayed Puberty. In Bandeira, F., Gharib, H., Golbert, A., Griz, L., & Faria, M. (Eds.). Endocrinology and Diabetes (pp. 203–217). New York: Springer. [DOI:10.1007/978-1-4614-8684-8_17]
  • Cowie, A. T., & Folley, S. J. (1961). The Mammary Gland and Lactation. In Young, W. C. (Ed.). Sex and Internal Secretions, 3rd Edition, Volume I (pp. 590–642). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Cowie, A. T., Forsyth, I. A., & Hart, I. C. (1980). Growth and Development of the Mammary Gland. In Cowie, A. T., Forsyth, I. A., & Hart, I. C. Hormonal Control of Lactation (Monographs on Endocrinology, Volume 15) (pp. 58–145). Berlin/Heidelberg: Springer Berlin Heidelberg. [DOI:10.1007/978-3-642-81389-4_3]
  • Cox, D. B., Kent, J. C., Casey, T. M., Owens, R. A., & Hartmann, P. E. (1999). Breast Growth and the Urinary Excretion of Lactose During Human Pregnancy and Early Lactation: Endocrine Relationships. Experimental Physiology, 84(2), 421–434. [DOI:10.1111/j.1469-445x.1999.01807.x]
  • Cox, C. B., Kent, J. C., Owens, R., & Hartmann, P. E. (1994). Mammary morphological and functional changes during pregnancy in women. In Thompson, J. (Ed.). Proceedings of the Twenty-Sixth Annual Conference, Hilton Hotel, Brisbane, 26–28 September, 1994 [The Australian Society for Reproductive Biology Inc., Twenty Sixth Annual Conference, The Hilton Hotel, Brisbane, September 26 - 28 1994, Programme and Miniposters of Papers] (pp. 47–47). Australia: Australian Society for Reproductive Biology. [Google Scholar] [WorldCat] [URL] [PDF]
  • Coxon, J., & Seal, L. (2018). Hormone management of trans women. Trends in Urology & Men’s Health, 9(6), 10–14. [DOI:10.1002/tre.663]
  • Cregan, M. D., & Hartmann, P. E. (1999). Computerized Breast Measurement from Conception to Weaning: Clinical Implications. Journal of Human Lactation, 15(2), 89–96. [DOI:10.1177/089033449901500202]
  • Crowley, L. G., & Macdonald, I. (1965). Delalutin and estrogens for the treatment of advanced mammary carcinoma in the postmenopausal woman. Cancer, 18(4), 436–446. [DOI:10.1002/1097-0142(196504)18:4<436::aid-cncr2820180407>3.0.co;2-d]
  • Crowley, W. F., & Pitteloud, N. (2020). Approach to the patient with delayed puberty. UpToDate. [Google Scholar] [URL]
  • Cruz-Korchin, N., Korchin, L., González-Keelan, C., Climent, C., & Morales, I. (2002). Macromastia. Plastic and Reconstructive Surgery, 109(1), 64–68. [DOI:10.1097/00006534-200201000-00011]
  • Curtis, R. J. (2009 July 10). The Lowdown on Progesterone. London: The London Gender Clinic. [Google Scholar] [URL] [PDF]
  • Dallmann, A., Ince, I., Meyer, M., Willmann, S., Eissing, T., & Hempel, G. (2017). Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy. Clinical Pharmacokinetics, 56(11), 1303–1330. [DOI:10.1007/s40262-017-0539-z]
  • Dancey, A., Khan, M., Dawson, J., & Peart, F. (2008). Gigantomastia – a classification and review of the literature. Journal of Plastic, Reconstructive & Aesthetic Surgery, 61(5), 493–502. [DOI:10.1016/j.bjps.2007.10.041]
  • Davajan, V., & Kletzky, O. A. (1979). Amenorrhea without Galactorrhea or Hirsutism. In Mishell, D. R., & Davajan, V. (Eds.). Reproductive Endocrinology, Infertility, and Contraception (pp. 219–248). Philadelphia: F. A. Davis Co. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Davis, M. E., Boynton, M. W., Ferguson, J. H., & Rothman, S. (1945). Studies on Pigmentation of Endocrine Origin. The Journal of Clinical Endocrinology & Metabolism, 5(3), 138–146. [DOI:10.1210/jcem-5-3-138]
  • de Blok, C. J., Dijkman, B. A., Wiepjes, C. M., Staphorsius, A. S., Timmermans, F. W., Smit, J. M., Dreijerink, K. M., & den Heijer, M. (2021). Sustained Breast Development and Breast Anthropometric Changes in 3 Years of Gender-Affirming Hormone Treatment. The Journal of Clinical Endocrinology & Metabolism, 106(2), e782–e790. [DOI:10.1210/clinem/dgaa841]
  • de Blok, C. J., Klaver, M., Wiepjes, C. M., Nota, N. M., Heijboer, A. C., Fisher, A. D., Schreiner, T., T’Sjoen, G., & den Heijer, M. (2017). Breast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study. The Journal of Clinical Endocrinology & Metabolism, 103(2), 532–538. [DOI:10.1210/jc.2017-01927]
  • de Lignières, B. (2002). Effects of progestogens on the postmenopausal breast. Climacteric, 5(3), 229–235. [DOI:10.1080/cmt.5.3.229.235]
  • de Lignières, B., & Mauvais-Jarvis, P. (1981). Hormonal Dependence of Benign Breast Disease, Gynecomastia and Breast Cancer. In Hollman, K. H., Brux, J., & Verley, J. M. (Eds.). New Frontiers in Mammary Pathology (pp. 287–308). Boston: Springer US. [DOI:10.1007/978-1-4757-0019-0_17]
  • de Vries, A. L., Steensma, T. D., Wagemaar, E. C. F., Doreleijers, T. A., & Cohen-Kettenis, P. T. (2010). Puberty suppression followed by cross-sex hormones and gender reassignment surgery: A prospective follow-up of gender dysphoric adolescents into adulthood. In de Vries, A. L. (Ed.). Gender Dysphoria in Adolescents: Mental Health and Treatment Evaluation (pp. 91–106). (Doctoral thesis, Vrije Universiteit Amsterdam.) [Google Scholar] [URL] [PDF]
  • Deeb, A., Al Suwaidi, H., Attia, S., & Al Ameri, A. (2015). 17-hydroxylase/17,20-lyase deficiency due to a R96Q mutation causing hypertension and poor breast development. Endocrinology, Diabetes & Metabolism Case Reports, 2015(1), 15-0069. [DOI:10.1530/EDM-15-0069]
  • Deepinder, F., & Braunstein, G. D. (2012). Drug-induced gynecomastia: an evidence-based review. Expert Opinion on Drug Safety, 11(5), 779–795. [DOI:10.1517/14740338.2012.712109]
  • Dennerstein, L., Burrows, G. D., Hyman, G. J., & Sharpe, K. (1980). Some clinical effects of oestrogen-progestogen therapy in surgically castrated women. Maturitas, 2(1), 19–28. [DOI:10.1016/0378-5122(80)90056-0]
  • Dewhurst, C. J. (1967). The XY Female. BJOG, 74(3), 353–366. [DOI:10.1111/j.1471-0528.1967.tb03959.x]
  • Dewhurst, C. J. (1971). Sex Chromosome Abnormalities and the Gynaecologist. BJOG, 78(12), 1058–1076. [DOI:10.1111/j.1471-0528.1971.tb00227.x]
  • Dewhurst, C. J. (1971). The XY female. American Journal of Obstetrics and Gynecology, 109(5) [Transactions of the Eighty-First Annual Meeting of the American Association of Obstetricians and Gynecologists], 675–688. [DOI:10.1016/0002-9378(71)90753-8]
  • Dewhurst, C. J., & Spence, J. E. (1977). The XY female. British Journal of Hospital Medicine, 17(5), 498, 501–506. [Google Scholar] [PubMed] [PDF]
  • Dewhurst, J. (1982). Breast Hypoplasia. In Bruni, V., Gasparri, F., Dewhurst, J., & Rey-Stocker, I. (Eds.). Pediatric and Adolescent Gynaecology [Proceedings of the IVth International Symposium, Florence, October 5-7, 1978] (pp. 205–212). Rome, Italy: Serono Symposia. [Google Scholar] [Google Books] [WorldCat] [PDF]
  • Di Lorenzo, G., Autorino, R., Perdonà, S., & De Placido, S. (2005). Management of gynaecomastia in patients with prostate cancer: a systematic review. The Lancet Oncology, 6(12), 972–979. [DOI:10.1016/s1470-2045(05)70464-2]
  • Dickson, L. M., & Hewer, E. E. (1950). The structure of the breast. In Saner, F. D. (Ed.). The Breast: Structure, Function, Disease (pp. 1–52). Baltimore: William & Wilins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [PDF]
  • Dijkman, B. A., Blok, C. J., Dreijerink, K. M., & den Heijer, M. (2023). Progestin-related breast volume changes in a woman with complete androgen insensitivity syndrome (CAIS). Endocrinology, Diabetes & Metabolism Case Reports, 2023(2), 22-0346. [DOI:10.1530/edm-22-0346]
  • Dijkman, B. A., Helder, D., Boogers, L. S., Gieles, N. C., van Heesewijk, J. O., Slaa, S. t., Liberton, N. P., Wiepjes, C. M., de Blok, C. J., den Heijer, M., & Dreijerink, K. M. (2023). Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial. BMC Pharmacology and Toxicology, 24(1), 80. [DOI:10.1186/s40360-023-00724-4]
  • Dittrich, R., Binder, H., Cupisti, S., Hoffmann, I., Beckmann, M., & Mueller, A. (2005). Endocrine Treatment of Male-to-Female Transsexuals Using Gonadotropin-Releasing Hormone Agonist. Experimental and Clinical Endocrinology & Diabetes, 113(10), 586–592. [DOI:10.1055/s-2005-865900]
  • Donaldson, M., Kriström, B., Ankarberg-Lindgren, C., Verlinde, S., van Alfen-van der Velden, J., Gawlik, A., van Gelder, M., Sas, T., & (2019). Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy. Hormone Research in Paediatrics, 91(3), 153–163. [DOI:10.1159/000500050]
  • Dorgan, J. F., Klifa, C., Deshmukh, S., Egleston, B. L., Shepherd, J. A., Kwiterovich, P. O., Van Horn, L., Snetselaar, L. G., Stevens, V. J., Robson, A. M., Lasser, N. L., & Hylton, N. M. (2013). Menstrual and reproductive characteristics and breast density in young women. Cancer Causes & Control, 24(11), 1973–1983. [DOI:10.1007/s10552-013-0273-2]
  • Döring, G. K. (1963). Über die relative Häufigkeit des anovulatorischen Cyclus im Leben der Frau. [On the relative frequency of the anovulatory cycle in women’s lives.] Archiv für Gynäkologie, 199(2), 115–123. [DOI:10.1007/bf00668062]
  • Drąsutis, J. (2017). Changes in breast morphological parameters, body size and shape, blood serum prolactin and lipids during pregnancy, multiple relationships of these indicators and morphological markers for health risk. (Doctoral dissertation, Vilniaus Universitetas.) [Google Scholar] [URL]
  • Drife, J. O. (1982). The effects of parity and the menstrual cycle on the normal mammary gland and their possible relationship to malignant change. (Doctoral dissertation, University of Edinburgh). [Google Scholar] [Google Books] [WorldCat] [URL] [PDF]
  • Drife, J. O. (1984). The pill and the breast. IPPF Medical Bulletin, 18(6), 1–2. [Google Scholar] [PubMed]
  • Drife, J. O. (1986). Breast Development in Puberty. Annals of the New York Academy of Sciences, 464(1) [Endocrinology of the Breast: Basic and Clinical Aspects], 58–65. [DOI:10.1111/j.1749-6632.1986.tb15993.x]
  • Drife, J. O. (1989). Breast modifications during the menstrual cycle. Supplement to International Journal of Gynecology and Obstetrics, 1, 19–24. / International Journal of Gynecology and Obstetrics, 1989(Suppl 1), 19–24. [Google Scholar] [PubMed] [Archive.org]
  • Drife, J. O. (1990). Premenopausal Hormone Therapy. In Drife, J. O., & Studd, J. W. W. (Eds.). HRT and Osteoporosis (pp. 351–362). London: Springer London. [DOI:10.1007/978-1-4471-1799-5_25]
  • Duncan, M. (2010). Sexual Selection and Human Breast Morphology. (Doctoral dissertation, Te Herenga Waka-Victoria University of Wellington.) [Google Scholar] [URL]
  • Edmonds, D. K. (1989). Normal Puberty. In Edmonds, D. K. Dewhurst’s Practical Paediatric and Adolescent Gynaecology, 2nd Edition (pp. 56–62). London: Butterworths. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [Archive.org]
  • Elling, S. V., & Powell, F. C. (1997). Physiological changes in the skin during pregnancy. Clinics in Dermatology, 15(1), 35–43. [DOI:10.1016/s0738-081x(96)00108-3]
  • Engman, M., Skoog, L., Soderqvist, G., & Gemzell-Danielsson, K. (2008). The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology. Human Reproduction, 23(9), 2072–2079. [DOI:10.1093/humrep/den228]
  • Federici, S., Goggi, G., Quinton, R., Giovanelli, L., Persani, L., Cangiano, B., & Bonomi, M. (2021). New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature. Endocrine Reviews, 43(5), 824–851. [DOI:10.1210/endrev/bnab043]
  • Fernández-Cancio, M., García-García, E., González-Cejudo, C., Martínez-Maestre, M., Mangas-Cruz, M., Guerra-Junior, G., Pandi de Mello, M., Arnhold, I. J., Nishi, M. Y., Bilharinho Mendonça, B., García-Arumí, E., Audí, L., Tizzano, E., & Carrascosa, A. (2017). Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients. Sexual Development, 11(2), 70–77. [DOI:10.1159/000468160]
  • Fernandez-Valdivia, R., Mukherjee, A., Mulac-Jericevic, B., Conneely, O. M., DeMayo, F. J., Amato, P., & Lydon, J. P. (2005). Revealing Progesterone’s Role in Uterine and Mammary Gland Biology: Insights from the Mouse. Seminars in Reproductive Medicine, 23(1), 22–37. [DOI:10.1055/s-2005-864031]
  • Finkenzeller, D. A., & Loveless, M. B. (2007). Pediatric Gynecology. In Fortner, K. B., Szymanski, L. M., Fox, H. E., & Wallach, E. E. (Eds.). The Johns Hopkins Manual of Gynecology and Obstetrics, 3rd Edition (Spiral Manual Series) (pp. 363–379). Philadelphia: Lippincott Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Fisher, A. D., Castellini, G., Ristori, J., Casale, H., Cassioli, E., Sensi, C., Fanni, E., Amato, A. M., Bettini, E., Mosconi, M., Dèttore, D., Ricca, V., & Maggi, M. (2016). Cross-Sex Hormone Treatment and Psychobiological Changes in Transsexual Persons: Two-Year Follow-Up Data. The Journal of Clinical Endocrinology & Metabolism, 101(11), 4260–4269. [DOI:10.1210/jc.2016-1276]
  • Foidart, J. M., Colin, C., Denoo, X., Desreux, J., Fournier, S., & de Linières, B. (1996). Influence of percutaneous administration of estradiol and progesterone on the proliferation of human breast epithelial cells. In Calvo, F., Crépin, M., & Magdelenat, H. (Eds.). Breast Cancer: Advances in Biology and Therapeutics [21st Meeting of the International Association for Breast Cancer Research, July 3-4-5, 1996, Paris] (pp. 329–334). Montrouge/Paris: John Libbey Eurotext. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Foidart, J., Colin, C., Denoo, X., Desreux, J., Béliard, A., Fournier, S., & de Lignières, B. (1998). Estradiol and Progesterone Regulate the Proliferation of Human Breast Epithelial Cells. Fertility and Sterility, 69(5), 963–969. [DOI:10.1016/s0015-0282(98)00042-9]
  • Folley, S. J. (1940). Lactation. Biological Reviews, 15(4), 421–458. [DOI:10.1111/j.1469-185x.1940.tb00947.x]
  • Folley, S. J. (1947). Endocrine Control of the Mammary Gland. British Medical Bulletin, 5(2–3), 130–134. [DOI:10.1093/oxfordjournals.bmb.a073121]
  • Folley, S. J. (1950). Lactational Physiology. In Bowes, K. (Ed.). Modern Trends in Obstetrics and Gynaecology (pp. 441–453). London: Butterworth. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Folley, S. J. (1952). Lactation. In Parkes, A. S. (Ed.). Marshall’s Physiology of Reproduction, 3rd Edition, Volume II (pp. 525–647). Longmans, Green & Co.: London. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Folley, S. J. (1956). Recent Studies on the Development of the Mammary Gland. In Folley, S. J. The Physiology and Biochemistry of Lactation, 1st Edition (pp. 1–22). Edinburgh: Oliver & Boyd. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Folley, S. J., & Malpress, F. H. (1948). Hormonal Control of Mammary Growth. In Pincus, G., & Thimann, K. V. (Eds.). The Hormones: Physiology, Chemistry and Applications, Volume I (pp. 695–743). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Fourcade, R., & McLeod, D. (2004). Tolerability of Antiandrogens in the Treatment of Prostate Cancer. UroOncology, 4(1), 5–13. [DOI:10.1080/1561095042000191655]
  • Fowler, P. A., Casey, C. E., Cameron, G. G., Foster, M. A., & Knight, C. H. (1990). Cyclic changes in composition and volume of the breast during the menstrual cycle, measured by magnetic resonance imaging. BJOG, 97(7), 595–602. [DOI:10.1111/j.1471-0528.1990.tb02546.x]
  • Fridriksdottir, A. J., Petersen, O. W., & Rnnov-Jessen, L. (2011). Mammary gland stem cells: current status and future challenges. The International Journal of Developmental Biology, 55(7–8–9), 719–729. [DOI:10.1387/ijdb.113373af]
  • Fuqua, J. S., & Eugster, E. A. (2022). History of Puberty: Normal and Precocious. Hormone Research in Paediatrics, 95(6), 568–578. [DOI:10.1159/000526464]
  • Gaede, P., Trolle, D., & Pedersen, H. (1978). Extremely low placental lactogen hormone (hpl) values in an otherwise uneventful pregnancy preceding delivery of a normal baby. Acta Obstetricia et Gynecologica Scandinavica, 57(3), 203–209. [DOI:10.3109/00016347809154883]
  • Galani, A., Kitsiou-Tzeli, S., Sofokleous, C., Kanavakis, E., & Kalpini-Mavrou, A. (2008). Androgen insensitivity syndrome: clinical features and molecular defects. Hormones, 7(3), 217–229. [DOI:10.14310/horm.2002.1201]
  • Galbarczyk, A. (2011). Unexpected changes in maternal breast size during pregnancy in relation to infant sex: An evolutionary interpretation. American Journal of Human Biology, 23(4), 560–562. [DOI:10.1002/ajhb.21177]
  • Gawlik, A., Hankus, M., Such, K., Drosdzol-Cop, A., Madej, P., Borkowska, M., Zachurzok, A., & Malecka-Tendera, E. (2016). Hypogonadism and Sex Steroid Replacement Therapy in Girls with Turner Syndrome. Journal of Pediatric and Adolescent Gynecology, 29(6), 542–550. [DOI:10.1016/j.jpag.2016.03.005]
  • Gershon-Cohen, J. (1970). The Normal Breast. In Gershon-Cohen, J. Atlas of Mammography (pp. 23–38). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-85678-5_4] [Google Books]
  • Gertig, D. M., Stillman, I. E., Byrne, C., Spiegelman, D., Schnitt, S. J., Connolly, J. L., Colditz, G. A., & Hunter, D. J. (1999). Association of age and reproductive factors with benign breast tissue composition. Cancer Epidemiology, Biomarkers & Prevention, 8(10), 873–879. [Google Scholar] [PubMed] [URL]
  • Geschickter, C. F. (1945). Endocrine Physiology of the Breast. In Geschickter, C. F. Diseases of the Breast: Diagnosis, Pathology, Treatment, 2nd Edition (pp. 42–81). Philadelphia: J.B. Lippincott. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Glenn, J. F. (1976). Testicular feminization syndrome current clinical considerations. Urology, 7(6), 569–577. [DOI:10.1016/0090-4295(76)90079-0]
  • Gliosci, A., & Presutti, F. (1993). Virginal gigantomastia: Validity of combined surgical and hormonal treatments. Aesthetic Plastic Surgery, 17(1), 61–65. [DOI:10.1007/bf00455051]
  • Gompel, A., & Plu-Bureau, G. (2018). Progesterone, progestins and the breast in menopause treatment. Climacteric, 21(4), 326–332. [DOI:10.1080/13697137.2018.1476483]
  • Goodman, H. M. (2009). Hormonal Control of Pregnancy and Lactation. In Goodman, H. M. Basic Medical Endocrinology, 4th Edition (pp. 277–301). Amsterdam: Academic Press/Elsevier. [DOI:10.1016/b978-0-12-373975-9.00014-8]
  • Gooren, L. J. (2016). Hormone Treatment of Adult Transgender People. In Ettner, R., Monstrey, S., & Coleman, E. (Eds.). Principles of Transgender Medicine and Surgery, 2nd Edition (pp. 167–179). New York: Routledge. [Google Scholar] [Google Books] [DOI:10.4324/9781315718972-11]
  • Gordon, C. M., & Laufer, M. R. (2005) The Physiology of Puberty. In Emans, S. J., Laufer, M. R., & Goldstein, D. P. (Eds.). Pediatric and Adolescent Gynecology, 5th Edition (pp. 120–155). Philadelphia: Lippincott Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Göretzlehner, G. & Lauritzen, C. (1992). Hormontherapie bei Gynäkologischen Erkrankungen [Hormone Therapy for Gynecological Diseases]. In Göretzlehner, G. & Lauritzen, C. Praktische Hormontherapie in der Gynäkologie, 1. Auflage [Practical Hormone Therapy in Gynecology, 1st Edition] (pp. 245–299). Berlin/New York: de Gruyter. [DOI:10.1515/9783112417706-007] [Google Books] [PDF] [Translation]
  • Graham, J. D., & Clarke, C. L. (1997). Physiological Action of Progesterone in Target Tissues. Endocrine Reviews, 18(4), 502–519. [DOI:10.1210/edrv.18.4.0308]
  • Graham, S. J., Stanchev, P. L., Lloyd‐Smith, J. O., Bronskill, M. J., & Plewes, D. B. (1995). Changes in Fibroglandular Volume and Water Content of Breast Tissue During the Menstrual Cycle Observed by MR Imaging at 1.5 T. Journal of Magnetic Resonance Imaging, 5(6), 695–701. [DOI:10.1002/jmri.1880050613]
  • Greydanus, D. E., Omar, H. A., Matytsina, L. A., & Tsitsika, A. (2010). Breast Disorders in Children and Adolescents. In Omar, H. A., Greydanus, D. E., Tsitsika, A. K., Patel, D. R., & Merrick, J. (Eds.). Pediatric and Adolescent Sexuality and Gynecology: Principles for the Primary Care Clinician (pp. 245–316). Hauppauge: Nova Science Publishers. [Google Scholar] [Google Books] [URL] [OpenLibrary] [WorldCat] [PDF]
  • Guaragna-Filho, G., Guerra-Junior, G., Tadokoro-Cuccaro, R., Hughes, I. A., Barros, B. A., Hiort, O., Balsamo, A., Guran, T., Holterhus, P. M., Hannema, S., Poyrazoglu, S., Darendeliler, F., Bryce, J., Ahmed, S. F., & Quigley, C. A. (2023). Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls. Sexual Development, 17(1), 16–25. [DOI:10.1159/000526997]
  • Gunn, H. M., Tsai, M., McRae, A., & Steinbeck, K. S. (2018). Menstrual Patterns in the First Gynecological Year: A Systematic Review. Journal of Pediatric and Adolescent Gynecology, 31(6), 557–565.e6. [DOI:10.1016/j.jpag.2018.07.009]
  • Günzel, P., Hasan, S. H., Düsterberg, B., Hümpel, M., Putz, B., & Lehmann, M. (1987). Zur toxikologischen Prüfung von Steroidhormonen. [For the Toxicological Testing of Steroid Hormones.] In Burger, O. K., Grosdanoff, P., Henschler, D., Kraupp, O., & Schnieders, B. (Eds.). Aktuelle Probleme der Biomedizin (pp. 93–112). Berlin/New York: De Gruyter. [Google Scholar] [Google Books] [DOI:10.1515/9783110898231-014]
  • Hagisawa, S., Shimura, N., & Arisaka, O. (2012). Effect of Excess Estrogen on Breast and External Genitalia Development in Growth Hormone Deficiency. Journal of Pediatric and Adolescent Gynecology, 25(3), e61–e63. [DOI:10.1016/j.jpag.2011.11.005]
  • Hamburger, C., & Benjamin, H. (1969). Endocrine Treatment of Male and Female Transsexualism / Appendix for the Practicing Physician: Suggestions and Guidelines for the Management of Transsexuals. In Green, R., & Money, J. (Eds.). Transsexualism and Sex Reassignment (pp. 291–307). Baltimore: John Hopkins University Press. [Google Scholar] [Google Books] [PDF]
  • Hannan, F. M., Elajnaf, T., Vandenberg, L. N., Kennedy, S. H., & Thakker, R. V. (2022). Hormonal regulation of mammary gland development and lactation. Nature Reviews Endocrinology, 19(1), 46–61. [DOI:10.1038/s41574-022-00742-y]
  • Hannema, S. E., Schagen, S. E., Cohen-Kettenis, P. T., & Delemarre-van de Waal, H. A. (2017). Efficacy and Safety of Pubertal Induction Using 17β-Estradiol in Transgirls. The Journal of Clinical Endocrinology & Metabolism, 102(7), 2356–2363. [DOI:10.1210/jc.2017-00373]
  • Harley, J. M. G. (1969). The endocrine control of the breasts. The Practitioner, 203(1214), 153–157. [Google Scholar] [Google Books] [PubMed] [DOI:10.5555/19700402477] [HathiTrust]
  • Hartmann, B. W., Laml, T., Albrecht, A. E., Huber, J. C., & Kirchengast, S. (1998). Hormonal Breast Augmentation: Prognostic Relevance of Insulin-Like Growth Factor-I. Gynecological Endocrinology, 12(2), 123–127. [DOI:10.3109/09513599809024960]
  • Hartmann, P. E., Owens, R. A., Cox, D. B., & Kent, J. C. (1996). Breast Development and Control of Milk Synthesis. Food and Nutrition Bulletin, 17(4), 1–12. [DOI:10.1177/156482659601700404]
  • Hasan, S. (1974). Steroid Hormone Levels During Pregnancy in Various Species. In Bernhard, S., & Raspé, G. (Ed.). Hormones and Embryonic Development (Advances in the Biosciences, Volume 13) (pp. 181–197). Oxford/New York: Pergamon Press. [Google Scholar] [Google Books] [DOI:10.1016/b978-0-08-018239-1.50014-3] [OpenLibrary] [Archive.org]
  • Hassiotou, F., & Geddes, D. (2012). Anatomy of the human mammary gland: Current status of knowledge. Clinical Anatomy, 26(1), 29–48. [DOI:10.1002/ca.22165]
  • Heath, R. A., & Wynne, K. (2019). Children and Adolescents. In Heath, R. A., & Wynne, K. A Guide to Transgender Health: State-of-the-art Information for Gender-Affirming People and Their Supporters (pp. 87–106). Santa Barbara: Praeger/ABC-CLIO. [Google Books]
  • Heath, R. A., & Wynne, K. (2019). Hormone and Surgical Therapies for Adults. In Heath, R. A., & Wynne, K. A Guide to Transgender Health: State-of-the-art Information for Gender-Affirming People and Their Supporters (pp. 107–146). Santa Barbara: Praeger/ABC-CLIO. [Google Books]
  • Hertz, R., Odell, W. D., & Ross, G. T. (1966). Diagnostic Implications of Primary Amenorrhea: Combined Clinical Staff Conference at the National Institutes of Health. Annals of Internal Medicine, 65(4), 800–820. [DOI:10.7326/0003-4819-65-4-800]
  • Hillard, P. J. A. (2007). Benign Diseases of the Female Reproductive Tract. In Berek, J. S., & Novak, E. (Eds.). Berek & Novak’s Gynecology, 14th Edition (pp. 431–496). Philadelphia: Lippincott Williams and Wilkins. [Google Scholar] [OpenLibrary] [WorldCat] [Archive.org]
  • Hoppe, I. C., Patel, P. P., Singer-Granick, C. J., & Granick, M. S. (2011). Virginal Mammary Hypertrophy: A Meta-Analysis and Treatment Algorithm. Plastic and Reconstructive Surgery, 127(6), 2224–2231. [DOI:10.1097/prs.0b013e3182131bd1]
  • Hovey, R. C., Trott, J. F., Ginsburg, E., Goldhar, A., Sasaki, M. M., Fountain, S. J., Sundararajan, K., & Vonderhaar, B. K. (2001). Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in the mammary gland. Developmental Dynamics, 222(2), 192–205. [DOI:10.1002/dvdy.1179]
  • Howard, B. A., & Gusterson, B. A. (2000). Human Breast Development. Journal of Mammary Gland Biology and Neoplasia, 5(2), 119–137. [DOI:10.1023/a:1026487120779]
  • Huffman, J., Dewhurst, C. J., & Capraro, V. J. (1981). The Breast and its Disorders in Childhood and Adolescence. In Huffman, J., Dewhurst, J., & Capraro, V. The Gynecology of Childhood and Adolescence, 2nd Edition (pp. 542–559). Philadelphia: Saunders. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org] [PDF]
  • Hussain, Z., Brooks, J., & Percy, D. (2008). Menstrual variation of breast volume and T2 relaxation times in cyclical mastalgia. Radiography, 14(1), 8–16. [DOI:10.1016/j.radi.2006.07.003]
  • Hussain, Z., Roberts, N., Whitehouse, G. H., García-Fiñana, M., & Percy, D. (1999). Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology. The British Journal of Radiology, 72(855), 236–245. [DOI:10.1259/bjr.72.855.10396212]
  • Hutson, S. W., Cowen, P. N., & Bird, C. C. (1985). Morphometric studies of age related changes in normal human breast and their significance for evolution of mammary cancer. Journal of Clinical Pathology, 38(3), 281–287. [DOI:10.1136/jcp.38.3.281]
  • Hytten, F. E. (1954). Clinical and Chemical Studies in Human Lactation–VI. BMJ, 1(4867), 912–915. [DOI:10.1136/bmj.1.4867.912]
  • Hytten, F. E. (1954). Observations on Human Lactation. (Doctor’s thesis, University of Aberdeen.) [Google Scholar] [Google Books] [URL] [WorldCat]
  • Hytten, F. E. (1976). The physiology of lactation. International Journal of Food Sciences and Nutrition, 30(4), 225–232. [DOI:10.3109/09637487609142745]
  • Hytten, F. E., & Baird, D. (1958). The Development of the Nipple in Pregnancy. The Lancet, 271(7032), 1201–1204. [DOI:10.1016/s0140-6736(58)91908-1]
  • Hytten, F. E., & Leitch, I. (1971). Preparations for Breast Feeding. In Hytten, F. E., & Leitch, I. The Physiology of Human Pregnancy, 2nd Edition (pp. 234–241). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Leitch, I. (1971). Preparations for Breast Feeding. In Hytten, F. E., & Leitch, I. The Physiology of Human Pregnancy, 2nd Edition (pp. 234–241). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Thomson, A. M. (1965). Pregnancy, childbirth and lactation. In Edholm, O. G., & Bacharach, A. L. (Eds.). The Physiology of Human Survival (pp. 327–350). London/New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Thomson, A. M. (1968). Maternal physiological adjustments. In Assali, N. S. (Ed.). The Maternal Organism, Volume I (Biology of Gestation) (pp. 449–479). New York: Academic Press. [Google Scholar] [Google Books] [WorldCat]
  • Igo, J., & Visram, H. (2021). Progesterone Therapy Use and Safety in Male to Female Transgender Patients. Canadian Journal of Diabetes, 45(7 Suppl), S39–S39 (abstract no. 109). [DOI:10.1016/j.jcjd.2021.09.119]
  • Ingleby, H. (1949). Changes in breast volume in a group of normal young women. Bulletin of the International Association of Medical Museums, 29, 87–92. [Google Scholar] [Google Books] [HathiTrust]
  • Ingleby, H., Moore, L., & Gershon-Cohen, J. (1957). Gestational breast changes: x-ray studies of the human breast. Obstetrics & Gynecology, 10(2), 149–157. [Google Scholar] [PubMed] [URL]
  • Ismail, P. M., Amato, P., Soyal, S. M., DeMayo, F. J., Conneely, O. M., O’Malley, B. W., & Lydon, J. P. (2003). Progesterone involvement in breast development and tumorigenesis—as revealed by progesterone receptor “knockout” and “knockin” mouse models. Steroids, 68(10–13), 779–787. [DOI:10.1016/s0039-128x(03)00133-8]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 204201881987116. [DOI:10.1177/2042018819871166]
  • Jacobsohn, D. (1961). Hormonal Regulation of Mammary Gland Growth. In Kon, S. K., & Cowie, A. T. (Eds.). Milk: The Mammary Gland and Its Secretion, Volume 1 (pp. 127–160). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • Jamal, N., Ng, K., McLean, D., Looi, L., & Moosa, F. (2004). Mammographic Breast Glandularity in Malaysian Women: Data Derived from Radiography. American Journal of Roentgenology, 182(3), 713–717. [DOI:10.2214/ajr.182.3.1820713]
  • Jemstrom, H., & Olsson, H. (1997). Breast Size in Relation to Endogenous Hormone Levels, Body Constitution, and Oral Contraceptive Use in Healthy Nulligravid Women Aged 19-25 Years. American Journal of Epidemiology, 145(7), 571–580. [DOI:10.1093/oxfordjournals.aje.a009153]
  • Jernström, H., Sandberg, T., Bågeman, E., Borg, Å., & Olsson, H. (2005). Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families. British Journal of Cancer, 92(5), 857–866. [DOI:10.1038/sj.bjc.6602389]
  • Jeruss, J. S. (2006). Molecular Basis of Breast Cancer. In Winchester, D. J., Winchester, D. P., Hudis, C. A., & Norton, L. (Eds.). Breast Cancer, 2nd Edition (pp. 83–95). Hamilton: B.C. Decker. [Google Scholar] [Google Books] [WorldCat]
  • Johnson, M. C., & Cutler, M. L. (2016). Anatomy and Physiology of the Breast. In Jatoi, I., & Rody, A. (Eds.). Management of Breast Diseases (pp. 1–39). Cham: Springer. [DOI:10.1007/978-3-319-46356-8_1]
  • Kaiser, R. (1993). Gestagen-Östrogen-Kombinationen in der Gynäkologie. Zur Geschichte, Dosierung und Anwendung eines Hormonprinzips. [Gestagen-Oestrogen Combinations in Gynaecology. History, Dosage and Use of a Hormonal Principle.] Geburtshilfe und Frauenheilkunde, 53(7), 503–513. [Google Scholar] [PubMed] [DOI:10.1055/s-2007-1022924]
  • Kaiser, R., & Leidenberger, F. (1991). Hormonbehandlung bei Benign Mammaerkrankungen: Mammahypoplasie. [Hormonal Treatment in Benign Breast Diseases: Breast Hypoplasia.] In Kaiser, R., & Leidenberger, F. Hormonbehandlung in der Gynäkologischen Praxis, 7. Auflage [Hormone Treatment in Gynecological Practice, 7th Edition] (pp. 138–138). Stuttgart: Georg Thieme Verlag. [Google Books] [OpenLibrary] [WorldCat] [PDF] [Translation]
  • Kaiser, U., & Ho, K. K. (2015). Pituitary Physiology and Diagnostic Evaluation. In Melmed, S., Polonsky, K. S., Larsen, P. R., Kronenberg, & H. M. (Eds.). Williams Textbook of Endocrinology, 13th Edition (pp. 176–231). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-29738-7.00008-3] [Google Books]
  • Kanhai, R. C., Hage, J. J., Asscheman, H., Mulder, W. J., & Hage, J. J. (1999). Augmentation Mammaplasty in Male-to-Female Transsexuals. Plastic and Reconstructive Surgery, 104(2), 542–549. [DOI:10.1097/00006534-199908000-00040]
  • Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E., & Mulder, J. W. (2000). Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men. The American Journal of Surgical Pathology, 24(1), 74–80. [DOI:10.1097/00000478-200001000-00009]
  • Kardelen, A. D., Toksoy, G., Baş, F., Yavaş Abalı, Z., Gençay, G., Poyrazoğlu, Ş., Bundak, R., Altunoğlu, U., Avcı, Ş., Najaflı, A., Uyguner, O., Karaman, B., Başaran, S., & Darendeliler, F. (2018). A Rare Cause of Congenital Adrenal Hyperplasia: Clinical and Genetic Findings and Follow-up Characteristics of Six Patients with 17-Hydroxylase Deficiency Including Two Novel Mutations. Journal of Clinical Research in Pediatric Endocrinology, 10(3), 206–215. [DOI:10.4274/jcrpe.0032]
  • Kariagina, A., Xie, J., Leipprandt, J. R., & Haslam, S. Z. (2010). Amphiregulin Mediates Estrogen, Progesterone, and EGFR Signaling in the Normal Rat Mammary Gland and in Hormone-Dependent Rat Mammary Cancers. Hormones and Cancer, 1(5), 229–244. [DOI:10.1007/s12672-010-0048-0]
  • Karp, N. S. (2022). Discussion: The Impact of Combined Oral Contraceptives on Adolescents with Macromastia. Plastic & Reconstructive Surgery, 150(4), 739–740. [DOI:10.1097/prs.0000000000009514]
  • Kasielska-Trojan, A., Mikołajczyk, M., & Antoszewski, B. (2020). BreastIdea Volume Estimator: A New Tool for Breast Volume Estimation—Presentation and Validation for Women. Plastic & Reconstructive Surgery, 146(6), 744e–748e. [DOI:10.1097/prs.0000000000007373]
  • Kasielska-Trojan, A., Zawadzki, T., & Antoszewski, B. (2022). Breast Fluctuating Asymmetry in Women with Macromastia/Gigantomastia. International Journal of Environmental Research and Public Health, 19(24), 16895. [DOI:10.3390/ijerph192416895]
  • Kauli, R., Pertzelan, A., Ben‐Zeev, Z., Lewin, R. P., Kaufman, H., Schally, A. C., Schally, A. V., & Laron, Z. (1984). Treatment of precocious puberty with LHRH analogue in combination with cyproterone acetate—further experience. Clinical Endocrinology, 20(4), 377–387. [DOI:10.1111/j.1365-2265.1984.tb03433.x]
  • Keller, P. J. (1984). Diagnostik und Therapie wichtiger hormonaler Störungen: Mammahypoplasie. [Diagnosis and Treatment of Important Hormonal Disorders: Mammary Hypoplasia.] In Keller, P. J. Hormonale Störungen in der Gynäkologie: Diagnostik und Behandlung, 3. Auflage [Hormonal Disorders in Gynecology: Diagnosis and Treatment, 3rd Edition] (Kliniktaschenbücher) (pp. 133–134). Berlin/Heidelberg: Springer. [Google Books] [DOI:10.1007/978-3-662-00442-5_3]
  • Keller, P. J. (1995). Diagnostik und Therapie wichtiger Störungen: Mammahypoplasie. [Diagnosis and Treatment of Important Disorders: Mammary Hypoplasia.] In Keller, P. J. Hormon- und Fertilitätsstörungen in der Gynäkologie, 4. Auflage [Hormonal and Fertility Disorders in Gynecology, 4th Edition] (pp. 145–146). Berlin/Heidelberg: Springer. [Google Books] [DOI:10.1007/978-3-662-12026-2_3]
  • Kennedy, B. J. (1953). Effects of intensive sex steroid hormone therapy in advanced breast cancer. JAMA, 152(12), 1135–1141. [DOI:10.1001/jama.1953.63690120004013]
  • Kent, J. C., Mitoulas, L., Cox, D. B., Owens, R. A., & Hartmann, P. E. (1999). Breast Volume and Milk Production During Extended Lactation in Women. Experimental Physiology, 84(2), 435–447. [DOI:10.1111/j.1469-445x.1999.01808.x]
  • Khoo, S. K., & Mackay, E. V. (1972). Testicular Feminization: The Clinical Features, Endocrine Function and Gonadal Pathology in Six Patients. Australian and New Zealand Journal of Obstetrics and Gynaecology, 12(1), 1–13. [DOI:10.1111/j.1479-828x.1972.tb00721.x]
  • Klein, R., Aichinger, H., Dierker, J., Jansen, J. T., Joite-Barfuß, S., Säbel, M., Schulz-Wendtland, R., & Zoetelief, J. (1997). Determination of average glandular dose with modern mammography units for two large groups of patients. Physics in Medicine and Biology, 42(4), 651–671. [DOI:10.1088/0031-9155/42/4/004]
  • Kleinberg, D. L. (2006). Endocrinology of lactation. In DeGroot, L. J., & Jameson, J. L. (Eds). Endocrinology, 5th Edition (pp. 3461–3473). Philadelphia: Elsevier Saunders. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Kleinberg, D. L., & Barcellos-Hoff, M. H. (2011). The Pivotal Role of Insulin-Like Growth Factor I in Normal Mammary Development. Endocrinology and Metabolism Clinics of North America, 40(3), 461–471. [DOI:10.1016/j.ecl.2011.06.001]
  • Kleinberg, D. L., & Ruan, W. (2008). IGF-I, GH, and Sex Steroid Effects in Normal Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 13(4), 353–360. [DOI:10.1007/s10911-008-9103-7]
  • Kleinberg, D. L., Wood, T. L., Furth, P. A., & Lee, A. V. (2008). Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions. Endocrine Reviews, 30(1), 51–74. [DOI:10.1210/er.2008-0022]
  • Kühnel, W. (2000). IMMULITE® and IMMULITE® 2000 Reference Range Compendium, First English Edition. Los Angeles, California: Diagnostic Products Corporation. [Google Scholar] [URL] [PDF 1] [PDF 2]
  • Kustin, J., & Rebar, R. W. (1987). Menstrual Disorders in the Adolescent Age Group. Primary Care: Clinics in Office Practice, 14(1), 139–166. [DOI:10.1016/s0095-4543(21)01004-6]
  • Kutten, F., Malet, C., & Leygue, E. (1994). Antiestrogen action of progestogens in human breast cells. In Berg, G., & Hammar, M. (Eds.). The Modern Management of the Menopause: A Perspective for the 21st Century [The Proceedings of the VII International Congress on the Menopause, Stockholm, Sweden 1993] (pp. 419–433). Canforth: Parthenon. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org] [PDF]
  • Ladjouze, A., & Donaldson, M. (2019). Primary gonadal failure. Best Practice & Research Clinical Endocrinology & Metabolism, 33(3), 101295. [DOI:10.1016/j.beem.2019.101295]
  • Laessle, R. G., Tuschi, R. J., Schweiger, U., & Pirke, K. M. (1990). Mood changes and physical complaints during the normal menstrual cycle in healthy young women. Psychoneuroendocrinology, 15(2), 131–138. [DOI:10.1016/0306-4530(90)90021-z]
  • LaMarca, H. L., & Rosen, J. M. (2007). Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Research, 9(4), 304. [DOI:10.1186/bcr1740]
  • Laron, Z., & Kauli, R. (2000). Experience with Cyproterone Acetate in the Treatment of Precocious Puberty. Journal of Pediatric Endocrinology and Metabolism, 13(Suppl 1), 805–810. [DOI:10.1515/jpem.2000.13.s1.805]
  • Lauritzen, C. (1980 October 27). Hormonkur Kann Hypoplastischer Mamma Aufhelfen. [Hormone Therapy Can Help Hypoplastic Breasts.] Selecta: Medizin aktuell; das Magazin für ärztliche Fortbildung [Selecta: Medicine Currently; the Magazine for Medical Training], 22(43), 3798–3801. Planegg: Selecta-Verlag. [ISSN:0582-4877] [WorldCat] [PDF] [Translation]
  • Lauritzen, C. (1982). Treatment of mammary- and uterus hypoplasia by estrogen-progestagen pseudopregnancy. In Richter, K., Huber, A., Terruhn, V. (Eds.) 1. Europäisches Symposium für Kinder- und Jugendgynäkologie. München 19.-21.3.1981, Band 2 [First European Symposium on Pediatric and Adolescent Gynaecology. München, March 19–21, 1981, Volume 2] (pp. 487–489). Friedrichsdorf/Taunus: Milupa-Aktiengesellschaft, Wissenschaftliche Abteilung. [Google Scholar] [PDF]
  • Lauritzen, C. (1989). Hormonelle Substitutionstherapie zur Brustvergrößerung. [Hormonal Substitution Therapy for Breast Enlargement.] In Beller, F. K. & Seitzer, D. (Eds.). 7. Siebte Wissenschaftliche Tagung der Deutschen Gesellschaft für Senologie, Münster, 25. - 27. September 1987: Ausgewählte Referate [7th Scientific Conference of the German Society for Senology, Münster, [Germany,] September 25–27, 1987: Selected Papers] (pp. 39–41). Mülheim, Germany: H.U.F. Verlag. [Google Scholar] [WorldCat 1] [WorldCat 2] [WorldCat 3] [Cited By 1] [Cited By 2] [Cited By 3] [PDF] [Translation]
  • Lawrence, R. A., & Lawrence, R. M. (2015). Physiology of Lactation. In Lawrence, R. A., & Lawrence, R. M. Breastfeeding: A Guide for the Medical Profession, 8th Edition (pp. 56–90). Philadelphia: Elsevier. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Lee, H. J., & Ormandy, C. J. (2012). Interplay between progesterone and prolactin in mammary development and implications for breast cancer. Molecular and Cellular Endocrinology, 357(1–2), 101–107. [DOI:10.1016/j.mce.2011.09.020]
  • Lee, P. A. (2001). Physiology of Puberty. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Nylén, E. S., Rebar, R. W., Robertson, G. L., Snider, R. H., Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 3rd Edition (pp. 885–893). Philadelphia: Lippincott Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Lee, S. W., Kwak, D. S., Jung, I. S., Kwak, J. H., Park, J. H., Hong, S. M., Lee, C. B., Park, Y. S., Kim, D. S., Choi, W. H., & Ahn, Y. H. (2015). Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia. Endocrinology and Metabolism, 30(2), 226–230. [DOI:10.3803/enm.2015.30.2.226]
  • Lejour, M. (1994). Vertical Mammaplasty and Liposuction of the Breast. Plastic and Reconstructive Surgery, 94(1), 100–114. [DOI:10.1097/00006534-199407000-00010]
  • Lejour, M. (1997). Evaluation of Fat in Breast Tissue Removed by Vertical Mammaplasty. Plastic and Reconstructive Surgery, 99(2), 386–393. [DOI:10.1097/00006534-199702000-00012]
  • Lemarchand-Béraud, T., Zufferey, M., Reymond, M., & Rey, I. (1982). Maturation of the Hypothalamo-Pituitary-Ovarian Axis in Adolescent Girls. The Journal of Clinical Endocrinology & Metabolism, 54(2), 241–246. [DOI:10.1210/jcem-54-2-241]
  • Lewin, R. (2016). Breast Hypertrophy and Outcome of Breast Reduction Surgery. (Doctoral thesis, University of Gothenburg. Sahlgrenska Academy.) [Google Scholar] [URL]
  • Lim, L. Y., Ho, P. J., Liu, J., Chay, W. Y., Tan, M., Hartman, M., & Li, J. (2018). Determinants of breast size in Asian women. Scientific Reports, 8(1), 1201. [DOI:10.1038/s41598-018-19437-4]
  • Lloyd, C. W., & Leathem, J. H. (1964). Growth and development of the breast and lactation. In Lloyd, C. W. (Ed.). Human Reproduction and Sexual Behavior (pp. 117–134). Philadelphia: Lea & Febiger. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Lopez, X., Panton, J., Nagarkar, P., Preston, S., Abramowitz, J., & Amirlak, B. (2023). Initial Assessment of VECTRA Three-Dimensional Imaging to Accurately Simulate Breast Volume Changes in Transfeminine Patients: A Mannequin Study. Aesthetic Surgery Journal Open Forum, 5, online ahead of print. [DOI:10.1093/asjof/ojad015]
  • Lorincz, A. M., & Sukumar, S. (2006). Molecular links between obesity and breast cancer. Endocrine-Related Cancer, 13(2), 279–292. [DOI:10.1677/erc.1.00729]
  • Lucien, J. N., Ortega, M. T., Calvert, M. E., Smith, C., White, X., Rogers, H., Mosley, B., Agrawal, R., Drude, A., McGee, C., George, M., Brown, A., Downey, K., Wild, C., Njunge, A., Kuzmiak, C. M., Zava, D., Zava, T., Pollard, J., Francis, J., Beery, B. L., Harlin, M., Gonzalez, G. R., & Shaw, N. D. (2022). The Launch of A Girl’s First Period Study: Demystifying Reproductive Hormone Profiles in Adolescent Girls. Journal of Pediatric and Adolescent Gynecology, 35(4), 420–425. [DOI:10.1016/j.jpag.2021.12.018]
  • Lydon, J. P., DeMayo, F. J., Funk, C. R., Mani, S. K., Hughes, A. R., Montgomery, C. A., Shyamala, G., Conneely, O. M., & O’Malley, B. W. (1995). Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes & Development, 9(18), 2266–2278. [DOI:10.1101/gad.9.18.2266]
  • Lyon, A. J., De Bruyn, R., & Grant, D. B. (1985). Isosexual Precocious Puberty in Girls. Acta Paediatrica, 74(6), 950–955. [DOI:10.1111/j.1651-2227.1985.tb10063.x]
  • Lyons, W. R. (1958). Hormonal synergism in mammary growth. Proceedings of the Royal Society of London. Series B - Biological Sciences, 149(936), 303–325. [DOI:10.1098/rspb.1958.0071]
  • Lyons, W. R., & McGinty, D. A. (1941). Effects of estrone and progesterone on male rabbit mammary glands. I. Varying doses of progesterone. Proceedings of the Society for Experimental Biology and Medicine, 48(1), 83–86. [DOI:10.3181/00379727-48-13227]
  • Lyons, W. R., Li, C. H., & Johnson, R. E. (1958). The Hormonal Control of Mammary Growth and Lactation. In Pincus, G. (Ed.). Recent Progress in Hormone Research, Volume 14 [Proceedings of the Laurentian Hormone Conference 1957, Held at Mont Tremblant, Quebec] (pp. 219–254). New York/London: Academic Press. [Google Scholar] [Google Books] [PubMed] [OpenLibrary] [WorldCat] [PDF]
  • MacBryde, C. M. (1939). The Production of Breast Growth in the Human Female. Journal of the American Medical Association, 112(11), 1045–1049. [DOI:10.1001/jama.1939.02800110025006]
  • Malet, C., Gompel, A., Yaneva, H., Cren, H., Fidji, N., Mowszowicz, I., Kuttenn, F., & Mauvais-Jarvis, P. (1991). Estradiol and Progesterone Receptors in Cultured Normal Human Breast Epithelial Cells and Fibroblasts: Immunocytochemical Studies. The Journal of Clinical Endocrinology & Metabolism, 73(1), 8–17. [DOI:10.1210/jcem-73-1-8]
  • Malini, S., Smith, E. O., & Goldzieher, J. W. (1985). Measurement of breast volume by ultrasound during normal menstrual cycles and with oral contraceptive use. Obstetrics and Gynecology, 66(4), 538–541. [Google Scholar] [PubMed] [URL] [PDF]
  • Marshall, W. A. (1978). Puberty. In Falkner, F., & Tanner, J. M. (Eds.). Human Growth: Postnatal Growth (pp. 141–181). Boston: Springer US. [DOI:10.1007/978-1-4684-2622-9_6]
  • Marshall, W. A., & Tanner, J. M. (1969). Variations in pattern of pubertal changes in girls. Archives of Disease in Childhood, 44(235), 291–303. [DOI:10.1136/adc.44.235.291]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1986). Antiestrogen action of progesterone in breast tissue. Breast Cancer Research and Treatment, 8(3), 179–188. [DOI:10.1007/bf01807330]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1986). Estradiol/Progesterone Interaction in Normal and Pathologic Breast Cells. Annals of the New York Academy of Sciences, 464(1), 152–167. [DOI:10.1111/j.1749-6632.1986.tb16002.x]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1987). Antiestrogen Action of Progesterone in Breast Tissue. Hormone Research, 28(2–4), 212–218. [DOI:10.1159/000180946]
  • Mauvais-Jarvis, P., Kuttenn, F., Gompel, A., & Benotmane, A. (1987). Action anti-estrogène de la progestérone dans le sein. [Antiestrogen action of progesterone in the breast]. Pathologie-Biologie, 35(7), 1081–1086. [Google Scholar 1] [Google Scholar 2] [PubMed]
  • Mauvais-Jarvis, P., Sitruk-Ware, R., & Kuttenn, F. (1981). Benign Breast Disease. In McGuire, W. L. (Ed.). Breast Cancer 4: Advances in Research and Treatment (pp. 51–94). Boston: Springer US. [DOI:10.1007/978-1-4615-6571-0_3]
  • McArthur, J. W. (1966). The Reproductive Endocrinology of Adolescence. In Heald, F. P. (Ed.). Adolescent Gynecology (pp. 9–20). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • McBryan, J., Howlin, J., Napoletano, S., & Martin, F. (2008). Amphiregulin: Role in Mammary Gland Development and Breast Cancer. Journal of Mammary Gland Biology and Neoplasia, 13(2), 159–169. [DOI:10.1007/s10911-008-9075-7]
  • McDonough, P. G., Spicer, D. V., Ursin, G., & Pike, M. C. (1996). Progesterone Concentrations—Physiologic or Pharmacologic? Fertility and Sterility, 65(5), 1077–1078. [DOI:10.1016/s0015-0282(16)58295-8]
  • McMillan, M. (1966). Five cases of testicular feminisation including one with a teratoma of the testis. The Journal of Pathology and Bacteriology, 91(2), 417–427. [DOI:10.1002/path.1700910216]
  • McNally, S., & Stein, T. (2016). Overview of Mammary Gland Development: A Comparison of Mouse and Human. In Martin, F., Stein, T., & Howlin, J. (Eds.). Mammary Gland Development (Methods in Molecular Biology, Volume 1501) (pp. 1–17). New York: Springer New York. [DOI:10.1007/978-1-4939-6475-8_1]
  • McPhaul, M. J. (2002). Androgen receptor mutations and androgen insensitivity. Molecular and Cellular Endocrinology, 198(1–2), 61–67. [DOI:10.1016/s0303-7207(02)00369-6]
  • Meites, J. (1966). Control of mammary growth and lactation. In Martini, L., & Ganong, W. F. (Eds.). Neuroendocrinology, Volume I (pp. 669–707). New York: Academic Press. [Google Scholar] [Google Books] [DOI:10.1016/B978-1-4832-3228-7.50023-2] [OpenLibrary] [WorldCat]
  • Mesiano, S. (2019). Endocrinology of Human Pregnancy and Fetal-Placental Neuroendocrine Development. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 256–284.e9). Philadelphia: Elsevier. [Google Books] [DOI:10.1016/b978-0-323-47912-7.00011-1]
  • Meyer, G., Mayer, M., Mondorf, A., Flügel, A. K., Herrmann, E., & Bojunga, J. (2020). Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. European Journal of Endocrinology, 182(2), 149–156. [DOI:10.1530/eje-19-0463]
  • Meyer, W. J., Finkelstein, J. W., Stuart, C. A., Webb, A., Smith, E. R., Payer, A. F., & Walker, P. A. (1981). Physical and hormonal evaluation of transsexual patients during hormonal therapy. Archives of Sexual Behavior, 10(4), 347–356. [DOI:10.1007/bf01565538]
  • Meyer, W. J., Webb, A., Stuart, C. A., Finkelstein, J. W., Lawrence, B., & Walker, P. A. (1986). Physical and hormonal evaluation of transsexual patients: A longitudinal study. Archives of Sexual Behavior, 15(2), 121–138. [DOI:10.1007/bf01542220]
  • Mikołajczyk, M., Kasielska-Trojan, A., & Antoszewski, B. (2019). A New Tool for Breast Anthropometric Measurements: Presentation and Validation for Women and Men. Aesthetic Plastic Surgery, 43(5), 1160–1170. [DOI:10.1007/s00266-019-01467-6]
  • Milionis, C., Ilias, I., & Koukkou, E. (2022). Progesterone in gender-affirming therapy of trans women. World Journal of Biological Chemistry, 13(3), 66–71. [DOI:10.4331/wjbc.v13.i3.66]
  • Milligan, D., Drife, J. O., & Short, R. V. (1975). Changes in breast volume during normal menstrual cycle and after oral contraceptives. BMJ, 4(5995), 494–496. [DOI:10.1136/bmj.4.5995.494]
  • Morris, J. M. (1953). The syndrome of testicular feminization in male pseudohermaphrodites. American Journal of Obstetrics and Gynecology, 65(6), 1192–1211. [DOI:10.1016/0002-9378(53)90359-7]
  • Morris, J. M., & Mahesh, V. B. (1963). Further observations on the syndrome, “testicular feminization”. American Journal of Obstetrics and Gynecology, 87(6), 731–748. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF]
  • Moss, W. M. (1968). Gigantomastia With Pregnancy. Archives of Surgery, 96(1), 27–32. [DOI:10.1001/archsurg.1968.01330190029007]
  • Muallem, M. M., & Rubeiz, N. G. (2006). Physiological and biological skin changes in pregnancy. Clinics in Dermatology, 24(2), 80–83. [DOI:10.1016/j.clindermatol.2005.10.002]
  • Müller, C. (1953). Zur Hormonalen Kosmetik der Weiblichen Brust: Wirkung und Nebenwirkung Östrogenhaltiger Kosmetischer Präparate. [Hormonal Cosmetics of the Female Breast: Effects and Side Effects of Estrogen-Containing Cosmetic Preparations.] Schweizerische Medizinische Wochenschrift [Swiss Medical Weekly], 83(4), 81–84. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF] [Translation]
  • Muzaffar, F., Hussain, I., & Haroon, T. S. (1998). Physiologic skin changes during pregnancy: a study of 140 cases. International Journal of Dermatology, 37(6), 429–431. [DOI:10.1046/j.1365-4362.1998.00281.x]
  • Naik, M., Diwakar, R. K., Patre, S., & Singh, S. (2015). Gigantomastia: A Rare Complication In Pregnancy. Journal of Medical Science and Clinical Research, 3(7), 6873–6876. [Google Scholar] [URL] [PDF]
  • Naseem, H., Lokman, M., & Fitzgerald, C. (2021). Management of congenital hypogonadotropic hypogonadism in females. Human Fertility, 26(3), 622–631. [DOI:10.1080/14647273.2021.1998929]
  • Nelson, W. O. (1936). Endocrine Control of the Mammary Gland. Physiological Reviews, 16(3), 488–526. [DOI:10.1152/physrev.1936.16.3.488]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study. Endocrine Connections, 11(5), e220170. [DOI:10.1530/EC-22-0170]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects Of Low-dose Oral Micronised Progesterone On Sleep, Psychological Distress And Breast Development In Transgender Individuals Undergoing Feminising Hormone Therapy: A Prospective Controlled Study. Journal of the Endocrine Society, 6(Suppl 1), A653–A654 (abstract no. LBODP089). [DOI:10.1210/jendso/bvac150.1351]
  • Nussbaum, R., & Benedetto, A. V. (2006). Cosmetic aspects of pregnancy. Clinics in Dermatology, 24(2), 133–141. [DOI:10.1016/j.clindermatol.2005.10.007]
  • Nuzzi, L. C., Pramanick, T., Massey, G. G., Walsh, L. R., McNamara, C. T., Firriolo, J. M., DiVasta, A. D., & Labow, B. I. (2021). The Impact of Progestin-only Contraception on Adolescents with Macromastia. Plastic and Reconstructive Surgery - Global Open, 9(2), e3421. [DOI:10.1097/gox.0000000000003421]
  • Nuzzi, L. C., Pramanick, T., Massey, G. G., Walsh, L. R., McNamara, C. T., Firriolo, J. M., DiVasta, A. D., & Labow, B. I. (2022). The Impact of Combined Oral Contraceptives on Adolescents with Macromastia. Plastic and Reconstructive Surgery, 150(4), 731–738. [DOI:10.1097/prs.0000000000009513]
  • Oakes, M. B., Eyvazzadeh, A. D., Quint, E., & Smith, Y. R. (2008). Complete Androgen Insensitivity Syndrome—A Review. Journal of Pediatric and Adolescent Gynecology, 21(6), 305–310. [DOI:10.1016/j.jpag.2007.09.006]
  • Obr, A. E., & Edwards, D. P. (2012). The biology of progesterone receptor in the normal mammary gland and in breast cancer. Molecular and Cellular Endocrinology, 357(1–2), 4–17. [DOI:10.1016/j.mce.2011.10.030]
  • Olanrewaju, F., Onayemi, O., Olasode, O., Adeyemi, A., Oninla, A., Oripelaye, M., Ezejiofor, O., & Oke, O. (2017). Prevalence and Pattern of Pigmentary Changes among Primigravidae Attending a Tertiary Health Facility in South-Western Nigeria. British Journal of Medicine and Medical Research, 21(5), 1–9. [DOI:10.9734/bjmmr/2017/33382]
  • Orentreich, N., & Durr, N. P. (1974). Mammogenesis in Transsexuals. Journal of Investigative Dermatology, 63(1), 142–146. [DOI:10.1111/1523-1747.ep12678272]
  • Pandya, S., & Moore, R. G. (2011). Breast Development and Anatomy. Clinical Obstetrics & Gynecology, 54(1), 91–95. [DOI:10.1097/grf.0b013e318207ffe9]
  • Park, I. Y., Kim, M. R., Jo, H. H., Lee, M. K., & Kim, M. J. (2014). Association of the Nipple-Areola Complexes with Age, Parity, and Breastfeeding in Korean Premenopausal Women. Journal of Human Lactation, 30(4), 474–479. [DOI:10.1177/0890334414549049]
  • Pasqualini, J. R. (2007). Progestins and breast cancer. Gynecological Endocrinology, 23(Suppl 1), 32–41. [DOI:10.1080/09513590701585003]
  • Pasqualini, J. R. (2009). Breast cancer and steroid metabolizing enzymes: The role of progestogens. Maturitas, 65(Suppl 1), S17–S21. [DOI:10.1016/j.maturitas.2009.11.006]
  • Pasqualini, J. R., & Kincl, F. A. (1985). Hormone Production and Concentrations During Pregnancy in Humans and in Other Mammalian Species. In Pasqualini, J. R., & Kincl, F. A. Hormones and the Fetus, Volume I: Production, Concentration and Metabolism During Pregnancy (pp. 173–334). Oxford: Pergamon Press. [DOI:10.1016/b978-0-08-019708-1.50007-6]
  • Patel, H., Arruarana, V., Yao, L., Cui, X., & Ray, E. (2020). Effects of hormones and hormone therapy on breast tissue in transgender patients: a concise review. Endocrine, 68(1), 6–15. [DOI:10.1007/s12020-020-02197-5]
  • Patel, K. T., Adeel, S., Rodrigues Miragaya, J., & Tangpricha, V. (2022). Progestogen Use in Gender-Affirming Hormone Therapy: A Systematic Review. Endocrine Practice, 28(12), 1244–1252. [DOI:10.1016/j.eprac.2022.08.012]
  • Patterson, M. N., McPhaul, M. J., & Hughes, I. A. (1994). Androgen insensitivity syndrome. Baillière’s Clinical Endocrinology and Metabolism, 8(2), 379–404. [DOI:10.1016/s0950-351x(05)80258-7]
  • Pawłowski, B., & Żelaźniewicz, A. (2021). The evolution of perennially enlarged breasts in women: a critical review and a novel hypothesis. Biological Reviews, 96(6), 2794–2809. [DOI:10.1111/brv.12778]
  • Perez-Palacios, G., & Jaffe, R. B. (1972). The Syndrome of Testicular Feminization. Pediatric Clinics of North America, 19(3), 653–667. [DOI:10.1016/s0031-3955(16)32744-4]
  • Petrakis, N. (1978). Recurrent extreme breast involution following pregnancy and susceptibility to breast cancer: A hypothesis. Medical Hypotheses, 4(3), 268–272. [DOI:10.1016/0306-9877(78)90006-3]
  • Pfeiffer, C. A. (1943). Endocrinology of Reproduction. Annual Review of Physiology, 5(1), 413–452. [DOI:10.1146/annurev.ph.05.030143.002213]
  • Pipkin, F. B. (2019). Physiological Changes in Pregnancy. In Symonds, I. M., & Arulkumaran, S. (Eds.). Essential Obstetrics and Gynaecology, 6th Edition (pp. 22–40). Edinburgh: Elsevier. [Google Books] [OpenLibrary] [WorldCat]
  • Plu-Bureau, G., Touraine, P., & Mauvais-Jarvis, P. (1999). Interactions Between Estradiol and Progesterone in Normal Breast: Implications for Mammary Carcinogenesis. In Manni, A. (Ed.). Endocrinology of Breast Cancer (Contemporary Endocrinology, Volume 11) (pp. 21–37). Totowa, New Jersey: Humana Press. [DOI:10.1007/978-1-59259-699-7_2] [OpenLibrary] [Archive.org]
  • Pocock, G., Richards, C. D., & Richards, D. A. (2013). Fertilization, Pregnancy, and Lactation. In Pocock, G., Richards, C. D., & Richards, D. A. Human Physiology, 4th Edition (pp. 655–752). Oxford: Oxford University Press. [Google Scholar] [Google Books]
  • Polani, P. E. (1970). Hormonal and clinical aspects of hermaphroditism and the testicular feminizing syndrome in man. Philosophical Transactions of the Royal Society of London. B, Biological Sciences, 259(828), 187–206. [DOI:10.1098/rstb.1970.0058]
  • Price, S., McManus, J., & Barrett, J. (2019). The transgender population: improving awareness for gynaecologists and their role in the provision of care. The Obstetrician & Gynaecologist, 21(1), 11–20. [DOI:10.1111/tog.12521]
  • Prior, J. C. (2011). Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause. Facts, Views & Vision in ObGyn, 3(2), 109–120. [PubMed] [PubMed Central] [PDF]
  • Prior, J. C. (2019). Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen. The Journal of Clinical Endocrinology & Metabolism, 104(4), 1181–1186. [DOI:10.1210/jc.2018-01777]
  • Prior, J. C. (2019). Response to Letter to the Editor: “Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”. The Journal of Clinical Endocrinology & Metabolism, 104(8), 3129–3130. [DOI:10.1210/jc.2019-00524]
  • Prior, J. C. (2020). Women’s Reproductive System as Balanced Estradiol and Progesterone Actions—A revolutionary, paradigm-shifting concept in women’s health. Drug Discovery Today: Disease Models, 32(Part B), 31–40. [DOI:10.1016/j.ddmod.2020.11.005]
  • Prior, J. C., Vigna, Y. M., & Watson, D. (1989). Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Archives of Sexual Behavior, 18(1), 49–57. [DOI:10.1007/bf01579291]
  • Prior, J. C., Vigna, Y. M., Watson, D., Diewold, P., & Robinow, O. (1986). Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic. Journal of Sex Information & Education Council of Canada, 1(1), 1–7. [Google Scholar] [PDF]
  • Quigley, C. A. (1998). The androgen receptor: Physiology and pathophysiology. In Nieschlag, E., & Behre, H. M. (Eds.). Testosterone: Action · Deficiency · Substitution, 2nd Edition (pp. 33–106). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-72185-4_2]
  • Quigley, C. A., Bellis, A. D., Marschke, K. B., El-Awady, M. K., Wilson, E. M., & French, F. S. (1995). Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives. Endocrine Reviews, 16(3), 271–321. [DOI:10.1210/edrv-16-3-271]
  • Radisky, D. C., & Hartmann, L. C. (2009). Mammary Involution and Breast Cancer Risk: Transgenic Models and Clinical Studies. Journal of Mammary Gland Biology and Neoplasia, 14(2), 181–191. [DOI:10.1007/s10911-009-9123-y]
  • Ramos, L., Chávez, B., Mares, L., Valdés, E., & Vilchis, F. (2018). Mutational analysis of the androgen receptor (NR3C4) gene in patients with 46,XY DSD. Gene, 641, 86–93. [DOI:10.1016/j.gene.2017.10.038]
  • Ramsay, D. T., Kent, J. C., Hartmann, R. A., & Hartmann, P. E. (2005). Anatomy of the lactating human breast redefined with ultrasound imaging. Journal of Anatomy, 206(6), 525–534. [DOI:10.1111/j.1469-7580.2005.00417.x]
  • Randolph, J. F. (2018). Gender-Affirming Hormone Therapy for Transgender Females. Clinical Obstetrics & Gynecology, 61(4), 705–721. [DOI:10.1097/grf.0000000000000396]
  • Rauh, C., Faschingbauer, F., Haeberle, L., Jud, S. M., Heusinger, K., Fasching, P. A., Goecke, T. W., Rajakaruna, N., Voigt, F., Bani, M. R., Lux, M. P., Renner, S. P., Loehberg, C. R., Hartmann, A., Schulz-Wendtland, R., Beckmann, M. W., & Bayer, C. M. (2013). Factors influencing breast changes after pregnancy. European Journal of Cancer Prevention, 22(3), 259–261. [DOI:10.1097/cej.0b013e328359cb81]
  • Rebar, R. W. (1988). The Ovaries. In Wyngaarden, J. B., & Smith, L. H. (Eds.). Cecil Textbook of Medicine, 18th Edition (pp. 1425–1446). Philadelphia: W. B. Saunders. [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1990). Disorders of Menstruation, Ovulation, and Sexual Response. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Rebar, R. W., Robertson, G. L., & Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 1st Edition (pp. 798–814). Philadelphia: Lippincott. [Google Scholar—3rd/2001 Edition] [Google Books—3rd/2001 Edition] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1993). Normal and Abnormal Sexual Differentiation and Pubertal Development. In Moore, T. R., Reiter, R. C., Rebar, R. W., & Baker, W. (Eds.). Gynecology & Obstetrics: A Longitudinal Approach (pp. 97–133). New York: Churchill Livingstone. [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1996). Puberty. In Berek, J. S., Adashi, E. Y., & Hillard, P. A. (Eds.). Novak’s Gynecology, 12th Edition (pp. 771–807). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Reisman, T., Goldstein, Z., & Safer, J. D. (2019). A Review of Breast Development in Cisgender Women and Implications for Transgender Women. Endocrine Practice, 25(12), 1338–1345. [DOI:10.4158/ep-2019-0183]
  • Richards, C., & Barrett, J. (2020). Physical Treatments for Trans People and Their Interactions with Psychiatric Treatments. In Richards, C., & Barrett, J. Trans and Non-binary Gender Healthcare for Psychiatrists, Psychologists, and Other Health Professionals (pp. 31–44). Cambridge: Cambridge University Press. [DOI:10.1017/9781108628419.003]
  • Richert, M. M., Schwertfeger, K. L., Ryder, J. W., & Anderson, S. M. (2000). An Atlas of Mouse Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 5(2), 227–241. [DOI:10.1023/a:1026499523505]
  • Rix, J., Mills, C., Ross, E., Allen, S., Lai, A., & Wakefield-Scurr, J. (2023). Breast volume fluctuations are associated with oestradiol and progesterone changes across the menstrual cycle. Research Square, preprint. [Google Scholar] [DOI:10.21203/rs.3.rs-3753080/v1] [PDF]
  • Rodari, G. (2022). Pubertal induction in girls with hypogonadism: estrogen replacement therapy outcomes and optimization of progesterone introduction. (Doctoral thesis, Università degli Studi di Milano.) [URL]
  • Rodari, G., Federici, S., Cattoni, A., Todisco, T., Ubertini, G., Giacchetti, F., Profka, E., Dall’Antonia, A., Cangiano, B., Arosio, M., Bonomi, M., Cappa, M., & Giavoli, C. (2022). Pubertal induction in girls with hypogonadism: insight into estrogen replacement therapy outcomes and optimization of progesterone introduction. Endocrine Abstracts, 81 [24th European Congress of Endocrinology 2022 21–24 May 2022, Milan, Italy], 107–107 (abstract no. RC12.7). [DOI:10.1530/endoabs.81.rc12.7] [PDF]
  • Rodari, G., Federici, S., Todisco, T., Ubertini, G., Cattoni, A., Pagano, M., Giacchetti, F., Profka, E., Citterio, V., Messetti, D., Collini, V., Soranna, D., Carbone, E., Arosio, M., Mantovani, G., Persani, L., Cappa, M., Bonomi, M., & Giavoli, C. (2023). Towards an individualized management of pubertal induction in girls with hypogonadism: insight into the best replacement outcomes from a large multicentre registry. European Journal of Endocrinology, 188(6), 467–476. [DOI:10.1093/ejendo/lvad056]
  • Rohn, R. D. (1989). Nipple (papilla) development in girls: III. Journal of Adolescent Health Care, 10(1), 39–40. [DOI:10.1016/0197-0070(89)90045-4]
  • Rosenfield, R. L. (2013). Adolescent Anovulation: Maturational Mechanisms and Implications. The Journal of Clinical Endocrinology & Metabolism, 98(9), 3572–3583. [DOI:10.1210/jc.2013-1770]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2021). Puberty in the Female and Its Disorders. In Sperling, M. A., Majzoub, J. A., Menon, R. K., & Stratakis, C. A. (Eds.). Sperling Pediatric Endocrinology, 5th Edition (pp. 528–626). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-62520-3.00016-6]
  • Rothman, M. S., & Iwamoto, S. J. (2022). Feminizing Gender-Affirming Hormone Therapy: Special Considerations for Older Adults. In Davis, T. F. (Ed.). A Case-Based Guide to Clinical Endocrinology (pp. 513–523). Cham: Springer. [DOI:10.1007/978-3-030-84367-0_58]
  • Ruan, W., Monaco, M. E., & Kleinberg, D. L. (2005). Progesterone Stimulates Mammary Gland Ductal Morphogenesis by Synergizing with and Enhancing Insulin-Like Growth Factor-I Action. Endocrinology, 146(3), 1170–1178. [DOI:10.1210/en.2004-1360]
  • Rutgers, J. L., & Scully, R. E. (1991). The Androgen Insensitivity Syndrome (Testicular Feminization). International Journal of Gynecological Pathology, 10(2), 126–144. [DOI:10.1097/00004347-199104000-00002]
  • Ryan, R. F., & Pernoll, M. L. (1985). Virginal Hypertrophy. Plastic and Reconstructive Surgery, 75(5), 737–742. [DOI:10.1097/00006534-198505000-00024]
  • Saito, R., Yamamoto, Y., Goto, M., Araki, S., Kubo, K., Kawagoe, R., Kawada, Y., Kusuhara, K., Igarashi, M., & Fukami, M. (2014). Tamoxifen Treatment for Pubertal Gynecomastia in Two Siblings with Partial Androgen Insensitivity Syndrome. Hormone Research in Paediatrics, 81(3), 211–216. [DOI:10.1159/000356923]
  • Sandhu, R., Chollet-Hinton, L., Kirk, E. L., Midkiff, B., & Troester, M. A. (2016). Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma. Human Pathology, 48, 60–68. [DOI:10.1016/j.humpath.2015.09.031]
  • Santen, R. J., Karaguzel, G., Livaoglu, M., Yue, W., Cline, J. M., Ratan, A., & Sasano, H. (2024). Role of ERα and aromatase in juvenile gigantomastia. The Journal of Clinical Endocrinology and Metabolism, online ahead of print. [DOI:10.1210/clinem/dgae019]
  • Sanuki, J., Fukuma, E., & Uchida, Y. (2008). Morphologic Study of Nipple-Areola Complex in 600 Breasts. Aesthetic Plastic Surgery, 33(3), 295–297. [DOI:10.1007/s00266-008-9194-y]
  • Satoh, K., Hovey, R. C., Malewski, T., Warri, A., Goldhar, A. S., Ginsburg, E., Saito, K., Lydon, J. P., & Vonderhaar, B. K. (2007). Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2. Oncogene, 26(54), 7526–7534. [DOI:10.1038/sj.onc.1210555]
  • Schauffler, G. C. (1942). Disorders During Adolescence—The Onset of Menstruation. In Schauffler, G. C. Pediatric Gynecology; with Sections on Urology and Proctology, 1st Edition (pp. 169–211). Chicago: Year Book. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL]
  • Schindler, A. E. (2010). Dydrogesterone and other progestins in benign breast disease: an overview. Archives of Gynecology and Obstetrics, 283(2), 369–371. [DOI:10.1007/s00404-010-1456-7]
  • Scott, P. P., Greene, R., Lane-Roberts, C. S., & Swain, V. (1950). The Function of the Breast. In Saner, F. D. (Ed.). The Breast: Structure, Function, Disease (pp. 53–86). Baltimore: Williams and Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [PDF]
  • Seal, L. (2017). Adult Endocrinology. In Richards, C., Bouman, W. P., & Barker, M.-J. (Eds.). Genderqueer and Non-Binary Genders (Critical and Applied Approaches in Sexuality, Gender and Identity) (pp. 183–223). London: Palgrave Macmillan UK. [DOI:10.1057/978-1-137-51053-2_10]
  • Seal, L. J., Franklin, S., Richards, C., Shishkareva, A., Sinclaire, C., & Barrett, J. (2012). Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens. The Journal of Clinical Endocrinology & Metabolism, 97(12), 4422–4428. [DOI:10.1210/jc.2012-2030]
  • Seibert, B., & Günzel, P. (1994). Animal toxicity studies performed for risk assessment of the once-a-month injectable contraceptive Mesigyna®. Contraception, 49(4), 303–333. [DOI:10.1016/0010-7824(94)90030-2]
  • Shapiro, L. R. (1982). Disorders of Female Sex Differentiation. In Blaustein, A. (Ed.). Pathology of the Female Genital Tract, 2nd Edition (pp. 479–510). New York: Springer New York. [DOI:10.1007/978-1-4757-1767-9_20]
  • Shearman, R. P. (1972). Ovarian Function and its Control. In Shearman, R. P. (Ed.). Human Reproductive Physiology, 1st Edition (pp. 45–90). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Shearman, R. P. (1972). Primary Ammenorhoea. In Dewhurst, C. J. (Ed.). Integrated Obstetrics and Gynaecology for Postgraduates, 1st Edition (pp. 55–62). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Shi, H. Y., Lydon, J. P., & Zhang, M. (2004). Hormonal Defect in Maspin Heterozygous Mice Reveals a Role of Progesterone in Pubertal Ductal Development. Molecular Endocrinology, 18(9), 2196–2207. [DOI:10.1210/me.2004-0052]
  • Shuttleworth, F. K. (1938). The Adolescent Period: A Graphic and Pictorial Atlas (Monographs of the Society for Research in Child Development, Volume 3, Number 3 / Serial No. 16). Washington, D. C.: Society for Research in Child Development. [Google Scholar] [Google Books] [DOI:10.2307/1165482]
  • Simmer, H. H., Pion, R. J., & Dignam, W. J. (1965). Testicular Feminization: Endocrine Function of Feminizing Testes, Comparison with Normal Testes. Springfield, Illinois: Thomas. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Simpson, J. L., & Rebar, R. W. (1990). Normal and Abnormal Sexual Differentiation and Development. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Rebar, R. W., Robertson, G. L., & Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 1st Edition (pp. 710–739). Philadelphia: Lippincott. [Google Scholar] [Google Books—3rd/2001 Edition] [OpenLibrary] [WorldCat] [Archive.org]
  • Sindi, R., Sá Dos Reis, C., Bennett, C., Stevenson, G., & Sun, Z. (2019). Quantitative Measurements of Breast Density Using Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine, 8(5), 745. [DOI:10.3390/jcm8050745]
  • Sitruk-Ware, R., Basdevant, A., de Lignières, B., & Mauvais-Jarvis, P. (1984). Percutaneous oestrogen therapy. In van Herendael, H., van Herendael, B., Riphagen, F. E., Goessens, L., & van der Plas, H. (Eds.). The Climacteric: An Update: Proceedings of the fourth Jan Palfijn Symposium, European Conference on the Menopause, held in Antwerp, Belgium, on September 1–2, 1983, under the auspices of ‘De Vereniging voor Nederlandstalige gynecologen van België’ and ‘The International Menopause Society’ (pp. 127–139). Lancaster: MTP Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [DOI:10.1007/978-94-009-5608-7_14]
  • Sizonenko, P. C. (1978). Endocrinology in Preadolescents and Adolescents. American Journal of Diseases of Children, 132(7), 704–712. [DOI:10.1001/archpedi.1978.02120320064015]
  • Škarda, J., Fremrová, V., & Bezecný, I. (1989). Progesterone alone is responsible for stimulation of the growth of ducts and of mammary alveolar structures in mice. Endocrinologia Experimentalis, 23(1), 17–28. [Google Scholar] [PubMed] [PDF]
  • Sobrinho, L. G., Kase, N., & Grunt, J. A. (1971). Spontaneous pubertal breast growth in a castrated patient with the syndrome of testicular feminization. The Yale Journal of Biology and Medicine, 44(2), 225–9. [Google Scholar] [PubMed] [PubMed Central] [PDF]
  • Sosa, M., Jódar, E., Arbelo, E., Domínguez, C., Saavedra, P., Torres, A., Salido, E., de Tejada, M. J., & Hernández, D. (2003). Bone Mass, Bone Turnover, Vitamin D, and Estrogen Receptor Gene Polymorphisms in Male to Female Transsexuals. Journal of Clinical Densitometry, 6(3), 297–304. [DOI:10.1385/jcd:6:3:297]
  • Sosa, M., Jódar, E., Arbelo, E., Domı́nguez, C., Saavedra, P., Torres, A., Salido, E., Limiñana, J., Gómez de Tejada, M. J., & Hernández, D. (2004). Serum lipids and estrogen receptor gene polymorphisms in male-to-female transsexuals: effects of estrogen treatment. European Journal of Internal Medicine, 15(4), 231–237. [DOI:10.1016/j.ejim.2004.04.009]
  • Soyal, S., Ismail, P. M., Li, J., Mulac-Jericevic, B., Conneely, O. M., & Lydon, J. P. (2002). Progesterone receptors - animal models and cell signaling in breast cancer: Progesterone’s role in mammary gland development and tumorigenesis as disclosed by experimental mouse genetics. Breast Cancer Research, 4(5), 191. [DOI:10.1186/bcr451]
  • Sperling, R. L., & Gold, J. J. (1973). Use of an anti-estrogen after a reduction mammaplasty to prevent recurrence of virginal hypertrophy of breasts. Plastic and Reconstructive Surgery, 52(4), 439–442. [DOI:10.1097/00006534-197352040-00030]
  • Spitz, I. M., Shoupe, D., Sitruk-Ware, R., & Mishell, D. R. (1989). Response to the antiprogestagen RU 486 (mifepristone) during early pregnancy and the menstrual cycle in women. Journal of Reproduction and Fertility Supplement, 37, 253–260. [Google Scholar] [PubMed]
  • Spitz, I., Croxatto, H., Lahteenmaki, P., Heikinheimo, O., & Bardin, C. (1994). Effect of mifepristone on inhibition of ovulation and induction of luteolysis. Human Reproduction, 9(Suppl 1), 69–76. [DOI:10.1093/humrep/9.suppl_1.69]
  • Spitz, I. M. (2010). Mifepristone: where do we come from and where are we going? Contraception, 82(5), 442–452. [DOI:10.1016/j.contraception.2009.12.012]
  • Sridhar, G. R., & Sinha, M. J. (1995). Macromastia in adolescent girls. Indian Pediatrics, 32(4), 496–499. [Google Scholar] [PubMed] [PDF]
  • Sun, B. Z., Kangarloo, T., Adams, J. M., Sluss, P. M., Welt, C. K., Chandler, D. W., Zava, D. T., McGrath, J. A., Umbach, D. M., Hall, J. E., & Shaw, N. D. (2018). Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity. The Journal of Clinical Endocrinology & Metabolism, 104(2), 613–623. [DOI:10.1210/jc.2018-00595]
  • Sun, S. X., Bostanci, Z., Kass, R. B., Mancino, A. T., Rosenbloom, A. L., Klimberg, V. S., & Bland, K. I. (2018). Breast Physiology: Normal and Abnormal Development and Function. In Bland, K. I., Copeland, E. M., Klimberg, V. S., Gradishar, W. J., White, J., & Korourian, S. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 5th Edition (pp. 37–56.e6). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-35955-9.00003-9]
  • Swelstad, M. R., Swelstad, B. B., Rao, V. K., & Gutowski, K. A. (2006). Management of Gestational Gigantomastia. Plastic and Reconstructive Surgery, 118(4), 840–848. [DOI:10.1097/01.prs.0000232364.40958.47]
  • Tack, L. J., Heyse, R., Craen, M., Dhondt, K., Bossche, H. V., Laridaen, J., & Cools, M. (2017). Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents. The Journal of Sexual Medicine, 14(5), 747–757. [DOI:10.1016/j.jsxm.2017.03.251]
  • Talbert, L. M., Hammond, M. G., Groff, T., & Udry, J. R. (1985). Relationship of age and pubertal development to ovulation in adolescent girls. Obstetrics & Gynecology, 66(4), 542–544. [Google Scholar] [PubMed] [URL]
  • Tanos, T., & Brisken, C. (2008). What Signals Operate in the Mammary Niche? Breast Disease, 29(1), 69–82. [DOI:10.3233/bd-2008-29108]
  • Thanaboonyawat, I., Chanprapaph, P., Lattalapkul, J., & Rongluen, S. (2013). Pilot Study of Normal Development of Nipples during Pregnancy. Journal of Human Lactation, 29(4), 480–483. [DOI:10.1177/0890334413493350]
  • Thody, A. J., & Smith, A. G. (1977). Hormones and Skin Pigmentation in the Mammal. International Journal of Dermatology, 16(8), 657–664. [DOI:10.1111/j.1365-4362.1977.tb01876.x]
  • Thoresen, M., & Wesche, J. (1988). Doppler measurements of changes in human mammary and uterine blood flow during pregnancy and lactation. Acta Obstetricia et Gynecologica Scandinavica, 67(8), 741–745. [DOI:10.3109/00016349809004301]
  • Tiefenbacher, K., & Daxenbichler, G. (2008). The Role of Androgens in Normal and Malignant Breast Tissue. Breast Care, 3(5), 325–331. [DOI:10.1159/000158055]
  • Tim, F., Jeroen, V., & T’Sjoen, G. (2023). Dose Reduction of Cyproterone Acetate in Trans Women and the Effect on Patient-reported Outcomes: Results from the ENIGI Study. Endocrine Abstracts, 97 [Belgian Endocrine Society 2023], 5–5 (abstract no. 007). [URL] [PDF]
  • Trabert, B., Sherman, M. E., Kannan, N., & Stanczyk, F. Z. (2019). Progesterone and Breast Cancer. Endocrine Reviews, 41(2), 320–344. [DOI:10.1210/endrev/bnz001]
  • Tucker, H. (2000). Hormones, Mammary Growth, and Lactation: a 41-Year Perspective. Journal of Dairy Science, 83(4), 874–884. [DOI:10.3168/jds.s0022-0302(00)74951-4]
  • Turan, S., Bereket, A., Guran, T., Akcay, T., Papari-Zareei, M., & Auchus, R. J. (2009). Puberty in a case with novel 17-hydroxylase mutation and the putative role of estrogen in development of pubic hair. European Journal of Endocrinology, 160(2), 325–330. [DOI:10.1530/eje-08-0632]
  • Turner, C. W. (1939). The Mammary Glands. In Allen, E., Danforth, C. H., & Doisy, E. A. (Eds.). Sex and Internal Secretions: A Survey of Recent Research, 2nd Edition (pp. 740–803). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Ulrich, U., Pfeifer, T., & Lauritzen, C. (1994). Rapid Increase in Lumbar Spine Bone Density in Osteopenic Women by High-Dose Intramuscular Estrogen-Progestogen Injections. Hormone and Metabolic Research, 26(9), 428–431. [DOI:10.1055/s-2007-1001723]
  • Ulrich, U., Pfeifer, T., Buck, G., Keckstein, J., & Lauritzen, C. (1995). High-dose estrogen-progestogen injections in gonadal dysgenesis, ovarian hypoplasia, and androgen insensitivity syndrome: Impact on bone density. Adolescent and Pediatric Gynecology, 8(1), 20–23. [DOI:10.1016/s0932-8610(12)80156-3]
  • Valentine, G. H. (1969). Chromosome Anomalies in the Female. In Valentine, G. H. The Chromosome Disorders: An Introduction for Clinicians, 2nd Edition (pp. 126–143). London: W. Heinemann Medical Books. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • van der Meulen, A. J. (1974). An unusual case of massive hypertrophy of the breasts. South African Medical Journal=Suid-Afrikaanse Tydskrif vir Geneeskunde, 48(34), 1465–1466. [Google Scholar] [PubMed] [URL 1] [URL 2]
  • Vandeweyer, E., & Hertens, D. (2002). Quantification of glands and fat in breast tissue: An experimental determination. Annals of Anatomy - Anatomischer Anzeiger, 184(2), 181–184. [DOI:10.1016/s0940-9602(02)80016-4]
  • Venturoli, S., Fabbri, R., Porcu, E., Paradisi, R., Orsini, L. F., Brondelli, L., Ruggeri, S., & Flamigni, C. (1989). Endocrine and ovarian parameters at various frequencies of ovulation in adolescents. Archives of Gynecology and Obstetrics, 246(2), 107–114. [DOI:10.1007/bf00934127]
  • Venturoli, S., Porcu, E., Fabbri, R., Magrini, O., Paradisi, R., Pallotti, G., Gammi, L., & Flamigni, C. (1987). Postmenarchal evolution of endocrine pattern and ovarian aspects in adolescents with menstrual irregularities. Fertility and Sterility, 48(1), 78–85. [DOI:10.1016/s0015-0282(16)59294-2]
  • Vorherr, H. (1974). Development of the Female Breast. In Vorherr, H. The Breast: Morphology, Physiology, and Lactation (pp. 1–19). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Vorherr, H. (1974). Morphology of the Mature Female Breast. In Vorherr, H. The Breast: Morphology, Physiology, and Lactation (pp. 20–70). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Wade, T. R., Wade, S. L., & Jones, H. E. (1978). Skin changes and diseases associated with pregnancy. Obstetrics and Gynecology, 52(2), 233–242. [Google Scholar] [PubMed] [URL]
  • Walker, M., Baker, G., & Lamb, M. (2013). Physiology of the Breast During Pregnancy and Lactation. In Mannel, R., Martens, P. J., & Walker, M. (Eds.). Core Curriculum for Lactation Consultant Practice, 3rd Edition (pp. 287–300). Burlington: Jones & Bartlett Learning. [Google Scholar] [Google Books—2013/3rd Edition] [Google Books—2008/2nd Edition] [OpenLibrary] [WorldCat]
  • Wang, C., Luan, J., Cheng, H., Chen, L., Li, Z., Panayi, A. C., & Liu, C. (2018). Menstrual Cycle-Related Fluctuations in Breast Volume Measured Using Three-Dimensional Imaging: Implications for Volumetric Evaluation in Breast Augmentation. Aesthetic Plastic Surgery, 43(1), 1–6. [DOI:10.1007/s00266-018-1243-6]
  • Wang, Q. A., & Scherer, P. E. (2019). Remodeling of Murine Mammary Adipose Tissue during Pregnancy, Lactation, and Involution. Journal of Mammary Gland Biology and Neoplasia, 24(3), 207–212. [DOI:10.1007/s10911-019-09434-2]
  • Weisberg, M. G., Malkasian, G. D., & Pratt, J. H. (1970). Testicular feminization syndrome. American Journal of Obstetrics and Gynecology, 107(8), 1181–1187. [DOI:10.1016/s0002-9378(15)30367-7]
  • Wellons, M. F., & Rebar, R. W. (2013). Amenorrhea. In Falcone, T., & Hurd, W. W. (Eds.). Clinical Reproductive Medicine and Surgery: A Practical Guide, 2nd Edition (pp. 105–112). New York: Springer New York. [DOI:10.1007/978-1-4614-6837-0_7]
  • Wellons, M. F., Weeber, K. M., & Rebar, R. W. (2017). Amenorrhea. In Falcone, T., & Hurd, W. W. (Eds.). Clinical Reproductive Medicine and Surgery, 3rd Edition (pp. 109–122). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-52210-4_6]
  • Werner, A. A. (1935). Experiment to produce lactation in castrate women. Endocrinology, 19(2), 144–150. [DOI:10.1210/endo-19-2-144]
  • Whiteley, S. (1994). Predictors of Milk Production in Lactating Women. (Master’s thesis, The Open University.) [Google Scholar] [DOI:10.21954/ou.ro.0000fe02] [URL]
  • Wierckx, K., Gooren, L., & T’Sjoen, G. (2014). Clinical Review: Breast Development in Trans Women Receiving Cross-Sex Hormones. The Journal of Sexual Medicine, 11(5), 1240–1247. [DOI:10.1111/jsm.12487]
  • Wierckx, K., Van Caenegem, E., Schreiner, T., Haraldsen, I., Fisher, A., Toye, K., Kaufman, J. M., & T’Sjoen, G. (2014). Cross‐Sex Hormone Therapy in Trans Persons Is Safe and Effective at Short‐Time Follow‐Up: Results from the European Network for the Investigation of Gender Incongruence. The Journal of Sexual Medicine, 11(8), 1999–2011. [DOI:10.1111/jsm.12571]
  • Wilson, J. D. (1968 March 28). Medical Grand Rounds: Testicular Feminization. Parkland Memorial Hospital, UT Southwestern Medical Center. [Google Scholar] [URL] [PDF]
  • Wilson, C. L., Sims, A. H., Howell, A., Miller, C. J., & Clarke, R. B. (2006). Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocrine-Related Cancer, 13(2), 617–628. [DOI:10.1677/erc.1.01165]
  • Winkler, U. H., Schindler, A. E., Brinkmann, U. S., Ebert, C., & Oberhoff, C. (2001). Cyclic progestin therapy for the management of mastopathy and mastodynia. Gynecological Endocrinology, 15(Suppl 6), 37–43. [DOI:10.1080/gye.15.s6.37.43]
  • Wisniewski, A. B., Migeon, C. J., Meyer-Bahlburg, H. F., Gearhart, J. P., Berkovitz, G. D., Brown, T. R., & Money, J. (2000). Complete Androgen Insensitivity Syndrome: Long-Term Medical, Surgical, and Psychosexual Outcome. The Journal of Clinical Endocrinology & Metabolism, 85(8), 2664–2669. [DOI:10.1210/jcem.85.8.6742]
  • Wong, R. C., & Ellis, C. N. (1984). Physiologic skin changes in pregnancy. Journal of the American Academy of Dermatology, 10(6), 929–940. [DOI:10.1016/s0190-9622(84)80305-9]
  • Wren, B. G., & Eden, J. A. (1996). Do Progestogens Reduce The Risk of Breast Cancer? A Review of the Evidence. Menopause, 3(1), 4–12. [DOI:10.1097/00042192-199603010-00003]
  • Wright, E. M. (2015). Breastfeeding and the Mother–Newborn Dyad (pp. 1157–1182). In King, T. L., Brucker, M. C., Kriebs, J. M., Fahey, J. O., Gegor, C. L., & Varney, H. (Eds.). Varney’s Midwifery, 5th Edition. Burlington: Jones & Bartlett Learning. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Xu, P., Ye, W., Zhong, S., Li, H., Feng, E., Lin, S. H., Kuo, C. T., Liu, J. Y., & Lin, Y. C. (2010). Leptin and zeranol up-regulate cyclin D1 expression in primary cultured normal human breast pre-adipocytes. Molecular Medicine Reports, 3(6), 983–990. [DOI:10.3892/mmr.2010.370]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]
  • Zacharin, M. (2000). Use of androgens and oestrogens in adolescents - A review of hormone replacement treatment. Journal of Pediatric Endocrinology and Metabolism, 13(1), 3–12. [DOI:10.1515/JPEM.2000.13.1.3]
  • Zachmann, M., Prader, A., Sobel, E. H., Crigler, J. F., Ritzén, E. M., Atarés, M., & Ferrandez, A. (1986). Pubertal growth in patients with androgen insensitivity: Indirect evidence for the importance of estrogens in pubertal growth of girls. The Journal of Pediatrics, 108(5), 694–697. [DOI:10.1016/s0022-3476(86)81043-5]
  • Żelaźniewicz, A., & Pawłowski, B. (2015). Breast size and asymmetry during pregnancy in dependence of a fetus’s sex. American Journal of Human Biology, 27(5), 690–696. [DOI:10.1002/ajhb.22716]
  • Żelaźniewicz, A., & Pawłowski, B. (2018). Maternal breast volume in pregnancy and lactation capacity. American Journal of Physical Anthropology, 168(1), 180–189. [DOI:10.1002/ajpa.23734]
  • Zhang, D., Yao, F., Tian, T., Deng, S., Luo, M., & Tian, Q. (2021). Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center. Fertility and Sterility, 115(5), 1270–1279. [DOI:10.1016/j.fertnstert.2020.12.008]
\ No newline at end of file +A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People - Transfeminine Science Link

A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People

By Aly | First published February 14, 2020 | Last modified April 11, 2024

Abstract / TL;DR

The major female sex hormones are estrogen and progesterone. Both of these hormones are known to be importantly involved in the development of the breasts at different stages of life. Speculation, use, and anecdotes of progestogens for enhancing breast development in transfeminine people date back to at least the 1960s. A limited number of clinical studies have assessed breast development with progestogens in transfeminine people, but current evidence on progestogens for improving breast development is of very low quality and is inconclusive. Studies of progestogens and breast development in cisgender girls and women are similarly limited. In any case, more studies evaluating progestogens and breast development are currently underway. The possible role of progestogens in enhancing breast development can also be informed by indirect and circumstantial evidence, including notably findings on progesterone and breast changes during normal puberty, the menstrual cycle, and pregnancy in humans and animals. Available evidence overall is not suggestive of an essential role for progesterone in breast growth during puberty, but progesterone does have a clear and key role in lobuloalveolar development of the breasts during pregnancy. However, breast changes in pregnancy revert following cessation of lactation and breastfeeding. Progesterone may additionally contribute to reversible breast enlargement during the luteal phase of the menstrual cycle. There are some findings to suggest that progestogens may have antiestrogenic effects in the breasts and may have a stunting influence on breast development if introduced too early following initiation of hormone therapy. However, more research is needed to assess this possibility. In any case, if progestogens are used, it may be advisable to delay their introduction until most or all estrogen-mediated breast development is complete. Options for progestogen therapy in transfeminine people include bioidentical progesterone and progestins. However, oral progesterone has major bioavailability problems and does not achieve satisfactory progesterone levels. Progestogens, including progesterone, have been variously linked to significant health risks, which is an important consideration in terms of their use in transfeminine people. Overall, based on current knowledge, progestogens do not seem to be promising for lastingly improving breast development in transfeminine people, but more research and data are still needed for clear conclusions.

Introduction

Breast development in terms of size and shape is often less than desired in transfeminine people, and there is a need for therapeutic approaches that improve breast growth in this population. There are two major types of female hormones, estrogens and progestogens. Estrogens are almost universally employed in transfeminine hormone therapy, while progestogens are used in a subset of transfeminine people. Progestogens that have been commonly employed in transfeminine people include bioidentical progesterone, the progestin (synthetic progestogen) medroxyprogesterone acetate (MPA), and the strongly progestogenic antiandrogen cyproterone acetate (CPA). Estrogens are the major mediators of feminization and breast development in females. However, progestogens also have physiological effects on the breasts, and in relation to this, may or may not provide benefits to breast development as well.

The topic of progestogens and breast development has been discussed for many years in the transgender community and is a controversial subject (Coleman et al., 2012). Use of progestogens to improve breast development in transfeminine people goes back at least as far as Harry Benjamin and Christian Hamburger in the 1960s (Benjamin, 1966; Benjamin, 1967; Hamburger & Benjamin, 1969; Wiki). Arguments have been made both for (e.g., Bevan, 2012; Bellwether, 2019; Bevan, 2019) and against (e.g., Curtis, 2009) a possible role of progestogens in terms of breast development. It is often claimed that progestogens can enhance breast development or are even required for full breast development in cisgender females and transfeminine people. With respect to the latter, it is sometimes said that progestogens are necessary for people to move from Tanner stage 4 to Tanner stage 5 pubertal breast development and that progestogens help to fill and round out the breasts (e.g., Vorherr, 1974a; Basson & Prior, 1998; Kaiser & Ho, 2015; Prior, 2011; Prior, 2019a; Prior, 2020). It has even been claimed by some that without progestogens, the breasts will remain conical and “pointy” like they are in the earlier Tanner stages. On the other extreme, certain critics have claimed that there are “no biologically significant progesterone receptor sites for biological males” and that progesterone is not produced during normal female puberty until after breast development has been fully completed (Barrett, 2009; Seal, 2017; Coxon & Seal, 2018; Price, McManus, & Barrett, 2019; Richards & Barrett, 2020). In turn, these particular authors have argued against the use of progestogens in transfeminine people in various of their publications (Google Scholar). In general, the use of progestogens in transfeminine people has longstandingly been controversial, with positions both for and against (Sam, 2020).

The purpose of this article is to review the available direct and circumstantial evidence on the topic of progestogens and breast development in order to help inform whether progestogen therapy may be able to enhance breast development in transfeminine people. Aside from an involvement in breast development, progestogens are not otherwise currently thought to be or known to be involved in physical feminization (e.g., Coleman et al., 2012; Gooren, 2016). In relation to this, the present article will limit its discussion to breast development with progestogens, and will not explore feminization in general.

Progestogen Therapy and Breast Development in Humans

Progestogens and Breast Development in Transfeminine People

At present, only a limited number of studies have assessed breast development with progestogen therapy in transfeminine people. These studies have employed either bioidentical progesterone or a progestin like MPA or CPA. The subject of and the available data on progestogens and breast development in transfeminine people has also been partly reviewed in papers including Wierckx, Gooren, & T’Sjoen (2014), Reisman, Goldstein, & Safer (2019), Patel et al. (2020), Patel et al. (2022), Milionis, Ilias, & Koukkou (2022), Coleman et al. (2022), and Berliere et al. (2023).

Orentreich & Durr (1974) was one of the earliest studies on breast development in transfeminine people. They employed combinations of estrogens and progestogens as well as gonadectomy to produce feminization and breast development in a case series of 5 transfeminine people. The employed estrogens were estradiol valerate 30 mg/2 weeks by intramuscular injection and oral conjugated estrogens 1.25–5.0 mg/day and the used progestogens were “60 mg medroxyprogesterone caproate” every 2 weeks by intramuscular injection and oral medroxyprogesterone acetate 0–10 mg/day. Medroxyprogesterone caproate (MPC) has never been used pharmaceutically, so this was likely a typo and the actual progestogen employed was likely either MPA or hydroxyprogesterone caproate (OHPC). The authors reported that estrogen and progestogen therapy produced modest to significant breast development in the transfeminine people that was not strictly dose-related and included clinical photographs of the breasts. They concluded that the breast development was comparable to that of adult cisgender women. Orentreich and colleagues also discussed the topic of lobuloalveolar maturation of the breasts, which was known to be progestogen-dependent, but noted that they had not done histological assessment and that the degree of lobuloalveolar development of the breasts does not necessarily correlate with clinical breast size per findings in cisgender women. The findings of Orentreich and colleagues are limited by methodological problems like lack of objective measurements, lack of estrogen-only controls, and the small sample size of only 5 transfeminine people, and hence the study is of limited value in terms of assessing the involvement of progestogens in breast development.

Meyer et al. (1986) assessed the effects of progestogens added to estrogen therapy on breast development and other clinical parameters in transfeminine people. Of the 60 transfeminine people in the study, 15 (25%) received an oral progestogen, usually MPA at a dosage of 10 mg/day, for “at least for a short time”, and with only 8 (13.3%) receiving progestogen therapy for the full treatment period. In an earlier report of the study, it was noted that in 90% of observation periods the dose was 10 mg/day and for the remainder it was 20 mg/day (Meyer et al., 1981). A dosage of 10 mg/day MPA is roughly comparable to luteal-phase progesterone exposure in terms of progestogenic potency (Wiki). Breast development was measured in the study via breast hemicircumference (Diagram). Progestogen therapy was reported to not modify estrogen-induced changes, including laboratory measurements, hormone levels, and physical parameters like weight and breast growth. The lack of apparent changes in hormone levels is unexpected, as MPA in higher-quality studies has shown clear testosterone suppression (e.g., Jain, Kwan, & Forcier, 2019; Wiki). Meyer and colleagues concluded that adding progestogens to estrogen does not seem to enhance breast development in transfeminine people. However, they noted that the number of individuals who received progestogens was small and further studies were needed.

Prior et al. (1986) and Prior, Vigna, & Watson (1989) studied estrogen, high-dose spironolactone (100–600 mg/day), and MPA (10–20 mg/day cylically or continuously) in transfeminine people who were either pre-hormone therapy or had previously been on higher doses of estrogens (and/or progestogens) without spironolactone prior to the study. The researchers reported that following 12 months of treatment with the study’s hormone therapy regimen, there was increased breast size and increased nipple development. Most individuals reached an A cup size, or approximately 8 to 14 cm in diameter of breast tissue, by the end of the study. Breast development was measured in part with photographic documentation. Although breast development reportedly improved, the researchers themselves noted that it was difficult to determine whether the enhanced breast development could be attributed to spironolactone or to MPA. Moreover, testosterone suppression was inadequate before the study and improved with the study’s hormone therapy regimen, which may have helped to improve breast development regardless of any potential direct progestogenic action of MPA on the breasts. Finally, it is possible that breast development with estrogen may not yet have been complete, and that the improved breast development may have simply been continued progression due to estrogen alone. In other publications, Jerilynn Prior, the lead study author, has claimed that progesterone enhances breast development, and has cited the preceding studies by her in support of this claim (Prior, 2011; Prior, 2019a; Prior, 2019b; Prior, 2020). However, her claim is not well-supported due to the study limitations discussed.

Dittrich et al. (2005) reported that the combination of oral estradiol valerate and a gonadotropin-releasing hormone (GnRH) agonist for 2 years in transfeminine people resulted in self-reported breast cup sizes of C cup or greater in 5%, B cup in 30%, A cup in 35%, and less than A cup in 30%. They noted however that 70% of the individuals were unsatisfied with their breast development and wished to undergo breast augmentation surgery. The researchers claimed that the regimen had similar effectiveness in terms of feminization, including increases in breast size, compared to prior reported treatment regimens of ethinylestradiol and CPA. No other details or specifics were given. The claim about similar breast development to regimens containing CPA is relevant as CPA is a very strong progestogen at the doses used historically in transfeminine people (Aly, 2019). It should be cautioned however that this study did not actually employ or study progestogen therapy itself. In addition, self-reported breast cup size is a subjective and low-quality means of measuring breast development and size. As such, the findings of this study are of questionable value in terms of understanding progestogens and breast development.

Estrogen is primarily involved in ductal development of the breasts, whereas progesterone is mainly involved in lobuloalveolar development. Kanhai et al. (2000) compared internal histological breast tissue changes with estrogen and CPA 100 mg/day (i.e. very-high-dose progestogen) therapy in 14 transfeminine people versus nonsteroidal antiandrogen monotherapy with flutamide or bicalutamide in 2 cisgender men with prostate cancer. Both types of treatments block androgens, increase estrogen levels, and are known to induce breast development or gynecomastia at similarly high rates. However, nonsteroidal antiandrogen monotherapy differs from combined estrogen and progestogen therapy in that it lacks any progestogenic effects. In the transfeminine people, full lobuloalveolar formation was apparent in the biopsied breast tissue, whereas in the men with prostate cancer, only “moderate” and incomplete lobuloalveolar maturation was found. It was also noted that lobuloalveolar formation tended to regress upon discontinuation of CPA following gonadectomy in transfeminine people. The researchers concluded that progestogenic exposure is needed for the breasts to fully develop on a histological level and for the breast tissue of transfeminine people to completely mimic the histology of the mature female breast. While the findings of this study are interesting, they only concern tissue characteristics and do not actually provide any information about breast development in terms of physical form or appearance. With regard to this, tissue-level differences may or may not translate to relevant differences in for instance breast size or shape. As such, the study is of limited value in understanding whether progestogens improve breast development in transfeminine people in the ways that are actually valued.

Seal and colleagues conducted a retrospective chart review assessing clinical predictors for surgical breast augmentation in transfeminine people (Seal et al., 2012). In the transfeminine people who underwent breast augmentation, significantly more of them were taking spironolactone than were those who did not undergo breast augmentation. Conversely, the differential rates of use of specific antiandrogens were not significantly discordant between those who did and did not undergo breast augmentation in the case of the other prescribed antiandrogens, including cyproterone acetate, the 5α-reductase inhibitors, and GnRH analogues. However, this study had many methodological limitations, including the use of almost three dozen t-tests with no adjustment for multiple comparisons (and hence risk of false positives and concerns about p-hacking), small sample sizes for individual antiandrogens, use of undergoing breast augmentation as a surrogate for breast development with no actual physical measurement of the breasts or breast sizes, and a correlational design with lack of control for potential confounding variables. As such, the study does not show that different antiandrogens result in differences in breast development, and its findings must be considered with due caution.

Jain, Kwan, & Forcier (2019) studied sublingual estradiol and spironolactone with and without MPA in 92 transfeminine people. MPA was given at a dose of 5 to 10 mg/day sublingually or at a dose of 150 mg once every 3 months by intramuscular injection. Of 39 transfeminine people who received MPA, 26 (67%) self-reported improved breast development. No further details were provided, but measurement of breast development was presumably subjective and anecdotal. Igo & Visram (2021) studied addition of progesterone to hormone therapy in transfeminine people. Progesterone was provided as 100 mg micronized progesterone (probably oral) and was prescribed when progesterone was specifically requested by the patient or when the patient expressed dissatisfaction with feminization and/or breast development. Of 190 individuals, 51 (26.8%) received progesterone therapy. Treatment with progesterone on average began after 12.7 months of estradiol therapy, and the mean total follow-up time was 14.3 months of hormone therapy. Of those who received progesterone, only 6 (11.8%) reported benefit to breast development. No further details were provided, but as with other studies, breast development was likely quantified anecdotally via self-report. As breast development does not appear to have been objectively measured or compared to a control group in either Jain, Kwan, & Forcier (2019) or Igo & Visram (2021), the findings of these studies are limitedly informative.

Nolan and colleagues assessed the short-term effects of low-dose oral micronized progesterone on breast development in transfeminine people on stable hormone therapy in a prospective controlled study (Nolan et al., 2022a; Nolan et al., 2022b). Progesterone was given at a dose of 100 mg/day for 3 months to 23 transfeminine people and findings were compared to those of a control group of 19 transfeminine people. Breast development was measured using self-reported Tanner stage, with participants provided photographs of different Tanner stages to self-select from. At the end of the 3 months, Tanner stage was not significantly different between groups (mean 3.5, 95% CI 3.2–3.7 for progesterone vs. mean 3.6, 95% CI 3.3–3.9 for controls; p = 0.42). A limitation of this study is that oral progesterone has very low bioavailability and 100 mg/day oral progesterone achieves very low progesterone levels that are well below normal luteal-phase progesterone levels (Aly, 2018a; Wiki). As such, progestogenic exposure in this study, and notably also in Igo & Visram (2021) and other studies, is likely to have been inadequate. Besides the issue of progestogenic strength, the very short duration of the study (3 months) and the reliance on self-reported subjective Tanner stages (as opposed to more objective physical breast measurements) are also major limitations. In any case, this study is of higher quality than previous studies, and is notably likely to continue and report further follow-up at later points in the future.

Bahr et al. (2024) conducted a retrospective chart review at their clinic and compared 29 transfeminine people who had received progestogens versus 59 transfeminine people who had not. The form of progestogen used was oral or rectal progesterone in 93% of cases and MPA by intramuscular injection in the remaining 7% of cases. Of those who took progesterone, 25 (93%) used it orally and 2 (7%) used oral progesterone capsules rectally. Progestogen doses were not reported, except that 100 mg progesterone capsules were employed. Most of those in the progestogen-treated group (59%) had started it 1 to 6 months following initiation of standard hormone therapy. The researchers found that progestogen-treated group had significantly better self-reported breast development satisfaction (rated as satisfied, neutral, or unsatisfied) compared to the group that did not receive progestogens at 6 months (satisfied: 53.8% vs. 19.6%; p = 0.004) and 9 months (satisfied: 71.4% vs. 20.8%; p = 0.003) of hormone therapy. Limitations of this study include the lack of objective measurement of breast development, the restrospective nature of the study, and the lack of randomization of treatment, among others.

Aside from the above studies, a variety of other studies have also reported breast development with estrogen and CPA in transfeminine people. These studies have often employed objective physical measurements of breast development (e.g., breast volume, breast–chest difference, breast cup size, breast hemicircumference). However, they have lacked comparison groups, thereby precluding comparison of progestogenic versus non-progestogenic hormone therapy. In addition, CPA is unusual among progestogens in that it is employed at very high doses in transfeminine people (Aly, 2019), which may result in different and potentially stunted outcomes in terms of breast development than more physiological progestogenic exposure. As such, most studies of breast development with estrogen and CPA in transfeminine people have not been discussed in the present section and are instead discussed elsewhere in this article (see the section below). In any case, to briefly summarize the findings, breast development in transfeminine people with estrogen and CPA has generally been poor in these studies. The outcomes have included incomplete maturation in terms of Tanner staging (stage 2–4), small cup sizes, small breast volumes, and breasts much smaller in size than those in cisgender women.

The findings from the preceding studies in transfeminine people are of very low-quality due to methodological limitations, including lack of control groups, lack of randomization, reliance on poor measures of breast development (e.g., subjective and self-report) rather than objective physical measurements (Wiki), short treatment durations, and small sample sizes, among others. This may explain the conflicting results of the studies. More research is still needed to assess the influence of progestogens on breast development in transfeminine people. There is specifically a need for randomized controlled trials (RCTs) of feminizing hormone therapy with versus without progestogen therapy that employ objective measures of breast development, have adequate sample sizes, and have sufficient follow-up durations. Additional variables like progestogen type, route, dose, and timing of introduction would also be of value to explore. A 2014 review on hormone therapy in transfeminine people summarizes the state of research on progestogens and breast development in transfeminine people, with their conclusions still holding true today (Wierckx, Gooren, & T’Sjoen, 2014):

Our knowledge concerning the natural history and effects of different cross-sex hormone therapies on breast development in trans women is extremely sparse and based on low quality of evidence. Current evidence does not provide evidence that progestogens enhance breast development in trans women. Neither do they prove the absence of such an effect. This prevents us from drawing any firm conclusion at this moment and demonstrates the need for further research to clarify these important clinical questions.

Accordingly, reviews and guidelines have concluded that there is currently no reliable evidence that progestogens included in hormone therapy are of benefit or are not of benefit for breast development in transfeminine people (Wierckx, Gooren, & T’Sjoen, 2014; Reisman, Goldstein, & Safer, 2019; Patel et al., 2022; Milionis, Ilias, & Koukkou, 2022; Coleman et al., 2022; Berliere et al., 2023).

Future Studies Currently Underway

Several studies of progesterone and other progestogens in transfeminine people are currently underway. These studies include (1) an RCT of oral progesterone added to hormone therapy by Sandeep Dhindsa and colleagues in St. Louis, Missouri in the United States (ClinicalTrials.gov; MediFind; ICH GCP); (2) a prospective observational study and/or RCT of addition of oral progesterone to hormone therapy by Ada Cheung and colleagues in Melbourne, Australia (University of Melbourne; University of Melbourne); (3) an RCT of estradiol plus spironolactone versus estradiol plus CPA also by Ada Cheung and colleagues (update: see below) (ANZCTR; WHO ICTRP; Trans Health Research [Flyer] [Poster]; University of Melbourne); and (4) a large RCT of oral progesterone at different doses added to hormone therapy by Martin den Heijer and colleagues at the Vrije Universiteit University Medical Center (VUMC) in Amsterdam, the Netherlands (Dijkman et al., 2023a; General Info/Links; Info Sheet Dutch; Info Sheet English Translated). Unfortunately however, all of the studies using progesterone employ oral progesterone, which has major bioavailability and potency problems (Aly, 2018a; Wiki). In any case, it was said that the VUMC researchers may follow their trial up with studies of other progesterone routes (General Info/Links). The preceding studies may provide more insight on the question of whether progestogen therapy is of therapeutic benefit to breast development in transfeminine people.

Progestogens and Breast Development in Cisgender Females

To date, there appear to be no useful studies on breast development with progesterone or other progestogens in cisgender females. There seem to mostly only be a few brief and conflicting anecdotal clinical statements in this area that are scattered throughout the literature. These include the following literature excerpts, which are specifically in the context of progestogens as part of puberty induction in cisgender girls and women with delayed or absent puberty due to hypogonadism:

I […] performed studies on three women lacking mammary development and exhibiting signs of marked hypogonadism. […] Corpus luteum extract, 5 international units daily for a period of thirty days, when given alone produced no detectable change in the breasts. This is in accord with the experimental observations on animals of Turner,2 Corner 3 and others. When, however, patients were given alternate daily injections of 1 international unit of progesterone and from 20,000 to 50,000 international units of estrone or of estradiol benzoate, breast growth was more rapid than that produced by the estrogenic hormones alone. The simultaneous use of the corpus luteum and estrogenic therapy definitely produced a much firmer breast growth, which was distinctly lobular to palpation, whereas the growth produced by the estrogenic hormones alone was smooth and the borders of the glandular tissue were difficult to define. Rapid regression in the size of the breasts followed the omission of the hormone injections, but the regression was less rapid when the combined therapy had been used. [MacBryde (1939)]

There are authorities who consider that breast growth is better if a progestogen is combined with oestrogen for the latter part of the cycle of treatment (Capraro, 1971). Shearman (1971) employs sequential therapy in his cases. Huffman (1971) however, does not believe that there is any improvement with the addition of progestogens. [Dewhurst (1971a)]

The effects of progesterone on the human breast remain obscure. Although widely stated to cause glandular development, the evidence for this is slender (Benson et al 1959). [Shearman (1972a)]

Many people use oestrogens alone, but the addition of a progestin for 6 or 10 days each month gives much better cycle control and appears to cause better breast development. [Shearman (1972b)]

Some authorities consider that breast growth is better if a progestogen is given for the latter part of each course of treatment. [Capraro & Dewhurst (1975)]

It has been suggested that progestins be added during the last week of each cycle of estrogen therapy in order to develop more rounded breasts rather than the conical breasts many of these patients develop, but we have been unable to detect any difference in breast contour with or without progestins. [Davajan & Kletzky (1979)]

I have been satisfied that the addition of a progestogen was necessary to get a good breast response to hormone treatment although the progestogen, as I have said, is required after the first year if the uterus is present. [Dewhurst (1982)]

In addition to the preceding instances, Werner (1935) and Geschickter (1945) assessed the effects of progesterone on the breasts in cisgender women. Werner (1935) attempted to induce lactation in 8 surgically gonadectomized cisgender women with combinations of estrogen, progesterone, and prolactin, all in the form of crude extracts by injection. In two women who were given progesterone, he claimed that a marked increase in the size of the breasts beyond that with estrogen alone was observed. Additionally, he claimed that the breasts were more firm, the glandular tissue “more tortuous and nodular”, and the nipples more prominent. He was not successful in inducing lactation in the women in this study. The doses of hormones used were unclear as they were in the form of extracts, and were likely supraphysiological, potentially pregnancy-like due to the nature of the experiment. Werner’s study was also briefly discussed by Nelson (1936), among other citations. Geschickter (1945) observed lobuloalveolar growth on histological examination with administration of progesterone for 6 weeks to 2 months in one woman but not in another woman. However, the exterior physical changes of the breasts were not assessed or reported by this author and hence his findings are limitedly informative.

Surprisingly, there have been few analogous studies of the effects of progestogens on the breasts in cisgender girls and women following the preceding reports and anecdotes. Although there are very little data on progestogens and breast growth in cisgender females, clinical studies are finally starting to look more closely at the specifics of hormonal medications, including progestogens, in terms of breast development in girls undergoing puberty induction (e.g., Rodari et al., 2023). As such, future studies may provide more insight on the subject of progestogens and breast development in cisgender females.

Progesterone and its Physiological Role in Breast Development in Humans

Progesterone and Breast Development in Puberty

The role of progesterone in breast development and its possible usefulness for helping with breast development in transfeminine hormone therapy can be informed by the normal biological circumstances of puberty in cisgender females. Puberty in cisgender girls usually starts around age 11 (range 8–13 years) and completes around age 15 years (range 12–19 years), taking on average 3 to 4 years (but with a range of about 1.5–6 years in most cases) (Schauffler, 1942; Marshall & Tanner, 1969; Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986). Progesterone essentially does not appear during puberty until ovulatory menstrual cycles begin. Menarche, the onset of menstruation and hence of menstrual cycling, occurs on average at Tanner breast stage 4 or about 13 years of age, although it occurs at Tanner breast stage 3 or Tanner breast stage 5 in significant subsets of girls (26% for Tanner stage 3, 62% for Tanner stage 4, and 10% for Tanner stage 5) (Marshall & Tanner, 1969; Marshall, 1978; Drife, 1986; Hillard, 2007). Hence, the appearance of progesterone in normal female puberty is a relatively late event (Scott et al., 1950; Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986), and most breast development appears to be complete by menarche and thus by the time that progesterone is first produced (Huffman, Dewhurst, & Capraro, 1981; Drife, 1982). Moreover, a small but significant subset of girls reaches Tanner breast stage 5 and hence fully developed breasts before menarche (Edmonds, 1989), which suggests that progesterone may not be essential for complete pubertal breast development.

The reproductive axis in pubertal and adolescent cisgender girls is immature (Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019; Sun et al., 2019). In the first 1 to 2 years postmenarche, most menstrual cycles are anovulatory (i.e., ovulation does not occur) (Döring, 1963 [Table]; Apter, 1980; Lemarchand-Béraud et al., 1982; Talbert et al., 1985; Venturoli et al., 1987; Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019). Without ovulation, the corpus luteum doesn’t form from a ruptured ovarian follicle and progesterone production doesn’t commence. Only about half of menstrual cycles are ovulatory by Tanner breast stage 5 (Talbert et al., 1985). In addition, menstrual cycles are unusually long for some time after menarche (e.g., 50 days vs. 28 days for adult cycles) and thus there are fewer menstrual cycles per reproductive year (Rosenfield, 2013; Gunn et al., 2018; Carlson & Shaw, 2019). Luteal-phase progesterone levels are also lower in postmenarche adolescents than in adulthood even when ovulation does occur (McArthur, 1966 [Figure]; Lemarchand-Béraud et al., 1982; Apter et al., 1987; Venturoli et al., 1987; Venturoli et al., 1989; Sun et al., 2019). Consequently, progesterone exposure is sporadic and relatively limited even during late female puberty. Moreover, this is the case not only by the time of Tanner stage 5, but for many years after it as well. It takes more than 6 years after menarche for menstrual cycling to become fully mature and consistently ovulatory (Lemarchand-Béraud et al., 1982; Venturoli et al., 1987; Carlson & Shaw, 2019). Over this period of time, the rate of ovulatory cycles increases progressively until it reaches approximately 100% (Lemarchand-Béraud et al., 1982; Venturoli et al., 1987; Carlson & Shaw, 2019). Only then is full adult-level exposure to progesterone finally achieved (Lemarchand-Béraud et al., 1982; Venturoli et al., 1987).

Only a handful of studies and sources have reported progesterone levels during puberty across Tanner stages or by age in cisgender girls (e.g., Sizonenko, 1978 [Graph]; Kühnel, 2000; Lee, 2001 [Table]; Aly, 2020a). They corroborate the above findings with regard to limited progesterone exposure during puberty. The “A Girl’s First Period Study” is an ambitious research project announced in 2022 that aims to better characterize reproductive hormone levels in pubertal and adolescent girls and may shed more light on the physiological role of progesterone during puberty (Lucien et al., 2022). The researchers have specifically highlighted the possible role of progesterone in breast development as part of their interests:

Does exposure to low levels of [progesterone (P4)], as occurs before menarche, during anovulatory cycles with some degree of follicle luteinization, and during early, immature ovulatory cycles play an important role in normal breast development during puberty? This question has important clinical implications as hormone replacement during puberty does not typically include low-dose P4; rather, it is conducted using a staggered approach of estrogen-only therapy followed by the addition of full adult doses of exogenous P4 only after 2 years or when breakthrough bleeding occurs.27 This is done to avoid development of tubular breasts, although there are limited data linking early P4 exposure to suboptimal breast development.28

Taken together, production of progesterone is a late event in normal female puberty, and even once it does begin, exposure to progesterone is low and sporadic until well after puberty has completed. Moreover, a subset of girls complete breast development before progesterone production starts. These facts call into some question the role of progesterone in breast development in female puberty, as most breast development appears to be complete prior to the appearance of progesterone. However, more research is still needed on the role of progesterone in breast development during normal puberty.

On the basis of normal female puberty, it seems it may be advisable that if progestogens are introduced in an attempt to enhance breast development in transfeminine people, their introduction be delayed until after 2 or 3 years of hormone therapy, so as to mimic the normal progestogenic exposure of puberty.

Progesterone and Breast Development in Pregnancy

During pregnancy, under the influence of ovarian hyperstimulation and placental formation, there are profound changes in hormonal profiles, including of hormones like estrogen, progesterone, and prolactin, among many others (Table 1). Comparing hormone levels during the menstrual cycle to those during the third trimester of pregnancy, estradiol levels increase on the order of 100-fold, progesterone levels increase on the order of 10- to 20-fold, and prolactin levels increase by around 10-fold (Table 1). Levels of numerous other hormones also change considerably during pregnancy, for instance other estrogens besides estradiol, androgens, gonadotropins (e.g., human choronic gonadotropin or hCG), human placental lactogen (hPL), relaxin, adrenocorticotropic hormone (ACTH), cortisol, aldosterone, growth hormone (GH), and insulin-like growth factor 1 (IGF-1), among others (Goodman, 2009 [Figure]; Mesiano, 2019). These hormones are variously produced by the ovaries, the placenta, and the pituitary gland, among other glands. In response to the myriad hormonal changes during pregnancy, there are dramatic changes to the breasts, which prepare the mother for postpartum lactation and breastfeeding.

Table 1: Changes in hormone levels (estradiol, progesterone, and prolactin) during normal pregnancy:

HormoneNon-PregnantFirst TrimesterSecond TrimesterThird Trimester
Estradiol100 (~5–750) pg/mL1,000–5,000 pg/mL5,000–15,000 pg/mL10,000–40,000 pg/mL
Progesterone8.9 (1.0–24) ng/mLa22 (5–75 ng/mL)35 (15–85) ng/mL102 (25–280) ng/mL
Prolactin13.0 (4.6–37) ng/mL16 (3.2–43 ng/mL)49 (13–166) ng/mL113 (13–318) ng/mL

Note: Values are median (range) or range. Footnotes: a Specifically during the luteal phase of the menstrual cycle. Sources: estradiol (Aly, 2018b; Wiki; Wiki); progesterone (Kühnel, 2000; Aly, 2020a; Wiki; Wiki); and prolactin (Kühnel, 2000; Wiki).

Prior to pregnancy, there is significant although fairly minimal lobuloalveolar development of the breasts with each menstrual-cycle luteal phase (Scott et al., 1950; Drife, 1984; Drife, 1989; Drife, 1990; Pocock, Richards, & Richards, 2013; Johnson & Cutler, 2016; Alekseev, 2021). During pregnancy however, the breasts undergo much more considerable lobuloalveolar development and achieve full maturity. This allows for milk production and lactation following childbirth. During pregnancy, the breasts progressively and considerably increase in size (Hytten, 1954a; Hytten, 1954b; Baird, Hytten, & Thomson,1958; Hytten & Thomson, 1965; Hytten & Leitch, 1971a; Hytten & Leitch, 1971b; Hytten, 1976; Thoresen & Wesche, 1988; Cox et al., 1994; Whiteley, 1994; Cox et al., 1999; Cregan & Hartmann, 1999; Kent et al., 1999; Galbarczyk, 2011; Abduljalil et al., 2012; Bayer et al., 2014; Lawrence & Lawrence, 2015; Żelaźniewicz & Pawłowski, 2015; Dallman et al., 2017; Drąsutis, 2017; Żelaźniewicz & Pawłowski, 2019). Quantitative clinical studies have found the breasts to increase on average by about 100 to 300 mL (range -20 to 880 mL) in volume, or by about 200 to 400 g in mass, going from early pregnancy to late pregnancy or early postpartum (Hytten & Thomson, 1965; Hytten & Thomson, 1968; Hytten & Leitch, 1971a; Hytten & Leitch, 1971b; Hytten, 1976; Thoresen & Wesche, 1988; Whiteley, 1994; Hartmann et al., 1996; Cox et al., 1999; Cregan & Hartmann, 1999; Kent et al., 1999; Wright, 2015; Bayer et al., 2014; Żelaźniewicz & Pawłowski, 2015; Drąsutis, 2017; Żelaźniewicz & Pawłowski, 2019). The breasts can reportedly increase as much two to three times in size in some women (Greydanus et al., 2010). There is marked variation between individuals in the breast size increases during pregnancy (Hytten & Thomson, 1965; Hytten & Leitch, 1971a; Hassiotou & Geddes, 2013; Bayer et al., 2014). Increases in breast size are inversely associated with age, with considerably greater increases in younger women than in older women (e.g., +234–258 mL in <20 years vs. +79–131 mL in >30 years) (Hytten & Baird, 1958; Hytten & Leitch, 1971a [Excerpt]; Hytten, 1976). In addition to overall breast size, the nipples and areolae increase in size during pregnancy (Hytten & Baird, 1958; Hytten & Leitch, 1971a; Rohn, 1989; Cox et al., 1999; Hassiotou & Geddes, 2013; Thanaboonyawat et al., 2013; Park et al., 2014). They also become more darkly pigmented, reaching a dark brown or even black color (Dickson & Hewer, 1950; Thody & Smith, 1977; Wade, Wade, & Jones, 1978; Wong & Ellis, 1984; Elling & Powell, 1997; Muzaffar, Hussain, & Haroon, 1998; Muallem & Rubeiz, 2006; Nussbaum & Benedetto, 2006; Olanrewaju et al., 2017). The breasts become capable of lactation by 3 to 4 months of pregnancy (Walker, Baker, & Lamb, 2013; Pipkin, 2019; Pocock, Richards, & Richards, 2013; Wright, 2015; Lawrence & Lawrence, 2015). However, maturation of the breasts for lactation does not appear to be complete until at least about 6.5 months of pregnancy (Hassiotou & Geddes, 2013). Photographic timelines of women throughout pregnancy provide a visual impression of the breast changes that occur during this time (caution—NSFW: Reddit; More).

There are large and dramatic changes in levels of numerous hormones during pregnancy, and the exact hormones responsible for the breast changes during pregnancy are not known (Hytten & Leitch, 1971a; Hytten, 1976). However, it is considered likely, on the basis of animal studies, that a variety of hormones, including estrogen, progesterone, prolactin, placental lactogen, glucocorticoids, and growth hormone, are all importantly involved in different aspects of the maturation (Hytten & Leitch, 1971a; Hytten, 1976; Cox et al., 1999). Moreover, in a quantitative clinical study of breast changes during pregnancy, increases in breast volume and areola size were positively correlated with levels of hPL, while increases in nipple size were positively correlated with levels of prolactin (Cox et al., 1999). Progesterone and prolactin have specifically been implicated in the lobuloalveolar development of the breasts during pregnancy (Bässler, 1970; Lee & Ormandy, 2012; Obr & Edwards, 2012). Both hormones appear to be independently essential in normal lobuloalveolar growth per animal studies (Obr & Edwards, 2012; McNally & Stein, 2017; Hannan et al., 2023). Prolactin likewise appears to be essential in humans, based on case reports of lactation failure in women with isolated prolactin deficiency (Buhimschi, 2004). Conversely, hPL may not be essential for lactation based on case reports of normal lactation in women with very low levels of hPL during pregnancy (Gaede, Trolle, & Pedersen, 1978; Hannan et al., 2023).

Following childbirth and lactation, the breasts undergo a process known as post-lactational involution and return to a pre-pregnancy-like state (Dickson & Hewer, 1950; Ingleby, Moore, & Gershon-Cohen, 1957; Harley, 1969; Gershon-Cohen, 1970; Petrakis, 1978; Huffman, Dewhurst, & Capraro, 1981; Drife, 1986; Caro, 1987; Tanos & Brisken, 2008; Radisky & Hartmann, 2009; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; Hassiotou & Geddes, 2013; Sun et al., 2018; Alex, Bhandary, & McGuire, 2020). This involves massive cell death and regression of the lobuloalveolar development and other breast changes that occurred during pregnancy (Radisky & Hartmann, 2009; Alex, Bhandary, & McGuire, 2020). With involution, there is, on the basis of quantitative clinical studies, a complete reversion to pre-pregnancy breast size, or even to a slightly smaller breast size (Kent et al., 1999 [Figure]; Jernström et al., 2005; Dorgan et al., 2013; Lim et al., 2018). The same reversion has also been observed in gestational macromastia (breast hypertrophy of pregnancy), with striking and complete or near-complete regressions in breast size reported—although often with concomitant sagging and deformity that necessitates surgical intervention (Moss, 1968; van der Meulen, 1974 [Figure]; Swelstad et al., 2006; Naik et al., 2015). Following involution, it is also impossible to reliably distinguish between nulliparous and parous breasts even with internal histological examination (Drife, 1986). However, the parous breasts are not exactly the same as they were before pregnancy—the breasts remain more complex on a histological level (Dickson & Hewer, 1950; Gershon-Cohen, 1970; Hytten, 1976; Drife, 1986; Drife, 1989; Jeruss, 2006; Fridriksdottir, Petersen, & Rønnov-Jessen, 2011; Hassiotou & Geddes, 2013; Lewin, 2016; Sun et al., 2019), tend to be looser, more flaccid, and more pendulous due to stretching of skin and ligaments (Begley, Firth, & Hoult, 1980; Duncan, 2010; Rauh et al., 2013; Lewin, 2016), and the nipples and areolae remain more maturely developed and pigmented (Dickson & Hewer, 1950; Hytten & Baird, 1958; Hytten, 1976; Nussbaum & Benedetto, 2006; Sanuki, Fukuma, & Uchida, 2009; Thanaboonyawat et al., 2013; Park et al., 2014). In terms of subjective perceptions, some women perceive their breasts to be larger following pregnancy, whereas others perceive them to be smaller (Rauh et al., 2013; Lewin, 2016). Pregnancy can temporarily improve breast size in women with small breasts (Capraro & Dewhurst, 1975; Petrakis, 1978; Huffman, Dewhurst, & Capraro, 1981), but it has been said that the subsequent regressions in breast size after pregnancy can be “disturbing” (Capraro & Dewhurst, 1975). Following the first pregnancy and post-lactational involution, the breasts undergo the same cycle of expansion and regression with each subsequent pregnancy (Hassiotou & Geddes, 2013).

On the basis of the preceding, in spite of rather extreme hormonal stimulation, the breast changes of pregnancy, although quite dramatic, are essentially temporary and fully reversible, remaining only as long as continuous hormonal exposure is maintained. This hormonal stimulation includes exposure to extremely high levels of progesterone. It would seem, based on pregnancy, that once pubertal breast development is completed, the breasts are rather unamenable to permanent further growth, whether that involves exposure to progestogens or to a variety of other hormones known to act on the breasts.

Breast Composition and Lobuloalveolar Tissue Proportion

The breasts are made up of two main types of tissue: (1) epithelial tissue, the actual functional internal mammary glandular tissue, including ducts and alveoli or lobules; and (2) stromal tissue, a mixture of connective tissue and adipose (fat) tissue. Lobuloalveolar development refers to growth and maturation of the alveoli and lobules, and hence is a form of epithelial or glandular development. Progestogens are involved primarily in lobuloalveolar development of the breasts, which is the type of breast development that is necessary for lactation and breastfeeding and that occurs mainly during pregnancy.

In women who are not pregnant or lactating, studies have found that only about 5 to 20% of the volume of the breasts is composed of epithelial tissue on average, while the remaining 80 to 95% is composed of stromal tissue (Hutson, Cowen, & Bird, 1985; Drife, 1986; Drife, 1989; Bryant et al., 1998; Gertig et al., 1999; Howard & Gusterson, 2000; Cline & Wood, 2006; Lorincz & Sukumar, 2006; Wilson et al., 2006; Xu et al., 2010; Pandya & Moore, 2011; Hagisawa, Shimura, & Arisaka, 2012; Sandhu et al., 2016; Rosenfield, Cooke, & Radovick, 2021; Wiki). More specifically, one major study in in reproductive-age women found that the breasts are about 10 to 20% epithelial tissue, 10 to 35% fat tissue, and 60 to 80% connective tissue (Hutson, Cowen, & Bird, 1985; Wilson et al., 2006). Conflictingly however, a couple of studies that employed mammography have reported higher breast glandular proportions ranging from 35 to 48% (Klein et al., 1997; Jamal et al., 2004; Duncan, 2010). Aside from glandular tissue, other studies have found breast fat percentages of mean 26 to 48% (range 2 to 78%) (Lejour, 1994; Lejour, 1997; Vandeweyer & Hertens, 2002). Similarly to the findings of most studies of women’s breasts in general, only a small proportion of the breasts is glandular tissue (e.g., 1–7%) in women who have macromastia (breast hypertrophy, or extremely large breasts) (Bames, 1948; Cruz-Korchin et al., 2001).

During pregnancy and lactation in humans, the breasts undergo dramatic changes, and epithelial tissue comes to make up a much greater proportion of the breasts (Ramsay et al., 2005; Bland, Copeland, & Klimberg, 2018). In fact, sources state that glandular tissue comprises a majority of the breast during pregnancy and lactation, with one study of lactating women finding that the breasts were composed 63% (range 46–83%) of glandular tissue (Ramsay et al., 2005). This is not merely due to lobuloalveolar development and glandular growth, but is also due to a marked reversible reduction in mammary adipose tissue (Wang & Scherer, 2019; Alex, Bhandary, & McGuire, 2020). In any case, under more normal physiological circumstances and progesterone exposure, the contribution of lobuloalveolar tissue to the size of the breasts would appear to be quite small. In relation to this, outside of pregnancy levels of progesterone, the significance of progestogen-mediated breast lobuloalveolar growth in terms of breast size is unclear but seemingly questionable (Orentreich & Durr, 1974; Wierkcx, Gooren, & T’Sjoen, 2014).

Breast Development in Cisgender Women with Complete Androgen Insensitivity Syndrome and Consequent Absence of Progesterone

It has been claimed that progesterone helps to move transfeminine people and cisgender females from Tanner stage 4 to 5 breast development and that it helps to round out the breasts (e.g., Vorherr, 1974a; Prior, 2011; Prior, 2019a; Prior, 2020). It has also sometimes been claimed in the online transgender community that cisgender women with complete androgen insensitivity syndrome (CAIS), an experiment of nature of women who lack progesterone, are stuck at Tanner stage 4 breast growth and have “cone-shaped” breasts due to their absence of progesterone. In actuality however, there is no good evidence at this time that progesterone is required for normal pubertal breast development, that progesterone is needed to reach Tanner stage 5, or that it helps to round out the breasts. Such claims are contradicted by extensive available literature and evidence, including notably the literature on CAIS women themselves.

Women with CAIS are individuals who have a 46,XY karyotype (i.e., are genetically “male”), testes, and who would otherwise have physically developed as males, but did not because they have a mutation in the gene encoding the androgen receptor that makes them completely insensitive to the effects of androgens. There are also incomplete forms of the syndrome, like partial androgen insensitivity syndrome (PAIS) and mild androgen insensitivity syndrome (MAIS). CAIS women have a male-typical hormonal profile, generated by their testes, including high male-range levels of testosterone, low female-range estradiol levels, and negligible progesterone levels (Wiki; Table). Instead of developing physically as males however, CAIS women are perfectly phenotypically female, with a normal female body, vagina, and breasts (Wiki; Photo). Their testosterone has been unable to masculinize them, while their estradiol, unopposed by androgens, is able to fully feminize them. The internal reproductive system in CAIS women is essentially that of an underdeveloped male, with testes instead of ovaries, and no uterus. The vagina is often short and is blind-ending with no cervix, which is related to their lack of a uterus. CAIS women are also described as feminine in terms of behavior, gender, and sexuality.

Women with CAIS have breast development that is described throughout the literature as “good”, “excellent”, “normal”, “full”, “complete”, “well-developed”, “overdeveloped”, “generous”, “enhanced”, “typically above-average”, “large”, and even “voluptuous” (Morris, 1953; Simmer, Pion, & Dignam, 1965; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971b; Perez-Palacios & Jaffe, 1972; Glenn, 1976; Dewhurst & Spence, 1977; Rutgers & Scully, 1991; Patterson, McPhaul, & Hughes, 1994; Quigley et al., 1995; McPhaul, 2002; Galani et al., 2008; Oakes et al., 2008; Tiefenbacher & Daxenbichler, 2008; Barbieri, 2019). John McLean Morris, the gynecologist who reviewed and summarized all of the existing scientific literature on CAIS women in 1953 (including 82 cases) and gave their condition the now-abandoned name “testicular feminization”, described their breasts as “unusually large” and “jumbo-sized” (Morris, 1953; Quigley et al., 1995). He additionally said in his famous 1953 review that they had “normal female breasts, often with a tendency to be overdeveloped” (Morris, 1953). Per another author, “Probably under no other circumstance does breast development in the [‘male’] reach the florid degree seen in testicular feminization” (Wilson, 1968).

Despite claims that CAIS women have generous breast sizes however, in actuality, some CAIS women have large breasts, while some have small breasts, with one study finding a wide range of breast size measurements of 16×14 cm to 41×31 cm (Wisniewski et al., 2000). Moreover, the breasts of CAIS women have never been directly compared to those of normal women. Hence, there are no clear data at this time that the breasts of CAIS women are actually larger than average for women. The variation in breast growth in CAIS women parallels the same large variation in breast size between individuals that is seen in cisgender women in general. Here is a collection of photos of CAIS women and their breast development from published case reports and reviews throughout the literature. As can be seen from these photos, breast development in CAIS women is normal and often excellent, although subject to considerable variation between individuals in terms of breast size and shape as in women generally.

If CAIS women truly do have enhanced breast development and breast sizes compared to normal women, it may be that their androgen insensitivity, and hence lack of inhibition of estrogen-mediated breast development by androgens, is responsible for this (Wilson, 1968; Sobrinho, Kase, & Grunt, 1971; Andler & Zachmann, 1979; Zachmann et al., 1986; Patterson, McPhaul, & Hughes, 1994; Barbieri, 2019). Another theoretical possibility is that the high testosterone levels may be aromatized into greater amounts of estradiol locally within the breasts and other tissues in CAIS women and that this may somehow allow for enhanced breast development (Ladjouze & Donaldson, 2019).

Baron evaluated a total of 41 people with androgen insensitivity syndrome (AIS) and found that 97% of CAIS women had normal breast development while 63% of individuals with “incomplete AIS” (likely PAIS) had normal breast development (Baron, 1993; Baron, 1994a; Baron, 1994b). In another earlier published study of 50 CAIS females, by Sir Christopher John Dewhurst, 76% were rated as having full breast development, 14% as having moderate breast development, 10% as having “mild” breast development, and 0% as having absent breast development (Dewhurst, 1971b). Hence, based on findings in large samples of CAIS females, most to almost all have normal or full breast development. That a minority of CAIS females have had less breast growth may be due to factors like low and inadequate estradiol levels in some individuals, young age at time of assessment by which breast development has not fully completed, and/or a small subset of women in general having underdeveloped or small breasts.

CAIS women have never been described in the literature as having “cone-shaped”, “pointy”, or otherwise abnormal breasts. The only exception is that they are often said to have nipples and areolas that are described as “juvenile”, “infantile”, “small”, “pale”, and “non-pigmented” (e.g., Photo) (e.g., Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; Dewhurst, 1967; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977). This has been said to be the case regardless of breast size or maturation (Khoo & Mackay, 1972). A possible reason for this phenomenon is that estradiol levels in CAIS women are relatively low, only about 35 pg/mL (130 pmol/L) on average (Wiki; Table). This is relevant as estrogens are known to concentration-dependently produce nipple and areolar pigmentation and enlargement (e.g., Davis et al., 1945 [Figure]; Kennedy & Nathanson, 1953). In contrast to estrogens, progestogens have not been implicated in nipple or areolar pigmentation. Hence, it seems that higher estrogen levels may be necessary for full ault-like nipple and areolar maturation.

CAIS women are able to reach Tanner stage 5 breast development and hence full maturation of the breasts similarly to normal women (Quigley, 1988; Quigley et al., 1995; Gordon & Laufer, 2005; Finkenzeller & Loveless, 2007; Cheikhelard et al., 2008; Ramos et al., 2018; Arya et al., 2021; Zhang et al., 2021). One gynecologist, Robert Rebar, has claimed in his publications over several decades, including in reviews and book chapters, that CAIS women usually only reach Tanner stage 3 breast development (Kustin & Rebar, 1987; Rebar, 1988; Rebar, 1990; Simpson & Rebar, 1990; Rebar, 1993; Rebar, 1996; Wellons & Rebar, 2013; Wellons, Weeber, & Rebar, 2017). However, this claim conflicts with the statements of other researchers and with studies and case reports of CAIS women. In one book chapter, Rebar said that CAIS females undergo breast development and feminization and that the breasts contain normal ductal and glandular tissue, but stated that “the areolae are pale and poorly developed (Tanner stage 3)” (Rebar, 1993). This suggests that he may have been meant Tanner stage 3 in terms of nipple and areolar maturation rather than breast growth as a whole (Rebar, 1993). Aside from CAIS females, even individuals with PAIS often have substantial breast growth and female-like breasts (e.g., Saito et al., 2014; Lee et al., 2015). Additionally, PAIS females treated with estrogen therapy have similarly been reported to reach Tanner breast stage 5 (Guaragna-Filho et al., 2023).

Despite their often large breasts, CAIS women are said to have relatively little breast glandular tissue, as opposed to fat and connective tissue, and to have minimal breast lobuloalveolar development (Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982). This is in accordance with the lack of progesterone in CAIS women, since progesterone is important in mediating lobuloalveolar growth. The retained breast sizes of CAIS women despite reduced glandular and lobuloalveolar structures is consistent with the fact that the breasts are composed mostly of stromal adipose and connective tissue. Hence, as touched on previously in this article, greater glandular or lobuloalveolar formation in the breasts may not necessarily translate to greater breast size, which seems readily apparent in CAIS women.

The normal and excellent breast development of CAIS women is notable because these individuals, owing to their testes and hence absence of significant gonadal progesterone production, have very low and negligible levels of progesterone (Wiki; Table; Barbieri, 2019). CAIS womens’ normal breast development, often large breasts, and ability to reach complete breast maturation, as measured by the Tanner scale, are collectively suggestive that progesterone is not required for normal or complete pubertal breast development (Barbieri, 2019). In any case, it must be noted and cautioned again that the breasts of CAIS women have never been directly compared to those in normal women. In addition, quantitative studies of the breasts of CAIS women are very scarce, and much of our knowledge in this area is based on anecdotal clinical experience and subjective breast evaluation. This is in large part due to the rarity of CAIS women and the difficulty in obtaining decent samples of them for study. Furthermore, CAIS women also have other differences from regular women besides their lack of progesterone, for instance their relatively low circulating estradiol levels, high testosterone levels (which can be aromatized into estradiol within tissues like the breasts), androgen insensitivity, and XY karyotype, among others. Hence, the insights into breast development provided by CAIS women come with a variety of caveats.

Interestingly, in spite of their well-developed breasts, breast cancer has never been reported in CAIS women, and would appear to be very rare in these individuals (Aly, 2020b; Aly, 2020c). This may be related to factors like the lack of progesterone and lobuloalveolar maturation in CAIS women and/or their absence of a second X chromosome (Aly, 2020b; Aly, 2020c). CAIS women suggest that breast cancer is not an inherent eventual consequence of excellent breast development.

Menstrual Cycles and Temporary Cyclic Breast Enlargement

The breasts fluctuate in size across the menstrual cycle, with significant enlargement apparent during the luteal phase of each cycle (Shuttleworth, 1938 [Figure]; Ingleby, 1949; Scott et al., 1950; Milligan, Drife, & Short, 1975; Drife, 1982; Malini, Smith, & Goldzieher, 1985; Drife, 1989; Fowler et al., 1990; Graham et al., 1995; Jemström & Olsson, 1997; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Wang et al., 2019; Rix et al., 2023). This is experienced by women as a sense of fullness, as well as tingling sensations and tenderness (Shuttleworth, 1938 [Figure]; Milligan, Drife, & Short, 1975; Laessle et al., 1990; Jemström & Olsson, 1997). The change in the volume of the breasts has been reported to be approximately 75 to 100 mL on average, with volume falling to as low as 90% of mean volume during the follicular phase or at ovulation and increasing to up to 110% of average volume during the luteal phase (or about 15 to 20% mean total change from smallest to largest volume) (Milligan, Drife, & Short, 1975; Malini et al., 1985; Drife, 1989; Fowler et al., 1990; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Rix et al., 2023). However, more recent studies using better measurement methods of breast volume suggest more modest changes, like a decrease in breast volume of 4 to 10% during the follicular phase and an increase in breast volume of 3 to 21% during the luteal phase (Rix et al., 2023). The changes in breast size have also been described as an increase of one-third of a bra cup size (37 mL or 35 g) on average and up to one bra cup size in some (Rix et al., 2023). There is substantial variation between individuals in the changes in breast volume across the menstrual cycle, ranging from no change to up to a 40 to 45% increase in the most extreme cases (Ingleby, 1949; Malini, Smith, & Goldzieher, 1985; Fowler et al., 1990; Hussain et al., 1999; Hussain, Brooks, & Percy, 2008; Rix et al., 2023).

The enlargement of the breasts during the luteal phase of the menstrual cycle is believed to be due to temporary glandular and stromal tissue growth, luminal dilation of the ducts and alveoli, fluid retention in the glandular and stromal structures, and increased vascularization and blood flow (Scott et al., 1950; Drife, 1989; Fowler et al., 1990; Hussain et al., 1999; Alekseev, 2021; Biswas et al., 2022). However, studies suggest that most of the changes are merely due to water fluctuations and that change in breast glandular volume change is relatively small (Rix et al., 2023). The breast changes during the menstrual cycle have been positively correlated with increased levels of estradiol and progesterone during the luteal phase (Jemström & Olsson, 1997; Clendenen et al., 2013; Rix et al., 2023). In addition, estrogen therapy has been found to reversibly increase breast size (e.g., Hartmann et al., 1998) and estradiol levels are positively associated with breast tenderness (e.g., de Lignières & Mauvais-Jarvis, 1981 [Figures]; Sitruk-Ware et al., 1984). Both estradiol and progesterone can promote water retention via distinct hormonal mechanisms as well as mediate breast glandular growth and changes (Rix et al., 2023). As such, the breast changes during the menstrual cycle are assumed to be due to changing levels of estradiol and progesterone, though it is noteworthy that progesterone has been particularly implicated owing to the breast volume increase occurring during the luteal phase (Lawrence & Lawrence, 2015; Rix et al., 2023). There is a delay in breast volume increases following the peaks of estradiol and progesterone levels during the menstrual cycle and hence the changes are not instantaneous (Rix et al., 2023).

Combined oral contraceptives, which are estrogen–progestogen preparations, as well as menopausal estrogen–progestogen hormone therapy, may produce temporary breast enlargement and feelings of breast fullness analogous to those that occur during the luteal phase of the menstrual cycle (Milligan, Drife, & Short, 1975; Dennerstein et al., 1980 [Figure]; Malini, Smith, & Goldzieher, 1985; Jemström & Olsson, 1997; Jernström et al., 2005). In one study, breast volume was around 100 mL greater (~30% higher) in women who were currently taking oral contraceptives relative to those who had not taken or had previously taken oral contraceptives (Jemström & Olsson, 1997). In some women, the increase in breast size with oral contraceptives was subjectively reported to be up to a single bra cup size in volume (Jemström & Olsson, 1997). However, in another study by the same group of researchers that had a much larger sample size (n=258 vs. n=65), breast volumes were not significantly different between current hormonal contraceptive users and non-users (Jernström et al., 2005). Additionally, another study found no significant differences in breast volume in women between different estrogen–progestogen oral contraceptives that had 6.25-fold variation in dose of the same progestin (0.4 to 2.5 mg/day norethisterone) as well as non-users (Malini, Smith, & Goldzieher, 1985). However, this study was underpowered due to small sample sizes (n=5 to n=15 per group) (Malini, Smith, & Goldzieher, 1985).

Engman et al. (2008) conducted an RCT of treatment with mifepristone, a selective progesterone receptor modulator (SPRM) with predominantly antiprogestogenic effects, versus placebo for 3 months in normally cycling premenopausal cisgender women, and evaluated the effects of this progesterone receptor blockade on the breasts. They found that mifepristone significantly reduced Ki-67 index, a measure of cellular proliferation in the breasts, and reduced subjectively rated symptom scores on the Breast Symptom Index (BSI). More specifically, breast soreness, breast swelling, sense of increased breast volume, and the total breast symptoms score were all significantly reduced on the BSI. However, breast volume was not objectively measured in this study. A major limitation of this study is that mifepristone inhibits ovulation and modifies levels of estradiol and other hormones (Spitz et al., 1989; Spitz et al., 1994; Engman et al., 2008, Spitz, 2010). As such, it is unclear whether the effects observed by Engman and colleagues were specifically due to progesterone receptor antagonism in the breasts or due to disruption of the hypothalamic–pituitary–gonadal (HPG) axis, for instance lowered estradiol levels.

An interesting case report of an adult woman with CAIS documented a significant increase in breast volume with combined estrogen–progestogen therapy relative to estrogen monotherapy (Dijkman et al., 2023b). The woman was started on cyclic oral estradiol 2 mg/day and dydrogesterone 10 mg/day and subjectively experienced breast pain and fluctuations in breast volume of about one cup size while on this regimen. Subsequently, she was switched to oral estradiol valerate 3 mg/day monotherapy and the fluctuations in breast volume ceased. However, her overall breast volume was reduced as well, and the woman decided to resume combined estradiol and dydrogesterone therapy. Her clinicians proceeded to measure her breast volume using 3D body scanning. Her left breast was 758 mL and right breast was 673 mL with estrogen monotherapy, and her breasts increased to respective volumes of 875 mL and 784 mL during combined estrogen–progestogen therapy, giving net volume increases of 117 mL (+16%) and 111 mL (+17%). These differences in volume corresponded to an almost one bra cup difference in size. The researchers noted that estradiol and progesterone are associated with cyclical breast changes, and hypothesized that the changes in their patient were due to increased fluid retention in the breasts. Taken together, the case report demonstrates that progestogens can cause rapid and considerable reversible breast enlargement in some women analogous to that during the normal menstrual cycle.

Progesterone and Mammary Development in Animals

Progesterone and Pubertal Mammary Development in Animals

Knockout of the progesterone receptor (PR) in female mice results in complete infertility and severely compromised ovarian and uterine functions (Lydon et al., 1995; Ismail et al., 2003). On the other hand, pubertal mammary development in progesterone-receptor knockout mice is normal and morphologically indistinguishable from that of regular mice (Soyal et al., 2002; Ismail et al., 2003; Fernandez-Valdivia et al., 2005). This is in contrast to the case of estrogen receptor alpha (ERα) knockout mice, in which pubertal mammary development is abolished (Ismail et al., 2003; Fernandez-Valdivia et al., 2005; Wiki; Wiki). However, subsequent studies revealed that mammary ductal development during puberty, while eventually normal, is delayed in female mice that have loss of progesterone production, loss of the progesterone receptor, or progesterone receptor antagonism with mifepristone (Shi, Lydon, & Zhang, 2004). In other words, progesterone stimulates and accelerates ductal development during puberty, and hence appears to have a significant physiological role in early mammary development during puberty. The stimulation of ductal development by progesterone appears to be mediated by induction of the expression of amphiregulin in mammary ducts and terminal end buds (Kariagina et al., 2010; Aupperlee et al., 2013). This growth factor is an agonist of the epidermal growth factor receptor (EGFR), and is also notably the major growth factor that estrogen induces the expression of to mediate mammary gland development during puberty (Ciarloni, Mallepell, & Brisken, 2007; LaMarca & Rosen, 2007; McBryan et al., 2008). In any case, as mammary ductal development during puberty without progesterone is delayed, but eventually normal, it has been concluded that progesterone is dispensable for pubertal mammary gland development in mice (Soyal et al., 2002; Ismail et al., 2003; Fernandez-Valdivia et al., 2005).

Although progesterone does not seem to be essential in normal pubertal mammary development in mice, studies have interestingly found that it is able to substitute for estrogen in mediating pubertal ductal mammary development in this species. Ruan, Monaco, & Kleinberg (2005) studied the effects of various combinations of exogenous estradiol, progesterone, and IGF-1 on mammary development in oophorectomized female IGF-1-knockout mice. In terms of stimulation of ductal development to occupy the mammary gland fat pad, the combination of progesterone and IGF-1 produced 92% occupation, estradiol and IGF-1 resulted in 92% occupation, estradiol, progesterone, and IGF-1 achieved 96% occupation, and IGF-1 alone resulted in only 28% occupation (Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008). In terms of gross anatomical appearance, the ductal tree with progesterone and IGF-1 was said to resemble that of a normal fully developed pubertal mammary gland (Ruan, Monaco, & Kleinberg, 2005). However, differences in mammary development between the combination of estradiol and IGF-1 and the combination of progesterone and IGF-1 were apparent, with estradiol and IGF-1 having greater effect on terminal end bud formation, ductal decorations, and slight alveolar maturation, and progesterone and IGF-1 having more effect on ductal formation, extension, and branching (Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008). The effects of progesterone on mammary development were reversed by the progesterone receptor antagonist mifepristone (Ruan, Monaco, & Kleinberg, 2005). Only the combination of estradiol, progesterone, and IGF-1 produced mammary development that resembled that during mid-pregnancy, with full maturation of secretory alveolar structures (Ruan, Monaco, & Kleinberg, 2005; Kleinberg & Ruan, 2008).

Aside from the preceding studies, a number of other studies have also found increased ductal branching of mammary glands during puberty with exogenous progesterone administration in mice (Atwood et al., 2000; Hovey et al., 2001; Satoh et al., 2007; Aupperlee et al., 2013).

A limitation of studies that have used exogenous progesterone to stimulate pubertal ductal mammary development in mice is that the doses of progesterone employed, in conjunction with other hormones like estradiol, have been sufficient to mediate mammary growth to a level typical of pregnancy, with robust maturation of mammary lobuloalveolar structures (e.g., Škarda, Fremrová, & Bezecný, 1989; Ruan, Monaco, & Kleinberg, 2005). Pregnancy is a time when hormone levels are much higher than usual. Hence, the progesterone exposure in these studies may have been supraphysiological relative to normal puberty, and may have produced effects on mammary growth that would not otherwise occur during this time. Accordingly, Škarda, Fremrová, & Bezecný (1989) found that whereas untreated normal female mice naturally grew to a mammary gland area of 26.4 mm2 and normal female mice treated with exogenous estradiol grew to a mammary gland area of 25.3 mm2, normal female mice treated with exogenous estradiol and progesterone grew to a mammary gland area of 43.5 mm2 and with exogenous progesterone alone to a mammary gland area of 64.6 mm2. The untreated control mice did not show alveolar buds, whereas the progesterone-treated groups did have alveolar maturation, indicating supraphysiological and pregnancy-like development compared to non-pregnant mice (Škarda, Fremrová, & Bezecný, 1989). In any case, one study employed low doses of progesterone (0.1 mg/day), one-tenth of that used in most other studies (1 mg/day), and found that progesterone still stimulated significant ductal development in mice at these doses (Aupperlee et al., 2013; Berryhill, Trott, & Hovey, 2016). Hence, progesterone is still able to stimulate some level of ductal growth in mice even at lower levels.

Although progestogens by themselves can apparently stimulate normal pubertal mammary development in lieu of estrogen exposure in mice, it is not clear that they do so similarly in humans. It is well-known that progestogens alone, without concomitant estrogenic activity, do not generally produce breast development in humans. As an example, progestogens, for instance MPA and CPA, have been used as puberty blockers in boys and girls at very high doses, and do not produce breast development in this context, instead causing arrest and regression of breast development via gonadal suppression (Lyon, De Bruyn, & Grant, 1985; Fuqua & Eugster, 2022). Cases of gynecomastia in boys have occurred with CPA, but only in a minority and with this easily attributable to other causes than progestogenic activity, for instance the antiandrogenic activity of CPA and disruption of the HPG axis (Kauli et al., 1984; Laron & Kauli, 2000). Similarly, progestogens like MPA and CPA have been used at very high doses in men to treat prostate conditions and sexual disorders, and likewise do not usually produce gynecomastia under these circumstances. Rates of gynecomastia with CPA used in the treatment of prostate cancer are low and are not noticeably different from the rates with surgical or medical castration (~10%) (Fourcade & McLeod, 2004; Di Lorenzo et al., 2005). This is in major contrast to the high rates of gynecomastia with estrogens and nonsteroidal antiandrogens (up to 70–80%) (Fourcade & McLeod, 2004; Di Lorenzo et al., 2005; Deepinder & Braunstein, 2012). Species differences may be present such that progestogens can produce robust pubertal mammary development in mice but do not do so in humans.

Progesterone and Gestational Mammary Development in Animals

As in humans, pregnancy results in increased levels of estrogen, progesterone, prolactin, and many other hormones in various animal species like rodents and non-human primates (Hasan, 1974; Cowie, Forsyth, & Hart, 1980; Pasqualini & Kincl, 1985; Günzel et al., 1987; Seibert & Günzel, 1994). Along with this, there are dramatic changes in the mammary glands (Cowie, Forsyth, & Hart, 1980; Richert et al., 2000; Cline & Wood, 2008; McNally & Stein, 2017). This includes extensive lobuloalveolar maturation of the mammary glands in preparation of lactation and nursing (Cowie, Forsyth, & Hart, 1980; Richert et al., 2000; Cline & Wood, 2008; McNally & Stein, 2017). Permanently enlarged breasts, mainly due to accumulation of abundant adipose tissue during puberty, is unique to humans, and in animal species, although there is significant growth with puberty (e.g., Geschickter, 1945 [Figure]), the exterior mammae enlarge considerably only with pregnancy (Pawłowski & Żelaźniewicz, 2021). In the case of macaques, there is a roughly 10- to 20-fold increase in the glandular tissue during pregnancy (Cline & Wood, 2008).

Administration of exogenous estradiol and progesterone in specific amounts to virgin adult females of various animal species, including rodents, results in mammary development that is very similar to that which occurs normally during pregnancy (Nelson, 1936; Turner, 1939; Folley, 1940; Folley, 1947; Folley & Malpress, 1948; Folley, 1950; Folley, 1952; Folley, 1956; Lyons, 1958; Lyons, Li, & Johnson, 1958; Cowie & Folley, 1961; Jacbosohn, 1961; Cole & Hopkins, 1962; Lloyd & Leathem, 1964; Meites, 1966; Bässler, 1970; Ceriani, 1974; Vorherr, 1974b; Cowie, Forsyth, & Hart, 1980; Tucker, 2000; Kleinberg, 2006; Kleinberg & Ruan, 2008; Kleinberg et al., 2009; Kleinberg & Barcellos-Hoff, 2011). High levels of prolactin also occur in this context, as estrogen and progesterone induce production and secretion of prolactin from the pituitary gland (Ceriani, 1974; Bethea, Kohama, & Pecins-Thompson, 1997; Camilletti et al., 2019). Although estradiol and progesterone alone seem to be adequate for producing full pregnancy-type mammary development in many species, the combination of estradiol, progesterone, and placental lactogen in rhesus monkeys produced considerably less lactational activity than occurs during normal pregnancy in this species (Beck, 1972; Cowie, Forsyth, & Hart, 1980). In relation to this, placental lactogen and/or additional hormonal factors may also be necessary for complete pregnancy-like mammary gland maturation in primates (Beck, 1972; Cowie, Forsyth, & Hart, 1980).

As with humans, following cessation of lactation and nursing, the mammary glands are well-known to undergo post-lactational involution and to return to a pre-pregnancy-like state in animals, including in rodents and monkeys (Richert et al., 2000; Cline & Wood, 2006; Cline & Wood, 2008; Fridriksdottir, Petersen, & Rnnov-Jessen, 2011; McNally & Stein, 2017).

Breast Changes with Therapeutic Pseudopregnancy

Therapeutic or pharmacological pseudopregnancy is a type of hormone therapy that attempts to replicate the hormonal mileu of pregnancy for certain medical indications in cisgender females by administering exogenous hormones. In practice, this has involved the administration of very high doses of estrogens and progestogens, with most other pregnancy hormones not included. Therapeutic pseudopregnancy was first developed in the 1950s and is largely no longer used in medicine today (Kaiser, 1993).

The effects of therapeutic pseudopregnancy on the breasts are of interest due to the breast changes that occur during pregnancy, for instance lobuloalveolar development and substantial reversible breast enlargement. In the 1980s, Lauritzen and colleagues conducted a study of therapeutic pseudopregnancy for treatment of breast hypoplasia (small/underdeveloped breasts) in cisgender women (Lauritzen, 1980; Lauritzen, 1982; Lauritzen, 1989; Göretzlehner & Lauritzen, 1992). They employed the estrogen estradiol valerate 40 mg/week and the progestogen hydroxyprogesterone caproate (OHPC) 250 to 500 mg/week both by intramuscular injection for 4 to 5 months. The estradiol valerate dosage employed was very high, with other studies by the same authors reporting that this dosage of estradiol valerate resulted in first-trimester pregnancy levels of estradiol in women (~3,000 pg/mL [~11,000 pmol/L]) (Ulrich, Pfeifer, & Lauritzen, 1994; Ulrich et al., 1995). These estradiol levels are roughly 30 times the normal concentrations outside of pregnancy (Aly, 2018b). Similarly, the OHPC doses were very high, with 250 to 500 mg per month being similar in strength to luteal-phase progestogenic exposure (Wiki). Hence, as the same OHPC doses were used weekly in the study, the doses were roughly around 4.5 times luteal-phase exposure and thus were analogously similar to first- or second-trimester progesterone levels in terms of strength (Aly, 2020d). The authors noted that they had initially tried lower hormone doses, similar to those originally used in the 1950s, but did not achieve significant breast growth with these doses, and so increased the dosage. Breast changes were measured in the study with a tape measure (applied horizontally and vertically to the breast area), photographs, breast imaging using mammography and sonography, and, later in the study, plasticine impressions/molds with determination of the filling volume.

Lauritzen and colleagues reported the study findings in four different publications with different follow-up times and growing sample sizes. In the final follow-up, a total of 221 women had been treated. In the second follow-up, when 78 women had been treated, it was noted that 29 of the cases (37%) were less than 18 years old. However, in the final follow-up of 221 women, the age range was listed as 18 to 42 years. The researchers found that breast volume increased by 10 to 30% above baseline in 65% of the women. This was also accompanied by breast tenderness in almost all of the women, though the breast tenderness progressively declined during the treatment period. Other breast-related side effects like pigmentation and stretch marks were rarely observed. Prolactin levels slightly increased to 14 to 28 pg/mL by the end of treatment. Breast imaging showed an increase in the density of breast glandular tissue. The researchers claimed that the increase in breast size in their study was due to increased adipose tissue, water retention, and moderate hypertrophy of the glandular tissue.

Following treatment discontinuation, the increases in breast volume gradually and partially regressed in 40% of the women, to an increase of 10 to 20% above baseline. However, the authors claimed that the regression in breast volume could be reduced with adequate-dose combined estrogen–progestogen birth control pills or with topical estrogen and progestogen therapy applied to the breasts. In addition, they noted that therapeutic pseudopregnancy could be repeated to increase breast volume again. This was performed in a subset of the women, with treatment repeated 1 to 2 times after 6 months. In the second follow-up, which had 78 women, it was noted that 12 women (15%) had undergone multiple treatments. Aside from Lauritzen and colleagues, many other researchers have also reported substantial or full regression in breast size following estrogen and/or progestogen therapy to increase breast size in cisgender women (e.g., Cernea, 1944; Müller, 1953; Anderson, 1962; Bruck & Müller, 1967; Keller, 1984; Kaiser & Leidenberger, 1991; Keller, 1995; Hartmann et al., 1998).

The findings of Lauritzen and colleagues were reported very informally, in the form of non-peer-reviewed book chapters, conference papers, and medical magazines, and were never published in a peer-reviewed journal article. In relation to this, the methodology and results of the study were only briefly and imprecisely described. There are also additional concerns related to study design, such as lack of controls, randomization, and the quality of the breast measurement methods. As a result of the preceding issues, it is difficult to fully interpret the results of the study and to have complete confidence in its findings. In any case, Lauritzen and colleages’ results suggest that treatment with high-dose combined estrogen–progestogen therapy, achieving earlier-pregnancy estrogenic and progestogenic exposure, may be able to produce a significant temporary increase in breast size and a smaller long-term increase. The findings of a permanent increase in breast size conflict with those of other researchers who have reported complete regression in breast changes following treatment discontinuation. Moreover, the results are contradicted by findings in pregnant women, who, as described previously, show complete reversion to pre-pregnancy breast size or to even slightly smaller breasts following cessation of lactation.

It is difficult to evaluate the relative roles of the estrogen and the progestogen in the findings of Lauritzen and colleagues, as there were no comparison groups employing estrogen or progestogen therapy alone in the study. Both estrogens and progestogens have been implicated in causing breast enlargement and plausibly could have contributed to the breast changes. As such, it is unclear to what extent the breast changes were specifically due to progestogenic exposure rather than to estrogenic exposure.

The breast size increases observed by Lauritzen and colleagues were seemingly more modest relative to those that occur normally during pregnancy. They also lacked certain characteristics of pregnancy-related breast changes, like nipple and areolar pigmentation. The reasons for this are not fully clear. The subject populations between these studies were different, for instance in terms of factors like initial breast size and age, which may be contributing reasons. Another possible contributing factor is that only estrogen and progestogen levels increased in the study, whereas levels of other pregnancy hormones, besides the slight increase in prolactin levels, did not increase. These other pregnancy hormones, for instance hPL and IGF-1, may also be involved in breast development during pregnancy. Finally, the treatment duration was only 4 to 5 months, and the estrogen and progestogen exposure was only similar to that during early-to-mid pregnancy, whereas normal pregnancy lasts 9 months and involves continued dramatic increases in estrogen and progesterone levels through to childbirth.

It should be noted that, owing to the highly supraphysiological estrogen and progestogen levels required, which can cause serious health complications like blood clots and cardiovascular problems (Aly, 2020e), as well as the small to negligible lasting increase in breast volume, therapeutic pseudopregnancy is inadvisable for transfeminine people and should not be pursued or employed. Nonetheless, the historical findings of therapeutic pseudopregnancy for increasing breast size in cisgender females are of significant theoretical interest in exploring the roles of estrogens and progestogens in breast growth.

Early Progestogen Exposure and the Possibility of Suboptimal Breast Development

While progestogens are typically sought after by transfeminine people for their potential in improving breast development, there have also been various suggestions in the literature that early or premature exposure to progestogens may result in suboptimal breast development and that progestogens may suppress or reduce estrogen-mediated breast development. These suggestions include progestogens having known antiestrogenic effects in the breasts, animal studies finding stunted mammary development with high doses of progestogens, clinical publications cautioning against premature introduction of progestogens in female puberty induction due to concerns about possibly stunted breast growth, clinical use of progestogens to treat macromastia in cisgender females, poor breast development with estrogen therapy in cisgender girls with a disorder of sexual development that results in high progesterone exposure, and breast development with estrogen and CPA (a very strong progestogen) typically being poor in transfeminine people. As with the question of whether progestogens can enhance breast development, it is currently unknown whether progestogens could worsen breast development. It is also unknown what dosage level and timing of introduction would be required for such an effect. In any case, for informational purposes, the preceding topics will each be discussed in the subsequent sections.

Antiestrogenic Effects of Progestogens in the Breasts

Progestogens are well-known to have potent functional antiestrogenic effects in tissues such as the uterus, vagina, and cervix (Wiki). The antiestrogenic effects of progestogens in the uterus are in fact the reason that they are used in menopausal hormone therapy—to prevent the risks of endometrial hyperplasia and endometrial cancer that unopposed estrogen therapy otherwise produces (Wiki). Progestogens also appear to have antiestrogenic effects in the breasts (Mauvais-Jarvis, Kuttenn, & Gompel, 1986a; Mauvais-Jarvis, Kuttenn, & Gompel, 1986b; Mauvais-Jarvis, Kuttenn, & Gompel, 1987; Mauvais-Jarvis et al., 1987; Kuttenn et al., 1994; Wren & Eden, 1996; Plu-Bureau, Touraine, & Mauvais-Jarvis, 1999; Wiki). This may include by inhibiting estrogen synthesis and enhancing estrogen inactivation in the breasts (Pasqualini, 2007; Pasqualini, 2009) and by reducing expression of the estrogen receptors in the breasts (Mauvais-Jarvis, Kuttenn, & Gompel, 1986b; Malet et al., 1991; Kuttenn et al., 1994; Wren & Eden, 1996; Graham & Clarke, 1997; Plu-Bureau, Touraine, & Mauvais-Jarvis, 1999). Clinical studies have found that direct application of topical progesterone to the breasts suppresses estradiol-mediated breast cell proliferation, although this may be due to the delivery of supraphysiological levels of progesterone in the breasts (Barrat et al., 1990; Chang et al., 1995; Foidart et al., 1996; Spicer, Ursin, & Pike, 1996; Foidart et al., 1998; de Lignières, 2002; Gompel & Plu-Bureau, 2018; Trabert et al., 2020). In accordance with their antiestrogenic effects in the breasts, progestogens are considered to be useful in treating estrogen-dependent benign breast disorders such as breast pain, nodularity, and fibrocystic breast disease (Mauvais-Jarvis, Sitruk-Ware, & Kuttenn, 1981; Winkler et al., 2001; Schindler, 2011; Wiki; Wiki; Wiki). Progestogens have also been reported to antagonize nipple and areolar hyperpigmentation induced by high-dose estrogen therapy (Crowley & Macdonald, 1965). In contrast to the preceding findings however, the addition of a progestogen to an estrogen in menopausal hormone therapy has been shown to significantly increase the risk of breast cancer (Aly, 2020a; Wiki). In any case, the antiestrogenic effects of progestogens in the breasts provide a plausible potential mechanism by which they might limit estrogen-mediated breast development. However, an alternative possible mechanism is that such actions may be related to simultaneous induction of ductal development and lobuloalveolar maturation, the latter of which is notably not normal for puberty (Randolph, 2018).

Stunted Mammary Growth with Progestogens in Animal Studies

Animal studies using progestogens including bioidentical progesterone and chlormadinone acetate (CMA), a progestin closely related to CPA, have found that high doses of these progestogens substantially stunt mammary gland development in rabbits, whereas lower doses do not do so (Lyons & McGinty, 1941; Beyer, Cruz, & Martinez-Manautou, 1970). See here for relevant literature excerpts as well as figures from these studies. Lyons & McGinty (1941) [Figure] found that estrogen alone induced ductal mammary development and estrogen plus progesterone 0.25 to 1 mg/day produced ductal development and slight to “fair” lobuloalveolar development. Conversely, estrogen plus progesterone 4 to 8 mg/day, which were 4- to 8-fold higher doses of progesterone than the most optimal dose, produced stunted mammary development with inhibited ductal development, only slight lobuloalveolar development, and, at the highest dosage, resulted in a much smaller mammary gland in terms of size than in the ≤1 mg/day groups. They concluded that high doses of progesterone are inhibitory and result in relatively poor mammary development. In the paper, doses of progesterone in international units (IU) were reported, but a citing review, Pfeiffer (1943), indicated that 1 IU progesterone is equal to 1 mg progesterone. As such, the milligram doses are listed above instead. Beyer, Cruz, & Martinez-Manautou (1970) [Figure] found that estrogen alone produced good ductal development without lobuloalveolar growth (mean mammary area = 376 mm2) and both estrogen plus CMA 0.5 mg/day and estrogen plus progesterone 2.5 mg/day produced optimal ductal and lobuloalveolar development (mean mammary area = 765 mm2 and mean mammary area = 688 mm2, respectively). Conversely, estrogen plus CMA 2.5 mg/day, a 5-fold higher dose of CMA than the optimal dose, resulted in dramatically reduced ductal development and mammary gland size albeit with significant lobuloalveolar growth (mean mammary area = 284 mm2). The authors concluded that moderate doses of progestogens stimulate mammary gland growth whereas large doses inhibit mammary gland development.

While these animal studies are suggestive that high doses of progestogens may be able to stunt breast development in humans, this is far from a certainty. There are species differences in hormone-mediated mammary development such that findings in one species, such as rabbits, may not translate to another species, like humans, or sometimes even to closely related species, like rats or guinea pigs (Bässler, 1970). As far as the present author is aware, stunted mammary development with high doses of progestogens has not been studied or reported in other animal species, for instance other rodent species or monkeys. It is also unclear that the doses employed in these animal studies are necessarily relevant to progestogen therapy in humans. This is because pregnancy levels of progesterone, which are much higher than luteal-phase progesterone levels, are necessary for substantial mammary lobuloalveolar development, and the doses of progestogens used in these studies were above that magnitude of progestogenic exposure. Hence, the doses may have corresponded to what in humans would be extremely high doses. However, such doses could still be relevant in the case of CPA used as an antiandrogen in humans, as CPA is used in this context at very high doses (see section below). The present author is unaware of any animal studies finding that physiological non-pregnancy levels of progesterone have any stunting or other adverse influence on mammary development, suggesting that only high doses of progestogens may have such effects. Finally, it seems notable that the estrogen and progestogen were initiated simultaneously in these animal studies and yet produced optimal pregnancy-like mammary development at the right doses. This suggests that early or immediate progestogen exposure might not be unfavorable in terms of breast development in humans. However, once again species differences may be present and confirmatory clinical studies are needed in humans.

Clinical Publications Cautioning Against Premature Introduction of Progestogens Due to Possibly Stunted Breast Development

A large number of clinical publications largely in the pediatric endocrinology literature have warned that premature exposure to progestogens during for instance puberty induction may result in suboptimal breast development in cisgender girls and/or transfeminine people (Zacharin, 2000; Bondy et al., 2007; Colvin, Devineni, & Ashraf, 2014; Wierckx, Gooren, & T’Sjoen, 2014; Kaiser & Ho, 2015; Bauman, Novello, & Kreitzer, 2016; Gawlik et al., 2016; Randolph, 2018; Donaldson et al., 2019; Heath & Wynne, 2019a; Heath & Wynne, 2019b; Iwamoto et al., 2019; Crowley & Pitteloud, 2020; Naseem, Lokman, & Fitzgerald, 2021; Federici et al., 2022; Lucien et al., 2022; Rothman & Iwamoto, 2022). The full relevant excerpts from these sources can be found here. In relation to these claims, and in order to mimic normal female puberty, a progestogen is not typically added to estrogen therapy during puberty induction in cisgender girls with delayed puberty until after about 2 to 3 years of treatment, by which point breast growth is generally considered complete. Additionally, progestogens are generally never added as part of puberty induction in transfeminine adolescents. Despite the preceding widespread literature statements and accepted clinical practices in the field of puberty induction however, it is important to note that the claims that premature introduction of progestogens might stunt breast development in this context are currently not based on any actual reliable clinical evidence and hence remain unsubstantiated. It is not even clear that these statements are based on anecdotal clinical experience as opposed to simple conjecture. The absence of data in this area may finally change in the future as more clinical studies of progestogens in puberty induction in cisgender girls are conducted (e.g., Rodari et al., 2023).

Rodari and colleagues studied optimization of puberty induction with estrogen therapy followed by eventual introduction of progestogen therapy in 49 cisgender girls with hypogonadism (e.g., Rodari et al., 2022; Rodari, 2022; Rodari et al., 2023). The researchers employed incrementally titrated low-dose transdermal estradiol to mimic the low and gradually increasing estradiol levels during normal puberty and added a progestogen only once menstrual bleeding began. The total duration of treatment was mean 2.65 ± 1 years, the time of first menstrual bleeding occurrence was 2.3 ± 1 years, and the time of progestogen introduction was median 2.22 years (IQR 1.56–2.87 years). Of the girls, 90% reached Tanner breast stage 4, but only 41% reached Tanner breast stage 5. Reaching the final Tanner breast stage was significantly associated with the number of estradiol dose increases (i.e., gradual estradiol dose titration) and the estradiol dose at progestogen introduction. The researchers interpreted the latter finding as progestogen exposure potentially hampering breast development. They questioned introducing progestogen therapy in the presence of incompletely developed breasts and suggested that instead of adding a progestogen upon onset of menstrual bleeding, clinicians should consider slightly reducing the estradiol dosage to delay progestogen introduction until the breasts complete maturation. While interesting, it must be noted that the findings of Rodari and colleagues are merely correlational, are open to multiple interpretations, and do not causally show that progestogens impair breast maturation.

Progestogens in the Treatment of Breast Hypertrophy

Low progesterone levels have been suggested as a possible contributing factor in the development of pubertal macromastia (breast hypertrophy) (Sun et al., 2018). A number of case reports and series of progestogens in the treatment of pubertal macromastia have been published (Sperling & Gold, 1973; Boyce, Hoffman, & Mathes, 1984; Ryan & Pernoll, 1985; Aritaki et al., 1992; Gliosci & Presutti, 1993; Sridhar & Jaya Sinha, 1995; Baker et al., 2001; Dancey et al., 2008; Bland, Howard, Romrell, 2009; Hoppe et al., 2011; Sun et al., 2018). Progestogens such as dydrogesterone, MPA, and CPA were used for this purpose in an attempt to stop or slow the growth of the breasts under the assumption that they are functionally antiestrogenic in breast tissue. Clinical success in these limited cases was mixed. Due to the self-resolving nature of pubertal macromastia (i.e., breast development stops on its own eventually) and other methodological limitations, such as very small numbers of individuals and lack of untreated control groups, it is difficult to draw any reliable conclusions about effectiveness from these reports.

More recently, a couple of studies, both by the same group of researchers, assessed the impact of different types of hormonal contraception on macromastia in adolescent cisgender females with macromastia (Nuzzi et al., 2021; Nuzzi et al., 2022). They found that use of progestin-only contraceptives were associated with significantly more breast tissue removed upon surgical breast reduction (959.9 g/m2 vs. 735.9 g/m2 [+30%]; p = 0.04) and worse clinical symptoms (e.g., breast pain—odds ratio, 4.94, p = 0.005) relative to non-users of hormonal contraception (Nuzzi et al., 2021). Conversely, use of combined oral contraceptives, which are estrogen–progestogen preparations, were associated with significantly less breast tissue removed with breast reduction (639.5 g/m2 vs. 735.9 g/m2 [−13%]; p = 0.003), though not with any differences in clinical symptoms, relative to those naive to hormonal contraception (Nuzzi et al., 2022). It should be noted that progestin-only contraceptives suppress the HPG axis and result in low estradiol levels, whereas combined oral contraceptives suppress the HPG axis and lower estradiol production but simultaneously supplement estrogen signaling by delivering exogenous estrogen. This difference may somehow be responsible for the opposite influence of estrogen–progestogen therapy versus progestogen-alone therapy on macromastia severity. While the findings of Nuzzi and colleagues are interesting, it is noteworthy that the methodology and findings of their research were criticized on various grounds in a letter to the editor concerning one of the articles (Karp, 2022).

Santen et al. (2024), in a case series of cisgender girls with juvenile gigantomastia, noted that breast growth continues for only a number of years following onset and hence there must be some form of stop signal that is activated and that prevents further breast growth. They speculated that this signal may be related to apoptosis (programmed cell death). Santen and colleagues noted that in adult cisgender women, proliferation of breast cells is increased during the follicular phase of the menstrual cycle, whereas apoptosis in breast cells is increased during the luteal phase of the cycle. They hypothesized that the apoptosis during the luteal phase may block further breast development. Since progesterone is produced during the luteal phase and may mediate said apoptosis, this would substantiate the use of progestogens in the treatment of breast hypertrophy. However, the researchers noted that no data exist on apoptosis in the breasts of girls with juvenile gigantomastia. Moreover, an important point against the authors’ hypothesis is that breast growth gradually ceases in people without luteal phases or progestogenic exposure, for instance CAIS women, transfeminine people, and other examples.

Poor Breast Development in 17α-Hydroxylase/17,20-Lyase Deficiency

Poor breast development with exogenous estrogen therapy has been reported in cisgender girls with 17α-hydroxylase/17,20-lyase deficiency, and prior exposure to high progesterone levels consequent to the condition has been hypothesized to be responsible for this (Turan et al., 2009; Athanasoulia et al., 2013; Deeb et al., 2015; Çamtosun et al., 2017; Fernández-Cancio et al., 2017; Kardelen et al., 2018). However, this is only speculation, and at this time, there is no causal evidence or other substantiation that progesterone specifically is responsible for the observations of poor breast growth.

Non-Comparative Clinical Studies of Breast Development with Estrogen and Cyproterone Acetate in Transfeminine People

The possibility of suboptimal breast development with premature exposure to progestogens is of particular relevance in the case of CPA used as an antiandrogen in transfeminine people. This is because CPA is a potent progestogen in addition to antiandrogen, starts to be taken at the initiation of hormone therapy, and happens to be used in transfeminine people at doses that result in very strong to profound progestogenic exposure (Aly, 2019). In terms of progestogenic strength, CPA at a dosage of 2 mg/day is comparable to the progesterone exposure during the luteal phase of the menstrual cycle (Aly, 2019; Wiki). For comparison, CPA has been used in transfeminine people at doses ranging from 10 to 100 mg/day (Aly, 2019). This would mean that CPA provides roughly 6.25 times the progestogenic impact of luteal-phase progesterone exposure at a dosage of 12.5 mg/day, 12.5 times the impact at 25 mg/day, 25 times the impact at 50 mg/day, and 50 times the impact at 100 mg/day. Moreover, this does not consider the fact that progesterone is only produced during the luteal phase, or half of the menstrual cycle, whereas CPA is taken continuously every day of the month. The preceding magnitudes of progestogenic exposure with CPA are on par with and even beyond those during pregnancy. Only recently have lower doses of CPA (e.g., ≤12.5 mg/day) started to be used in transfeminine hormone therapy.

Studies in pubertal and adolescent transfeminine people given GnRH agonists to block puberty plus estrogen therapy have reported good breast development in these individuals as assessed by subjective clinical impression or Tanner staging (de Vries et al., 2010; Hannema et al., 2017). However, quality objective measures of breast development were not employed in these studies. Conversely, non-comparative studies using estrogen plus CPA in adult transfeminine people have commonly reported modest breast development, including incomplete breast development only to Tanner stage 2 to 4, small breast cup sizes, and small breast volumes (Kanhai et al., 1999; Sosa et al., 2003; Sosa et al., 2004; Wierckx et al., 2014; Fisher et al., 2016; Tack et al., 2017; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019; Meyer et al., 2020; de Blok et al., 2021). Additionally, breast sizes smaller than those in cisgender women have been reported (Asscheman & Gooren, 1992; Kanhai et al., 1999). In one study, breast development with estrogen plus CPA was also poor in late-adolescent transfeminine people (Tack et al., 2017). However, in this particular study, the estrogen dose used was likely too low and resulted in inadequate estradiol levels, as noted by the authors themselves, and this is a potential confounding factor in their findings (Tack et al., 2017). In any case, breast growth with estrogen plus CPA in transfeminine people would seem to consistently be poor. In contrast to the regimen of estrogen and CPA, breast development with other hormone therapy regimens, for instance estrogen with non-progestogenic antiandrogens like spironolactone, bicalutamide, and GnRH modulators, has not been nearly as well-studied in comparison, and hence comparisons of outcomes between regimens is difficult.

In one of the highest quality studies of estrogen and CPA and breast development in adult transfeminine people, breast volume measured with 3D body scanning (Vectra XT) was approximately mean 100 mL (95% CI ~75–125 mL; range up to ~750 mL), equating to less than an A cup size on average, after 3 years of hormone therapy with estrogen and CPA in 69 transfeminine people (de Blok et al., 2021 [Figure]). In this study, breast changes over time had clearly plateaued, suggesting that breast development was either complete or was nearly so (de Blok et al., 2021 [Figure]). Although most of the transfeminine people in this study had less than an A cup breast size (71%), a minority had cup sizes ranging from an A cup (9%), B cup (16%), C cup (3%), to E cup (1%) (de Blok et al., 2021 [Figure]). For comparison, a study of normative data on breast volumes in cisgender women, using a different 3D body scanning device (Artec Eva 3D), found breast volumes of median ~515 mL and mean ~650 mL (IQR ~310–850 mL; range ~50–3,100 mL) in 378 cisgender women (Coltman, Steele, & McGhee, 2017). As such, adult transfeminine people treated with estrogen and CPA would appear to have substantially smaller breasts than cisgender women. However, it must be emphasized that the preceding data come from separate clinical studies and hence are not directly comparative. It is noteworthy in this regard that breast volumes can vary considerably between different studies even using similar measurement methods (e.g., magnetic resonance imaging) (Sindi et al., 2019 [Table]). Hence, there is a need for studies directly comparing breast volumes in transfeminine people to those in cisgender women using the same measurement method in order to comparatively evaluate breast development.

Regardless of the preceding, transfeminine people could simply have poor breast development in general without this necessarily being related to CPA or progestogenic exposure. Indeed, a more recent study in transfeminine people who underwent pubertal suppression in adolescence, presumably with GnRH agonists and then estrogen therapy, found similarly poor breast development as has been reported in adults (Boogers et al., 2022; c.f. de Blok et al., 2021). This study used breast volume via 3D body scanning to measure breast development and found a mean breast volume of 114 mL (IQR 58–203 mL), equating to less than an A cup size, after 4.2 years of hormone therapy (Boogers et al., 2022). It was notably conducted by the same group of researchers who did the earlier higher-quality study in adult transfeminine people, and hence likely used the same 3D scanning method (de Blok et al., 2021).

No directly comparative studies of breast development with CPA versus other antiandrogens in transfeminine people are currently available. Hence, it’s not fully known whether the findings are specific to CPA or also generalize to other antiandrogens that are not also strongly progestogenic. The RCT of estradiol and spironolactone versus estradiol and CPA in transfeminine people by Ada Cheung and colleagues underway in Australia may provide more insight on this issue, as spironolactone is only a weakly or clinically non-progestogenic antiandrogen (Aly, 2018b; Wiki; update: see below).

Additional Considerations for Progestogen Therapy and Breast Development in Transfeminine People

Anecdotes About Progestogens and Breast Development

Many transfeminine people who have taken progestogens as part of hormone therapy have anedotally reported that the progestogens improved their breast development. At the same time, many other transfeminine people have anecdotally reported no benefit of progestogens to breast development. It must be cautioned in general that anecdotal reports are unreliable and represent a very low form of medical evidence. This is because subjective observations and attributions are often erroneous. Perceptions can be faulty and inaccurate, especially with slowly developing physical changes, and true physical changes can be due to coincidence and unrelated confounding factors rather than due to a person’s causal attributions. A couple notable examples of potential confounding factors with regard to progestogens and breast development include: (1) continued breast development from estrogen acting on its own; and (2) temporary breast enlargement due to local fluid retention, increased blood flow, and reversible lobuloalveolar growth caused by progestogens. Such factors have the potential to mislead, and may contribute significantly to anecdotal reports of enhanced breast development with progestogens in transfeminine people. Clinical studies that are well-designed, controlled, and employ reliable objective measures, with long-term follow-up and eventual discontinuation of the progestogen to control for reversible effects, are needed to properly evaluate the effects of progestogens on breast development.

Therapeutic Limitations of Oral Progesterone

Oral progesterone producles very low progesterone levels and has only weak progestogenic effects even at high doses (Aly, 2018a; Wiki). These low progesterone levels are likely to be inadequate in terms of desired physiological progestogenic effects, for instance in the breasts. Oral progesterone also uniquely has potent neurosteroid actions via active metabolites like allopregnanolone, which can result in prominent side effects such as alcohol-like central nervous system inhibition as well as mood swings (Aly, 2018b; Wiki; Wiki). These neurosteroid effects are dose-dependent and are more severe at high doses. Non-oral progesterone forms like rectal or injectable progesterone or progestins, which do not have the preceding problems, can be used instead to avoid such concerns (Aly, 2018a; Aly, 2018b).

Tolerability and Safety Considerations for Progestogens

Progestogens have a variety of tolerability issues and safety risks (Aly, 2018b). Examples of such risks variously include adverse mood changes, breast cancer, blood clots, cardiovascular complications, benign brain tumors including prolactinomas and meningiomas, and off-target actions with undesirable effects (e.g., androgenic or glucocorticoid activity), among others (Aly, 2018b). CPA at high doses also uniquely has a significant risk of serious liver toxicity (Aly, 2018b). The risks of progestogens vary depending on the specific progestogen and dosage, but all progestogens, including even bioidentical progesterone, have significant known risks. The risks of progestogens, along with lack of evidence of beneficial effects in terms of feminization, well-being, and health, in transfeminine people, are why there are concerns about and restrictions on their use in transfeminine people (Aly, 2018b). However, cisgender women naturally have progesterone in their bodies, and the absolute risks of progestogens are low (Aly, 2018b). The risks of progestogens can be minimized by use for a limited duration of time (e.g., a few years), by using the lowest dosages expected to be effective in terms of desired effects, and by selection of progestogens with more favorable pharmacological profiles (Aly, 2018a; Aly, 2018b).

Updates

Update 1: Angus et al. (2023–2024)

It was previously reported in this article that an RCT assessing breast development with estradiol plus spironolactone versus estradiol plus CPA in transfeminine people was being conducted by Ada Cheung and colleagues. This study could provide more insight into breast development with progestogens, as CPA is a very potent progestogen whereas spironolactone is not meaningfully progestogenic. Cheung and colleagues’ study, led by Lachlan Angus, has now been published in the form of the following two conference abstracts, with a journal article also currently in the process of being published:

  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]

The study assessed estradiol plus spironolactone 100 mg/day versus estradiol plus CPA 12.5 mg/day in 55 transfeminine people, with 27 in the spironolactone group and 28 in the CPA group. Hormone therapy duration, at least at this follow-up point in the study, was 6 months. The measures of breast development included breast–chest difference (primary) and estimated breast volume (secondary).

Breast development, measured by breast–chest difference (mean ± SD), was 8.3 ± 2.7 cm with spironolactone and 9.2 ± 3.0 cm with CPA, with the differences between groups not statistically significant (p = 0.27). In addition, breast development, measured by estimated breast volume (mean ± SD), was 158 ± 112 mL with spironolactone and 190 ± 159 mL with CPA, with the differences between groups not statistically significant (p = 0.39). There was variability between individuals in estimated breast volume, with breast volume measurements ranging from 20 to 788 mL. Besides breast growth, the researchers found that CPA also resulted in a greater increase in body fat percentage and gynoid fat compared to spironolactone. Estradiol levels were comparable between antiandrogen groups, whereas total testosterone levels were (mean ± SD) 4.29 ± 5.44 nmol/L (124 ± 157 ng/dL) with spironolactone and 1.48 ± 3.45 nmol/L (43 ± 99 ng/dL) with CPA, a difference that was statistically significant (p = 0.04).

The researchers concluded that there was no difference in breast development with spironolactone versus CPA in their study and that antiandrogen choice should be individualized based on patient and clinician preference as well as consideration of associated side effects. Moreover, they concluded that further research is needed to optimize breast development in transfeminine people.

The measure of breast volume in the study was the BreastIdea Volume Estimator, a freely available web app that employs 2D photography to provide an estimate of breast volume (Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019; Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020). This breast volume measure has been validated in both cisgender women and cisgender men (Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019; Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020). Additionally, Cheung and Angus, along with other colleagues, notably including some of the original developers of the BreastIdea Volume Estimator, validated the BreastIdea Volume Estimator in cisgender men and transfeminine people in the following 2022 conference abstract study:

  • Angus, L., Mikolajczyk, M., Cheung, A., Zajac, J., Antoszewski, B., & Kasielska-Trojan, A. (2022). Estimation of breast volume in transgender women using 2D photography: validation of the BreastIdea Volume Estimator in men and transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 279). [URL] [PDF] [Full Abstract Book]

In studies by the developers of the BreastIdea Volume Estimator, they reported breast volumes measured with the tool in cisgender women. These estimated breast volumes can provide comparison to the breast-volume findings in transfeminine people by Cheung and Angus and colleagues. The developers of the BreastIdea Volume Estimator reported that breast volume (mean ± SD) in cisgender women with normal breasts (n=30) was 283 ± 144 mL and in cisgender women with macromastia or gigantomastia (n=35) was 888 ± 277 mL (Kasielska-Trojan, Zawadzki, & Antoszewski, 2022). In another study, they reported that breast volume (mean ± SD) in cisgender women was 272 ± 150 mL, with a range of 99 to 694 mL (Kasielska-Trojan, Mikołajczyk, & Antoszewski, 2020).

Although the BreastIdea Volume Estimator is an interesting and promising tool for quantifying breast development, it has notable limitations, such as its resolution and accuracy being much less than that with 3D scanners like the Artec Eva and Vectra XT (Mikołajczyk, Kasielska-Trojan, & Antoszewski, 2019). Vectra and Artec 3D scanners have been and are being employed to measure breast development with hormone therapy in other studies in transfeminine people (de Blok et al., 2021; Boogers et al., 2022; Dijkman et al., 2023a; Dijkman et al., 2023b; Lopez et al., 2023). The accuracy limitations of the BreastIdea Volume Estimator may explain why the breast volume findings with it in transfeminine people and cisgender women were different from those seen in other studies that employed more advanced 3D scanning methods. Aside from the breast volume measurement, breast–chest difference also has limitations as a measure of breast development in transfeminine people, for instance failing to identify continued breast growth that can be detected with breast volume measurement (de Blok et al., 2021).

Besides the employed measurement methods for breast development, limitations of Lachlan Angus and colleagues’ RCT of breast development with spironolactone and CPA in transfeminine people include its limited duration of follow-up of only 6 months, the fact that testosterone levels were non-equivalent between the spironolactone and CPA groups, and its limited sample size. The incompletely suppressed testosterone levels with spironolactone are notable as androgens oppose estrogen-mediated breast development and could have reduced breast development in the spironolactone group. The limited sample size of the study was responsible for the numeric difference in breast measurements between antiandrogen groups not being statistically significant. In any case, Angus and colleagues’ findings are suggestive that CPA, which is highly progestogenic, neither enhances nor stunts breast development, at least relative to non-progestogenic spironolactone for up to 6 months of hormone therapy. It seems likely that the RCT will continue to longer follow-up times and durations of hormone therapy in the future.

Update 2: Flamant, Vervalcke, & T’Sjoen (2023) and Yang et al. (2024)

The following two recent studies provide additional information on the topic of breast development with progestogen exposure—specifically with CPA—in transfeminine people:

  • Flamant, T., Vervalcke, J., & T’Sjoen, G. (November 2023). Dose Reduction of Cyproterone Acetate in Trans Women and the Effect on Patient-reported Outcomes: Results from the ENIGI Study. Endocrine Abstracts, 97 [Belgian Endocrine Society 2023], 5–5 (abstract no. 007). [URL] [PDF]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]

In the first study, Flamant, Vervalcke, & T’Sjoen (2023), clinical outcomes in transfeminine people at the University of Ghent, Belgium clinic were compared in 72 people taking CPA at low doses (10–12.5 mg/day) or high doses (25–50 mg/day). Testosterone suppression was equivalent between the two dose groups. Breast development satisfaction, measured with the Body Image Scale, was not significantly different with low-dose CPA versus high-dose CPA following 1 year of hormone therapy (p = 0.078). However, the p-value indicates that there was almost a statistically significant difference between groups, though it was not stated which group was numerically higher in terms of satisfaction. In any case, the researchers stated that breast development satisfaction was “non-inferior” with low-dose CPA compared to high-dose CPA, which seems suggestive that satisfaction may have been higher in the high-dose CPA group. These findings suggest that higher doses of CPA may not stunt breast development relative to doses of CPA that are lower, although still quite high in terms of progestogenic activity.

In the second study, Yang et al. (2024), clinical outcomes in transfeminine people at the Peking University Third Hospital in China with estradiol plus spironolactone (n=43) versus estradiol plus CPA (n=53) were retrospectively compared. Testosterone levels were much higher in the spironolactone group relative to the CPA group (374 ng/dL [13.0 nmol/L] vs. 20 ng/dL [0.7 nmol/L]; p < 0.001) and duration of hormone therapy was shorter in the spironolactone group than in the CPA group (median 12 months vs. 18 months). Breast development satisfaction, measured with a visual analogue scale (VAS), was median 6.0 (IQR 4.0–7.0) with spironolactone and 6.0 (IQR 4.0–7.0) with CPA, and was not statistically different. On the other hand, the CPA group outperformed the spironolactone group in terms of several other VAS-based clinical-outcome measures, including figure feminization, testicular atrophy, decreased penile erections, and in terms of a composite overall satifaction score. These findings suggest, as with the RCT by Lachlan Angus and colleagues, that spironolactone and CPA result in similar breast development in transfeminine people despite differences in testosterone levels and other clinical outcomes.

A major limitation of both Flamant, Vervalcke, & T’Sjoen (2023) and Yang et al. (2024) is the use of subjective self-report measures of breast development as opposed to objective physical measurements.

References

  • Abduljalil, K., Furness, P., Johnson, T. N., Rostami-Hodjegan, A., & Soltani, H. (2012). Anatomical, Physiological and Metabolic Changes with Gestational Age during Normal Pregnancy. Clinical Pharmacokinetics, 51(6), 365–396. [DOI:10.2165/11597440-000000000-00000]
  • Adams, R. D., Kliman, B., Federman, D. D., Ulfelder, H. S., & Holmes, L. B. (1970). Syndromes of Testicular Feminization. Clinical Pediatrics, 9(3), 165–178. [DOI:10.1177/000992287000900312]
  • Alekseev, N. P. (2021). Origin and Development of the Mammary Glands. In Alekseev, N. P. Physiology of Human Female Lactation (pp. 11–66). Cham: Springer. [DOI:10.1007/978-3-030-66364-3_2]
  • Alex, A., Bhandary, E., & McGuire, K. P. (2020). Anatomy and Physiology of the Breast during Pregnancy and Lactation. In Alipour, S., & Omranipour, R. (Eds.). Diseases of the Breast during Pregnancy and Lactation (Advances in Experimental Medicine and Biology, Volume 1252) (pp. 3–7). Cham: Springer. [DOI:10.1007/978-3-030-41596-9]
  • Anderson, W. A. (1962). Experimental stimulation of breast development in the teen-age female. The Journal of the Medical Society of New Jersey, 59, 541–543. [Google Scholar] [PubMed] [PDF]
  • Andler, W., & Zachmann, M. (1979). Spontaneous breast development in an adolescent girl with testicular feminization after castration in early childhood. The Journal of Pediatrics, 94(2), 304–305. [DOI:10.1016/s0022-3476(79)80852-5]
  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
  • Angus, L., Mikolajczyk, M., Cheung, A., Zajac, J., Antoszewski, B., & Kasielska-Trojan, A. (2022). Estimation of breast volume in transgender women using 2D photography: validation of the BreastIdea Volume Estimator in men and transgender women. ESA/SRB/APEG/NZSE ASM 2022, November 13-16, Christchurch, Abstracts and Programme, 127–127 (abstract no. 279). [URL] [PDF] [Full Abstract Book]
  • Apter, D. (1980). Serum steroids and pituitary hormones in female puberty: a partly longitudinal study. Clinical Endocrinology, 12(2), 107–120. [DOI:10.1111/j.1365-2265.1980.tb02125.x]
  • Apter, D., Räisänen, I., Ylöstalo, P., & Vihko, R. (1987). Follicular growth in relation to serum hormonal patterns in adolescent compared with adult menstrual cycles. Fertility and Sterility, 47(1), 82–88. [DOI:10.1016/s0015-0282(16)49940-1]
  • Aritaki, S., Miyazawa, H., Ogihara, M., Ushio, M., & Izumizawa, A. (1992). An Endocrinological Study of Persistent Pubertal Macromastia. The Tohoku Journal of Experimental Medicine, 167(3), 189–196. [DOI:10.1620/tjem.167.189]
  • Arya, S., Barnabas, R., Lila, A. R., Sarathi, V., Memon, S. S., Bhandare, V. V., Thakkar, K., Patil, V., Shah, N. S., Kunwar, A., & Bandgar, T. (2021). Clinical, Hormonal, Genetic, and Molecular Characteristics in Androgen Insensitivity Syndrome in an Asian Indian Cohort from a Single Centre in Western India. Sexual Development, 15(4), 253–261. [DOI:10.1159/000517763]
  • Asscheman, H., & Gooren, L. J. (1992). Hormone Treatment in Transsexuals. In Bocking, W. O., Coleman, E. (Eds). Gender Dysphoria: Interdisciplinary Approaches in Clinical Management (pp. 39–54). Binghamton: Haworth Press. / Journal of Psychology & Human Sexuality, 5(4), 39–54. [Google Scholar] [Google Books] [DOI:10.1300/J056v05n04_03]
  • Athanasoulia, A., Auer, M., Riepe, F., & Stalla, G. (2013). Rare Missense P450c17 (CYP17A1) Mutation in Exon 1 as a Cause of 46,XY Disorder of Sexual Development: Implications of Breast Tissue ‘Unresponsiveness’ despite Adequate Estradiol Substitution. Sexual Development, 7(4), 212–215. [DOI:10.1159/000348301]
  • Atwood, C., Hovey, R., Glover, J., Chepko, G., Ginsburg, E., Robison, W., & Vonderhaar, B. (2000). Progesterone induces side-branching of the ductal epithelium in the mammary glands of peripubertal mice. Journal of Endocrinology, 167(1), 39–52. [DOI:10.1677/joe.0.1670039]
  • Aupperlee, M. D., Leipprandt, J. R., Bennett, J. M., Schwartz, R. C., & Haslam, S. Z. (2013). Amphiregulin mediates progesterone-induced mammary ductal development during puberty. Breast Cancer Research, 15(3), R44. [DOI:10.1186/bcr3431]
  • Bahr, C., Ewald, J., Dragovich, R., & Gothard, M. D. (2024). Effects of progesterone on gender affirmation outcomes as part of feminizing hormone therapy. Journal of the American Pharmacists Association, 64(1), 268–272. [DOI:10.1016/j.japh.2023.08.001]
  • Baird, D., Hytten, F. E., & Thomson, A. M. (1958). Age and Human Reproduction. BJOG, 65(6), 865–876. [DOI:10.1111/j.1471-0528.1958.tb08582.x]
  • Baker, S. B., Burkey, B. A., Thornton, P., & LaRossa, D. (2001). Juvenile Gigantomastia: Presentation of Four Cases and Review of the Literature. Annals of Plastic Surgery, 46(5), 517–526. [DOI:10.1097/00000637-200105000-00011]
  • Bames, H. O. (1948). Reduction of massive breast hypertrophy. Plastic and Reconstructive Surgery, 3(5), 560–569. [DOI:10.1097/00006534-194809000-00006]
  • Barbieri, R. L. (2019). Breast. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 248–255.e3). Philadelphia: Elsevier. [Google Books] [DOI:10.1016/B978-0-323-47912-7.00010-X]
  • Baron, J. (1993). Zespół braku wrazliwości na androgeny. Studium kliniczne i endokrynologiczne 40 osobników [Androgen insensitivity syndrome. Clinical and endocrinologic study of 40 cases]. Endokrynologia Polska, 44(2), 175–186. [Google Scholar] [PubMed]
  • Baron, J. (1994). Klasyczne i niepełne zespoły braku wrazliwości na androgeny [Classical and incomplete androgen insensitivity syndromes]. Ginekologia Polska, 65(7), 377–386. [Google Scholar] [PubMed]
  • Baron, J. (1994). Niepełny lub cześciowy zespół braku wrazliwości na androgeny [Partial androgen insensitivity syndrome]. Ginekologia Polska, 65(6), 319–325. [Google Scholar] [PubMed]
  • Barrat, J., de Lignières, B., Marpeau, L., Larue, L., Fournier, S., Nahoul, K., Linares, G., Giorgi, H., & Contesso, G. (1990). Effet in vivo de l’administration locale de progestérone sur l’activité mitotique des galactophores humains. Résultat d’une étude pilote. [The in vivo effect of the local administration of progesterone on the mitotic activity of human ductal breast tissue. Results of a pilot study.] Journal de Gynecologie, Obstetrique et Biologie de la Reproduction, 19(3), 269–274. [Google Scholar 1] [Google Scholar 2] [PubMed]
  • Barrett, J. (2009). The clinical risks associated with the diagnosis and management of disorders of gender identity. Clinical Risk, 15(4), 131–134. [DOI:10.1258/cr.2008.080069]
  • Bässler, R. (1970). The Morphology of Hormone Induced Structural Changes in the Female Breast. In Altmann, H.-W., et al. (Eds.). Current Topics in Pathology: Ergebnisse der Pathology, Volume 53 (pp. 1–89). Heidelberg: Springer Berlin. [DOI:10.1007/978-3-662-30514-0_1] [PDF]
  • Basson, R., & Prior, J. C. (1998). Hormonal Therapy of Gender Dysphoria: The Male-to-Female Transsexual. In Denny, D. (Ed.). Concepts in Transgender Identity (Garland Gay and Lesbian Studies, Volume 11) (pp. 277–296). New York: Garland Publishing Inc. [Google Scholar] [Google Books] [DOI:10.4324/9780203775134-19] [PDF]
  • Bauman, A., Novello, L., & Kreitzer, P. (2016). Endocrine Disorders and Delayed Puberty. In Appelbaum, H. (Ed.). Abnormal Female Puberty: A Clinical Casebook (pp. 87–107). Cham: Springer. [DOI:10.1007/978-3-319-27225-2_5]
  • Bayer, C. M., Bani, M. R., Schneider, M., Dammer, U., Raabe, E., Haeberle, L., Faschingbauer, F., Schneeberger, S., Renner, S. P., Fischer, D., Schulz-Wendtland, R., Fasching, P. A., Beckmann, M. W., & Jud, S. M. (2014). Assessment of breast volume changes during human pregnancy using a three-dimensional surface assessment technique in the prospective CGATE study. European Journal of Cancer Prevention, 23(3), 151–157. [DOI:10.1097/cej.0b013e3283651ccb]
  • Beck, P. (1972). Lactogenic Activity of Human Chorionic Somatomammotropin in Rhesus Monkeys. Experimental Biology and Medicine, 140(1), 183–187. [DOI:10.3181/00379727-140-36422]
  • Begley, D. J., Firth, J. A., & Hoult, J. R. (1980). The Breast and Lactation. In Begley, D. J., Firth, J. A., & Hoult, J. R. Human Reproduction and Developmental Biology (pp. 204–219). London: Macmillan Education UK. [DOI:10.1007/978-1-349-16260-4_14]
  • Bellwether, C. J. (2020). Why Should a Transfeminine Person Consider Progesterone? Google Docs. [URL]
  • Benjamin, H. (1966). Nonsurgical Management of Transsexualism. In Benjamin, H. The Transsexual Phenomenon (pp. 86–99). New York: Julian Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Benjamin, H. (1967). Transvestism and Transsexualism in the male and female. Journal of Sex Research, 3(2), 107–127. [DOI:10.1080/00224496709550519]
  • Berliere, M., Coche, M., Lacroix, C., Riggi, J., Coyette, M., Coulie, J., Galant, C., Fellah, L., Leconte, I., Maiter, D., Duhoux, F. P., & François, A. (2022). Effects of Hormones on Breast Development and Breast Cancer Risk in Transgender Women. Cancers, 15(1), 245. [DOI:10.3390/cancers15010245]
  • Berryhill, G. E., Trott, J. F., & Hovey, R. C. (2016). Mammary gland development—It’s not just about estrogen. Journal of Dairy Science, 99(1), 875–883. [DOI:10.3168/jds.2015-10105]
  • Bethea, C. L., Kohama, S. G., & Pecins-Thompson, M. (1997). Pituitary and Brain Actions of Estrogen and Progesterone in the Regulation of Primate Prolactin Secretion. In Pavlik, E. J. (Ed.). Estrogens, Progestins, and Their Antagonists: Functions and Mechanisms of Action (pp. 3–46). Boston: Birkhäuser. [DOI:10.1007/978-1-4612-2004-6_1]
  • Bevan, D. J. (2012). Progesterone for Breast Development? / Should Male-to-Female Transsexuals Take Progesterone as part of Hormone Therapy (HT) for Better Breast Development? Biopsychology of TSTG / Transgender Forum. [URL 1] [URL 2]
  • Bevan, D. J. (2019). Grow Your Own : Breast Development Update. Transgender Forum. [URL]
  • Beyer, C., Cruz, M. L., & Martinez-Manautou, J. (1970). Effect of Chlormadinone Acetate on Mammary Development and Lactation in the Rabbit. Endocrinology, 86(5), 1172–1174. [DOI:10.1210/endo-86-5-1172]
  • Biswas, S. K., Banerjee, S., Baker, G. W., Kuo, C., & Chowdhury, I. (2022). The Mammary Gland: Basic Structure and Molecular Signaling during Development. International Journal of Molecular Sciences, 23(7), 3883. [DOI:10.3390/ijms23073883]
  • Bland, K. I., Copeland, E. M., & Klimberg, V. S. (2018). Anatomy of the Breast, Axilla, Chest Wall, and Related Metastatic Sites. In Bland, K. I., Copeland, E. M., Klimberg, V. S., Gradishar, W. J., White, J., & Korourian, S. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 5th Edition (pp. 20–36.e2). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-35955-9.00002-7]
  • Bland, K. I., Harrison Howard, J., & Romrell, L. J. (2009). Congenital and Acquired Disturbances of Breast Development and Growth. In Bland, K. I., & Copeland, E. M. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 4th Edition (pp. 189–207). Philadelphia: Saunders/Elsevier. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Bondy, C. A., & Turner Syndrome Consensus Study Group. (2007). Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. The Journal of Clinical Endocrinology & Metabolism, 92(1), 10–25. [DOI:10.1210/jc.2006-1374]
  • Boogers, L., Infirri, S. S., Bouchareb, A., de Blok, C., Liberton, N., van Trotsenburg, P., Dreijerink, K., den Heijer, M., Wiepjes, C., & Hannema, S. (2022). The effect of timing of puberty suppression on breast development in trans girls; a cross-sectional study. Hormone Research in Paediatrics, 95(Suppl 2) [60th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE), Rome, Italy, September 15–17, 2022], 390–391 (abstract no. P1-379). [Google Scholar] [DOI:10.1159/000525606] [URL] [PDF 1] [PDF 2]
  • Boyce, S. W., Hoffman, P. G., & Mathes, S. J. (1984). Recurrent Macromastia after Subcutaneous Mastectomy. Annals of Plastic Surgery, 13(6), 511–518. [DOI:10.1097/00000637-198412000-00008]
  • Bruck, H. G., & Müller, G. (1967). Zur Hormontherapie der Hypoplastischen Weiblichen Brust. [On Hormonal Therapy of the Hypoplastic Female Breast.] Ästhetische Medizin [Ästhetische Medizin : Kongreß-Organ der Deutschen Gesellschaft für die Ästhetische Medizin und ihre Grenzgebiete], 16(12), 365–366. [ISSN:0400-6755] [Google Scholar] [PubMed] [WorldCat] [PDF] [Translation]
  • Bryant, R., Underwood, A., Robinson, A., Stephenson, T., & Underwood, J. (1998). Determination of breast tissue composition for improved accuracy in estimating radiation doses and risks in mammographic screening. The Breast, 7(2), 95–98. [DOI:10.1016/s0960-9776(98)90064-9]
  • Buhimschi, C. S. (2004). Endocrinology of lactation. Obstetrics and Gynecology Clinics of North America, 31(4), 963–979. [DOI:10.1016/j.ogc.2004.08.002]
  • Camilletti, M. A., Abeledo-Machado, A., Faraoni, E. Y., Thomas, P., & Díaz-Torga, G. (2019). New insights into progesterone actions on prolactin secretion and prolactinoma development. Steroids, 152, 108496. [DOI:10.1016/j.steroids.2019.108496]
  • Çamtosun, E., Şıklar, Z., Ceylaner, S., Kocaay, P., & Berberoğlu, M. (2017). Delayed Diagnosis of a 17-Hydroxylase/17,20-Lyase Deficient Patient Presenting as a 46,XY Female: A Low Normal Potassium Level Can Be an Alerting Diagnostic Sign. Journal of Clinical Research in Pediatric Endocrinology, 9(2), 163–167. [DOI:10.4274/jcrpe.3839]
  • Capraro, V. J., & Dewhurst, C. J. (1975). Breast Disorders in Childhood and Adolescence. Clinical Obstetrics and Gynecology, 18(2), 25–50. [DOI:10.1097/00003081-197506000-00003]
  • Carlson, L. J., & Shaw, N. D. (2019). Development of Ovulatory Menstrual Cycles in Adolescent Girls. Journal of Pediatric and Adolescent Gynecology, 32(3), 249–253. [DOI:10.1016/j.jpag.2019.02.119]
  • Caro, T. M. (1987). Human breasts: Unsupported hypotheses reviewed. Human Evolution, 2(3), 271–282. [DOI:10.1007/bf03016112]
  • Ceriani, R. L. (1974). Hormones and Other Factors Controlling Growth in the Mammary Gland: A Review. Journal of Investigative Dermatology, 63(1), 93–108. [DOI:10.1111/1523-1747.ep12678104]
  • Cernea, R. (1944). Lokale Hormonbehandlung bei Mammaatrophie und Unterentwicklung. [Local Hormone Treatment in Mammary Atrophy and Underdevelopment.] Medizinische Klinik, 40(11/12), 169–170. [Google Scholar] [PDF] [Translation]
  • Chang, K., Lee, T. T., Linares-Cruz, G., Fournier, S., & de Ligniéres, B. (1995). Influences of percutaneous administration of estradiol and progesterone on human breast epithelial cell cycle in vivo. Fertility and Sterility, 63(4), 785–791. [DOI:10.1016/s0015-0282(16)57482-2]
  • Cheikhelard, A., Morel, Y., Thibaud, E., Lortat-Jacob, S., Jaubert, F., Polak, M., & Nihoul-Fekete, C. (2008). Long-Term Followup and Comparison Between Genotype and Phenotype in 29 Cases of Complete Androgen Insensitivity Syndrome. Journal of Urology, 180(4), 1496–1501. [DOI:10.1016/j.juro.2008.06.045]
  • Ciarloni, L., Mallepell, S., & Brisken, C. (2007). Amphiregulin is an essential mediator of estrogen receptor α function in mammary gland development. Proceedings of the National Academy of Sciences, 104(13), 5455–5460. [DOI:10.1073/pnas.0611647104]
  • Clendenen, T. V., Kim, S., Moy, L., Wan, L., Rusinek, H., Stanczyk, F. Z., Pike, M. C., & Zeleniuch-Jacquotte, A. (2013). Magnetic Resonance Imaging (MRI) of hormone-induced breast changes in young premenopausal women. Magnetic Resonance Imaging, 31(1), 1–9. [DOI:10.1016/j.mri.2012.06.022]
  • Cline, J. M., & Wood, C. E. (2006). Hormonal Effects on the Mammary Gland of Postmenopausal Nonhuman Primates. Breast Disease, 24(1), 59–70. [DOI:10.3233/bd-2006-24105]
  • Cline, J. M., & Wood, C. E. (2008). The Mammary Glands of Macaques. Toxicologic Pathology, 36(7 Suppl), 130S–141S. [DOI:10.1177/0192623308327411]
  • Cole, R. D., & Hopkins, T. R. (1962). A Biochemical Test of Artificial Mammogenesis and Lactogenesis As Models of the Natural Processes. Endocrinology, 70(3), 375–380. [DOI:10.1210/endo-70-3-375]
  • Coleman, E., Bockting, W., Botzer, M., Cohen-Kettenis, P., DeCuypere, G., Feldman, J., Fraser, L., Green, J., Knudson, G., Meyer, W. J., Monstrey, S., Adler, R. K., Brown, G. R., Devor, A. H., Ehrbar, R., Ettner, R., Eyler, E., Garofalo, R., Karasic, D. H., Lev, A. I., Mayer, G., Meyer-Bahlburg, H., Hall, B. P., Pfaefflin, F., Rachlin, K., Robinson, B., Schechter, L. S., Tangpricha, V., van Trotsenburg, M., Vitale, A., Winter, S., Whittle, S., Wylie, K. R., & Zucker, K. (2012). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People, Version 7. International Journal of Transgenderism, 13(4), 165–232. [DOI:10.1080/15532739.2011.700873] [URL] [PDF]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Coltman, C. E., Steele, J. R., & McGhee, D. E. (2017). Breast volume is affected by body mass index but not age. Ergonomics, 60(11), 1576–1585. [DOI:10.1080/00140139.2017.1330968]
  • Colvin, C., Devineni, G., & Ashraf, A. P. (2014). Delayed Puberty. In Bandeira, F., Gharib, H., Golbert, A., Griz, L., & Faria, M. (Eds.). Endocrinology and Diabetes (pp. 203–217). New York: Springer. [DOI:10.1007/978-1-4614-8684-8_17]
  • Cowie, A. T., & Folley, S. J. (1961). The Mammary Gland and Lactation. In Young, W. C. (Ed.). Sex and Internal Secretions, 3rd Edition, Volume I (pp. 590–642). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Cowie, A. T., Forsyth, I. A., & Hart, I. C. (1980). Growth and Development of the Mammary Gland. In Cowie, A. T., Forsyth, I. A., & Hart, I. C. Hormonal Control of Lactation (Monographs on Endocrinology, Volume 15) (pp. 58–145). Berlin/Heidelberg: Springer Berlin Heidelberg. [DOI:10.1007/978-3-642-81389-4_3]
  • Cox, D. B., Kent, J. C., Casey, T. M., Owens, R. A., & Hartmann, P. E. (1999). Breast Growth and the Urinary Excretion of Lactose During Human Pregnancy and Early Lactation: Endocrine Relationships. Experimental Physiology, 84(2), 421–434. [DOI:10.1111/j.1469-445x.1999.01807.x]
  • Cox, C. B., Kent, J. C., Owens, R., & Hartmann, P. E. (1994). Mammary morphological and functional changes during pregnancy in women. In Thompson, J. (Ed.). Proceedings of the Twenty-Sixth Annual Conference, Hilton Hotel, Brisbane, 26–28 September, 1994 [The Australian Society for Reproductive Biology Inc., Twenty Sixth Annual Conference, The Hilton Hotel, Brisbane, September 26 - 28 1994, Programme and Miniposters of Papers] (pp. 47–47). Australia: Australian Society for Reproductive Biology. [Google Scholar] [WorldCat] [URL] [PDF]
  • Coxon, J., & Seal, L. (2018). Hormone management of trans women. Trends in Urology & Men’s Health, 9(6), 10–14. [DOI:10.1002/tre.663]
  • Cregan, M. D., & Hartmann, P. E. (1999). Computerized Breast Measurement from Conception to Weaning: Clinical Implications. Journal of Human Lactation, 15(2), 89–96. [DOI:10.1177/089033449901500202]
  • Crowley, L. G., & Macdonald, I. (1965). Delalutin and estrogens for the treatment of advanced mammary carcinoma in the postmenopausal woman. Cancer, 18(4), 436–446. [DOI:10.1002/1097-0142(196504)18:4<436::aid-cncr2820180407>3.0.co;2-d]
  • Crowley, W. F., & Pitteloud, N. (2020). Approach to the patient with delayed puberty. UpToDate. [Google Scholar] [URL]
  • Cruz-Korchin, N., Korchin, L., González-Keelan, C., Climent, C., & Morales, I. (2002). Macromastia. Plastic and Reconstructive Surgery, 109(1), 64–68. [DOI:10.1097/00006534-200201000-00011]
  • Curtis, R. J. (2009 July 10). The Lowdown on Progesterone. London: The London Gender Clinic. [Google Scholar] [URL] [PDF]
  • Dallmann, A., Ince, I., Meyer, M., Willmann, S., Eissing, T., & Hempel, G. (2017). Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy. Clinical Pharmacokinetics, 56(11), 1303–1330. [DOI:10.1007/s40262-017-0539-z]
  • Dancey, A., Khan, M., Dawson, J., & Peart, F. (2008). Gigantomastia – a classification and review of the literature. Journal of Plastic, Reconstructive & Aesthetic Surgery, 61(5), 493–502. [DOI:10.1016/j.bjps.2007.10.041]
  • Davajan, V., & Kletzky, O. A. (1979). Amenorrhea without Galactorrhea or Hirsutism. In Mishell, D. R., & Davajan, V. (Eds.). Reproductive Endocrinology, Infertility, and Contraception (pp. 219–248). Philadelphia: F. A. Davis Co. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Davis, M. E., Boynton, M. W., Ferguson, J. H., & Rothman, S. (1945). Studies on Pigmentation of Endocrine Origin. The Journal of Clinical Endocrinology & Metabolism, 5(3), 138–146. [DOI:10.1210/jcem-5-3-138]
  • de Blok, C. J., Dijkman, B. A., Wiepjes, C. M., Staphorsius, A. S., Timmermans, F. W., Smit, J. M., Dreijerink, K. M., & den Heijer, M. (2021). Sustained Breast Development and Breast Anthropometric Changes in 3 Years of Gender-Affirming Hormone Treatment. The Journal of Clinical Endocrinology & Metabolism, 106(2), e782–e790. [DOI:10.1210/clinem/dgaa841]
  • de Blok, C. J., Klaver, M., Wiepjes, C. M., Nota, N. M., Heijboer, A. C., Fisher, A. D., Schreiner, T., T’Sjoen, G., & den Heijer, M. (2017). Breast Development in Transwomen After 1 Year of Cross-Sex Hormone Therapy: Results of a Prospective Multicenter Study. The Journal of Clinical Endocrinology & Metabolism, 103(2), 532–538. [DOI:10.1210/jc.2017-01927]
  • de Lignières, B. (2002). Effects of progestogens on the postmenopausal breast. Climacteric, 5(3), 229–235. [DOI:10.1080/cmt.5.3.229.235]
  • de Lignières, B., & Mauvais-Jarvis, P. (1981). Hormonal Dependence of Benign Breast Disease, Gynecomastia and Breast Cancer. In Hollman, K. H., Brux, J., & Verley, J. M. (Eds.). New Frontiers in Mammary Pathology (pp. 287–308). Boston: Springer US. [DOI:10.1007/978-1-4757-0019-0_17]
  • de Vries, A. L., Steensma, T. D., Wagemaar, E. C. F., Doreleijers, T. A., & Cohen-Kettenis, P. T. (2010). Puberty suppression followed by cross-sex hormones and gender reassignment surgery: A prospective follow-up of gender dysphoric adolescents into adulthood. In de Vries, A. L. (Ed.). Gender Dysphoria in Adolescents: Mental Health and Treatment Evaluation (pp. 91–106). (Doctoral thesis, Vrije Universiteit Amsterdam.) [Google Scholar] [URL] [PDF]
  • Deeb, A., Al Suwaidi, H., Attia, S., & Al Ameri, A. (2015). 17-hydroxylase/17,20-lyase deficiency due to a R96Q mutation causing hypertension and poor breast development. Endocrinology, Diabetes & Metabolism Case Reports, 2015(1), 15-0069. [DOI:10.1530/EDM-15-0069]
  • Deepinder, F., & Braunstein, G. D. (2012). Drug-induced gynecomastia: an evidence-based review. Expert Opinion on Drug Safety, 11(5), 779–795. [DOI:10.1517/14740338.2012.712109]
  • Dennerstein, L., Burrows, G. D., Hyman, G. J., & Sharpe, K. (1980). Some clinical effects of oestrogen-progestogen therapy in surgically castrated women. Maturitas, 2(1), 19–28. [DOI:10.1016/0378-5122(80)90056-0]
  • Dewhurst, C. J. (1967). The XY Female. BJOG, 74(3), 353–366. [DOI:10.1111/j.1471-0528.1967.tb03959.x]
  • Dewhurst, C. J. (1971). Sex Chromosome Abnormalities and the Gynaecologist. BJOG, 78(12), 1058–1076. [DOI:10.1111/j.1471-0528.1971.tb00227.x]
  • Dewhurst, C. J. (1971). The XY female. American Journal of Obstetrics and Gynecology, 109(5) [Transactions of the Eighty-First Annual Meeting of the American Association of Obstetricians and Gynecologists], 675–688. [DOI:10.1016/0002-9378(71)90753-8]
  • Dewhurst, C. J., & Spence, J. E. (1977). The XY female. British Journal of Hospital Medicine, 17(5), 498, 501–506. [Google Scholar] [PubMed] [PDF]
  • Dewhurst, J. (1982). Breast Hypoplasia. In Bruni, V., Gasparri, F., Dewhurst, J., & Rey-Stocker, I. (Eds.). Pediatric and Adolescent Gynaecology [Proceedings of the IVth International Symposium, Florence, October 5-7, 1978] (pp. 205–212). Rome, Italy: Serono Symposia. [Google Scholar] [Google Books] [WorldCat] [PDF]
  • Di Lorenzo, G., Autorino, R., Perdonà, S., & De Placido, S. (2005). Management of gynaecomastia in patients with prostate cancer: a systematic review. The Lancet Oncology, 6(12), 972–979. [DOI:10.1016/s1470-2045(05)70464-2]
  • Dickson, L. M., & Hewer, E. E. (1950). The structure of the breast. In Saner, F. D. (Ed.). The Breast: Structure, Function, Disease (pp. 1–52). Baltimore: William & Wilins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [PDF]
  • Dijkman, B. A., Blok, C. J., Dreijerink, K. M., & den Heijer, M. (2023). Progestin-related breast volume changes in a woman with complete androgen insensitivity syndrome (CAIS). Endocrinology, Diabetes & Metabolism Case Reports, 2023(2), 22-0346. [DOI:10.1530/edm-22-0346]
  • Dijkman, B. A., Helder, D., Boogers, L. S., Gieles, N. C., van Heesewijk, J. O., Slaa, S. t., Liberton, N. P., Wiepjes, C. M., de Blok, C. J., den Heijer, M., & Dreijerink, K. M. (2023). Addition of progesterone to feminizing gender-affirming hormone therapy in transgender individuals for breast development: a randomized controlled trial. BMC Pharmacology and Toxicology, 24(1), 80. [DOI:10.1186/s40360-023-00724-4]
  • Dittrich, R., Binder, H., Cupisti, S., Hoffmann, I., Beckmann, M., & Mueller, A. (2005). Endocrine Treatment of Male-to-Female Transsexuals Using Gonadotropin-Releasing Hormone Agonist. Experimental and Clinical Endocrinology & Diabetes, 113(10), 586–592. [DOI:10.1055/s-2005-865900]
  • Donaldson, M., Kriström, B., Ankarberg-Lindgren, C., Verlinde, S., van Alfen-van der Velden, J., Gawlik, A., van Gelder, M., Sas, T., & (2019). Optimal Pubertal Induction in Girls with Turner Syndrome Using Either Oral or Transdermal Estradiol: A Proposed Modern Strategy. Hormone Research in Paediatrics, 91(3), 153–163. [DOI:10.1159/000500050]
  • Dorgan, J. F., Klifa, C., Deshmukh, S., Egleston, B. L., Shepherd, J. A., Kwiterovich, P. O., Van Horn, L., Snetselaar, L. G., Stevens, V. J., Robson, A. M., Lasser, N. L., & Hylton, N. M. (2013). Menstrual and reproductive characteristics and breast density in young women. Cancer Causes & Control, 24(11), 1973–1983. [DOI:10.1007/s10552-013-0273-2]
  • Döring, G. K. (1963). Über die relative Häufigkeit des anovulatorischen Cyclus im Leben der Frau. [On the relative frequency of the anovulatory cycle in women’s lives.] Archiv für Gynäkologie, 199(2), 115–123. [DOI:10.1007/bf00668062]
  • Drąsutis, J. (2017). Changes in breast morphological parameters, body size and shape, blood serum prolactin and lipids during pregnancy, multiple relationships of these indicators and morphological markers for health risk. (Doctoral dissertation, Vilniaus Universitetas.) [Google Scholar] [URL]
  • Drife, J. O. (1982). The effects of parity and the menstrual cycle on the normal mammary gland and their possible relationship to malignant change. (Doctoral dissertation, University of Edinburgh). [Google Scholar] [Google Books] [WorldCat] [URL] [PDF]
  • Drife, J. O. (1984). The pill and the breast. IPPF Medical Bulletin, 18(6), 1–2. [Google Scholar] [PubMed]
  • Drife, J. O. (1986). Breast Development in Puberty. Annals of the New York Academy of Sciences, 464(1) [Endocrinology of the Breast: Basic and Clinical Aspects], 58–65. [DOI:10.1111/j.1749-6632.1986.tb15993.x]
  • Drife, J. O. (1989). Breast modifications during the menstrual cycle. Supplement to International Journal of Gynecology and Obstetrics, 1, 19–24. / International Journal of Gynecology and Obstetrics, 1989(Suppl 1), 19–24. [Google Scholar] [PubMed] [Archive.org]
  • Drife, J. O. (1990). Premenopausal Hormone Therapy. In Drife, J. O., & Studd, J. W. W. (Eds.). HRT and Osteoporosis (pp. 351–362). London: Springer London. [DOI:10.1007/978-1-4471-1799-5_25]
  • Duncan, M. (2010). Sexual Selection and Human Breast Morphology. (Doctoral dissertation, Te Herenga Waka-Victoria University of Wellington.) [Google Scholar] [URL]
  • Edmonds, D. K. (1989). Normal Puberty. In Edmonds, D. K. Dewhurst’s Practical Paediatric and Adolescent Gynaecology, 2nd Edition (pp. 56–62). London: Butterworths. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [Archive.org]
  • Elling, S. V., & Powell, F. C. (1997). Physiological changes in the skin during pregnancy. Clinics in Dermatology, 15(1), 35–43. [DOI:10.1016/s0738-081x(96)00108-3]
  • Engman, M., Skoog, L., Soderqvist, G., & Gemzell-Danielsson, K. (2008). The effect of mifepristone on breast cell proliferation in premenopausal women evaluated through fine needle aspiration cytology. Human Reproduction, 23(9), 2072–2079. [DOI:10.1093/humrep/den228]
  • Federici, S., Goggi, G., Quinton, R., Giovanelli, L., Persani, L., Cangiano, B., & Bonomi, M. (2021). New and Consolidated Therapeutic Options for Pubertal Induction in Hypogonadism: In-depth Review of the Literature. Endocrine Reviews, 43(5), 824–851. [DOI:10.1210/endrev/bnab043]
  • Fernández-Cancio, M., García-García, E., González-Cejudo, C., Martínez-Maestre, M., Mangas-Cruz, M., Guerra-Junior, G., Pandi de Mello, M., Arnhold, I. J., Nishi, M. Y., Bilharinho Mendonça, B., García-Arumí, E., Audí, L., Tizzano, E., & Carrascosa, A. (2017). Discordant Genotypic Sex and Phenotype Variations in Two Spanish Siblings with 17α-Hydroxylase/17,20-Lyase Deficiency Carrying the Most Prevalent Mutated CYP17A1 Alleles of Brazilian Patients. Sexual Development, 11(2), 70–77. [DOI:10.1159/000468160]
  • Fernandez-Valdivia, R., Mukherjee, A., Mulac-Jericevic, B., Conneely, O. M., DeMayo, F. J., Amato, P., & Lydon, J. P. (2005). Revealing Progesterone’s Role in Uterine and Mammary Gland Biology: Insights from the Mouse. Seminars in Reproductive Medicine, 23(1), 22–37. [DOI:10.1055/s-2005-864031]
  • Finkenzeller, D. A., & Loveless, M. B. (2007). Pediatric Gynecology. In Fortner, K. B., Szymanski, L. M., Fox, H. E., & Wallach, E. E. (Eds.). The Johns Hopkins Manual of Gynecology and Obstetrics, 3rd Edition (Spiral Manual Series) (pp. 363–379). Philadelphia: Lippincott Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Fisher, A. D., Castellini, G., Ristori, J., Casale, H., Cassioli, E., Sensi, C., Fanni, E., Amato, A. M., Bettini, E., Mosconi, M., Dèttore, D., Ricca, V., & Maggi, M. (2016). Cross-Sex Hormone Treatment and Psychobiological Changes in Transsexual Persons: Two-Year Follow-Up Data. The Journal of Clinical Endocrinology & Metabolism, 101(11), 4260–4269. [DOI:10.1210/jc.2016-1276]
  • Foidart, J. M., Colin, C., Denoo, X., Desreux, J., Fournier, S., & de Linières, B. (1996). Influence of percutaneous administration of estradiol and progesterone on the proliferation of human breast epithelial cells. In Calvo, F., Crépin, M., & Magdelenat, H. (Eds.). Breast Cancer: Advances in Biology and Therapeutics [21st Meeting of the International Association for Breast Cancer Research, July 3-4-5, 1996, Paris] (pp. 329–334). Montrouge/Paris: John Libbey Eurotext. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Foidart, J., Colin, C., Denoo, X., Desreux, J., Béliard, A., Fournier, S., & de Lignières, B. (1998). Estradiol and Progesterone Regulate the Proliferation of Human Breast Epithelial Cells. Fertility and Sterility, 69(5), 963–969. [DOI:10.1016/s0015-0282(98)00042-9]
  • Folley, S. J. (1940). Lactation. Biological Reviews, 15(4), 421–458. [DOI:10.1111/j.1469-185x.1940.tb00947.x]
  • Folley, S. J. (1947). Endocrine Control of the Mammary Gland. British Medical Bulletin, 5(2–3), 130–134. [DOI:10.1093/oxfordjournals.bmb.a073121]
  • Folley, S. J. (1950). Lactational Physiology. In Bowes, K. (Ed.). Modern Trends in Obstetrics and Gynaecology (pp. 441–453). London: Butterworth. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Folley, S. J. (1952). Lactation. In Parkes, A. S. (Ed.). Marshall’s Physiology of Reproduction, 3rd Edition, Volume II (pp. 525–647). Longmans, Green & Co.: London. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Folley, S. J. (1956). Recent Studies on the Development of the Mammary Gland. In Folley, S. J. The Physiology and Biochemistry of Lactation, 1st Edition (pp. 1–22). Edinburgh: Oliver & Boyd. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Folley, S. J., & Malpress, F. H. (1948). Hormonal Control of Mammary Growth. In Pincus, G., & Thimann, K. V. (Eds.). The Hormones: Physiology, Chemistry and Applications, Volume I (pp. 695–743). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Fourcade, R., & McLeod, D. (2004). Tolerability of Antiandrogens in the Treatment of Prostate Cancer. UroOncology, 4(1), 5–13. [DOI:10.1080/1561095042000191655]
  • Fowler, P. A., Casey, C. E., Cameron, G. G., Foster, M. A., & Knight, C. H. (1990). Cyclic changes in composition and volume of the breast during the menstrual cycle, measured by magnetic resonance imaging. BJOG, 97(7), 595–602. [DOI:10.1111/j.1471-0528.1990.tb02546.x]
  • Fridriksdottir, A. J., Petersen, O. W., & Rnnov-Jessen, L. (2011). Mammary gland stem cells: current status and future challenges. The International Journal of Developmental Biology, 55(7–8–9), 719–729. [DOI:10.1387/ijdb.113373af]
  • Fuqua, J. S., & Eugster, E. A. (2022). History of Puberty: Normal and Precocious. Hormone Research in Paediatrics, 95(6), 568–578. [DOI:10.1159/000526464]
  • Gaede, P., Trolle, D., & Pedersen, H. (1978). Extremely low placental lactogen hormone (hpl) values in an otherwise uneventful pregnancy preceding delivery of a normal baby. Acta Obstetricia et Gynecologica Scandinavica, 57(3), 203–209. [DOI:10.3109/00016347809154883]
  • Galani, A., Kitsiou-Tzeli, S., Sofokleous, C., Kanavakis, E., & Kalpini-Mavrou, A. (2008). Androgen insensitivity syndrome: clinical features and molecular defects. Hormones, 7(3), 217–229. [DOI:10.14310/horm.2002.1201]
  • Galbarczyk, A. (2011). Unexpected changes in maternal breast size during pregnancy in relation to infant sex: An evolutionary interpretation. American Journal of Human Biology, 23(4), 560–562. [DOI:10.1002/ajhb.21177]
  • Gawlik, A., Hankus, M., Such, K., Drosdzol-Cop, A., Madej, P., Borkowska, M., Zachurzok, A., & Malecka-Tendera, E. (2016). Hypogonadism and Sex Steroid Replacement Therapy in Girls with Turner Syndrome. Journal of Pediatric and Adolescent Gynecology, 29(6), 542–550. [DOI:10.1016/j.jpag.2016.03.005]
  • Gershon-Cohen, J. (1970). The Normal Breast. In Gershon-Cohen, J. Atlas of Mammography (pp. 23–38). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-85678-5_4] [Google Books]
  • Gertig, D. M., Stillman, I. E., Byrne, C., Spiegelman, D., Schnitt, S. J., Connolly, J. L., Colditz, G. A., & Hunter, D. J. (1999). Association of age and reproductive factors with benign breast tissue composition. Cancer Epidemiology, Biomarkers & Prevention, 8(10), 873–879. [Google Scholar] [PubMed] [URL]
  • Geschickter, C. F. (1945). Endocrine Physiology of the Breast. In Geschickter, C. F. Diseases of the Breast: Diagnosis, Pathology, Treatment, 2nd Edition (pp. 42–81). Philadelphia: J.B. Lippincott. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Glenn, J. F. (1976). Testicular feminization syndrome current clinical considerations. Urology, 7(6), 569–577. [DOI:10.1016/0090-4295(76)90079-0]
  • Gliosci, A., & Presutti, F. (1993). Virginal gigantomastia: Validity of combined surgical and hormonal treatments. Aesthetic Plastic Surgery, 17(1), 61–65. [DOI:10.1007/bf00455051]
  • Gompel, A., & Plu-Bureau, G. (2018). Progesterone, progestins and the breast in menopause treatment. Climacteric, 21(4), 326–332. [DOI:10.1080/13697137.2018.1476483]
  • Goodman, H. M. (2009). Hormonal Control of Pregnancy and Lactation. In Goodman, H. M. Basic Medical Endocrinology, 4th Edition (pp. 277–301). Amsterdam: Academic Press/Elsevier. [DOI:10.1016/b978-0-12-373975-9.00014-8]
  • Gooren, L. J. (2016). Hormone Treatment of Adult Transgender People. In Ettner, R., Monstrey, S., & Coleman, E. (Eds.). Principles of Transgender Medicine and Surgery, 2nd Edition (pp. 167–179). New York: Routledge. [Google Scholar] [Google Books] [DOI:10.4324/9781315718972-11]
  • Gordon, C. M., & Laufer, M. R. (2005) The Physiology of Puberty. In Emans, S. J., Laufer, M. R., & Goldstein, D. P. (Eds.). Pediatric and Adolescent Gynecology, 5th Edition (pp. 120–155). Philadelphia: Lippincott Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Göretzlehner, G. & Lauritzen, C. (1992). Hormontherapie bei Gynäkologischen Erkrankungen [Hormone Therapy for Gynecological Diseases]. In Göretzlehner, G. & Lauritzen, C. Praktische Hormontherapie in der Gynäkologie, 1. Auflage [Practical Hormone Therapy in Gynecology, 1st Edition] (pp. 245–299). Berlin/New York: de Gruyter. [DOI:10.1515/9783112417706-007] [Google Books] [PDF] [Translation]
  • Graham, J. D., & Clarke, C. L. (1997). Physiological Action of Progesterone in Target Tissues. Endocrine Reviews, 18(4), 502–519. [DOI:10.1210/edrv.18.4.0308]
  • Graham, S. J., Stanchev, P. L., Lloyd‐Smith, J. O., Bronskill, M. J., & Plewes, D. B. (1995). Changes in Fibroglandular Volume and Water Content of Breast Tissue During the Menstrual Cycle Observed by MR Imaging at 1.5 T. Journal of Magnetic Resonance Imaging, 5(6), 695–701. [DOI:10.1002/jmri.1880050613]
  • Greydanus, D. E., Omar, H. A., Matytsina, L. A., & Tsitsika, A. (2010). Breast Disorders in Children and Adolescents. In Omar, H. A., Greydanus, D. E., Tsitsika, A. K., Patel, D. R., & Merrick, J. (Eds.). Pediatric and Adolescent Sexuality and Gynecology: Principles for the Primary Care Clinician (pp. 245–316). Hauppauge: Nova Science Publishers. [Google Scholar] [Google Books] [URL] [OpenLibrary] [WorldCat] [PDF]
  • Guaragna-Filho, G., Guerra-Junior, G., Tadokoro-Cuccaro, R., Hughes, I. A., Barros, B. A., Hiort, O., Balsamo, A., Guran, T., Holterhus, P. M., Hannema, S., Poyrazoglu, S., Darendeliler, F., Bryce, J., Ahmed, S. F., & Quigley, C. A. (2023). Pubertal and Gonadal Outcomes in 46,XY Individuals with Partial Androgen Insensitivity Syndrome Raised as Girls. Sexual Development, 17(1), 16–25. [DOI:10.1159/000526997]
  • Gunn, H. M., Tsai, M., McRae, A., & Steinbeck, K. S. (2018). Menstrual Patterns in the First Gynecological Year: A Systematic Review. Journal of Pediatric and Adolescent Gynecology, 31(6), 557–565.e6. [DOI:10.1016/j.jpag.2018.07.009]
  • Günzel, P., Hasan, S. H., Düsterberg, B., Hümpel, M., Putz, B., & Lehmann, M. (1987). Zur toxikologischen Prüfung von Steroidhormonen. [For the Toxicological Testing of Steroid Hormones.] In Burger, O. K., Grosdanoff, P., Henschler, D., Kraupp, O., & Schnieders, B. (Eds.). Aktuelle Probleme der Biomedizin (pp. 93–112). Berlin/New York: De Gruyter. [Google Scholar] [Google Books] [DOI:10.1515/9783110898231-014]
  • Hagisawa, S., Shimura, N., & Arisaka, O. (2012). Effect of Excess Estrogen on Breast and External Genitalia Development in Growth Hormone Deficiency. Journal of Pediatric and Adolescent Gynecology, 25(3), e61–e63. [DOI:10.1016/j.jpag.2011.11.005]
  • Hamburger, C., & Benjamin, H. (1969). Endocrine Treatment of Male and Female Transsexualism / Appendix for the Practicing Physician: Suggestions and Guidelines for the Management of Transsexuals. In Green, R., & Money, J. (Eds.). Transsexualism and Sex Reassignment (pp. 291–307). Baltimore: John Hopkins University Press. [Google Scholar] [Google Books] [PDF]
  • Hannan, F. M., Elajnaf, T., Vandenberg, L. N., Kennedy, S. H., & Thakker, R. V. (2022). Hormonal regulation of mammary gland development and lactation. Nature Reviews Endocrinology, 19(1), 46–61. [DOI:10.1038/s41574-022-00742-y]
  • Hannema, S. E., Schagen, S. E., Cohen-Kettenis, P. T., & Delemarre-van de Waal, H. A. (2017). Efficacy and Safety of Pubertal Induction Using 17β-Estradiol in Transgirls. The Journal of Clinical Endocrinology & Metabolism, 102(7), 2356–2363. [DOI:10.1210/jc.2017-00373]
  • Harley, J. M. G. (1969). The endocrine control of the breasts. The Practitioner, 203(1214), 153–157. [Google Scholar] [Google Books] [PubMed] [DOI:10.5555/19700402477] [HathiTrust]
  • Hartmann, B. W., Laml, T., Albrecht, A. E., Huber, J. C., & Kirchengast, S. (1998). Hormonal Breast Augmentation: Prognostic Relevance of Insulin-Like Growth Factor-I. Gynecological Endocrinology, 12(2), 123–127. [DOI:10.3109/09513599809024960]
  • Hartmann, P. E., Owens, R. A., Cox, D. B., & Kent, J. C. (1996). Breast Development and Control of Milk Synthesis. Food and Nutrition Bulletin, 17(4), 1–12. [DOI:10.1177/156482659601700404]
  • Hasan, S. (1974). Steroid Hormone Levels During Pregnancy in Various Species. In Bernhard, S., & Raspé, G. (Ed.). Hormones and Embryonic Development (Advances in the Biosciences, Volume 13) (pp. 181–197). Oxford/New York: Pergamon Press. [Google Scholar] [Google Books] [DOI:10.1016/b978-0-08-018239-1.50014-3] [OpenLibrary] [Archive.org]
  • Hassiotou, F., & Geddes, D. (2012). Anatomy of the human mammary gland: Current status of knowledge. Clinical Anatomy, 26(1), 29–48. [DOI:10.1002/ca.22165]
  • Heath, R. A., & Wynne, K. (2019). Children and Adolescents. In Heath, R. A., & Wynne, K. A Guide to Transgender Health: State-of-the-art Information for Gender-Affirming People and Their Supporters (pp. 87–106). Santa Barbara: Praeger/ABC-CLIO. [Google Books]
  • Heath, R. A., & Wynne, K. (2019). Hormone and Surgical Therapies for Adults. In Heath, R. A., & Wynne, K. A Guide to Transgender Health: State-of-the-art Information for Gender-Affirming People and Their Supporters (pp. 107–146). Santa Barbara: Praeger/ABC-CLIO. [Google Books]
  • Hertz, R., Odell, W. D., & Ross, G. T. (1966). Diagnostic Implications of Primary Amenorrhea: Combined Clinical Staff Conference at the National Institutes of Health. Annals of Internal Medicine, 65(4), 800–820. [DOI:10.7326/0003-4819-65-4-800]
  • Hillard, P. J. A. (2007). Benign Diseases of the Female Reproductive Tract. In Berek, J. S., & Novak, E. (Eds.). Berek & Novak’s Gynecology, 14th Edition (pp. 431–496). Philadelphia: Lippincott Williams and Wilkins. [Google Scholar] [OpenLibrary] [WorldCat] [Archive.org]
  • Hoppe, I. C., Patel, P. P., Singer-Granick, C. J., & Granick, M. S. (2011). Virginal Mammary Hypertrophy: A Meta-Analysis and Treatment Algorithm. Plastic and Reconstructive Surgery, 127(6), 2224–2231. [DOI:10.1097/prs.0b013e3182131bd1]
  • Hovey, R. C., Trott, J. F., Ginsburg, E., Goldhar, A., Sasaki, M. M., Fountain, S. J., Sundararajan, K., & Vonderhaar, B. K. (2001). Transcriptional and spatiotemporal regulation of prolactin receptor mRNA and cooperativity with progesterone receptor function during ductal branch growth in the mammary gland. Developmental Dynamics, 222(2), 192–205. [DOI:10.1002/dvdy.1179]
  • Howard, B. A., & Gusterson, B. A. (2000). Human Breast Development. Journal of Mammary Gland Biology and Neoplasia, 5(2), 119–137. [DOI:10.1023/a:1026487120779]
  • Huffman, J., Dewhurst, C. J., & Capraro, V. J. (1981). The Breast and its Disorders in Childhood and Adolescence. In Huffman, J., Dewhurst, J., & Capraro, V. The Gynecology of Childhood and Adolescence, 2nd Edition (pp. 542–559). Philadelphia: Saunders. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org] [PDF]
  • Hussain, Z., Brooks, J., & Percy, D. (2008). Menstrual variation of breast volume and T2 relaxation times in cyclical mastalgia. Radiography, 14(1), 8–16. [DOI:10.1016/j.radi.2006.07.003]
  • Hussain, Z., Roberts, N., Whitehouse, G. H., García-Fiñana, M., & Percy, D. (1999). Estimation of breast volume and its variation during the menstrual cycle using MRI and stereology. The British Journal of Radiology, 72(855), 236–245. [DOI:10.1259/bjr.72.855.10396212]
  • Hutson, S. W., Cowen, P. N., & Bird, C. C. (1985). Morphometric studies of age related changes in normal human breast and their significance for evolution of mammary cancer. Journal of Clinical Pathology, 38(3), 281–287. [DOI:10.1136/jcp.38.3.281]
  • Hytten, F. E. (1954). Clinical and Chemical Studies in Human Lactation–VI. BMJ, 1(4867), 912–915. [DOI:10.1136/bmj.1.4867.912]
  • Hytten, F. E. (1954). Observations on Human Lactation. (Doctor’s thesis, University of Aberdeen.) [Google Scholar] [Google Books] [URL] [WorldCat]
  • Hytten, F. E. (1976). The physiology of lactation. International Journal of Food Sciences and Nutrition, 30(4), 225–232. [DOI:10.3109/09637487609142745]
  • Hytten, F. E., & Baird, D. (1958). The Development of the Nipple in Pregnancy. The Lancet, 271(7032), 1201–1204. [DOI:10.1016/s0140-6736(58)91908-1]
  • Hytten, F. E., & Leitch, I. (1971). Preparations for Breast Feeding. In Hytten, F. E., & Leitch, I. The Physiology of Human Pregnancy, 2nd Edition (pp. 234–241). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Leitch, I. (1971). Preparations for Breast Feeding. In Hytten, F. E., & Leitch, I. The Physiology of Human Pregnancy, 2nd Edition (pp. 234–241). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Thomson, A. M. (1965). Pregnancy, childbirth and lactation. In Edholm, O. G., & Bacharach, A. L. (Eds.). The Physiology of Human Survival (pp. 327–350). London/New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Hytten, F. E., & Thomson, A. M. (1968). Maternal physiological adjustments. In Assali, N. S. (Ed.). The Maternal Organism, Volume I (Biology of Gestation) (pp. 449–479). New York: Academic Press. [Google Scholar] [Google Books] [WorldCat]
  • Igo, J., & Visram, H. (2021). Progesterone Therapy Use and Safety in Male to Female Transgender Patients. Canadian Journal of Diabetes, 45(7 Suppl), S39–S39 (abstract no. 109). [DOI:10.1016/j.jcjd.2021.09.119] [URL] [PDF]
  • Ingleby, H. (1949). Changes in breast volume in a group of normal young women. Bulletin of the International Association of Medical Museums, 29, 87–92. [Google Scholar] [Google Books] [HathiTrust]
  • Ingleby, H., Moore, L., & Gershon-Cohen, J. (1957). Gestational breast changes: x-ray studies of the human breast. Obstetrics & Gynecology, 10(2), 149–157. [Google Scholar] [PubMed] [URL]
  • Ismail, P. M., Amato, P., Soyal, S. M., DeMayo, F. J., Conneely, O. M., O’Malley, B. W., & Lydon, J. P. (2003). Progesterone involvement in breast development and tumorigenesis—as revealed by progesterone receptor “knockout” and “knockin” mouse models. Steroids, 68(10–13), 779–787. [DOI:10.1016/s0039-128x(03)00133-8]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 204201881987116. [DOI:10.1177/2042018819871166]
  • Jacobsohn, D. (1961). Hormonal Regulation of Mammary Gland Growth. In Kon, S. K., & Cowie, A. T. (Eds.). Milk: The Mammary Gland and Its Secretion, Volume 1 (pp. 127–160). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [PDF]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • Jamal, N., Ng, K., McLean, D., Looi, L., & Moosa, F. (2004). Mammographic Breast Glandularity in Malaysian Women: Data Derived from Radiography. American Journal of Roentgenology, 182(3), 713–717. [DOI:10.2214/ajr.182.3.1820713]
  • Jemstrom, H., & Olsson, H. (1997). Breast Size in Relation to Endogenous Hormone Levels, Body Constitution, and Oral Contraceptive Use in Healthy Nulligravid Women Aged 19-25 Years. American Journal of Epidemiology, 145(7), 571–580. [DOI:10.1093/oxfordjournals.aje.a009153]
  • Jernström, H., Sandberg, T., Bågeman, E., Borg, Å., & Olsson, H. (2005). Insulin-like growth factor-1 (IGF1) genotype predicts breast volume after pregnancy and hormonal contraception and is associated with circulating IGF-1 levels: implications for risk of early-onset breast cancer in young women from hereditary breast cancer families. British Journal of Cancer, 92(5), 857–866. [DOI:10.1038/sj.bjc.6602389]
  • Jeruss, J. S. (2006). Molecular Basis of Breast Cancer. In Winchester, D. J., Winchester, D. P., Hudis, C. A., & Norton, L. (Eds.). Breast Cancer, 2nd Edition (pp. 83–95). Hamilton: B.C. Decker. [Google Scholar] [Google Books] [WorldCat]
  • Johnson, M. C., & Cutler, M. L. (2016). Anatomy and Physiology of the Breast. In Jatoi, I., & Rody, A. (Eds.). Management of Breast Diseases (pp. 1–39). Cham: Springer. [DOI:10.1007/978-3-319-46356-8_1]
  • Kaiser, R. (1993). Gestagen-Östrogen-Kombinationen in der Gynäkologie. Zur Geschichte, Dosierung und Anwendung eines Hormonprinzips. [Gestagen-Oestrogen Combinations in Gynaecology. History, Dosage and Use of a Hormonal Principle.] Geburtshilfe und Frauenheilkunde, 53(7), 503–513. [Google Scholar] [PubMed] [DOI:10.1055/s-2007-1022924]
  • Kaiser, R., & Leidenberger, F. (1991). Hormonbehandlung bei Benign Mammaerkrankungen: Mammahypoplasie. [Hormonal Treatment in Benign Breast Diseases: Breast Hypoplasia.] In Kaiser, R., & Leidenberger, F. Hormonbehandlung in der Gynäkologischen Praxis, 7. Auflage [Hormone Treatment in Gynecological Practice, 7th Edition] (pp. 138–138). Stuttgart: Georg Thieme Verlag. [Google Books] [OpenLibrary] [WorldCat] [PDF] [Translation]
  • Kaiser, U., & Ho, K. K. (2015). Pituitary Physiology and Diagnostic Evaluation. In Melmed, S., Polonsky, K. S., Larsen, P. R., Kronenberg, & H. M. (Eds.). Williams Textbook of Endocrinology, 13th Edition (pp. 176–231). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-29738-7.00008-3] [Google Books]
  • Kanhai, R. C., Hage, J. J., Asscheman, H., Mulder, W. J., & Hage, J. J. (1999). Augmentation Mammaplasty in Male-to-Female Transsexuals. Plastic and Reconstructive Surgery, 104(2), 542–549. [DOI:10.1097/00006534-199908000-00040]
  • Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E., & Mulder, J. W. (2000). Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men. The American Journal of Surgical Pathology, 24(1), 74–80. [DOI:10.1097/00000478-200001000-00009]
  • Kardelen, A. D., Toksoy, G., Baş, F., Yavaş Abalı, Z., Gençay, G., Poyrazoğlu, Ş., Bundak, R., Altunoğlu, U., Avcı, Ş., Najaflı, A., Uyguner, O., Karaman, B., Başaran, S., & Darendeliler, F. (2018). A Rare Cause of Congenital Adrenal Hyperplasia: Clinical and Genetic Findings and Follow-up Characteristics of Six Patients with 17-Hydroxylase Deficiency Including Two Novel Mutations. Journal of Clinical Research in Pediatric Endocrinology, 10(3), 206–215. [DOI:10.4274/jcrpe.0032]
  • Kariagina, A., Xie, J., Leipprandt, J. R., & Haslam, S. Z. (2010). Amphiregulin Mediates Estrogen, Progesterone, and EGFR Signaling in the Normal Rat Mammary Gland and in Hormone-Dependent Rat Mammary Cancers. Hormones and Cancer, 1(5), 229–244. [DOI:10.1007/s12672-010-0048-0]
  • Karp, N. S. (2022). Discussion: The Impact of Combined Oral Contraceptives on Adolescents with Macromastia. Plastic & Reconstructive Surgery, 150(4), 739–740. [DOI:10.1097/prs.0000000000009514]
  • Kasielska-Trojan, A., Mikołajczyk, M., & Antoszewski, B. (2020). BreastIdea Volume Estimator: A New Tool for Breast Volume Estimation—Presentation and Validation for Women. Plastic & Reconstructive Surgery, 146(6), 744e–748e. [DOI:10.1097/prs.0000000000007373]
  • Kasielska-Trojan, A., Zawadzki, T., & Antoszewski, B. (2022). Breast Fluctuating Asymmetry in Women with Macromastia/Gigantomastia. International Journal of Environmental Research and Public Health, 19(24), 16895. [DOI:10.3390/ijerph192416895]
  • Kauli, R., Pertzelan, A., Ben‐Zeev, Z., Lewin, R. P., Kaufman, H., Schally, A. C., Schally, A. V., & Laron, Z. (1984). Treatment of precocious puberty with LHRH analogue in combination with cyproterone acetate—further experience. Clinical Endocrinology, 20(4), 377–387. [DOI:10.1111/j.1365-2265.1984.tb03433.x]
  • Keller, P. J. (1984). Diagnostik und Therapie wichtiger hormonaler Störungen: Mammahypoplasie. [Diagnosis and Treatment of Important Hormonal Disorders: Mammary Hypoplasia.] In Keller, P. J. Hormonale Störungen in der Gynäkologie: Diagnostik und Behandlung, 3. Auflage [Hormonal Disorders in Gynecology: Diagnosis and Treatment, 3rd Edition] (Kliniktaschenbücher) (pp. 133–134). Berlin/Heidelberg: Springer. [Google Books] [DOI:10.1007/978-3-662-00442-5_3]
  • Keller, P. J. (1995). Diagnostik und Therapie wichtiger Störungen: Mammahypoplasie. [Diagnosis and Treatment of Important Disorders: Mammary Hypoplasia.] In Keller, P. J. Hormon- und Fertilitätsstörungen in der Gynäkologie, 4. Auflage [Hormonal and Fertility Disorders in Gynecology, 4th Edition] (pp. 145–146). Berlin/Heidelberg: Springer. [Google Books] [DOI:10.1007/978-3-662-12026-2_3]
  • Kennedy, B. J. (1953). Effects of intensive sex steroid hormone therapy in advanced breast cancer. JAMA, 152(12), 1135–1141. [DOI:10.1001/jama.1953.63690120004013]
  • Kent, J. C., Mitoulas, L., Cox, D. B., Owens, R. A., & Hartmann, P. E. (1999). Breast Volume and Milk Production During Extended Lactation in Women. Experimental Physiology, 84(2), 435–447. [DOI:10.1111/j.1469-445x.1999.01808.x]
  • Khoo, S. K., & Mackay, E. V. (1972). Testicular Feminization: The Clinical Features, Endocrine Function and Gonadal Pathology in Six Patients. Australian and New Zealand Journal of Obstetrics and Gynaecology, 12(1), 1–13. [DOI:10.1111/j.1479-828x.1972.tb00721.x]
  • Klein, R., Aichinger, H., Dierker, J., Jansen, J. T., Joite-Barfuß, S., Säbel, M., Schulz-Wendtland, R., & Zoetelief, J. (1997). Determination of average glandular dose with modern mammography units for two large groups of patients. Physics in Medicine and Biology, 42(4), 651–671. [DOI:10.1088/0031-9155/42/4/004]
  • Kleinberg, D. L. (2006). Endocrinology of lactation. In DeGroot, L. J., & Jameson, J. L. (Eds). Endocrinology, 5th Edition (pp. 3461–3473). Philadelphia: Elsevier Saunders. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Kleinberg, D. L., & Barcellos-Hoff, M. H. (2011). The Pivotal Role of Insulin-Like Growth Factor I in Normal Mammary Development. Endocrinology and Metabolism Clinics of North America, 40(3), 461–471. [DOI:10.1016/j.ecl.2011.06.001]
  • Kleinberg, D. L., & Ruan, W. (2008). IGF-I, GH, and Sex Steroid Effects in Normal Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 13(4), 353–360. [DOI:10.1007/s10911-008-9103-7]
  • Kleinberg, D. L., Wood, T. L., Furth, P. A., & Lee, A. V. (2008). Growth Hormone and Insulin-Like Growth Factor-I in the Transition from Normal Mammary Development to Preneoplastic Mammary Lesions. Endocrine Reviews, 30(1), 51–74. [DOI:10.1210/er.2008-0022]
  • Kühnel, W. (2000). IMMULITE® and IMMULITE® 2000 Reference Range Compendium, First English Edition. Los Angeles, California: Diagnostic Products Corporation. [Google Scholar] [URL] [PDF 1] [PDF 2]
  • Kustin, J., & Rebar, R. W. (1987). Menstrual Disorders in the Adolescent Age Group. Primary Care: Clinics in Office Practice, 14(1), 139–166. [DOI:10.1016/s0095-4543(21)01004-6]
  • Kutten, F., Malet, C., & Leygue, E. (1994). Antiestrogen action of progestogens in human breast cells. In Berg, G., & Hammar, M. (Eds.). The Modern Management of the Menopause: A Perspective for the 21st Century [The Proceedings of the VII International Congress on the Menopause, Stockholm, Sweden 1993] (pp. 419–433). Canforth: Parthenon. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org] [PDF]
  • Ladjouze, A., & Donaldson, M. (2019). Primary gonadal failure. Best Practice & Research Clinical Endocrinology & Metabolism, 33(3), 101295. [DOI:10.1016/j.beem.2019.101295]
  • Laessle, R. G., Tuschi, R. J., Schweiger, U., & Pirke, K. M. (1990). Mood changes and physical complaints during the normal menstrual cycle in healthy young women. Psychoneuroendocrinology, 15(2), 131–138. [DOI:10.1016/0306-4530(90)90021-z]
  • LaMarca, H. L., & Rosen, J. M. (2007). Estrogen regulation of mammary gland development and breast cancer: amphiregulin takes center stage. Breast Cancer Research, 9(4), 304. [DOI:10.1186/bcr1740]
  • Laron, Z., & Kauli, R. (2000). Experience with Cyproterone Acetate in the Treatment of Precocious Puberty. Journal of Pediatric Endocrinology and Metabolism, 13(Suppl 1), 805–810. [DOI:10.1515/jpem.2000.13.s1.805]
  • Lauritzen, C. (1980 October 27). Hormonkur Kann Hypoplastischer Mamma Aufhelfen. [Hormone Therapy Can Help Hypoplastic Breasts.] Selecta: Medizin aktuell; das Magazin für ärztliche Fortbildung [Selecta: Medicine Currently; the Magazine for Medical Training], 22(43), 3798–3801. Planegg: Selecta-Verlag. [ISSN:0582-4877] [WorldCat] [PDF] [Translation]
  • Lauritzen, C. (1982). Treatment of mammary- and uterus hypoplasia by estrogen-progestagen pseudopregnancy. In Richter, K., Huber, A., Terruhn, V. (Eds.) 1. Europäisches Symposium für Kinder- und Jugendgynäkologie. München 19.-21.3.1981, Band 2 [First European Symposium on Pediatric and Adolescent Gynaecology. München, March 19–21, 1981, Volume 2] (pp. 487–489). Friedrichsdorf/Taunus: Milupa-Aktiengesellschaft, Wissenschaftliche Abteilung. [Google Scholar] [PDF]
  • Lauritzen, C. (1989). Hormonelle Substitutionstherapie zur Brustvergrößerung. [Hormonal Substitution Therapy for Breast Enlargement.] In Beller, F. K. & Seitzer, D. (Eds.). 7. Siebte Wissenschaftliche Tagung der Deutschen Gesellschaft für Senologie, Münster, 25. - 27. September 1987: Ausgewählte Referate [7th Scientific Conference of the German Society for Senology, Münster, [Germany,] September 25–27, 1987: Selected Papers] (pp. 39–41). Mülheim, Germany: H.U.F. Verlag. [Google Scholar] [WorldCat 1] [WorldCat 2] [WorldCat 3] [Cited By 1] [Cited By 2] [Cited By 3] [PDF] [Translation]
  • Lawrence, R. A., & Lawrence, R. M. (2015). Physiology of Lactation. In Lawrence, R. A., & Lawrence, R. M. Breastfeeding: A Guide for the Medical Profession, 8th Edition (pp. 56–90). Philadelphia: Elsevier. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Lee, H. J., & Ormandy, C. J. (2012). Interplay between progesterone and prolactin in mammary development and implications for breast cancer. Molecular and Cellular Endocrinology, 357(1–2), 101–107. [DOI:10.1016/j.mce.2011.09.020]
  • Lee, P. A. (2001). Physiology of Puberty. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Nylén, E. S., Rebar, R. W., Robertson, G. L., Snider, R. H., Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 3rd Edition (pp. 885–893). Philadelphia: Lippincott Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Lee, S. W., Kwak, D. S., Jung, I. S., Kwak, J. H., Park, J. H., Hong, S. M., Lee, C. B., Park, Y. S., Kim, D. S., Choi, W. H., & Ahn, Y. H. (2015). Partial Androgen Insensitivity Syndrome Presenting with Gynecomastia. Endocrinology and Metabolism, 30(2), 226–230. [DOI:10.3803/enm.2015.30.2.226]
  • Lejour, M. (1994). Vertical Mammaplasty and Liposuction of the Breast. Plastic and Reconstructive Surgery, 94(1), 100–114. [DOI:10.1097/00006534-199407000-00010]
  • Lejour, M. (1997). Evaluation of Fat in Breast Tissue Removed by Vertical Mammaplasty. Plastic and Reconstructive Surgery, 99(2), 386–393. [DOI:10.1097/00006534-199702000-00012]
  • Lemarchand-Béraud, T., Zufferey, M., Reymond, M., & Rey, I. (1982). Maturation of the Hypothalamo-Pituitary-Ovarian Axis in Adolescent Girls. The Journal of Clinical Endocrinology & Metabolism, 54(2), 241–246. [DOI:10.1210/jcem-54-2-241]
  • Lewin, R. (2016). Breast Hypertrophy and Outcome of Breast Reduction Surgery. (Doctoral thesis, University of Gothenburg. Sahlgrenska Academy.) [Google Scholar] [URL]
  • Lim, L. Y., Ho, P. J., Liu, J., Chay, W. Y., Tan, M., Hartman, M., & Li, J. (2018). Determinants of breast size in Asian women. Scientific Reports, 8(1), 1201. [DOI:10.1038/s41598-018-19437-4]
  • Lloyd, C. W., & Leathem, J. H. (1964). Growth and development of the breast and lactation. In Lloyd, C. W. (Ed.). Human Reproduction and Sexual Behavior (pp. 117–134). Philadelphia: Lea & Febiger. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Lopez, X., Panton, J., Nagarkar, P., Preston, S., Abramowitz, J., & Amirlak, B. (2023). Initial Assessment of VECTRA Three-Dimensional Imaging to Accurately Simulate Breast Volume Changes in Transfeminine Patients: A Mannequin Study. Aesthetic Surgery Journal Open Forum, 5, online ahead of print. [DOI:10.1093/asjof/ojad015]
  • Lorincz, A. M., & Sukumar, S. (2006). Molecular links between obesity and breast cancer. Endocrine-Related Cancer, 13(2), 279–292. [DOI:10.1677/erc.1.00729]
  • Lucien, J. N., Ortega, M. T., Calvert, M. E., Smith, C., White, X., Rogers, H., Mosley, B., Agrawal, R., Drude, A., McGee, C., George, M., Brown, A., Downey, K., Wild, C., Njunge, A., Kuzmiak, C. M., Zava, D., Zava, T., Pollard, J., Francis, J., Beery, B. L., Harlin, M., Gonzalez, G. R., & Shaw, N. D. (2022). The Launch of A Girl’s First Period Study: Demystifying Reproductive Hormone Profiles in Adolescent Girls. Journal of Pediatric and Adolescent Gynecology, 35(4), 420–425. [DOI:10.1016/j.jpag.2021.12.018]
  • Lydon, J. P., DeMayo, F. J., Funk, C. R., Mani, S. K., Hughes, A. R., Montgomery, C. A., Shyamala, G., Conneely, O. M., & O’Malley, B. W. (1995). Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. Genes & Development, 9(18), 2266–2278. [DOI:10.1101/gad.9.18.2266]
  • Lyon, A. J., De Bruyn, R., & Grant, D. B. (1985). Isosexual Precocious Puberty in Girls. Acta Paediatrica, 74(6), 950–955. [DOI:10.1111/j.1651-2227.1985.tb10063.x]
  • Lyons, W. R. (1958). Hormonal synergism in mammary growth. Proceedings of the Royal Society of London. Series B - Biological Sciences, 149(936), 303–325. [DOI:10.1098/rspb.1958.0071]
  • Lyons, W. R., & McGinty, D. A. (1941). Effects of estrone and progesterone on male rabbit mammary glands. I. Varying doses of progesterone. Proceedings of the Society for Experimental Biology and Medicine, 48(1), 83–86. [DOI:10.3181/00379727-48-13227]
  • Lyons, W. R., Li, C. H., & Johnson, R. E. (1958). The Hormonal Control of Mammary Growth and Lactation. In Pincus, G. (Ed.). Recent Progress in Hormone Research, Volume 14 [Proceedings of the Laurentian Hormone Conference 1957, Held at Mont Tremblant, Quebec] (pp. 219–254). New York/London: Academic Press. [Google Scholar] [Google Books] [PubMed] [OpenLibrary] [WorldCat] [PDF]
  • MacBryde, C. M. (1939). The Production of Breast Growth in the Human Female. Journal of the American Medical Association, 112(11), 1045–1049. [DOI:10.1001/jama.1939.02800110025006]
  • Malet, C., Gompel, A., Yaneva, H., Cren, H., Fidji, N., Mowszowicz, I., Kuttenn, F., & Mauvais-Jarvis, P. (1991). Estradiol and Progesterone Receptors in Cultured Normal Human Breast Epithelial Cells and Fibroblasts: Immunocytochemical Studies. The Journal of Clinical Endocrinology & Metabolism, 73(1), 8–17. [DOI:10.1210/jcem-73-1-8]
  • Malini, S., Smith, E. O., & Goldzieher, J. W. (1985). Measurement of breast volume by ultrasound during normal menstrual cycles and with oral contraceptive use. Obstetrics and Gynecology, 66(4), 538–541. [Google Scholar] [PubMed] [URL] [PDF]
  • Marshall, W. A. (1978). Puberty. In Falkner, F., & Tanner, J. M. (Eds.). Human Growth: Postnatal Growth (pp. 141–181). Boston: Springer US. [DOI:10.1007/978-1-4684-2622-9_6]
  • Marshall, W. A., & Tanner, J. M. (1969). Variations in pattern of pubertal changes in girls. Archives of Disease in Childhood, 44(235), 291–303. [DOI:10.1136/adc.44.235.291]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1986). Antiestrogen action of progesterone in breast tissue. Breast Cancer Research and Treatment, 8(3), 179–188. [DOI:10.1007/bf01807330]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1986). Estradiol/Progesterone Interaction in Normal and Pathologic Breast Cells. Annals of the New York Academy of Sciences, 464(1), 152–167. [DOI:10.1111/j.1749-6632.1986.tb16002.x]
  • Mauvais-Jarvis, P., Kuttenn, F., & Gompel, A. (1987). Antiestrogen Action of Progesterone in Breast Tissue. Hormone Research, 28(2–4), 212–218. [DOI:10.1159/000180946]
  • Mauvais-Jarvis, P., Kuttenn, F., Gompel, A., & Benotmane, A. (1987). Action anti-estrogène de la progestérone dans le sein. [Antiestrogen action of progesterone in the breast]. Pathologie-Biologie, 35(7), 1081–1086. [Google Scholar 1] [Google Scholar 2] [PubMed]
  • Mauvais-Jarvis, P., Sitruk-Ware, R., & Kuttenn, F. (1981). Benign Breast Disease. In McGuire, W. L. (Ed.). Breast Cancer 4: Advances in Research and Treatment (pp. 51–94). Boston: Springer US. [DOI:10.1007/978-1-4615-6571-0_3]
  • McArthur, J. W. (1966). The Reproductive Endocrinology of Adolescence. In Heald, F. P. (Ed.). Adolescent Gynecology (pp. 9–20). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • McBryan, J., Howlin, J., Napoletano, S., & Martin, F. (2008). Amphiregulin: Role in Mammary Gland Development and Breast Cancer. Journal of Mammary Gland Biology and Neoplasia, 13(2), 159–169. [DOI:10.1007/s10911-008-9075-7]
  • McDonough, P. G., Spicer, D. V., Ursin, G., & Pike, M. C. (1996). Progesterone Concentrations—Physiologic or Pharmacologic? Fertility and Sterility, 65(5), 1077–1078. [DOI:10.1016/s0015-0282(16)58295-8]
  • McMillan, M. (1966). Five cases of testicular feminisation including one with a teratoma of the testis. The Journal of Pathology and Bacteriology, 91(2), 417–427. [DOI:10.1002/path.1700910216]
  • McNally, S., & Stein, T. (2016). Overview of Mammary Gland Development: A Comparison of Mouse and Human. In Martin, F., Stein, T., & Howlin, J. (Eds.). Mammary Gland Development (Methods in Molecular Biology, Volume 1501) (pp. 1–17). New York: Springer New York. [DOI:10.1007/978-1-4939-6475-8_1]
  • McPhaul, M. J. (2002). Androgen receptor mutations and androgen insensitivity. Molecular and Cellular Endocrinology, 198(1–2), 61–67. [DOI:10.1016/s0303-7207(02)00369-6]
  • Meites, J. (1966). Control of mammary growth and lactation. In Martini, L., & Ganong, W. F. (Eds.). Neuroendocrinology, Volume I (pp. 669–707). New York: Academic Press. [Google Scholar] [Google Books] [DOI:10.1016/B978-1-4832-3228-7.50023-2] [OpenLibrary] [WorldCat]
  • Mesiano, S. (2019). Endocrinology of Human Pregnancy and Fetal-Placental Neuroendocrine Development. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 256–284.e9). Philadelphia: Elsevier. [Google Books] [DOI:10.1016/b978-0-323-47912-7.00011-1]
  • Meyer, G., Mayer, M., Mondorf, A., Flügel, A. K., Herrmann, E., & Bojunga, J. (2020). Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. European Journal of Endocrinology, 182(2), 149–156. [DOI:10.1530/eje-19-0463]
  • Meyer, W. J., Finkelstein, J. W., Stuart, C. A., Webb, A., Smith, E. R., Payer, A. F., & Walker, P. A. (1981). Physical and hormonal evaluation of transsexual patients during hormonal therapy. Archives of Sexual Behavior, 10(4), 347–356. [DOI:10.1007/bf01565538]
  • Meyer, W. J., Webb, A., Stuart, C. A., Finkelstein, J. W., Lawrence, B., & Walker, P. A. (1986). Physical and hormonal evaluation of transsexual patients: A longitudinal study. Archives of Sexual Behavior, 15(2), 121–138. [DOI:10.1007/bf01542220]
  • Mikołajczyk, M., Kasielska-Trojan, A., & Antoszewski, B. (2019). A New Tool for Breast Anthropometric Measurements: Presentation and Validation for Women and Men. Aesthetic Plastic Surgery, 43(5), 1160–1170. [DOI:10.1007/s00266-019-01467-6]
  • Milionis, C., Ilias, I., & Koukkou, E. (2022). Progesterone in gender-affirming therapy of trans women. World Journal of Biological Chemistry, 13(3), 66–71. [DOI:10.4331/wjbc.v13.i3.66]
  • Milligan, D., Drife, J. O., & Short, R. V. (1975). Changes in breast volume during normal menstrual cycle and after oral contraceptives. BMJ, 4(5995), 494–496. [DOI:10.1136/bmj.4.5995.494]
  • Morris, J. M. (1953). The syndrome of testicular feminization in male pseudohermaphrodites. American Journal of Obstetrics and Gynecology, 65(6), 1192–1211. [DOI:10.1016/0002-9378(53)90359-7]
  • Morris, J. M., & Mahesh, V. B. (1963). Further observations on the syndrome, “testicular feminization”. American Journal of Obstetrics and Gynecology, 87(6), 731–748. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF]
  • Moss, W. M. (1968). Gigantomastia With Pregnancy. Archives of Surgery, 96(1), 27–32. [DOI:10.1001/archsurg.1968.01330190029007]
  • Muallem, M. M., & Rubeiz, N. G. (2006). Physiological and biological skin changes in pregnancy. Clinics in Dermatology, 24(2), 80–83. [DOI:10.1016/j.clindermatol.2005.10.002]
  • Müller, C. (1953). Zur Hormonalen Kosmetik der Weiblichen Brust: Wirkung und Nebenwirkung Östrogenhaltiger Kosmetischer Präparate. [Hormonal Cosmetics of the Female Breast: Effects and Side Effects of Estrogen-Containing Cosmetic Preparations.] Schweizerische Medizinische Wochenschrift [Swiss Medical Weekly], 83(4), 81–84. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF] [Translation]
  • Muzaffar, F., Hussain, I., & Haroon, T. S. (1998). Physiologic skin changes during pregnancy: a study of 140 cases. International Journal of Dermatology, 37(6), 429–431. [DOI:10.1046/j.1365-4362.1998.00281.x]
  • Naik, M., Diwakar, R. K., Patre, S., & Singh, S. (2015). Gigantomastia: A Rare Complication In Pregnancy. Journal of Medical Science and Clinical Research, 3(7), 6873–6876. [Google Scholar] [URL] [PDF]
  • Naseem, H., Lokman, M., & Fitzgerald, C. (2021). Management of congenital hypogonadotropic hypogonadism in females. Human Fertility, 26(3), 622–631. [DOI:10.1080/14647273.2021.1998929]
  • Nelson, W. O. (1936). Endocrine Control of the Mammary Gland. Physiological Reviews, 16(3), 488–526. [DOI:10.1152/physrev.1936.16.3.488]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study. Endocrine Connections, 11(5), e220170. [DOI:10.1530/EC-22-0170]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects Of Low-dose Oral Micronised Progesterone On Sleep, Psychological Distress And Breast Development In Transgender Individuals Undergoing Feminising Hormone Therapy: A Prospective Controlled Study. Journal of the Endocrine Society, 6(Suppl 1), A653–A654 (abstract no. LBODP089). [DOI:10.1210/jendso/bvac150.1351]
  • Nussbaum, R., & Benedetto, A. V. (2006). Cosmetic aspects of pregnancy. Clinics in Dermatology, 24(2), 133–141. [DOI:10.1016/j.clindermatol.2005.10.007]
  • Nuzzi, L. C., Pramanick, T., Massey, G. G., Walsh, L. R., McNamara, C. T., Firriolo, J. M., DiVasta, A. D., & Labow, B. I. (2021). The Impact of Progestin-only Contraception on Adolescents with Macromastia. Plastic and Reconstructive Surgery - Global Open, 9(2), e3421. [DOI:10.1097/gox.0000000000003421]
  • Nuzzi, L. C., Pramanick, T., Massey, G. G., Walsh, L. R., McNamara, C. T., Firriolo, J. M., DiVasta, A. D., & Labow, B. I. (2022). The Impact of Combined Oral Contraceptives on Adolescents with Macromastia. Plastic and Reconstructive Surgery, 150(4), 731–738. [DOI:10.1097/prs.0000000000009513]
  • Oakes, M. B., Eyvazzadeh, A. D., Quint, E., & Smith, Y. R. (2008). Complete Androgen Insensitivity Syndrome—A Review. Journal of Pediatric and Adolescent Gynecology, 21(6), 305–310. [DOI:10.1016/j.jpag.2007.09.006]
  • Obr, A. E., & Edwards, D. P. (2012). The biology of progesterone receptor in the normal mammary gland and in breast cancer. Molecular and Cellular Endocrinology, 357(1–2), 4–17. [DOI:10.1016/j.mce.2011.10.030]
  • Olanrewaju, F., Onayemi, O., Olasode, O., Adeyemi, A., Oninla, A., Oripelaye, M., Ezejiofor, O., & Oke, O. (2017). Prevalence and Pattern of Pigmentary Changes among Primigravidae Attending a Tertiary Health Facility in South-Western Nigeria. British Journal of Medicine and Medical Research, 21(5), 1–9. [DOI:10.9734/bjmmr/2017/33382]
  • Orentreich, N., & Durr, N. P. (1974). Mammogenesis in Transsexuals. Journal of Investigative Dermatology, 63(1), 142–146. [DOI:10.1111/1523-1747.ep12678272]
  • Pandya, S., & Moore, R. G. (2011). Breast Development and Anatomy. Clinical Obstetrics & Gynecology, 54(1), 91–95. [DOI:10.1097/grf.0b013e318207ffe9]
  • Park, I. Y., Kim, M. R., Jo, H. H., Lee, M. K., & Kim, M. J. (2014). Association of the Nipple-Areola Complexes with Age, Parity, and Breastfeeding in Korean Premenopausal Women. Journal of Human Lactation, 30(4), 474–479. [DOI:10.1177/0890334414549049]
  • Pasqualini, J. R. (2007). Progestins and breast cancer. Gynecological Endocrinology, 23(Suppl 1), 32–41. [DOI:10.1080/09513590701585003]
  • Pasqualini, J. R. (2009). Breast cancer and steroid metabolizing enzymes: The role of progestogens. Maturitas, 65(Suppl 1), S17–S21. [DOI:10.1016/j.maturitas.2009.11.006]
  • Pasqualini, J. R., & Kincl, F. A. (1985). Hormone Production and Concentrations During Pregnancy in Humans and in Other Mammalian Species. In Pasqualini, J. R., & Kincl, F. A. Hormones and the Fetus, Volume I: Production, Concentration and Metabolism During Pregnancy (pp. 173–334). Oxford: Pergamon Press. [DOI:10.1016/b978-0-08-019708-1.50007-6]
  • Patel, H., Arruarana, V., Yao, L., Cui, X., & Ray, E. (2020). Effects of hormones and hormone therapy on breast tissue in transgender patients: a concise review. Endocrine, 68(1), 6–15. [DOI:10.1007/s12020-020-02197-5]
  • Patel, K. T., Adeel, S., Rodrigues Miragaya, J., & Tangpricha, V. (2022). Progestogen Use in Gender-Affirming Hormone Therapy: A Systematic Review. Endocrine Practice, 28(12), 1244–1252. [DOI:10.1016/j.eprac.2022.08.012]
  • Patterson, M. N., McPhaul, M. J., & Hughes, I. A. (1994). Androgen insensitivity syndrome. Baillière’s Clinical Endocrinology and Metabolism, 8(2), 379–404. [DOI:10.1016/s0950-351x(05)80258-7]
  • Pawłowski, B., & Żelaźniewicz, A. (2021). The evolution of perennially enlarged breasts in women: a critical review and a novel hypothesis. Biological Reviews, 96(6), 2794–2809. [DOI:10.1111/brv.12778]
  • Perez-Palacios, G., & Jaffe, R. B. (1972). The Syndrome of Testicular Feminization. Pediatric Clinics of North America, 19(3), 653–667. [DOI:10.1016/s0031-3955(16)32744-4]
  • Petrakis, N. (1978). Recurrent extreme breast involution following pregnancy and susceptibility to breast cancer: A hypothesis. Medical Hypotheses, 4(3), 268–272. [DOI:10.1016/0306-9877(78)90006-3]
  • Pfeiffer, C. A. (1943). Endocrinology of Reproduction. Annual Review of Physiology, 5(1), 413–452. [DOI:10.1146/annurev.ph.05.030143.002213]
  • Pipkin, F. B. (2019). Physiological Changes in Pregnancy. In Symonds, I. M., & Arulkumaran, S. (Eds.). Essential Obstetrics and Gynaecology, 6th Edition (pp. 22–40). Edinburgh: Elsevier. [Google Books] [OpenLibrary] [WorldCat]
  • Plu-Bureau, G., Touraine, P., & Mauvais-Jarvis, P. (1999). Interactions Between Estradiol and Progesterone in Normal Breast: Implications for Mammary Carcinogenesis. In Manni, A. (Ed.). Endocrinology of Breast Cancer (Contemporary Endocrinology, Volume 11) (pp. 21–37). Totowa, New Jersey: Humana Press. [DOI:10.1007/978-1-59259-699-7_2] [OpenLibrary] [Archive.org]
  • Pocock, G., Richards, C. D., & Richards, D. A. (2013). Fertilization, Pregnancy, and Lactation. In Pocock, G., Richards, C. D., & Richards, D. A. Human Physiology, 4th Edition (pp. 655–752). Oxford: Oxford University Press. [Google Scholar] [Google Books]
  • Polani, P. E. (1970). Hormonal and clinical aspects of hermaphroditism and the testicular feminizing syndrome in man. Philosophical Transactions of the Royal Society of London. B, Biological Sciences, 259(828), 187–206. [DOI:10.1098/rstb.1970.0058]
  • Price, S., McManus, J., & Barrett, J. (2019). The transgender population: improving awareness for gynaecologists and their role in the provision of care. The Obstetrician & Gynaecologist, 21(1), 11–20. [DOI:10.1111/tog.12521]
  • Prior, J. C. (2011). Progesterone for Symptomatic Perimenopause Treatment - Progesterone politics, physiology and potential for perimenopause. Facts, Views & Vision in ObGyn, 3(2), 109–120. [PubMed] [PubMed Central] [PDF]
  • Prior, J. C. (2019). Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen. The Journal of Clinical Endocrinology & Metabolism, 104(4), 1181–1186. [DOI:10.1210/jc.2018-01777]
  • Prior, J. C. (2019). Response to Letter to the Editor: “Progesterone Is Important for Transgender Women’s Therapy—Applying Evidence for the Benefits of Progesterone in Ciswomen”. The Journal of Clinical Endocrinology & Metabolism, 104(8), 3129–3130. [DOI:10.1210/jc.2019-00524]
  • Prior, J. C. (2020). Women’s Reproductive System as Balanced Estradiol and Progesterone Actions—A revolutionary, paradigm-shifting concept in women’s health. Drug Discovery Today: Disease Models, 32(Part B), 31–40. [DOI:10.1016/j.ddmod.2020.11.005]
  • Prior, J. C., Vigna, Y. M., & Watson, D. (1989). Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Archives of Sexual Behavior, 18(1), 49–57. [DOI:10.1007/bf01579291]
  • Prior, J. C., Vigna, Y. M., Watson, D., Diewold, P., & Robinow, O. (1986). Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic. Journal of Sex Information & Education Council of Canada, 1(1), 1–7. [Google Scholar] [PDF]
  • Quigley, C. A. (1998). The androgen receptor: Physiology and pathophysiology. In Nieschlag, E., & Behre, H. M. (Eds.). Testosterone: Action · Deficiency · Substitution, 2nd Edition (pp. 33–106). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-72185-4_2]
  • Quigley, C. A., Bellis, A. D., Marschke, K. B., El-Awady, M. K., Wilson, E. M., & French, F. S. (1995). Androgen Receptor Defects: Historical, Clinical, and Molecular Perspectives. Endocrine Reviews, 16(3), 271–321. [DOI:10.1210/edrv-16-3-271]
  • Radisky, D. C., & Hartmann, L. C. (2009). Mammary Involution and Breast Cancer Risk: Transgenic Models and Clinical Studies. Journal of Mammary Gland Biology and Neoplasia, 14(2), 181–191. [DOI:10.1007/s10911-009-9123-y]
  • Ramos, L., Chávez, B., Mares, L., Valdés, E., & Vilchis, F. (2018). Mutational analysis of the androgen receptor (NR3C4) gene in patients with 46,XY DSD. Gene, 641, 86–93. [DOI:10.1016/j.gene.2017.10.038]
  • Ramsay, D. T., Kent, J. C., Hartmann, R. A., & Hartmann, P. E. (2005). Anatomy of the lactating human breast redefined with ultrasound imaging. Journal of Anatomy, 206(6), 525–534. [DOI:10.1111/j.1469-7580.2005.00417.x]
  • Randolph, J. F. (2018). Gender-Affirming Hormone Therapy for Transgender Females. Clinical Obstetrics & Gynecology, 61(4), 705–721. [DOI:10.1097/grf.0000000000000396]
  • Rauh, C., Faschingbauer, F., Haeberle, L., Jud, S. M., Heusinger, K., Fasching, P. A., Goecke, T. W., Rajakaruna, N., Voigt, F., Bani, M. R., Lux, M. P., Renner, S. P., Loehberg, C. R., Hartmann, A., Schulz-Wendtland, R., Beckmann, M. W., & Bayer, C. M. (2013). Factors influencing breast changes after pregnancy. European Journal of Cancer Prevention, 22(3), 259–261. [DOI:10.1097/cej.0b013e328359cb81]
  • Rebar, R. W. (1988). The Ovaries. In Wyngaarden, J. B., & Smith, L. H. (Eds.). Cecil Textbook of Medicine, 18th Edition (pp. 1425–1446). Philadelphia: W. B. Saunders. [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1990). Disorders of Menstruation, Ovulation, and Sexual Response. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Rebar, R. W., Robertson, G. L., & Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 1st Edition (pp. 798–814). Philadelphia: Lippincott. [Google Scholar—3rd/2001 Edition] [Google Books—3rd/2001 Edition] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1993). Normal and Abnormal Sexual Differentiation and Pubertal Development. In Moore, T. R., Reiter, R. C., Rebar, R. W., & Baker, W. (Eds.). Gynecology & Obstetrics: A Longitudinal Approach (pp. 97–133). New York: Churchill Livingstone. [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Rebar, R. W. (1996). Puberty. In Berek, J. S., Adashi, E. Y., & Hillard, P. A. (Eds.). Novak’s Gynecology, 12th Edition (pp. 771–807). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Reisman, T., Goldstein, Z., & Safer, J. D. (2019). A Review of Breast Development in Cisgender Women and Implications for Transgender Women. Endocrine Practice, 25(12), 1338–1345. [DOI:10.4158/ep-2019-0183]
  • Richards, C., & Barrett, J. (2020). Physical Treatments for Trans People and Their Interactions with Psychiatric Treatments. In Richards, C., & Barrett, J. Trans and Non-binary Gender Healthcare for Psychiatrists, Psychologists, and Other Health Professionals (pp. 31–44). Cambridge: Cambridge University Press. [DOI:10.1017/9781108628419.003]
  • Richert, M. M., Schwertfeger, K. L., Ryder, J. W., & Anderson, S. M. (2000). An Atlas of Mouse Mammary Gland Development. Journal of Mammary Gland Biology and Neoplasia, 5(2), 227–241. [DOI:10.1023/a:1026499523505]
  • Rix, J., Mills, C., Ross, E., Allen, S., Lai, A., & Wakefield-Scurr, J. (2023). Breast volume fluctuations are associated with oestradiol and progesterone changes across the menstrual cycle. Research Square, preprint. [Google Scholar] [DOI:10.21203/rs.3.rs-3753080/v1] [PDF]
  • Rodari, G. (2022). Pubertal induction in girls with hypogonadism: estrogen replacement therapy outcomes and optimization of progesterone introduction. (Doctoral thesis, Università degli Studi di Milano.) [URL]
  • Rodari, G., Federici, S., Cattoni, A., Todisco, T., Ubertini, G., Giacchetti, F., Profka, E., Dall’Antonia, A., Cangiano, B., Arosio, M., Bonomi, M., Cappa, M., & Giavoli, C. (2022). Pubertal induction in girls with hypogonadism: insight into estrogen replacement therapy outcomes and optimization of progesterone introduction. Endocrine Abstracts, 81 [24th European Congress of Endocrinology 2022 21–24 May 2022, Milan, Italy], 107–107 (abstract no. RC12.7). [DOI:10.1530/endoabs.81.rc12.7] [PDF]
  • Rodari, G., Federici, S., Todisco, T., Ubertini, G., Cattoni, A., Pagano, M., Giacchetti, F., Profka, E., Citterio, V., Messetti, D., Collini, V., Soranna, D., Carbone, E., Arosio, M., Mantovani, G., Persani, L., Cappa, M., Bonomi, M., & Giavoli, C. (2023). Towards an individualized management of pubertal induction in girls with hypogonadism: insight into the best replacement outcomes from a large multicentre registry. European Journal of Endocrinology, 188(6), 467–476. [DOI:10.1093/ejendo/lvad056]
  • Rohn, R. D. (1989). Nipple (papilla) development in girls: III. Journal of Adolescent Health Care, 10(1), 39–40. [DOI:10.1016/0197-0070(89)90045-4]
  • Rosenfield, R. L. (2013). Adolescent Anovulation: Maturational Mechanisms and Implications. The Journal of Clinical Endocrinology & Metabolism, 98(9), 3572–3583. [DOI:10.1210/jc.2013-1770]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2021). Puberty in the Female and Its Disorders. In Sperling, M. A., Majzoub, J. A., Menon, R. K., & Stratakis, C. A. (Eds.). Sperling Pediatric Endocrinology, 5th Edition (pp. 528–626). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-62520-3.00016-6]
  • Rothman, M. S., & Iwamoto, S. J. (2022). Feminizing Gender-Affirming Hormone Therapy: Special Considerations for Older Adults. In Davis, T. F. (Ed.). A Case-Based Guide to Clinical Endocrinology (pp. 513–523). Cham: Springer. [DOI:10.1007/978-3-030-84367-0_58]
  • Ruan, W., Monaco, M. E., & Kleinberg, D. L. (2005). Progesterone Stimulates Mammary Gland Ductal Morphogenesis by Synergizing with and Enhancing Insulin-Like Growth Factor-I Action. Endocrinology, 146(3), 1170–1178. [DOI:10.1210/en.2004-1360]
  • Rutgers, J. L., & Scully, R. E. (1991). The Androgen Insensitivity Syndrome (Testicular Feminization). International Journal of Gynecological Pathology, 10(2), 126–144. [DOI:10.1097/00004347-199104000-00002]
  • Ryan, R. F., & Pernoll, M. L. (1985). Virginal Hypertrophy. Plastic and Reconstructive Surgery, 75(5), 737–742. [DOI:10.1097/00006534-198505000-00024]
  • Saito, R., Yamamoto, Y., Goto, M., Araki, S., Kubo, K., Kawagoe, R., Kawada, Y., Kusuhara, K., Igarashi, M., & Fukami, M. (2014). Tamoxifen Treatment for Pubertal Gynecomastia in Two Siblings with Partial Androgen Insensitivity Syndrome. Hormone Research in Paediatrics, 81(3), 211–216. [DOI:10.1159/000356923]
  • Sandhu, R., Chollet-Hinton, L., Kirk, E. L., Midkiff, B., & Troester, M. A. (2016). Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma. Human Pathology, 48, 60–68. [DOI:10.1016/j.humpath.2015.09.031]
  • Santen, R. J., Karaguzel, G., Livaoglu, M., Yue, W., Cline, J. M., Ratan, A., & Sasano, H. (2024). Role of ERα and aromatase in juvenile gigantomastia. The Journal of Clinical Endocrinology and Metabolism, online ahead of print. [DOI:10.1210/clinem/dgae019]
  • Sanuki, J., Fukuma, E., & Uchida, Y. (2008). Morphologic Study of Nipple-Areola Complex in 600 Breasts. Aesthetic Plastic Surgery, 33(3), 295–297. [DOI:10.1007/s00266-008-9194-y]
  • Satoh, K., Hovey, R. C., Malewski, T., Warri, A., Goldhar, A. S., Ginsburg, E., Saito, K., Lydon, J. P., & Vonderhaar, B. K. (2007). Progesterone enhances branching morphogenesis in the mouse mammary gland by increased expression of Msx2. Oncogene, 26(54), 7526–7534. [DOI:10.1038/sj.onc.1210555]
  • Schauffler, G. C. (1942). Disorders During Adolescence—The Onset of Menstruation. In Schauffler, G. C. Pediatric Gynecology; with Sections on Urology and Proctology, 1st Edition (pp. 169–211). Chicago: Year Book. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL]
  • Schindler, A. E. (2010). Dydrogesterone and other progestins in benign breast disease: an overview. Archives of Gynecology and Obstetrics, 283(2), 369–371. [DOI:10.1007/s00404-010-1456-7]
  • Scott, P. P., Greene, R., Lane-Roberts, C. S., & Swain, V. (1950). The Function of the Breast. In Saner, F. D. (Ed.). The Breast: Structure, Function, Disease (pp. 53–86). Baltimore: Williams and Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [PDF]
  • Seal, L. (2017). Adult Endocrinology. In Richards, C., Bouman, W. P., & Barker, M.-J. (Eds.). Genderqueer and Non-Binary Genders (Critical and Applied Approaches in Sexuality, Gender and Identity) (pp. 183–223). London: Palgrave Macmillan UK. [DOI:10.1057/978-1-137-51053-2_10]
  • Seal, L. J., Franklin, S., Richards, C., Shishkareva, A., Sinclaire, C., & Barrett, J. (2012). Predictive Markers for Mammoplasty and a Comparison of Side Effect Profiles in Transwomen Taking Various Hormonal Regimens. The Journal of Clinical Endocrinology & Metabolism, 97(12), 4422–4428. [DOI:10.1210/jc.2012-2030]
  • Seibert, B., & Günzel, P. (1994). Animal toxicity studies performed for risk assessment of the once-a-month injectable contraceptive Mesigyna®. Contraception, 49(4), 303–333. [DOI:10.1016/0010-7824(94)90030-2]
  • Shapiro, L. R. (1982). Disorders of Female Sex Differentiation. In Blaustein, A. (Ed.). Pathology of the Female Genital Tract, 2nd Edition (pp. 479–510). New York: Springer New York. [DOI:10.1007/978-1-4757-1767-9_20]
  • Shearman, R. P. (1972). Ovarian Function and its Control. In Shearman, R. P. (Ed.). Human Reproductive Physiology, 1st Edition (pp. 45–90). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Shearman, R. P. (1972). Primary Ammenorhoea. In Dewhurst, C. J. (Ed.). Integrated Obstetrics and Gynaecology for Postgraduates, 1st Edition (pp. 55–62). Oxford: Blackwell Scientific Publications. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • Shi, H. Y., Lydon, J. P., & Zhang, M. (2004). Hormonal Defect in Maspin Heterozygous Mice Reveals a Role of Progesterone in Pubertal Ductal Development. Molecular Endocrinology, 18(9), 2196–2207. [DOI:10.1210/me.2004-0052]
  • Shuttleworth, F. K. (1938). The Adolescent Period: A Graphic and Pictorial Atlas (Monographs of the Society for Research in Child Development, Volume 3, Number 3 / Serial No. 16). Washington, D. C.: Society for Research in Child Development. [Google Scholar] [Google Books] [DOI:10.2307/1165482]
  • Simmer, H. H., Pion, R. J., & Dignam, W. J. (1965). Testicular Feminization: Endocrine Function of Feminizing Testes, Comparison with Normal Testes. Springfield, Illinois: Thomas. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Simpson, J. L., & Rebar, R. W. (1990). Normal and Abnormal Sexual Differentiation and Development. In Becker, K. L., Bilezikian, J. P., Bremner, W. J., Hung, W., Kahn, C. R., Loriaux, D. L., Rebar, R. W., Robertson, G. L., & Wartofsky, L. (Eds.). Principles and Practice of Endocrinology and Metabolism, 1st Edition (pp. 710–739). Philadelphia: Lippincott. [Google Scholar] [Google Books—3rd/2001 Edition] [OpenLibrary] [WorldCat] [Archive.org]
  • Sindi, R., Sá Dos Reis, C., Bennett, C., Stevenson, G., & Sun, Z. (2019). Quantitative Measurements of Breast Density Using Magnetic Resonance Imaging: A Systematic Review and Meta-Analysis. Journal of Clinical Medicine, 8(5), 745. [DOI:10.3390/jcm8050745]
  • Sitruk-Ware, R., Basdevant, A., de Lignières, B., & Mauvais-Jarvis, P. (1984). Percutaneous oestrogen therapy. In van Herendael, H., van Herendael, B., Riphagen, F. E., Goessens, L., & van der Plas, H. (Eds.). The Climacteric: An Update: Proceedings of the fourth Jan Palfijn Symposium, European Conference on the Menopause, held in Antwerp, Belgium, on September 1–2, 1983, under the auspices of ‘De Vereniging voor Nederlandstalige gynecologen van België’ and ‘The International Menopause Society’ (pp. 127–139). Lancaster: MTP Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [DOI:10.1007/978-94-009-5608-7_14]
  • Sizonenko, P. C. (1978). Endocrinology in Preadolescents and Adolescents. American Journal of Diseases of Children, 132(7), 704–712. [DOI:10.1001/archpedi.1978.02120320064015]
  • Škarda, J., Fremrová, V., & Bezecný, I. (1989). Progesterone alone is responsible for stimulation of the growth of ducts and of mammary alveolar structures in mice. Endocrinologia Experimentalis, 23(1), 17–28. [Google Scholar] [PubMed] [PDF]
  • Sobrinho, L. G., Kase, N., & Grunt, J. A. (1971). Spontaneous pubertal breast growth in a castrated patient with the syndrome of testicular feminization. The Yale Journal of Biology and Medicine, 44(2), 225–9. [Google Scholar] [PubMed] [PubMed Central] [PDF]
  • Sosa, M., Jódar, E., Arbelo, E., Domínguez, C., Saavedra, P., Torres, A., Salido, E., de Tejada, M. J., & Hernández, D. (2003). Bone Mass, Bone Turnover, Vitamin D, and Estrogen Receptor Gene Polymorphisms in Male to Female Transsexuals. Journal of Clinical Densitometry, 6(3), 297–304. [DOI:10.1385/jcd:6:3:297]
  • Sosa, M., Jódar, E., Arbelo, E., Domı́nguez, C., Saavedra, P., Torres, A., Salido, E., Limiñana, J., Gómez de Tejada, M. J., & Hernández, D. (2004). Serum lipids and estrogen receptor gene polymorphisms in male-to-female transsexuals: effects of estrogen treatment. European Journal of Internal Medicine, 15(4), 231–237. [DOI:10.1016/j.ejim.2004.04.009]
  • Soyal, S., Ismail, P. M., Li, J., Mulac-Jericevic, B., Conneely, O. M., & Lydon, J. P. (2002). Progesterone receptors - animal models and cell signaling in breast cancer: Progesterone’s role in mammary gland development and tumorigenesis as disclosed by experimental mouse genetics. Breast Cancer Research, 4(5), 191. [DOI:10.1186/bcr451]
  • Sperling, R. L., & Gold, J. J. (1973). Use of an anti-estrogen after a reduction mammaplasty to prevent recurrence of virginal hypertrophy of breasts. Plastic and Reconstructive Surgery, 52(4), 439–442. [DOI:10.1097/00006534-197352040-00030]
  • Spitz, I. M., Shoupe, D., Sitruk-Ware, R., & Mishell, D. R. (1989). Response to the antiprogestagen RU 486 (mifepristone) during early pregnancy and the menstrual cycle in women. Journal of Reproduction and Fertility Supplement, 37, 253–260. [Google Scholar] [PubMed]
  • Spitz, I., Croxatto, H., Lahteenmaki, P., Heikinheimo, O., & Bardin, C. (1994). Effect of mifepristone on inhibition of ovulation and induction of luteolysis. Human Reproduction, 9(Suppl 1), 69–76. [DOI:10.1093/humrep/9.suppl_1.69]
  • Spitz, I. M. (2010). Mifepristone: where do we come from and where are we going? Contraception, 82(5), 442–452. [DOI:10.1016/j.contraception.2009.12.012]
  • Sridhar, G. R., & Sinha, M. J. (1995). Macromastia in adolescent girls. Indian Pediatrics, 32(4), 496–499. [Google Scholar] [PubMed] [PDF]
  • Sun, B. Z., Kangarloo, T., Adams, J. M., Sluss, P. M., Welt, C. K., Chandler, D. W., Zava, D. T., McGrath, J. A., Umbach, D. M., Hall, J. E., & Shaw, N. D. (2018). Healthy Post-Menarchal Adolescent Girls Demonstrate Multi-Level Reproductive Axis Immaturity. The Journal of Clinical Endocrinology & Metabolism, 104(2), 613–623. [DOI:10.1210/jc.2018-00595]
  • Sun, S. X., Bostanci, Z., Kass, R. B., Mancino, A. T., Rosenbloom, A. L., Klimberg, V. S., & Bland, K. I. (2018). Breast Physiology: Normal and Abnormal Development and Function. In Bland, K. I., Copeland, E. M., Klimberg, V. S., Gradishar, W. J., White, J., & Korourian, S. (Eds.). The Breast: Comprehensive Management of Benign and Malignant Diseases, 5th Edition (pp. 37–56.e6). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-35955-9.00003-9]
  • Swelstad, M. R., Swelstad, B. B., Rao, V. K., & Gutowski, K. A. (2006). Management of Gestational Gigantomastia. Plastic and Reconstructive Surgery, 118(4), 840–848. [DOI:10.1097/01.prs.0000232364.40958.47]
  • Tack, L. J., Heyse, R., Craen, M., Dhondt, K., Bossche, H. V., Laridaen, J., & Cools, M. (2017). Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents. The Journal of Sexual Medicine, 14(5), 747–757. [DOI:10.1016/j.jsxm.2017.03.251]
  • Talbert, L. M., Hammond, M. G., Groff, T., & Udry, J. R. (1985). Relationship of age and pubertal development to ovulation in adolescent girls. Obstetrics & Gynecology, 66(4), 542–544. [Google Scholar] [PubMed] [URL]
  • Tanos, T., & Brisken, C. (2008). What Signals Operate in the Mammary Niche? Breast Disease, 29(1), 69–82. [DOI:10.3233/bd-2008-29108]
  • Thanaboonyawat, I., Chanprapaph, P., Lattalapkul, J., & Rongluen, S. (2013). Pilot Study of Normal Development of Nipples during Pregnancy. Journal of Human Lactation, 29(4), 480–483. [DOI:10.1177/0890334413493350]
  • Thody, A. J., & Smith, A. G. (1977). Hormones and Skin Pigmentation in the Mammal. International Journal of Dermatology, 16(8), 657–664. [DOI:10.1111/j.1365-4362.1977.tb01876.x]
  • Thoresen, M., & Wesche, J. (1988). Doppler measurements of changes in human mammary and uterine blood flow during pregnancy and lactation. Acta Obstetricia et Gynecologica Scandinavica, 67(8), 741–745. [DOI:10.3109/00016349809004301]
  • Tiefenbacher, K., & Daxenbichler, G. (2008). The Role of Androgens in Normal and Malignant Breast Tissue. Breast Care, 3(5), 325–331. [DOI:10.1159/000158055]
  • Tim, F., Jeroen, V., & T’Sjoen, G. (2023). Dose Reduction of Cyproterone Acetate in Trans Women and the Effect on Patient-reported Outcomes: Results from the ENIGI Study. Endocrine Abstracts, 97 [Belgian Endocrine Society 2023], 5–5 (abstract no. 007). [URL] [PDF]
  • Trabert, B., Sherman, M. E., Kannan, N., & Stanczyk, F. Z. (2019). Progesterone and Breast Cancer. Endocrine Reviews, 41(2), 320–344. [DOI:10.1210/endrev/bnz001]
  • Tucker, H. (2000). Hormones, Mammary Growth, and Lactation: a 41-Year Perspective. Journal of Dairy Science, 83(4), 874–884. [DOI:10.3168/jds.s0022-0302(00)74951-4]
  • Turan, S., Bereket, A., Guran, T., Akcay, T., Papari-Zareei, M., & Auchus, R. J. (2009). Puberty in a case with novel 17-hydroxylase mutation and the putative role of estrogen in development of pubic hair. European Journal of Endocrinology, 160(2), 325–330. [DOI:10.1530/eje-08-0632]
  • Turner, C. W. (1939). The Mammary Glands. In Allen, E., Danforth, C. H., & Doisy, E. A. (Eds.). Sex and Internal Secretions: A Survey of Recent Research, 2nd Edition (pp. 740–803). Baltimore: Williams & Wilkins. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Ulrich, U., Pfeifer, T., & Lauritzen, C. (1994). Rapid Increase in Lumbar Spine Bone Density in Osteopenic Women by High-Dose Intramuscular Estrogen-Progestogen Injections. Hormone and Metabolic Research, 26(9), 428–431. [DOI:10.1055/s-2007-1001723]
  • Ulrich, U., Pfeifer, T., Buck, G., Keckstein, J., & Lauritzen, C. (1995). High-dose estrogen-progestogen injections in gonadal dysgenesis, ovarian hypoplasia, and androgen insensitivity syndrome: Impact on bone density. Adolescent and Pediatric Gynecology, 8(1), 20–23. [DOI:10.1016/s0932-8610(12)80156-3]
  • Valentine, G. H. (1969). Chromosome Anomalies in the Female. In Valentine, G. H. The Chromosome Disorders: An Introduction for Clinicians, 2nd Edition (pp. 126–143). London: W. Heinemann Medical Books. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org]
  • van der Meulen, A. J. (1974). An unusual case of massive hypertrophy of the breasts. South African Medical Journal=Suid-Afrikaanse Tydskrif vir Geneeskunde, 48(34), 1465–1466. [Google Scholar] [PubMed] [URL 1] [URL 2]
  • Vandeweyer, E., & Hertens, D. (2002). Quantification of glands and fat in breast tissue: An experimental determination. Annals of Anatomy - Anatomischer Anzeiger, 184(2), 181–184. [DOI:10.1016/s0940-9602(02)80016-4]
  • Venturoli, S., Fabbri, R., Porcu, E., Paradisi, R., Orsini, L. F., Brondelli, L., Ruggeri, S., & Flamigni, C. (1989). Endocrine and ovarian parameters at various frequencies of ovulation in adolescents. Archives of Gynecology and Obstetrics, 246(2), 107–114. [DOI:10.1007/bf00934127]
  • Venturoli, S., Porcu, E., Fabbri, R., Magrini, O., Paradisi, R., Pallotti, G., Gammi, L., & Flamigni, C. (1987). Postmenarchal evolution of endocrine pattern and ovarian aspects in adolescents with menstrual irregularities. Fertility and Sterility, 48(1), 78–85. [DOI:10.1016/s0015-0282(16)59294-2]
  • Vorherr, H. (1974). Development of the Female Breast. In Vorherr, H. The Breast: Morphology, Physiology, and Lactation (pp. 1–19). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Vorherr, H. (1974). Morphology of the Mature Female Breast. In Vorherr, H. The Breast: Morphology, Physiology, and Lactation (pp. 20–70). New York: Academic Press. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Wade, T. R., Wade, S. L., & Jones, H. E. (1978). Skin changes and diseases associated with pregnancy. Obstetrics and Gynecology, 52(2), 233–242. [Google Scholar] [PubMed] [URL]
  • Walker, M., Baker, G., & Lamb, M. (2013). Physiology of the Breast During Pregnancy and Lactation. In Mannel, R., Martens, P. J., & Walker, M. (Eds.). Core Curriculum for Lactation Consultant Practice, 3rd Edition (pp. 287–300). Burlington: Jones & Bartlett Learning. [Google Scholar] [Google Books—2013/3rd Edition] [Google Books—2008/2nd Edition] [OpenLibrary] [WorldCat]
  • Wang, C., Luan, J., Cheng, H., Chen, L., Li, Z., Panayi, A. C., & Liu, C. (2018). Menstrual Cycle-Related Fluctuations in Breast Volume Measured Using Three-Dimensional Imaging: Implications for Volumetric Evaluation in Breast Augmentation. Aesthetic Plastic Surgery, 43(1), 1–6. [DOI:10.1007/s00266-018-1243-6]
  • Wang, Q. A., & Scherer, P. E. (2019). Remodeling of Murine Mammary Adipose Tissue during Pregnancy, Lactation, and Involution. Journal of Mammary Gland Biology and Neoplasia, 24(3), 207–212. [DOI:10.1007/s10911-019-09434-2]
  • Weisberg, M. G., Malkasian, G. D., & Pratt, J. H. (1970). Testicular feminization syndrome. American Journal of Obstetrics and Gynecology, 107(8), 1181–1187. [DOI:10.1016/s0002-9378(15)30367-7]
  • Wellons, M. F., & Rebar, R. W. (2013). Amenorrhea. In Falcone, T., & Hurd, W. W. (Eds.). Clinical Reproductive Medicine and Surgery: A Practical Guide, 2nd Edition (pp. 105–112). New York: Springer New York. [DOI:10.1007/978-1-4614-6837-0_7]
  • Wellons, M. F., Weeber, K. M., & Rebar, R. W. (2017). Amenorrhea. In Falcone, T., & Hurd, W. W. (Eds.). Clinical Reproductive Medicine and Surgery, 3rd Edition (pp. 109–122). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-52210-4_6]
  • Werner, A. A. (1935). Experiment to produce lactation in castrate women. Endocrinology, 19(2), 144–150. [DOI:10.1210/endo-19-2-144]
  • Whiteley, S. (1994). Predictors of Milk Production in Lactating Women. (Master’s thesis, The Open University.) [Google Scholar] [DOI:10.21954/ou.ro.0000fe02] [URL]
  • Wierckx, K., Gooren, L., & T’Sjoen, G. (2014). Clinical Review: Breast Development in Trans Women Receiving Cross-Sex Hormones. The Journal of Sexual Medicine, 11(5), 1240–1247. [DOI:10.1111/jsm.12487]
  • Wierckx, K., Van Caenegem, E., Schreiner, T., Haraldsen, I., Fisher, A., Toye, K., Kaufman, J. M., & T’Sjoen, G. (2014). Cross‐Sex Hormone Therapy in Trans Persons Is Safe and Effective at Short‐Time Follow‐Up: Results from the European Network for the Investigation of Gender Incongruence. The Journal of Sexual Medicine, 11(8), 1999–2011. [DOI:10.1111/jsm.12571]
  • Wilson, J. D. (1968 March 28). Medical Grand Rounds: Testicular Feminization. Parkland Memorial Hospital, UT Southwestern Medical Center. [Google Scholar] [URL] [PDF]
  • Wilson, C. L., Sims, A. H., Howell, A., Miller, C. J., & Clarke, R. B. (2006). Effects of oestrogen on gene expression in epithelium and stroma of normal human breast tissue. Endocrine-Related Cancer, 13(2), 617–628. [DOI:10.1677/erc.1.01165]
  • Winkler, U. H., Schindler, A. E., Brinkmann, U. S., Ebert, C., & Oberhoff, C. (2001). Cyclic progestin therapy for the management of mastopathy and mastodynia. Gynecological Endocrinology, 15(Suppl 6), 37–43. [DOI:10.1080/gye.15.s6.37.43]
  • Wisniewski, A. B., Migeon, C. J., Meyer-Bahlburg, H. F., Gearhart, J. P., Berkovitz, G. D., Brown, T. R., & Money, J. (2000). Complete Androgen Insensitivity Syndrome: Long-Term Medical, Surgical, and Psychosexual Outcome. The Journal of Clinical Endocrinology & Metabolism, 85(8), 2664–2669. [DOI:10.1210/jcem.85.8.6742]
  • Wong, R. C., & Ellis, C. N. (1984). Physiologic skin changes in pregnancy. Journal of the American Academy of Dermatology, 10(6), 929–940. [DOI:10.1016/s0190-9622(84)80305-9]
  • Wren, B. G., & Eden, J. A. (1996). Do Progestogens Reduce The Risk of Breast Cancer? A Review of the Evidence. Menopause, 3(1), 4–12. [DOI:10.1097/00042192-199603010-00003]
  • Wright, E. M. (2015). Breastfeeding and the Mother–Newborn Dyad (pp. 1157–1182). In King, T. L., Brucker, M. C., Kriebs, J. M., Fahey, J. O., Gegor, C. L., & Varney, H. (Eds.). Varney’s Midwifery, 5th Edition. Burlington: Jones & Bartlett Learning. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Xu, P., Ye, W., Zhong, S., Li, H., Feng, E., Lin, S. H., Kuo, C. T., Liu, J. Y., & Lin, Y. C. (2010). Leptin and zeranol up-regulate cyclin D1 expression in primary cultured normal human breast pre-adipocytes. Molecular Medicine Reports, 3(6), 983–990. [DOI:10.3892/mmr.2010.370]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]
  • Zacharin, M. (2000). Use of androgens and oestrogens in adolescents - A review of hormone replacement treatment. Journal of Pediatric Endocrinology and Metabolism, 13(1), 3–12. [DOI:10.1515/JPEM.2000.13.1.3]
  • Zachmann, M., Prader, A., Sobel, E. H., Crigler, J. F., Ritzén, E. M., Atarés, M., & Ferrandez, A. (1986). Pubertal growth in patients with androgen insensitivity: Indirect evidence for the importance of estrogens in pubertal growth of girls. The Journal of Pediatrics, 108(5), 694–697. [DOI:10.1016/s0022-3476(86)81043-5]
  • Żelaźniewicz, A., & Pawłowski, B. (2015). Breast size and asymmetry during pregnancy in dependence of a fetus’s sex. American Journal of Human Biology, 27(5), 690–696. [DOI:10.1002/ajhb.22716]
  • Żelaźniewicz, A., & Pawłowski, B. (2018). Maternal breast volume in pregnancy and lactation capacity. American Journal of Physical Anthropology, 168(1), 180–189. [DOI:10.1002/ajpa.23734]
  • Zhang, D., Yao, F., Tian, T., Deng, S., Luo, M., & Tian, Q. (2021). Clinical characteristics and molecular genetics of complete androgen insensitivity syndrome patients: a series study of 30 cases from a Chinese tertiary medical center. Fertility and Sterility, 115(5), 1270–1279. [DOI:10.1016/j.fertnstert.2020.12.008]
\ No newline at end of file diff --git a/transfemscience.org/articles/spiro-testosterone/index.html b/transfemscience.org/articles/spiro-testosterone/index.html index f333efd29..a046d8a32 100644 --- a/transfemscience.org/articles/spiro-testosterone/index.html +++ b/transfemscience.org/articles/spiro-testosterone/index.html @@ -1 +1 @@ -A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People - Transfeminine Science Link

A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People

By Aly | First published December 19, 2018 | Last modified April 5, 2024

Abstract / TL;DR

Spironolactone is an antiandrogen used in transfeminine hormone therapy which is especially employed in the United States. It is widely considered to act as an androgen receptor antagonist and as an androgen synthesis inhibitor, both blocking the actions of testosterone and lowering testosterone levels in transfeminine people. A literature search was conducted to review studies assessing the influence of spironolactone on testosterone levels in cisgender men, cisgender women, and transfeminine people. The results of these studies were mixed, but in most studies spironolactone showed no apparent influence on testosterone levels. These findings suggest that spironolactone has inconsistent and limited effects on testosterone levels. Moreover, these data, as well as studies of estradiol alone, indicate that estradiol is mainly responsible for lowered testosterone levels when the combination of estradiol and spironolactone is used for hormone therapy in transfeminine people. Besides testosterone suppression, spironolactone also acts as a direct antagonist of the androgen receptor, and this importantly contributes to its antiandrogenic efficacy as well. However, studies in cisgender women suggest that spironolactone is a relatively weak androgen receptor antagonist, and is likely best-suited for blocking relatively low testosterone levels. Taken together, the antiandrogenic effectiveness of spironolactone in transfeminine people appears to be limited. Other antiandrogenic approaches may be more effective in transfeminine people, and may be considered instead or as alternatives to spironolactone in those in whom testosterone levels with estradiol plus spironolactone remain inadequately suppressed.

Introduction

Spironolactone, also known by its major brand name Aldactone, is an antiandrogen which is commonly used in transfeminine hormone therapy. It is used in combination with estrogen in transfeminine people to help reduce the effects of testosterone. Spironolactone is used in transfeminine hormone therapy particularly in the United States, where another antiandrogen, cyproterone acetate (CPA; brand name Androcur), is unavailable. Conversely, CPA is the main antiandrogen used in transfeminine people in Europe and most of the rest of the world. Another type of medication, gonadotropin-releasing hormone (GnRH) agonists, are the major antiandrogens used in certain places like the United Kingdom. The combination of estradiol with CPA or a GnRH agonist in transfeminine people consistently suppresses testosterone levels into the normal female range (<50 ng/dL or <1.8 nmol/L) (Aly, 2018; Aly, 2019). Hence, both CPA and GnRH agonists are very effective antiandrogens in transfeminine people.

Spironolactone acts as an androgen receptor antagonist, but is also known to function as an androgen synthesis inhibitor. As an example, spironolactone has been shown in preclinical research to inhibit several enzymes involved in gonadal and adrenal androgen production, including CYP17A1 (17α-hydroxylase/17,20-lyase) among others, and to substantially decrease concentrations of androgens in these studies (Loriaux et al., 1976; Callan, 1988; McMullen & Van Herle, 1993). However, the steroid synthesis inhibition of spironolactone appears to only occur at very high doses and concentrations of spironolactone (Loriaux et al., 1976; McMullen & Van Herle, 1993). For example, spironolactone is used at 10- to 20-fold smaller doses by body weight in humans than in animal studies that have demonstrated substantial steroid synthesis inhibition with the agent (McMullen & Van Herle, 1993).

A widespread notion in the transgender community, as well as in the transgender health community and in the medical literature, is that spironolactone decreases testosterone levels and that this is a major part of how it works as an antiandrogen in transfeminine people. In actuality however, the clinical evidence to support this notion appears to be limited, and available data from studies appear to be highly conflicting. The purpose of this article is to review the available clinical studies on spironolactone and testosterone levels in cisgender men, cisgender women, and transfeminine people in order to help elucidate whether and to what extent spironolactone lowers testosterone levels in humans. In addition, the role of androgen receptor blockade in the antiandrogenic effects of spironolactone is briefly reviewed.

Spironolactone and Testosterone Levels

A literature search was performed to identify studies assessing the influence of spironolactone on levels of testosterone as well as other relevant sex hormones in cisgender men and transfeminine people. Other sex hormones besides testosterone included dihydrotestosterone (DHT), androstenedione (A4), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin, among others. Search engines included PubMed/MEDLINE and Google Scholar and relevant keywords were employed (e.g., “spironolactone”, “aldactone”, “testosterone”). Both observational studies (e.g., retrospective and prospective cohort and case–control studies) as well as randomized controlled trials (RCTs) where available were included. Studies are discussed separately based on whether they used spironolactone alone in cisgender men, spironolactone in cisgender women, spironolactone alone in transfeminine people, or spironolactone combined with estrogen in transfeminine people.

Spironolactone Alone in Cisgender Males

A total of 22 studies of spironolactone and sex hormone levels in cisgender males were identified (Table 1). These studies assessed pre-treatment versus post-treatment hormone levels with spironolactone, hormone levels with spironolactone versus a comparator group, or both. Within the identified studies, testosterone levels were not significantly changed in 12 of 22 studies (55%), decreased in 4 of 22 (18%) studies, increased in 1 of 22 (4.5%) studies, and mixed or unknown (e.g. divergences in changes of total versus free testosterone levels or didn’t actually report testosterone levels) in 4 of 22 (18%) studies. Most of the studies were very small (fewer than 10 people), with several exceptions. The studies were of highly variable lengths, with some being several days and others lasting for weeks or months. Few of the studies were RCTs. Most of the studies were very old, with a majority published in the 1970s and the rest published in the 1980s and 1990s. In relation to the preceding, the quality of data was limited.

Table 1: Studies of sex hormone levels with spironolactone alone in cisgender males:

Treatment and subjectsFindingsSource(s)
100 mg/day for 2 weeks in 7 healthy men (23–34 years)T significantly decreased and LH significantly increased. No significant change in E1, E2, or E3. No change urinary total T excretion but significantly increased urinary total E excretion (including of E1 (7.72 to 10.54 µg/24 hrs), E2 (2.60 to 3.34 ug/24 hours), E3 (7.69 to 11.75 µg/24 hrs)). Slightly but significantly decreased excretion of 17-KS in urine.Pentikäinen et al. (1974)
400 mg/day for 5 days in 6 healthy men (21–33 years)Significant increase in P4 and 17α-OHP (approximately doubled) for whole duration. Small and transient increases in LH (+20%) and FSH on the 2nd but not on the 3rd or 5th days (only other days measured). No significant changes in T, E2, or PRL. E2 and PRL non-significantly increased (+56% and +34% on the 5th day, respectively).Stripp et al. (1975)
100 or 400 mg/day spironolactone for 8 weeks in 7 orchiectomized men (46–78 years) with metastatic prostate cancerT, A4, and DHEA significantly decreased with both doses of spironolactone and of similar magnitude between doses. Influence more apparent after 2–3 weeks of treatment.Walsh & Siiteri (1975)
5 mg/kg/day for 1 week (275 mg/day for a 55 kg person) in 7 boys with delayed puberty (14–16 years)Significant increase in LH (+60%) and non-significant increase in FSH (+60%); individual responses for FSH variable. Increased P4 and 17α-OHP. T and E2 not actually reported.Santen et al. (1976)
Initially 400 mg/day for 12 weeks; dosage later decreased in some due to hypotension (range 150–400 mg/day) in 5 men and 5 women (3 premenopausal, 2 postmenopausal) with normal or low renin hypertensionP4 and 17α-OHP increased by 2 to 4 times compared to pre-treatment and post-treatment. T, E2, LH, FSH, PRL, and 17-KS all unchanged.Taylor et al. (1976)
100 mg/day for 4 weeks, then 0 mg/day for 4 weeks, then 400 mg/day for 4 weeks in 9 healthy men (18–39 years; mean 25 years)Dialyzable fraction of T increased significantly (+20%). LH, FSH, T, and E2 unchanged. LH and FSH responses to GnRH agonist unchanged.Caminos-Torres, Ma, & Snyder (1977)
400 mg/day for 24 weeks in 9 healthy men (21–28 years)No changes in LH, FSH, T, or E2.Caminos-Torres, Ma, & Snyder (1977)
200–400 mg/day for 4–13 months (mean 7 months) in 6 men with hypertension (35–61 years; mean 47 years) vs. 10 untreated male controls with hypertension (mean age 45 years)Significantly greater LH and E2 (30 pg/mL vs. 13 pg/mL; +130%), significantly lower T (440 ng/dL vs. 270 ng/dL; –38%), no difference in FSH. Also, significantly greater metabolic clearance rate of T, significantly greater rate of peripheral conversion (conversion ratio and transfer constant) of T into E2, non-significantly greater metabolic clearance rate of E2, no difference in blood production rate of T, and significantly greater blood production rate of E2.Rose et al. (1977)
200–400 mg/day (mean 330 mg/day) for 20–27 days in 5 gonadally intact men (50–76 years) with prostate cancerP4 increased significantly from 0.25 ± 0.10 ng/mL (mean ± SD) to maximum of 1.3 ± 0.31 ng/mL by 20 days (increase of 5.2-fold or 420%). T decreased significantly from 427 ± 74.3 ng/dL to 200 ± 80.3 ng/dL (–53.2%). No significant change in E2, LH, or FSH.Baba (1977); Baba et al. (1978)
200 mg/day for 21 days in 4 healthy men (26–35 years)No change in total T or E2. Unbound T and E2 slightly but significantly increased. Thought to be due to a direct interaction of spironolactone metabolites with the plasma protein binding of T and E2. But not due to binding to SHBG as T binding to SHBG was not significantly altered.Horth et al. (1977); Horth et al. (1979)
200 mg/day for 1 week in 6 normal men (23–40 years) (RCT)No changes in T, LH, or P4.Huffman et al. (1978)
100 mg/day for 10 months in 10 normal men (23–40 years) (RCT)No changes in T, E2, E3, LH, FSH, P4, or PRL. No change in metabolic clearance of A4 or T.Huffman et al. (1978)
100 mg/day for 2 months, then 200 mg/day for 8 months in 8 normal men (23–40 years) (RCT)No changes in T, E2, E3, LH, FSH, P4, or PRL. No change in metabolic clearance of A4 or T.Huffman et al. (1978)
75–150 mg/day for 12 weeks in 6 men with essential hypertension (28–64 years; mean 48 years)E1 significantly increased. E2 small, gradual, non-significant increase. T, LH, and PRL not significantly changed. PRL responses to TRH normal/not significantly changed.Miyatake et al. (1978)
150–300 mg/day for 40 weeks in 2 men with idiopathic hyperaldosteronism (23 and 44 years)E1 increased. E2 fluctuated. E2 increased by 10-fold in one person by 16 weeks and this was associated with gynecomastia. T, LH, and PRL not altered significantly.Miyatake et al. (1978)
200 mg/day for 10 days (n=5) vs. placebo (n=5) in 10 healthy men (18–31 years) (RCT)Significantly greater urinary A4, urinary EC, and urinary total E excretion. Differences in T, E2, LH, and FSH as well as urinary DHEA, LH, and FSH not significant. Examination of interaction between treatment and time showed significant changes in T, LH, and urinary DHEA. Concluded that there was a transient rise in T and urine DHEA for 2–4 days followed by increase in LH and normalization of T and DHEA excretion after 4–10 days.Tidd et al. (1978)
300 mg/day for 7 days (n=5) vs. 200 mg/day triamterene (n=5) in 10 normal young men with diet-induced hyperaldosteronism (14 days of a diet modifying electrolyte intake)P4, 17α-OHP, unchanged. T near-but-non-significantly decreased (704.6 ± 55.5 ng/dL (mean ± SEM) to 508.4 ± 45.9 ng/dL on day 6; p < 0.10). Also assessed endogenous corticosteroids.Abshagen et al. (1978); Spörl (1978/1979)
100 mg/day for 3 months in treatment group of 47 men (age 60–80 years) with BPH; control group of 58 healthy men without BPH (also age 60–80 years)In spiro/BPH group, T decreased from 650 ng/dL to 290 ng/dL and DHT decreased from 450 ng/dL to 150 ng/dL. In control/non-BPH group, T was 280 ng/dL and DHT was 90 ng/dL. P4, E2, and LH increased in spiro/BPH group. FSH also assessed. The authors stated that prostate gland can be a source of androgen production, implying that BPH can produce elevated androgen levels and that spironolactone can normalize elevated androgen levels in the condition.Zgliczynski, Baranowska, & Szymanowski (1981)
150 mg/m2/day for 5 days in 6 boys with irregular puberty (11–13 years)No significant changes in T or urinary 17-KS excretion, elevated LH (by 600%—likely typo of “60%” (?)), and slightly increased FSH (from 0.75 ng/mL to 0.86 ng/mL).Skorodok, Savchenko, & Liss (1983)
50–200 mg/day for 3 months in 17 males and 19 females (36 people total; 18–38 years, mean 24 years) with severe acneMales no significant changes in T, SHBG, DHT, or FAI.Goodfellow et al. (1984)
50 mg/day for 4 weeks in 13 males (28–60 years, mean 47 years) with rosaceaNo changes in T, A4, DHT, or DHEA-S. 17α-OHP significantly increased (from 1.0 ± 0.65 ng/mL (mean ± SD) to 1.7 ± 0.98 ng/mL; +70%). E2 non-significantly increased (from 61 ± 29 pg/mL to 77 ± 45 pg/mL; +26%).Aizawa & Niimura (1992)
25–400 mg/day (median 100 mg/day) for 12 months in 32 males (59%) of a group of 54 males (17–64 years; mean 44 years) with non-alcoholic liver disease requiring liver transplantation vs. 469 healthy male controls (mean 31 years) with normal liver functionSignificantly decreased T with spironolactone in men with moderate-severity liver disease but not with low- or high-severity liver disease. SHBG not influenced by spironolactone dosage. No influence on gonadotropin responses to GnRH stimulation.Handelsman et al. (1995)

Abbreviations: T = testosterone; E2 = estradiol; E1 = estrone; E3 = estriol; E = estrogen(s); P4 = progesterone; 17α-OHP = 17α-hydroxyprogesterone; A4 = androstenedione; EC = etiocholanolone; DHT = dihydrotestosterone; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; 17-KS = 17-ketosteroids; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; PRL = prolactin; TRH = thyrotropin-releasing hormone; FAI = free androgen index; SHBG = sex hormone-binding globulin; BPH = benign prostatic hyperplasia; RCT = randomized controlled trial.

A few additional studies with the spironolactone-related drugs canrenone or potassium canrenoate (a prodrug of canrenone) (e.g., Soldactona) were also identified (Dymling, Nilsson, & Hökfelt, 1972; Dymling & Hökfelt, 1973; Erbler, 1974; Corvol et al., 1976; Dymling, 1978). These studies are notable as canrenone is a known active metabolite of spironolactone and as the studies consistently found decreased androgen levels with drugs delivering canrenone. In any case, the studies are excluded from the present review as they did not actually employ spironolactone.

Although the quality of these studies is limited, the findings of the studies, which are mixed but are overall more suggestive against spironolactone reducing testosterone levels than it doing so, are in notable contrast to similar studies of CPA and testosterone suppression in cisgender men that were published in the 1970s and 1980s. These studies consistently found that CPA suppressed testosterone levels by 40 to 70% on average (Aly, 2019). Subsequently, the findings were replicated in several more modern studies of CPA in cisgender men and transfeminine people, which likewise found that the drug given alone consistently suppressed testosterone levels by about 45 to 65% on average (Aly, 2019).

Spironolactone in Cisgender Women

Spironolactone has a long history of use in cisgender women in the treatment of androgen-dependent skin and hair conditions like acne, hirsutism, scalp hair loss, and hyperandrogenism (due to e.g. polycystic ovary syndrome (PCOS)). It has been used at similar doses for androgen-dependent conditions in cisgender women as it has in transfeminine people (e.g., 50–200 mg/day most typically). There are many dozens of studies of spironolactone as an antiandrogen in cisgender women (e.g., PubMed). Instead of attempting to individually review all of these studies, the present article will discuss the findings of several papers that have themselves reviewed substantial numbers of these studies and have summarized available findings on testosterone levels with spironolactone.

Callan (1988) reviewed the literature on spironolactone for treatment of acne and hirsutism in cisgender women and found that some clinical studies reported decreased levels of testosterone and/or other androgens with spironolactone (4 studies cited) whereas other studies reported no change in androgen levels (4 studies cited). The author cited several studies to support the claim that androgen receptor antagonism with spironolactone is more clinically important than any influence it has on androgen production (5 studies cited). For instance, clinical benefits against acne and hirsutism occurred with spironolactone both before androgen levels decrease as well as when androgen levels do not decrease.

McMullen & Van Herle (1993) reviewed 19 studies of spironolactone for treatment of androgen-dependent conditions in cisgender women, with a majority of these studies reporting long-term hormone levels. Most of the studies were open-label and uncontrolled, with only five studies having a control group and only two studies being double-blind placebo-controlled trials. Changes in hormone levels across studies were very heterogenous, with the majority of changes not reaching statistical significance. Only 1 of 7 (14%) studies found a decrease in DHEA-S levels. The review concluded that a clinically significant change in adrenal androgen levels with spironolactone in cisgender women was not supported. Conversely, testosterone levels were decreased with spironolactone in 13 of 16 (81%) of studies. However, in the only two RCTs, there were no differences in testosterone levels with spironolactone versus in the placebo control groups. As such, the review concluded that the decreased testosterone levels with spironolactone in cisgender women reported in many of the non-RCT studies may not actually be a real phenomenon. As with Callan (1988), the review noted that the major mechanism of action of spironolactone as an antiandrogen is likely to be androgen receptor blockade.

Bradstreet et al. (2007) cited and discussed a Cochrane review of spironolactone for treatment of acne and/or hirsutism in cisgender women (Farquhar et al., 2003). Cochrane reviews are rigorous high-quality systematic reviews of all of the available RCTs for a given medical intervention. The Cochrane review identified 19 RCTs, with 9 included in the review, 8 excluded due to methodological issues (e.g., with randomization), and two others which were described as “awaiting assessment” (Farquhar et al., 2003). Bradstreet and colleagues noted per the Cochrane review that spironolactone at a dosage of 100 mg/day had little influence on levels of DHEA, DHEA-S, or testosterone in the trials evaluated and said that this is because its mechanism of action as an antiandrogen is androgen receptor antagonism (Bradstreet et al., 2007). The Cochrane review itself did not discuss changes in androgen or testosterone levels with spironolactone in aggregate. An update of the Cochrane review was published in 2009, but with no new studies found and with the findings unchanged (Brown et al., 2009).

Layton et al. (2017) was a hybrid systematic review of spironolactone for acne in cisgender women. In a table discussing the mechanism of action of spironolactone and other antiandrogens for acne, the authors stated that “Data from over 50 articles reporting effects [of spironolactone] on serum androgens are equivocal” (i.e., ambiguous, uncertain, questionable) (Layton et al., 2017). The review further noted that inhibition of androgen synthesis by spironolactone in humans may be unlikely at therapeutic doses and may occur instead only at supraphysiological doses (with Menard et al. (1979) cited in support of these claims, presumably related to the very high doses required) (Layton et al., 2017).

Rozner et al. (2019) reviewed clinical studies of the endocrine effects of spironolactone in cisgender women to assess whether it is safe to use in women with past or present breast cancer receiving endocrine therapy. The review included 18 studies with 465 women (mostly having androgen-dependent conditions) assessing the influence of spironolactone on sex hormone levels. The assessed studies included retrospective cohort studies, case–control studies, and RCTs. Of the included studies, 10 (56%) studies (with 179 women) found no change in testosterone levels with spironolactone, 8 (44%) studies (with 253 women) found a decrease, and 1 (6%) study (with 33 women) found an increase in free but not total testosterone levels. Changes in levels of DHEA-S, androstenedione, and estrogen were also assessed and findings were similar, with no changes observed in majorities of studies for these hormones. The review concluded that there is no significant change in levels of androgens, estrogen, or gonadotropins with spironolactone in cisgender women.

Almalki et al. (2020) conducted a systematic review and network meta-analysis of RCTs on the comparative efficacy of several types of medications (statins, metformin, spironolactone, and combined birth control pills) on reducing testosterone levels in cisgender women specifically with PCOS. Nine RCTs including 613 women were included for all of the medications. The meta-analysis concluded that the statin atorvastatin was more effective than the other included medications in reducing testosterone levels. Only two of the included RCTs employed spironolactone, one of which was with spironolactone alone (n=34) versus metformin (n=35) (Ganie et al., 2004) and the other of which was with spironolactone plus metformin (n=62) versus spironolactone alone (n=51) versus metformin alone (n=56) (Ganie et al., 2013). Both of the included trials found that spironolactone alone significantly decreased testosterone levels in pre-treatment versus post-treatment comparisons (Ganie et al., 2004; Ganie et al., 2013). No trials of spironolactone versus placebo controls were included.

Taken together, the available studies of spironolactone and testosterone levels in cisgender women with androgen-dependent conditions are highly inconsistent and mixed, but with numerous studies finding no significant changes in testosterone levels. The reasons for the findings being so mixed are unclear, but may relate to study methodology and quality. Findings in this population seem particularly notable as regulation of the hypothalamic–pituitary–gonadal (HPG) axis by androgens in women is minimal to negligible, in turn making it such that androgen receptor antagonists will have little effect of upregulating gonadal sex hormone production as they can in cisgender men and transfeminine people. As a result, there is less homeostatic interference that could influence findings in evaluating the steroid synthesis inhibition of spironolactone in this sex, and hence these studies may provide a clearer picture of steroid synthesis inhibition as a possible clinical effect of spironolactone. However, as the findings are still so mixed, the results seem inconclusive. In any case, only a limited effect at best seems clear.

Spironolactone Alone in Transfeminine People

Only one study of spironolactone alone (without estrogen) and sex hormone levels in transfeminine people was identified (Table 2). It was conducted by Louis Gooren and colleagues of the Dutch Center of Expertise on Gender Dysphoria (CEGD) at the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands in the 1980s. The study compared levels of testosterone, DHT, estradiol, LH, FSH, and prolactin before and after treatment with 200 mg/day spironolactone for 6 weeks in 6 young pre-hormone-therapy transfeminine people. It found slightly but significantly increased testosterone levels, increased prolactin levels, and no change in levels of estradiol, DHT, LH, or FSH.

Table 2: Studies of sex hormone levels with spironolactone alone in transfeminine people:

Treatment and subjectsFindingsSource(s)
200 mg/day for 6 weeks in 6 pre-hormone therapy transfeminine people (21–39 years)T (mean ± SEM) increased significantly from 17.2 ± 0.8 nmol/L (496 ± 20 ng/dL) to 20.6 ± 1.7 nmol/L (594 ± 50 ng/dL) (+19.8%). No change in E2 (90 ± 20 pmol/L [25 ± 5.0 pg/mL] vs. 100 ± 30 pmol/L [27 ± 8.2 pg/mL] or 80 ± 20 pmol/L [22 ± 5.4 pg/mL]) or DHT (1.7 ± 0.8 nmol/L [49 ± 20 ng/dL] vs. 1.8 ± 0.9 nmol/L [52 ± 30 ng/dL]). LH, FSH, and GnRH-stimulated LH and FSH unchanged. PRL and TRH-stimulated PRL increased.Gooren et al. (1984a); Gooren et al. (1984b)

Abbreviations: T = testosterone; E2 = estradiol; DHT = dihydrotestosterone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; PRL = prolactin; TRH = thyrotropin-releasing hormone.

The fact that this study was done by the CEGD is notable as this institute is among the most prolific research centers on transgender hormone therapy in the world (Bakker, 2021), and, while they evaluated spironolactone as well as nilutamide as antiandrogens in studies in transfeminine people in the 1980s and 1990s (Wiki), the group ultimately settled on using only CPA instead. This was probably related to the lack of testosterone suppression with spironolactone and pure androgen receptor antagonists like nilutamide, as the researchers have touched on in other publications (e.g., Gooren, 1999).

Estrogen Plus Spironolactone in Transfeminine People

Eleven studies of the combination of estrogen and spironolactone and sex hormone levels in transfeminine people were identified (Table 3). The first study was conducted by Jerilynn Prior and colleagues in Canada in the 1980s. Subsequent studies were conducted over 25 years later by groups in the United States, Australia, Israel, and Thailand. All of the studies were retrospective chart reviews or prospective non-randomized studies, with the exception of a single RCT.

Table 3: Studies of testosterone levels with estrogen plus spironolactone in transfeminine people:

Treatment and subjectsFindingsSource(s)
Oral CEEs (0.625–5 mg/day cyclically—3 of 4 weeks per month), oral MPA (10–20 mg/day cyclically—3 of 4 weeks per month—or continuously—”if gonadotrophins increased or to aid in T reduction or breast development”), and spironolactone (100–600 mg/day continuously) for 12 months in 27 transfeminine people who had been on “high-dose” E alone for an extended duration (Group 1) and 23 transfeminine people who were pre-hormone-therapy (Group 2), or 50 transfeminine people total, at Vancouver General Hospital.T decreased in Group 1 from mean 169 ng/dL to 87.4 ng/dL (–48.2%) and in Group 2 from mean 642 ng/dL to 49.2 ng/dL (–92.3%). In the whole group, T after treatment would be mean 69.8 ng/dL. Per authors, spironolactone was intended to help reduce T and facilitate feminization while MPA was intended to help suppress gonadotropins and T and improve breast development. However, authors emphasized the decrease in T as being due to spironolactone despite inclusion of MPA, without data provided to substantiate this.Prior, Vigna, & Watson (1989); Prior et al. (1986)
Sublingual estradiol (4 mg/day—2 mg b.i.d.) (n=14), transdermal estradiol patch (100 μg/day) (n=1), or injectable estradiol valerate (20 mg/2 weeks) (n=1) with spironolactone (100–200 mg/day) for 6 months in 16 transfeminine people at an LGBT community health center in Los Angeles, California.T was median 405 ng/dL at baseline and 42 ng/dL after 6 months (–89.6%). Free T was median 11.4 ng/dL at baseline and 0.8 ng/dL at 6 months (–93.0%). 10 of 15 (66.7%) had total T in female range and 14 of 15 (93.3%) had free T in female range.Deutsch, Bhakri, & Kubicek (2015)
Oral E2 (1–8 mg/day) with or without spironolactone (200 mg/day) (n=61), finasteride (5 mg/day) (n=49), and/or MPA (2.5–10 mg/day) (n=38) for 0.3 to 10.5 years (mean 4.3 ± 3.1 years) in 156 transfeminine people at Albany Medical Center.Oral E2 dose-dependently and substantially but incompletely suppressed T. Relative to E2 alone (at equivalent E2 levels), E2 plus spironolactone had no significant influence on T (+10.6 ± 16 ng/dL (mean ± SE); p = 0.5) and no greater likelihood of achieving better T suppression (<100 ng/dL) (OR = 0.75; 95% CI = 0.44–1.29). T levels with E2 alone were mean ~80 ng/dL and with E2 plus spironolactone were mean ~95 ng/dL. Finasteride was also associated with greater T levels. MPA helped with T suppression in some (71% of subjects). More discussion and analysis including graphs (Aly, 2019).Leinung, Feustel, & Joseph (2018); Leinung (2014)
Oral E2 (0.5–10 mg/day) (n=67) or oral CEEs (0.625–5 mg/day) (n=12) and spironolactone (25–400 mg/day; mean/median 145 mg/day) for 12 months in 98 transfeminine people at Boston Medical Center.Combined E and spironolactone decreased T from median 385 ng/dL to 130 ng/dL (–66.2%). E alone vs. E and spironolactone not reported. No significant influence of spironolactone dosage on T. Incomplete suppression of T (>50 ng/dL) in all but the lowest quartile (25%) of individuals.Liang et al. (2018); Bonzagni (2014)
Oral EV (4–6 mg/day; median 5–6 mg/day) (88.3%) or transdermal E2 (11.7%) alone or in combination with CPA (25–50 mg/day; median 50 mg/day) or spironolactone (87.5–200 mg/day; median 100 mg/day) for 0.9 to 2.6 years (median 1.5 years) in 80 transfeminine people at two gender clinics in Melbourne, Australia.T was median 10.5 nmol/L (303 ng/dL) with E2 only, 2.0 nmol/L (58 ng/dL) with E2 plus spironolactone, and 0.8 nmol/L (23 ng/dL) with E2 plus CPA. 90% of those on E2 plus CPA and 40% of those on E2 plus spironolactone had T of <2 nmol/L (<58 ng/dL). T significantly lower with E2 plus CPA compared to E2 plus spironolactone and E2 alone. T with E2 plus spironolactone lower than with E2 alone but non-significantly. No significant differences between groups in age, hormone therapy duration, or E2 dosage or levels. Graph that visually summarizes the results.Angus et al. (2019); Cheung et al. (2018)
Sublingual estradiol (2–12 mg/day) and spironolactone (100–200 mg/day) with or without sublingual MPA (5–10 mg/day) or injectable MPA (150 mg/3 months) for 3.4 ± 1.7 years in 92 transfeminine people at Rhode Island Hospital.T (mean ± SD) was 215 ± 29 ng/dL with E2 plus spironolactone and 79 ± 18 ng/dL with E2 plus spironolactone and MPA.Jain, Kwan, & Forcier (2019)
Oral E2 (2–8 mg/day) (84.2%) or other E forms (15.8%) with spironolactone (80.4%; n=107) or without spironolactone (19.6%) for more than 6 months in 133 transfeminine people at three clinics in Dallas, Texas.T decreased from median 367 ng/dL (95% range 175–731 ng/dL) (n=70) at baseline to median 55 ng/dL (95% range 3–709 ng/dL) (n=131) in whole group (80.4% taking spironolactone). 65 of 133 (49%) had adequate T suppression (presumably <50 or <60 ng/dL) in whole group. T with E2 plus spironolactone at 25–75 mg/day (n=15) was mean 129.4 ng/dL (range <3—611 ng/dL), at 100–175 mg/day (n=61) was mean 180.4 ng/dL (range <3–1137 ng/dL), and at 200–300 mg/day (n=31) was mean 170.1 ng/dL (range <3–798 ng/dL). In the whole E2 plus spironolactone group (n=107), T would be mean 170.3 ng/dL.SoRelle et al. (2019); Allen et al. (2021)
Oral E2 (2–8 mg/day), transdermal E2 gel (2.5–5 mg/day), or transdermal E2 patches (50–200 μg/day) plus spironolactone (50–200 mg/day) (n=16), CPA (10–100 mg/day) (n=41), or a GnRH agonist (n=10) for 12 months in 67 transfeminine people at Tel Aviv-Sourasky Medical Center in Israel.With spironolactone, T (mean ± SD) decreased from 15.2 ± 8.1 nmol/L (438 ± 230 ng/dL) at baseline to 10.2 ± 5.7 nmol/L (294 ± 164 ng/dL) at 3 months (–32.9%), 3.5 ± 1.2 nmol/L (100 ± 35 ng/dL) at 6 months (–77.0%), and 4 ± 7.1 nmol/L (120 ± 200 ng/dL) at 12 months (–73.7%). T was in the female range (<1.8 nmol/L [52 ng/dL]) at all follow-ups after baseline for both CPA and GnRH agonist (–92.0% to –96.4%).Sofer et al. (2020)
Oral EV 4 mg/day plus spironolactone (100 mg/day) (n=26) or CPA (25 mg/day) (n=26) for 12 weeks in 52 transfeminine people at two clinics in Bangkok, Thailand (RCT).With intention-to-treat analysis, T decreased with E2 plus spironolactone from median 645.0 ng/dL (IQR 466.7−1027.7 ng/dL) to 468.3 ng/dL (IQR 287.0−765.4 ng/dL) (–27.4%) and with E2 plus CPA from 655.5 ng/dL (402.6−872.7 ng/dL) to 9.3 ng/dL (IQR 5.5−310.4 ng/dL) (–98.6%). Adequate suppression of testosterone (<50 ng/dL) was achieved by 4 of 26 (15%) in the E2 plus spironolactone group and by 18 of 26 (69%) in the E2 plus CPA group. Study also assessed and reported E2, SHBG, and PRL levels.Burinkul et al. (2021)
E2 (sublingual, transdermal, or injectable) with spironolactone (n=39) or without spironolactone (n=37) for 12 months in 93 transfeminine people at two LGBTQ-oriented clinics in Seattle, Washington and Iowa City, Iowa.T was median 11 to 18 ng/dL in different estradiol groups without spironolactone and median 10 to 12 ng/dL in different estradiol groups with spironolactone. T was significantly lower with spironolactone only for sublingual E2 group (median 11 ng/dL (IQR 6–35 ng/dL) [n=27] vs. median 18 ng/dL (IQR 13–205 ng/dL) [n=16]) and not for transdermal or injectable E2 groups.Cirrincione et al. (2021)
Oral E2 (4–12 mg/day, median 6 mg/day) (n=27) or injectable EV (2–5 mg/week, median 4 mg/week) (n=6) with spironolactone (n=31) or without spironolactone (n=2) for median 6.2 months (range 0.6–28.2 months) (time on optimized E2 dose specifically) in 33 transfeminine people at Maine Medical Center.T was median 13.0 ng/dL (range 2.7–559 ng/dL) for whole group (93.9% taking spironolactone). 28 of 33 (84.8%) of whole group had female-range T (<50 ng/dL). However, in earlier studies by the same group, similar T suppression with E2 alone was reported (Reardon et al., 2013; Spratt et al., 2014).Pappas et al. (2021); Pappas et al. (2020); Stewart et al. (2018)

Abbreviations: E = estrogen; E2 = estradiol; EV = estradiol valerate; CEEs = conjugated [equine] estrogens; CPA = cyproterone acetate; MPA = medroxyprogesterone acetate; GnRH = gonadotropin-releasing hormone; T = testosterone; DHEA-S = dehydroepiandrosterone sulfate; LH = luteinizing hormone; FSH = follicle-stimulating hormone; PRL = prolactin.

Findings of the above studies include inadequate testosterone suppression with estradiol plus spironolactone in most transfeminine people (Leinung et al., 2018; Liang et al., 2018; Jain, Kwan, & Forcier, 2019; Sofer et al., 2020; Burinkul et al., 2021), no difference in testosterone suppression with spironolactone versus without spironolactone (Leinung et al., 2018), lack of notable influence of spironolactone dosage on testosterone suppression (Liang et al., 2018; SoRelle et al., 2019), and inferior testosterone suppression with estradiol plus spironolactone compared to estradiol plus CPA or a GnRH agonist in transfeminine people (Angus et al., 2019; Sofer et al., 2020; Burinkul et al., 2021). Conversely, some studies have found adequate or near-adequate testosterone suppression with estradiol plus spironolactone in most or almost all transfeminine people (Deutsch, Bhakri, & Kubicek, 2015; Angus et al., 2019; SoRelle et al., 2019; Cirrincione et al., 2021; Pappas et al., 2021), and some studies have found indications of greater testosterone suppression with spironolactone versus without spironolactone (Angus et al., 2019; Cirrincione et al., 2021). On the other hand, some studies using estradiol alone without any antiandrogen at physiological estradiol levels (<200 pg/mL) have reported adequate testosterone suppression similarly to the preceding estradiol plus spironolactone studies (Reardon et al., 2013; Spratt et al., 2014; Cirrincione et al., 2021). One study was confounded by the concomitant use of the progestogen medroxyprogesterone acetate (MPA), which is known to suppress testosterone levels on its own, and hence reliable conclusions could not be drawn from it (Prior, Vigna, & Watson, 1989; Prior et al., 1986). A couple of studies found that testosterone levels progressively decline with time (particularly over the first 12 months) with estradiol plus spironolactone in most transfeminine people (Liang et al., 2018; Sofer et al., 2020). Whether the decreases in testosterone levels with time were more related to estradiol or to spironolactone is unclear, though estradiol seems more likely (e.g., Wiki).

Taken together, the findings of available studies on estradiol plus spironolactone and testosterone suppression in transfeminine people are highly variable and mixed, although overall more studies support spironolactone having poor or no testosterone-suppressing effectiveness. The reasons underlying the differences in findings on testosterone suppression between studies are unclear, but contributing factors may include varying estradiol doses, routes, and levels, durations of hormone therapy, differing laboratory assays of testosterone levels, and other differences in study methodologies, as well as limitations in study and evidence quality. In any case, the conflicting nature of the findings is in major contrast to the almost invariably strong to maximal testosterone suppression in studies of estradiol plus CPA and estradiol plus GnRH agonists in transfeminine people.

Spironolactone, Androgen Receptor Antagonism, and Clinical Antiandrogenic Effectiveness

The clinical antiandrogenic effectiveness of spironolactone in cisgender women with androgen-dependent skin and hair conditions, like acne, hirsutism, and scalp hair loss, is well-established (Brown et al., 2009; van Zuuren & Fedorowicz, 2016; Layton et al., 2017; Barrionuevo et al., 2018; James, Jamerson, & Aguh, 2022; Wang et al., 2023). Conversely, the clinical antiandrogenic efficacy of spironolactone in transfeminine people has been very limitedly assessed to date and is largely unknown (Angus et al., 2021). Spironolactone does not appear to be very effective for decreasing testosterone levels in either cisgender women or transfeminine people based on the findings of the present review. However, spironolactone is a competitive antagonist of the androgen receptor in addition to its actions a weak androgen synthesis inhibitor, and hence it also directly blocks androgens from mediating their effects in the body (Loriaux et al., 1976; McMullen & Van Herle, 1993). Based on studies in populations besides transfeminine people, for instance cisgender women (discussed above) and cisgender boys with gonadotropin-independent precocious puberty (e.g., Holland, 1991), in which spironolactone has not decreased testosterone levels but has nonetheless been effective as an antiandrogen, the androgen receptor blockade of spironolactone is likely to be its main mechanism of action as an antiandrogen and may account for most or all of its therapeutic antiandrogenic effectiveness.

However, while spironolactone is clearly effective as an androgen receptor antagonist, it appears to be a relatively weak androgen receptor blocker at typical doses used in cisgender women and transfeminine people. Numerous publications in the literature describe spironolactone as being only a weak androgen receptor antagonist (Wiki; Wiki). In relation to this, animal studies have found that spironolactone is a far less potent androgen receptor antagonist than other antiandrogens like CPA, flutamide, and bicalutamide (Bonne & Raynaud, 1974; Hecker, Hasan, & Neumann, 1980; Sivelle, Underwood, & Jelly, 1982; Weissmann et al., 1985; Labrie et al., 1987; Snyder, Winneker, & Batzold, 1989 [Table]; Yamasaki et al., 2004 [Graph]). Moreover, in cisgender women, the population in which spironolactone is most widely used as an antiandrogen, testosterone levels are relatively low, on average about 20-fold lower than in cisgender men (around 30 ng/dL on average compared to about 600 ng/dL on average, respectively) (Aly, 2018). However, many cisgender women with androgen-dependent conditions have PCOS, which is associated with limitedly elevated testosterone levels (e.g., perhaps around 60 ng/dL on average) (Aly, 2018). The typical therapeutic dose range of spironolactone in cisgender women with androgen-dependent conditions is 50 to 200 mg/day, in which its effectiveness may be assumed to be dose-dependent, and this is roughly the same general dosage range used in transfeminine people (though up to 300–400 mg/day may be used and are allowed for by guidelines) (Aly, 2018; Aly, 2020).

A relatively small amount of dose-ranging data on spironolactone in cisgender women with androgen-dependent conditions exists, but in any case substantiates its dose-dependent effectiveness across its clinically used dose range (partially reviewed in Hammerstein (1990) and Shaw (1996)). Spironolactone has been reported to be effective in the treatment of hirsutism in cisgender women at a dosage of as low as 50 mg/day (Diamanti-Kandarakis, Tolis, & Duleba, 1995). However, even a dosage of 100 mg/day did not appear to be maximally effective for hirsutism in a study that compared different doses of spironolactone; effectiveness was near-significantly greater at a dosage of 100 mg/day relative to a dosage of 200 mg/day (19% ± 8% and 30% ± 3% (mean ± SEM) reduction in hair shaft diameter, respectively; p = 0.07) (Lobo et al., 1985). Levels of free testosterone in this study were unchanged, suggesting that the effects of spironolactone was purely due to androgen receptor blockade. In addition, a study found that 100 mg/day spironolactone was significantly inferior to flutamide in improving androgen-dependent skin and hair symptoms in cisgender women (Cusan et al., 1994). However, in other studies, there were no significant differences between 100 mg/day spironolactone and flutamide for hirsutism (Erenus et al., 1994; Moghetti et al., 2000; Inal, Yildirim, & Taner, 2005; Karakurt et al., 2008). Spironolactone and flutamide were variably taken together with an ethinylestradiol-containing combined birth control pill in the preceding studies. This is likely to have limited detection of differences in effectiveness, as these birth control pills considerably suppress total and free testosterone levels and hence have substantial antiandrogenic effects themselves (Zimmerman et al., 2014; Amiri et al., 2018). Finally, a case report of a cisgender woman with female pattern hair loss and normal androgen levels found that treatment with spironolactone 200 mg/day for 5 years failed to improve her hair loss, in spite of almost complete loss of secondary sexual hair, but switching to flutamide resulted in a considerable improvement in hair loss after 12 months of treatment (Yazdabadi & Sinclair, 2011).

In a biochemical study, 100 mg/day spironolactone was numerically inferior to flutamide in reducing levels of prostate-specific antigen (PSA) in cisgender women (Negri et al., 2000). This is notable as PSA is a systemic biomarker of androgen action (Negri et al., 2000). However, the study had small sample sizes, and the differences between groups were not statistically significant (Negri et al., 2000). One study compared spironolactone at doses of 50 to 200 mg/day with placebo for treatment of acne in cisgender women and reported progressive increases in effectiveness with spironolactone up to the 200 mg/day dosage (Goodfellow et al., 1984). Similarly, another study found that progressively increasing the dosage of spironolactone from 100 mg/day, to 150 mg/day, and up to 200 mg/day, resulted in increased effectiveness in the treatment of acne in cisgender women (Charny, Choi, & James, 2017). Finally, a 2022 systematic review of spironolactone for treatment of androgen-related scalp hair loss in cisgender women reported that the drug was “largely ineffective” at doses of less than 100 mg/day, whereas doses of 100 to 200 mg/day were effective (James, Jamerson, & Aguh, 2022).

The preceding findings suggest that the clinical antiandrogenic effectiveness of spironolactone in cisgender women is not maximal at a dosage of below at least 200 mg/day despite the relatively low testosterone levels in these individuals. Put another way, spironolactone at typical doses seems best-suited for blocking female-range levels of testosterone. As many transfeminine people do not achieve female-range testosterone levels with estradiol plus spironolactone therapy, and in fact often have testosterone levels well above the normal female range or even in the male range, spironolactone may not be fully effective as an antiandrogen at the typical doses used in transfeminine hormone therapy. Higher doses of spironolactone, like 300 to 400 mg/day, may be to some degree more effective.

Summary, Discussion, and Conclusions

Numerous studies have assessed the influence of spironolactone on testosterone levels in cisgender men, cisgender women, and transfeminine people. Although the quality of these studies has often been limited, the studies have revealed highly inconsistent influences of spironolactone on testosterone levels in these populations, with many studies finding no changes, some studies finding decreases, and a small number of studies finding increases. The findings of studies of spironolactone and testosterone levels are in notable contrast to those of studies with estrogens, progestogens like CPA, and GnRH agonists, which consistently show substantial decreases in testosterone levels. This has been the case even in studies of similarly low quality to those of some of the included spironolactone studies (e.g., many of those in cisgender men). The fact that in the available studies testosterone levels with spironolactone have usually been unchanged, but have sometimes been decreased and have rarely been decreased, seems to suggest that spironolactone may be a clinically significant inhibitor of steroid hormone synthesis, but that it is only a weakly efficacious one, and that its effects may be variable depending on the individual and other clinical circumstances. In any case, the conflicting findings warrant more research with higher-quality study designs, particularly RCTs that have with spironolactone versus without comparison groups.

The notion that spironolactone decreases testosterone levels in transfeminine people, and the use of spironolactone in transfeminine hormone therapy in general, appear to have originated from the papers on spironolactone in transfeminine people published by Dr. Jerilynn Prior and colleagues in the 1980s (Prior, Vigna, & Watson, 1989; Prior et al., 1986). In their study, transfeminine people who were either already on high-dose estrogen therapy with inadequate testosterone suppression or had not yet started hormone therapy were put on physiological-dose estrogen therapy in combination with 200 to 600 mg/day spironolactone. Cyclic or continuous administration of the progestogen MPA at an oral dose of 10 mg/day was also given to all of the individuals. The authors reported that despite the lower estrogen dosage, testosterone levels decreased, from 169 ng/dL to 87 ng/dL (–49%) in those who had already been on hormone therapy and to 49 ng/dL in those who were pre-hormone therapy. Prior and her colleagues concluded that spironolactone helps to decrease testosterone levels in transfeminine people and that it can be used as a safer alternative to high doses of estrogen for this purpose.

However, the concomitant use of MPA in the study is a major confounding factor in terms of their results. This is because MPA is a progestogen, and progestogens, like estrogens, are antigonadotropins which are able to robustly suppress testosterone levels on their own (Aly, 2018; Aly, 2019). Indeed, MPA alone has been shown to dose-dependently lower testosterone levels in cisgender men (Wiki), and at a dosage of 10 mg/day, has been shown to considerably suppress testosterone levels in transfeminine people when added to estradiol and spironolactone therapy (Jain, Kwan, & Forcier, 2019). Hence, MPA may have been, and likely was, responsible for the decreases in testosterone levels seen in the study, rather than spironolactone. This point was also notably raised by other researchers, who were unable to replicate Prior and colleagues’ results on spironolactone and testosterone levels in transfeminine people (Leinung et al., 2018). Strangely, Prior and colleagues concluded that spironolactone was responsible for the decreased testosterone levels in their study even though they noted in their papers that MPA was also given to help suppress testosterone levels (as well as to help improve breast development). The work of Prior and colleagues likely resulted in the prominent and long-standing, but poorly supported, notion that spironolactone decreases testosterone levels in transfeminine people. Subsequent studies assessing the hypothesis that spironolactone decreases testosterone levels in transfeminine people were not published until 25 years after Prior and colleagues’ studies, with several of these studies, though not all of them, failing to replicate the earlier findings of Prior and colleagues.

Many people do not realize the capacity of estradiol to substantially and even completely suppress testosterone, and many mistakenly assume that it is the antiandrogen—which is often spironolactone—that is mostly or fully responsible for the decrease in testosterone levels seen with estradiol and antiandrogen therapy in transfeminine people. It is certainly true that antiandrogens like CPA and GnRH agonists play an important role in testosterone suppression in transfeminine people. However, as evidenced by the present review of studies of testosterone suppression with spironolactone, it is not necessarily always the case that the antiandrogen plays a major role—or potentially even any role—in reducing testosterone levels. This is notably also not the case with certain other antiandrogens besides spironolactone, for instance pure androgen receptor antagonists like bicalutamide, which likewise do not decrease testosterone levels but instead can actually increase them (Aly, 2019; Wiki). Clinicians and transfeminine people attributing observations of testosterone decreases to spironolactone rather than to estradiol with estradiol and spironolactone therapy may also have played a role in the perception that spironolactone considerably decreases testosterone levels in transfeminine people.

Due to its relatively weak strength as an androgen receptor antagonist and its limited efficacy in lowering testosterone levels, spironolactone is likely to be a limitedly effective antiandrogen in transfeminine people. Additionally, spironolactone is likely to be less effective than other antiandrogenic approaches used in transfeminine hormone therapy which either more robustly block androgens or more substantially reduce testosterone levels, for instance CPA, other progestogens (e.g., MPA, non-oral progesterone), GnRH agonists (and antagonists), bicalutamide, and high-dose parenteral estradiol monotherapy. These approaches can be used in transfeminine people instead of or in addition to spironolactone, or could be considered when testosterone suppression is inadequate with estradiol and spironolactone.

More studies are needed to evaluate the influence of spironolactone on testosterone levels, especially RCTs that compare estradiol alone versus estradiol plus spironolactone in transfeminine people. More research is also needed to clarify why some studies find highly inadequate testosterone suppression with estradiol alone or estradiol plus spironolactone while other studies find excellent or satisfactory testosterone suppression with these regimens. In any case, available data overall suggest that spironolactone does not consistently suppress testosterone levels, and that estradiol plus spironolactone produces inadequate testosterone suppression in many transfeminine people. Moreover, available data suggest that spironolactone is a relatively weak androgen receptor antagonist at the typical clinical doses used in cisgender women and transfeminine people, and is able to block only relatively low or female-range testosterone levels. Hence, spironolactone may not be fully effective in blocking the testosterone it fails to suppress, and may be particularly unsuitable for transfeminine people with testosterone levels that are well above the normal female range. In any case, more research is similarly needed to assess the androgen receptor antagonism and clinical antiandrogenic effectiveness of spironolactone.

Updates

Update 1: Spironolactone for Adult Female Acne (SAFA) Trial

A large new phase 3 RCT, the Spironolactone for Adult Female Acne (SAFA) trial, was published in May 2023 and assessed the effectiveness of spironolactone in the treatment of acne in cisgender women:

  • Santer, M., Lawrence, M., Renz, S., Eminton, Z., Stuart, B., Sach, T. H., Pyne, S., Ridd, M. J., Francis, N., Soulsby, I., Thomas, K., Permyakova, N., Little, P., Muller, I., Nuttall, J., Griffiths, G., Thomas, K. S., & Layton, A. M. (2023). Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ, 381, e074349. [DOI:10.1136/bmj-2022-074349]

The trial included a total of 342 women, including 176 treated with spironolactone and 166 in the placebo control group. The dose of spironolactone employed was 50 mg/day for the first 6 weeks and then 100 mg/day thereafter. The trial was 24 weeks (5.5 months) in duration. Women who might become pregnant were required to use a hormonal or barrier method of contraception.

Spironolactone significantly outperformed placebo in terms of improvement in mean Acne-QoL symptom scores (higher is better). Significant improvement was apparent within 12 weeks of treatment (+45% in scores with spironolactone, +38% with placebo) and was highest at 24 weeks (+61% in scores with spironolactone, +35% with placebo). There was no difference in the rates of women who reported improvement in acne scores at 12 weeks (72% with spironolactone, 68% with placebo), but there was a significant difference at 24 weeks (82% with spironolactone, 63% with placebo). In terms of the Investigator’s Global Assessment (IGA), treatment success at 12 weeks was 19% with spironolactone and 6% with placebo. Rates of hormonal contraceptive use in the spironolactone and placebo groups were not reported. Testosterone levels were also not reported. A small subset of the women had PCOS (15% in the spironolactone group, 23% in the placebo group).

Adverse effects occurred only slightly more often with spironolactone than with placebo (64% vs. 51%, p = 0.01). The only side effect that occurred significantly more often with spironolactone than with placebo was headache (20% vs. 12%; p = 0.02). However, a few other side effects trended towards occurring significantly more frequently with spironolactone than with placebo: “other” (17% vs. 11%; p = 0.06), dizziness/vertigo/lightheadness (19% vs. 12%; p = 0.07), vomiting/being sick (2% vs. 1%; p = 0.16), and polyuria (urinary frequency) (31% vs. 25%; p = 0.18). Rates of other potentially relevant side effects, like abdominal pain, breast enlargement, breast tenderness, drowsiness/sleepiness, fatigue/tiredness, menstrual irregularity, and reduced libido, were all not different between spironolactone and placebo. There were no serious adverse reactions in the trial. Rates of compliance were similar between the spironolactone and placebo groups, suggesting that spironolactone was well-tolerated.

This trial is the largest and most rigorous RCT of spironolactone in the treatment of androgen-dependent skin and hair conditions in cisgender women that has been conducted to date. Although spironolactone was found to be effective in this study and was about twice as effective as placebo in terms of Acne-QoL symptom scores and three times as effective as placebo in terms of IGA treatment success rates, the effectiveness of spironolactone was seemingly less than in previous clinical studies of spironolactone for acne. This may be related to the relatively low doses of spironolactone used in this study (50–100 mg/day), to the more rigorous and less-risk-of-bias design of the study (large phase 3 RCT), to a possibly too-short treatment duration (24 weeks/5.5 months), and to concomitant hormonal contraceptive use possibly blunting the degree of potential improvement. The latter is relevant as hormonal contraceptives containing ethinylestradiol provide a considerable improvement in acne via functional antiandrogenic effects all on their own. A final possibility however is that spironolactone is simply a less effective antiandrogen even in cisgender women than has been previously thought. On the other hand, similarly to findings in previous clinical studies, spironolactone was well-tolerated and produced few side effects.

Update 2: New Spironolactone and Testosterone Suppression Studies

The following new studies have additionally assessed and found inadequate testosterone suppression in transfeminine people treated with estradiol and spironolactone:

  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
  • Miro, E., Rizzone, K., Ho, T., Mark, B., Sullivan, E., & Cushman, D. (2024). 2024 AMSSM Research Podium Presentations: Testosterone Levels Among Transgender Women on Gender-affirming Hormone Therapy. Clinical Journal of Sports Medicine, 34(2), 152–152. [DOI:10.1097/JSM.0000000000001212]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]

Angus et al. (2023) and Yang et al. (2024) compared estradiol plus spironolactone to estradiol plus CPA and are described in-depth in a section of a different article located here. Yang et al. (2024) found that in addition to spironolactone resulting in much less testosterone suppression than CPA, it was also less effective than CPA as an antiandrogen on multiple clinical measures of demasculinization.

References

  • Abshagen, U., Spörl, S., Schöneshöfer, M., L’age, M., & Oelkers, W. (1978). Interference of spironolactone therapy with adrenal steroid metabolism in secondary hyperaldosteronism. [Zum Einfluß einer Spironolaktonbehandlung auf den adrenalen Steroidstoffwechsel bei sekundärem Hyperaldosteronismus.] Klinische Wochenschrift, 56(7), 341–349. [DOI:10.1007/bf01477394]
  • Aizawa, H., & Niimura, M. (1992). Oral Spironolactone Therapy in Male Patients with Rosacea. The Journal of Dermatology, 19(5), 293–297. [DOI:10.1111/j.1346-8138.1992.tb03227.x]
  • Allen, A. N., Jiao, R., Day, P., Pagels, P., Gimpel, N., & SoRelle, J. A. (2020). Dynamic Impact of Hormone Therapy on Laboratory Values in Transgender Patients over Time. The Journal of Applied Laboratory Medicine, 6(1), 27–40. [DOI:10.1093/jalm/jfaa192]
  • Almalki, H. H., Alshibani, T. M., Alhifany, A. A., & Almohammed, O. A. (2020). Comparative efficacy of statins, metformin, spironolactone and combined oral contraceptives in reducing testosterone levels in women with polycystic ovary syndrome: a network meta-analysis of randomized clinical trials. BMC Women’s Health, 20(1), 68. [DOI:10.1186/s12905-020-00919-5]
  • Amiri, M., Kabir, A., Nahidi, F., Shekofteh, M., & Ramezani Tehrani, F. (2018). Effects of combined oral contraceptives on the clinical and biochemical parameters of hyperandrogenism in patients with polycystic ovary syndrome: a systematic review and meta-analysis. The European Journal of Contraception & Reproductive Health Care, 23(1), 64–77. [DOI:10.1080/13625187.2018.1435779]
  • Angus, L., Leemaqz, S., Ooi, O., Cundill, P., Silberstein, N., Locke, P., Zajac, J. D., & Cheung, A. S. (2019). Cyproterone acetate or spironolactone in lowering testosterone concentrations for transgender individuals receiving oestradiol therapy. Endocrine Connections, 8(7), 935–940. [DOI:10.1530/ec-19-0272]
  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2021). A systematic review of antiandrogens and feminization in transgender women. Clinical Endocrinology, 94(5), 743–752. [DOI:10.1111/cen.14329]
  • Baba, S. (1977). Antiandrogenic effect of spironolactone. The Japanese Journal of Urology, 68(12), 1184–1192. [DOI:10.5980/jpnjurol1928.68.12_1184]
  • Baba, S., Murai, M., Jitsukawa, S., Hata, M., & Tazaki, H. (1978). Antiandrogenic Effects of Spironolactone: Hormonal and Ultrastructural Studies in Dogs and Men. Journal of Urology, 119(3), 375–380. [DOI:10.1016/s0022-5347(17)57495-9]
  • Bakker, A. (2021). Een halve eeuw transgenderzorg aan de VU [Half a Century of Transgender Care at the VU]. Amsterdam: Boom. [Google Books] [WorldCat] [URL]
  • Barrionuevo, P., Nabhan, M., Altayar, O., Wang, Z., Erwin, P. J., Asi, N., Martin, K. A., & Murad, M. H. (2018). Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism, 103(4), 1258–1264. [DOI:10.1210/jc.2017-02052]
  • Bonne, C., & Raynaud, J. (1974). Mode of spironolactone anti-androgenic action: Inhibition of androstanolone binding to rat prostate androgen receptor. Molecular and Cellular Endocrinology, 2(1), 59–67. [DOI:10.1016/0303-7207(74)90012-4]
  • Bonzagni, A. F. (2014). Understanding the effects of long-term hormone therapy in transgender individuals being provided care at Boston Medical Center Endocrinology Clinic: a quality assurance project. (Doctoral dissertation, Boston University.) [Google Scholar] [URL] [PDF]
  • Bradstreet, J. J., Smith, S., Granpeesheh, D., El-Dahr, J. M., & Rossignol, D. (2007). Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Medical Hypotheses, 68(5), 979–987. [DOI:10.1016/j.mehy.2006.10.015]
  • Brown, J., Farquhar, C., Lee, O., Toomath, R., & Jepson, R. G. (2003). Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews, 2003(4), CD000194. [DOI:10.1002/14651858.cd000194]
  • Brown, J., Farquhar, C., Lee, O., Toomath, R., & Jepson, R. G. (2009). Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews, 2009(2), CD000194. [DOI:10.1002/14651858.cd000194.pub2]
  • Burinkul, S., Panyakhamlerd, K., Suwan, A., Tuntiviriyapun, P., & Wainipitapong, S. (2021). Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. The Journal of Sexual Medicine, 18(7), 1299–1307. [DOI:10.1016/j.jsxm.2021.05.003] [PDF]
  • Callan, A. W. (1988). Spironolactone therapy in hirsutism and acne. Australasian Journal of Dermatology, 29(3), 135–139. [DOI:10.1111/j.1440-0960.1988.tb00385.x]
  • Caminos-Torres, R., MA, L., & Snyder, P. J. (1977). Gynecomastia and Semen Abnormalities Induced by Spironolactone in Normal Men. The Journal of Clinical Endocrinology & Metabolism, 45(2), 255–260. [DOI:10.1210/jcem-45-2-255]
  • Charny, J., Choi, J., & James, W. (2017). Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. International Journal of Women’s Dermatology, 3(2), 111–115. [DOI:10.1016/j.ijwd.2016.12.002]
  • Cheung, A. S., Ooi, O., Davidoff, D., Leemaqz, S. Y., Cundill, P., Silberstein, N., Bretherton, I., Grossmann, M., & Zajac, J. D. (2018). Cyproterone vs spironolactone as anti-androgen therapy for transgender females receiving oestradiol therapy. Clinical Endocrinology, 89(S1) [Abstracts of the Endocrine Society of Australia’s Annual Scientific Meeting 2017], 14–14 (abstract no. 62). [Google Scholar] [DOI:10.1111/cen.13727] [URL 1] [URL 2] [PDF]
  • Cirrincione, L. R., Winston McPherson, G., Rongitsch, J., Sadilkova, K., Drees, J. C., Krasowski, M. D., Dickerson, J. A., & Greene, D. N. (2021). Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults. LGBT Health, 8(2), 125–132. [DOI:10.1089/lgbt.2020.0249]
  • Corvol, P., Mahoudeau, J. A., Valcke, J. C., Ménard, J., & Bricaire, H. (1976). Effets sexuels secondaires des spirolactones. Mécanismes possibles de l’action antiandrogène. [Sexual side-effects of spironolactones. Possible mechanisms of their anti-androgen action]. La Nouvelle Presse Medicale, 5(11), 691–694. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF]
  • Cusan, L., Dupont, A., Gomez, J., Tremblay, R. R., & Labrie, F. (1994). Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertility and Sterility, 61(2), 281–287. [DOI:10.1016/s0015-0282(16)56518-2]
  • Deutsch, M. B., Bhakri, V., & Kubicek, K. (2015). Effects of Cross-Sex Hormone Treatment on Transgender Women and Men. Obstetrics & Gynecology, 125(3), 605–610. [DOI:10.1097/aog.0000000000000692]
  • Diamanti-Kandarakis, E., Tolis, G., & Duleba, A. J. (1995). Androgens and Therapeutic Aspects of Antiandrogens in Women. Journal of the Society for Gynecologic Investigation, 2(4), 577–592. [DOI:10.1177/107155769500200401]
  • Dymling, J., Nilsson, K. O., & Hökfelt, B. (1972). The effect of Soldactona® (canrenoate potassium) on plasma testosterone and androstenedione and urinary 17-ketosteroids and 17-hydroxycorticosteroids. Acta Endocrinologica, 70(1), 104–112. [DOI:10.1530/acta.0.0700104]
  • Dymling, J. F., & Hökfelt, B. (1973). Reduced plasma testosterone following spirolactone in man. Acta Endocrinologica, 73(Suppl 177) [9th Acta Endocrinologica Congress], 53–53 (abstract no. 53). [Google Scholar] [PDF 1] [PDF 2]
  • Dymling, J. F. (1978). The effect of spirolactone and spironolactone on plasma testosterone in man. In Addison, G. M., Asmussen, N. W., Corvol, P., Kloppernborg, P. W. C., Norman, N., Schroder, R., & Robertson, J. I. C. (Eds.). Aldosterone Antagonists in Clinical Medicine: Proceedings of the Searle Symposium, Nice, April 13–15, 1978 (pp. 297–302). Amsterdam: Excerpta Medica. [Google Scholar] [Google Books] [WorldCat] [PDF 1] [PDF 2]
  • Erbler, H. C. (1974). Suppression by the spironolactone metabolite canrenone of plasma testosterone in man. Naunyn-Schmiedeberg’s Archives of Pharmacology, 285(4), 403–406. [DOI:10.1007/bf00501468]
  • Erenus, M., Gürbüz, O., Durmuşoğlu, F., Demirçay, Z., & Pekin, S. (1994). Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertility and Sterility, 61(4), 613–616. [DOI:10.1016/s0015-0282(16)56634-5]
  • Ganie, M. A., Khurana, M. L., Eunice, M., Gulati, M., Dwivedi, S. N., & Ammini, A. C. (2004). Comparison of Efficacy of Spironolactone with Metformin in the Management of Polycystic Ovary Syndrome: An Open-Labeled Study. The Journal of Clinical Endocrinology & Metabolism, 89(6), 2756–2762. [DOI:10.1210/jc.2003-031780]
  • Ganie, M. A., Khurana, M. L., Nisar, S., Shah, P. A., Shah, Z. A., Kulshrestha, B., Gupta, N., Zargar, M. A., Wani, T. A., Mudasir, S., Mir, F. A., & Taing, S. (2013). Improved Efficacy of Low-Dose Spironolactone and Metformin Combination Than Either Drug Alone in the Management of Women With Polycystic Ovary Syndrome (PCOS): A Six-Month, Open-Label Randomized Study. The Journal of Clinical Endocrinology & Metabolism, 98(9), 3599–3607. [DOI:10.1210/jc.2013-1040]
  • Goodfellow, A., Alaghband-Zadeh, J., Carter, G., Cream, J., Holland, S., Scully, J., & Wise, P. (1984). Oral spironolactone improves acne vulgaris and reduces sebum excretion. British Journal of Dermatology, 111(2), 209–214. [DOI:10.1111/j.1365-2133.1984.tb04045.x]
  • Gooren, L. J., Veen, E. A., Kessel, H., Harmsen-Louman, W., & Wiegel, A. R. (1984). Prolactin secretion in the human male is increased by endogenous oestrogens and decreased by exogenous/endogenous androgens. International Journal of Andrology, 7(1), 53–60. [DOI:10.1111/j.1365-2605.1984.tb00759.x]
  • Gooren, L., Veen, E., Kessel, H., Harmsen-Louman, W., & Wiegel, A. (1984). Androgens in the Feedback Regulation of Gonadotropin Secretion in Men: Effects of Administration of Dihydrotestosterone to Eugonadal and Agonadal Subjects and of Spironolactone to Eugonadal Subjects. Andrologia, 16(4), 289–298. [DOI:10.1111/j.1439-0272.1984.tb00286.x]
  • Gooren, L. J. G. (1999). Hormonal Sex Reassignment. International Journal of Transgenderism, 3(3), 1–7. [Google Scholar] [URL 1] [URL 2]
  • Hammerstein, J. (1990). Antiandrogens: Clinical Aspects. In Orfanos, C. E., & Happle, R. (Eds.). Hair and Hair Diseases (pp. 827–886). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-74612-3_35]
  • Handelsman, D. J., Strasser, S., McDonald, J. A., Conway, A. J., & McCaughan, G. W. (1995). Hypothalamic-pituitary-testicular function in end-stage non-alcoholic liver disease before and after liver transplantation. Clinical Endocrinology, 43(3), 331–337. [DOI:10.1111/j.1365-2265.1995.tb02040.x]
  • Hecker, A., Hasan, S. H., & Neumann, F. (1980). Disturbances in sexual differentiation of rat foetuses following spironolactone treatment. Acta Endocrinologica, 95(4), 540–545. [DOI:10.1530/acta.0.0950540]
  • Holland, F. J. (1991). Gonadotropin-lndependent Precocious Puberty. Endocrinology and Metabolism Clinics of North America, 20(1), 191–210. [DOI:10.1016/s0889-8529(18)30288-3]
  • Horth, C., Lobo, P., Shelton, J., Asbury, M., Clarke, J., & Venning, G. (1977). Effects of spironolaetone on the plasma binding and unbound levels of testosterone and oestradiol in healthy men. Journal of Steroid Biochemistry, 8(12), xx–xx. [DOI:10.1016/0022-4731(77)90178-9]
  • Horth, C. E., Lobo, P. J., Shelton, J. R., Asbury, M. J., Clarke, J. M., & Venning, G. R. (1979). Effects of spironolactone on the plasma binding and unbound levels of testosterone and oestradiol in healthy men. In Klopper, A., Lerner, L., van der Molen, H. J., & Sciarra, F. (Eds.). Research on Steroids: Proceedings of the International Study Group for Steroid Hormones, Volume 8 / Research on Steroids Transactions of the Eighth Meeting of the International Study Group for Steroid Hormones (Proceedings of the Serono Symposia, Volume 21) (pp. 313–315). London/New York/San Francisco: Academic Press. [Google Scholar]
  • Huffman, D. H., Kampmann, J. P., Hignite, C. E., & Azarnoff, D. L. (1978). Gynecomastia induced in normal males by spironolactone. Clinical Pharmacology & Therapeutics, 24(4), 465–473. [DOI:10.1002/cpt1978244465]
  • Inal, M. M., Yildirim, Y., & Taner, C. E. (2005). Comparison of the clinical efficacy of flutamide and spironolactone plus Diane 35 in the treatment of idiopathic hirsutism: a randomized controlled study. Fertility and Sterility, 84(6), 1693–1697. [DOI:10.1016/j.fertnstert.2005.05.051]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • James, J. F., Jamerson, T. A., & Aguh, C. (2022). Efficacy and safety profile of oral spironolactone use for androgenic alopecia: A systematic review. Journal of the American Academy of Dermatology, 86(2), 425–429. [DOI:10.1016/j.jaad.2021.07.048]
  • Karakurt, F., Sahin, I., Güler, S., Demirbas, B., Culha, C., Serter, R., Aral, Y., & Bavbek, N. (2008). Comparison of the clinical efficacy of flutamide and spironolactone plus ethinyloestradiol/cyproterone acetate in the treatment of hirsutism: A randomised controlled study. Advances in Therapy, 25(4), 321–328. [DOI:10.1007/s12325-008-0039-5]
  • Labrie, C., Cusan, L., Plante, M., Lapointe, S., & Labrie, F. (1987). Analysis of the androgenic activity of synthetic “progestins” currently used for the treatment of prostate cancer. Journal of Steroid Biochemistry, 28(4), 379–384. [DOI:10.1016/0022-4731(87)91054-5]
  • Layton, A. M., Eady, E. A., Whitehouse, H., Del Rosso, J. Q., Fedorowicz, Z., & van Zuuren, E. J. (2017). Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. American Journal of Clinical Dermatology, 18(2), 169–191. [DOI:10.1007/s40257-016-0245-x]
  • Leinung, M. C. (2014). Variable Response to Oral Estradiol Therapy in Male to Female Transgender Patients. Endocrine Reviews, 35(Suppl 1) [Endocrine Society’s 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago], ?–? (abstract no. OR42-1). [Google Scholar] [DOI:10.1093/edrv/35.supp.1] [DOI:10.1210/endo-meetings.2014.RE.2.OR42-1] [URL] [MedPage Today]
  • Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
  • Liang, J. J., Jolly, D., Chan, K. J., & Safer, J. D. (2018). Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort. Endocrine Practice, 24(2), 135–142. [DOI:10.4158/ep-2017-0116]
  • Lobo, R. A., Shoupe, D., Serafini, P., Brinton, D., & Horton, R. (1985). The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertility and Sterility, 43(2), 200–205. [DOI:10.1016/s0015-0282(16)48373-1]
  • Loriaux, D. L. (1976). Spironolactone and Endocrine Dysfunction. Annals of Internal Medicine, 85(5), 630–630. [DOI:10.7326/0003-4819-85-5-630]
  • McMullen, G. R., & Van Herle, A. J. (1993). Hirsutism and the effectiveness of spironolactone in its management. Journal of Endocrinological Investigation, 16(11), 925–932. [DOI:10.1007/bf03348960]
  • Menard, R., Guenthner, T., Kon, H., & Gillette, J. (1979). Studies on the destruction of adrenal and testicular cytochrome P-450 by spironolactone. Requirement for the 7α-thio group and evidence for the loss of the heme and apoproteins of cytochrome P-450. Journal of Biological Chemistry, 254(5), 1726–1733. [DOI:10.1016/s0021-9258(17)37833-x]
  • Miro, E., Rizzone, K., Ho, T., Mark, B., Sullivan, E., & Cushman, D. (2024). 2024 AMSSM Research Podium Presentations: Testosterone Levels Among Transgender Women on Gender-affirming Hormone Therapy. Clinical Journal of Sports Medicine, 34(2), 152–152. [DOI:10.1097/JSM.0000000000001212]
  • Miyatake, A., Noma, K., Nakao, K., Morimoto, Y., & Yamamura, Y. (1978). Increased serum oestrone and oestradiol following spironolactone administration in hypertensive men. Clinical Endocrinology, 9(6), 523–533. [DOI:10.1111/j.1365-2265.1978.tb01510.x]
  • Moghetti, P., Tosi, F., Tosti, A., Negri, C., Misciali, C., Perrone, F., Caputo, M., Muggeo, M., & Castello, R. (2000). Comparison of Spironolactone, Flutamide, and Finasteride Efficacy in the Treatment of Hirsutism: A Randomized, Double Blind, Placebo-Controlled Trial. The Journal of Clinical Endocrinology & Metabolism, 85(1), 89–94. [DOI:10.1210/jcem.85.1.6245]
  • Negri, C., Tosi, F., Dorizzi, R., Fortunato, A., Spiazzi, G. G., Muggeo, M., Castello, R., & Moghetti, P. (2000). Antiandrogen Drugs Lower Serum Prostate-Specific Antigen (PSA) Levels in Hirsute Subjects: Evidence That Serum PSA Is a Marker of Androgen Action in Women. The Journal of Clinical Endocrinology & Metabolism, 85(1), 81–84. [DOI:10.1210/jcem.85.1.6230]
  • Pappas, I. I., Craig, W. Y., Spratt, L. V., & Spratt, D. I. (2020). Efficacy of Sex Steroid Therapy Without Progestin or GnRH Agonist for Gonadal Suppression in Adult Transgender Patients. The Journal of Clinical Endocrinology & Metabolism, 106(3), e1290–e1300. [DOI:10.1210/clinem/dgaa884]
  • Pappas, I. I., Craig, W., Spratt, L. V., & Spratt, D. I. (2020). Testosterone (T) and estradiol (E2) therapy alone can suppress gonadal function in transgender patients. Costas T. Lambrew Research Retreat 2020, 47. [Google Scholar] [URL] [PDF]
  • Pentikäinen, P. J., Pentikäinen, L. A., Huffman, D. H., & Azarnoff, D. L. (1974). The effect of spironolactone on plasma levels and excretion of testosterone and oestrogens in the urine in males. (A preliminary report). The Journal of International Medical Research, 2(6), 439–443. [Google Scholar] [PubMed] [PDF]
  • Prior, J. C., Vigna, Y. M., Watson, D., Diewold, P., & Robinow, O. (1986). Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic. Journal of Sex Information & Education Council of Canada, 1(1), 1–7. [Google Scholar] [PDF]
  • Prior, J. C., Vigna, Y. M., & Watson, D. (1989). Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Archives of Sexual Behavior, 18(1), 49–57. [DOI:10.1007/bf01579291]
  • Reardon, E., Farnell, P., Langzettel, J., & Spratt, D. (2013). Efficacy of single agent hormonal therapy in transgender patients to suppress endogenous hypothalamic-pituitary-gonadal (HPG) activity. Fertility and Sterility, 100(3 Suppl) [Scientific Program Supplement: Oral and Poster Session Abstracts 12 October 2013 - 17 October 2013], S333–S333 (abstract no. P-640). [Google Scholar] [DOI:10.1016/j.fertnstert.2013.07.914]
  • Rose, L. I. (1977). Pathophysiology of Spironolactone-Induced Gynecomastia. Annals of Internal Medicine, 87(4), 398–403. [DOI:10.7326/0003-4819-87-4-398]
  • Rozner, R. N., Freites-Martinez, A., Shapiro, J., Geer, E. B., Goldfarb, S., & Lacouture, M. E. (2018). Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies. Breast Cancer Research and Treatment, 174(1), 15–26. [DOI:10.1007/s10549-018-4996-3]
  • Santen, R. J., Kulin, H. E., Loriaux, D. L., & Friend, J. (1976). Spironolactone Stimulation of Gonadotropin Secretion in Boys with Delayed Adolescence. The Journal of Clinical Endocrinology & Metabolism, 43(6), 1386–1390. [DOI:10.1210/jcem-43-6-1386]
  • Santer, M., Lawrence, M., Renz, S., Eminton, Z., Stuart, B., Sach, T. H., Pyne, S., Ridd, M. J., Francis, N., Soulsby, I., Thomas, K., Permyakova, N., Little, P., Muller, I., Nuttall, J., Griffiths, G., Thomas, K. S., & Layton, A. M. (2023). Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ, 381, e074349. [DOI:10.1136/bmj-2022-074349]
  • Shaw, J. C. (1996). Antiandrogen and hormonal treatment of acne. Dermatologic Clinics, 14(4), 803–811. [DOI:10.1016/s0733-8635(05)70405-8]
  • Sivelle, P. C., Underwood, A. H., & Jelly, J. A. (1982). The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro. Biochemical Pharmacology, 31(5), 677–684. [DOI:10.1016/0006-2952(82)90449-x]
  • Skorodok, L. M., Savchenko, O. N., & Liss, V. L. (1983). Hypothalamo-hypophyseal-gonadal function in boys with irregular puberty. Neuroscience and Behavioral Physiology, 13(2), 141–145. [DOI:10.1007/bf01190800]
  • Snyder, B. W., Winneker, R. C., & Batzold, F. H. (1989). Endocrine profile of win 49596 in the rat: A novel androgen receptor antagonist. Journal of Steroid Biochemistry, 33(6), 1127–1132. [DOI:10.1016/0022-4731(89)90419-6]
  • Sofer, Y., Yaish, I., Yaron, M., Bach, M. Y., Stern, N., & Greenman, Y. (2020). Differential Endocrine and Metabolic Effects of Testosterone Suppressive Agents in Transgender Women. Endocrine Practice, 26(8), 883–890. [DOI:10.4158/ep-2020-0032]
  • SoRelle, J. A., Jiao, R., Gao, E., Veazey, J., Frame, I., Quinn, A. M., Day, P., Pagels, P., Gimpel, N., & Patel, K. (2019). Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clinical Chemistry, 65(1), 170–179. [DOI:10.1373/clinchem.2018.292730]
  • Spörl, S. (1978/1979). Über den Einfluß von Spironolacton (Aldactone®) auf den Stoffwechsel von Nebennierenrindenhormonen und von Testosteron bei Gesunden mit diätinduziertem Hyperaldosterismus. [On the influence of spironolactone (Aldactone®) on the metabolism of adrenocortical hormones and testosterone in healthy individuals with diet-induced hyperaldosteronism.] (Doctoral dissertation, Freie Universität, Berlin.) [Google Scholar] [Google Books] [WorldCat] [PDF]
  • Spratt, L. V., Reardon, E., Olshan, J. S., & Eimicke, T. (2014). Efficacy of Testosterone (T) or Estradiol (E2) Therapy without a GnRH Agonist or Progestin to Suppress Endogenous Gonadal Activity in Transsexual Patients. Endocrine Reviews, 35(Suppl 1) [Endocrine Society’s 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago], ?–? (abstract no. OR42-2). [DOI:10.1093/edrv/35.supp.1] [URL]
  • Stewart, I., Spratt, L., Craig, W., Olshan, J., & Spratt, D. (2018). The efficacy of testosterone or estradiol therapy without a GnRH agonist or progestin to suppress endogenous gonadal activity in transgender patients. Fertility and Sterility, 110(4 Suppl) [Scientific Congress Supplement: Oral and Poster Session Abstracts 06 October 2018 - 10 October 2018], e21–e21 (abstract no. O-44). [Google Scholar] [DOI:10.1016/j.fertnstert.2018.07.075]
  • Stripp, B., Taylor, A. A., Bartter, F. C., Gillette, J. R., Loriaux, D. L., Easley, R., & Menard, R. H. (1975). Effect of Spironolactone on Sex Hormones in Man. The Journal of Clinical Endocrinology & Metabolism, 41(4), 777–781. [DOI:10.1210/jcem-41-4-777]
  • Taylor, A. A., Rollins, D., Snodgrass, W., & Bartter, F. (1976). Effect of spironolactone (S) on adrenal and gonadal steroids in man. Clinical Research, 24(3), A279–A279. [Google Scholar] [PDF]
  • Tidd, M. J., Horth, C. E., Ramsay, L. E., Shelton, J. R., & Palmer, R. F. (1978). Endocrine effects of spironolactone in man. Clinical Endocrinology, 9(5), 389–399. [DOI:10.1111/j.1365-2265.1978.tb03578.x]
  • van Zuuren, E., & Fedorowicz, Z. (2016). Interventions for hirsutism excluding laser and photoepilation therapy alone: abridged Cochrane systematic review including GRADE assessments. British Journal of Dermatology, 175(1), 45–61. [DOI:10.1111/bjd.14486]
  • Walsh, P. C., & Siiteri, P. K. (1975). Suppression of Plasma Androgens by Spironolactone in Castrated Men with Carcinoma of the Prostate. Journal of Urology, 114(2), 254–256. [DOI:10.1016/s0022-5347(17)67001-0]
  • Wang, C., Du, Y., Bi, L., Lin, X., Zhao, M., & Fan, W. (2023). The Efficacy and Safety of Oral and Topical Spironolactone in Androgenetic Alopecia Treatment: A Systematic Review. Clinical, Cosmetic and Investigational Dermatology, 16, 603–612. [DOI:10.2147/ccid.s398950]
  • Weissmann, A. (1985). Antiandrogenic Effects of Topically Applied Spironolactone on the Hamster Flank Organ. Archives of Dermatology, 121(1), 57–62. [DOI:10.1001/archderm.1985.01660010061019]
  • Yamasaki, K., Sawaki, M., Noda, S., Muroi, T., Takakura, S., Mitoma, H., Sakamoto, S., Nakai, M., & Yakabe, Y. (2004). Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology, 195(2–3), 177–186. [DOI:10.1016/j.tox.2003.09.012]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]
  • Yazdabadi, A., & Sinclair, R. (2011). Treatment of female pattern hair loss with the androgen receptor antagonist flutamide. The Australasian Journal of Dermatology, 52(2), 132–134. [DOI:10.1111/j.1440-0960.2010.00735.x]
  • Zgliczynski, S., Baranowska, B., & Szymanowski, J. (1981). L’influence du spironolactone sur la concentration des gonatrophines et des hormones gonadiques dans l’hypertrophie prostatique. [The influence of spironolactone on the concentration of gonadotrophins and gonadal hormones in prostatic hypertrophy]. Journal d’Urologie, 87(9), 635–638. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF] [Translation]
  • Zimmerman, Y., Eijkemans, M. J., Coelingh Bennink, H. J., Blankenstein, M. A., & Fauser, B. C. (2013). The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Human Reproduction Update, 20(1), 76–105. [DOI:10.1093/humupd/dmt038]
\ No newline at end of file +A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People - Transfeminine Science Link

A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People

By Aly | First published December 19, 2018 | Last modified April 5, 2024

Abstract / TL;DR

Spironolactone is an antiandrogen used in transfeminine hormone therapy which is especially employed in the United States. It is widely considered to act as an androgen receptor antagonist and as an androgen synthesis inhibitor, both blocking the actions of testosterone and lowering testosterone levels in transfeminine people. A literature search was conducted to review studies assessing the influence of spironolactone on testosterone levels in cisgender men, cisgender women, and transfeminine people. The results of these studies were mixed, but in most studies spironolactone showed no apparent influence on testosterone levels. These findings suggest that spironolactone has inconsistent and limited effects on testosterone levels. Moreover, these data, as well as studies of estradiol alone, indicate that estradiol is mainly responsible for lowered testosterone levels when the combination of estradiol and spironolactone is used for hormone therapy in transfeminine people. Besides testosterone suppression, spironolactone also acts as a direct antagonist of the androgen receptor, and this importantly contributes to its antiandrogenic efficacy as well. However, studies in cisgender women suggest that spironolactone is a relatively weak androgen receptor antagonist, and is likely best-suited for blocking relatively low testosterone levels. Taken together, the antiandrogenic effectiveness of spironolactone in transfeminine people appears to be limited. Other antiandrogenic approaches may be more effective in transfeminine people, and may be considered instead or as alternatives to spironolactone in those in whom testosterone levels with estradiol plus spironolactone remain inadequately suppressed.

Introduction

Spironolactone, also known by its major brand name Aldactone, is an antiandrogen which is commonly used in transfeminine hormone therapy. It is used in combination with estrogen in transfeminine people to help reduce the effects of testosterone. Spironolactone is used in transfeminine hormone therapy particularly in the United States, where another antiandrogen, cyproterone acetate (CPA; brand name Androcur), is unavailable. Conversely, CPA is the main antiandrogen used in transfeminine people in Europe and most of the rest of the world. Another type of medication, gonadotropin-releasing hormone (GnRH) agonists, are the major antiandrogens used in certain places like the United Kingdom. The combination of estradiol with CPA or a GnRH agonist in transfeminine people consistently suppresses testosterone levels into the normal female range (<50 ng/dL or <1.8 nmol/L) (Aly, 2018; Aly, 2019). Hence, both CPA and GnRH agonists are very effective antiandrogens in transfeminine people.

Spironolactone acts as an androgen receptor antagonist, but is also known to function as an androgen synthesis inhibitor. As an example, spironolactone has been shown in preclinical research to inhibit several enzymes involved in gonadal and adrenal androgen production, including CYP17A1 (17α-hydroxylase/17,20-lyase) among others, and to substantially decrease concentrations of androgens in these studies (Loriaux et al., 1976; Callan, 1988; McMullen & Van Herle, 1993). However, the steroid synthesis inhibition of spironolactone appears to only occur at very high doses and concentrations of spironolactone (Loriaux et al., 1976; McMullen & Van Herle, 1993). For example, spironolactone is used at 10- to 20-fold smaller doses by body weight in humans than in animal studies that have demonstrated substantial steroid synthesis inhibition with the agent (McMullen & Van Herle, 1993).

A widespread notion in the transgender community, as well as in the transgender health community and in the medical literature, is that spironolactone decreases testosterone levels and that this is a major part of how it works as an antiandrogen in transfeminine people. In actuality however, the clinical evidence to support this notion appears to be limited, and available data from studies appear to be highly conflicting. The purpose of this article is to review the available clinical studies on spironolactone and testosterone levels in cisgender men, cisgender women, and transfeminine people in order to help elucidate whether and to what extent spironolactone lowers testosterone levels in humans. In addition, the role of androgen receptor blockade in the antiandrogenic effects of spironolactone is briefly reviewed.

Spironolactone and Testosterone Levels

A literature search was performed to identify studies assessing the influence of spironolactone on levels of testosterone as well as other relevant sex hormones in cisgender men and transfeminine people. Other sex hormones besides testosterone included dihydrotestosterone (DHT), androstenedione (A4), estradiol, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin, among others. Search engines included PubMed/MEDLINE and Google Scholar and relevant keywords were employed (e.g., “spironolactone”, “aldactone”, “testosterone”). Both observational studies (e.g., retrospective and prospective cohort and case–control studies) as well as randomized controlled trials (RCTs) where available were included. Studies are discussed separately based on whether they used spironolactone alone in cisgender men, spironolactone in cisgender women, spironolactone alone in transfeminine people, or spironolactone combined with estrogen in transfeminine people.

Spironolactone Alone in Cisgender Males

A total of 22 studies of spironolactone and sex hormone levels in cisgender males were identified (Table 1). These studies assessed pre-treatment versus post-treatment hormone levels with spironolactone, hormone levels with spironolactone versus a comparator group, or both. Within the identified studies, testosterone levels were not significantly changed in 12 of 22 studies (55%), decreased in 4 of 22 (18%) studies, increased in 1 of 22 (4.5%) studies, and mixed or unknown (e.g. divergences in changes of total versus free testosterone levels or didn’t actually report testosterone levels) in 4 of 22 (18%) studies. Most of the studies were very small (fewer than 10 people), with several exceptions. The studies were of highly variable lengths, with some being several days and others lasting for weeks or months. Few of the studies were RCTs. Most of the studies were very old, with a majority published in the 1970s and the rest published in the 1980s and 1990s. In relation to the preceding, the quality of data was limited.

Table 1: Studies of sex hormone levels with spironolactone alone in cisgender males:

Treatment and subjectsFindingsSource(s)
100 mg/day for 2 weeks in 7 healthy men (23–34 years)T significantly decreased and LH significantly increased. No significant change in E1, E2, or E3. No change urinary total T excretion but significantly increased urinary total E excretion (including of E1 (7.72 to 10.54 µg/24 hrs), E2 (2.60 to 3.34 ug/24 hours), E3 (7.69 to 11.75 µg/24 hrs)). Slightly but significantly decreased excretion of 17-KS in urine.Pentikäinen et al. (1974)
400 mg/day for 5 days in 6 healthy men (21–33 years)Significant increase in P4 and 17α-OHP (approximately doubled) for whole duration. Small and transient increases in LH (+20%) and FSH on the 2nd but not on the 3rd or 5th days (only other days measured). No significant changes in T, E2, or PRL. E2 and PRL non-significantly increased (+56% and +34% on the 5th day, respectively).Stripp et al. (1975)
100 or 400 mg/day spironolactone for 8 weeks in 7 orchiectomized men (46–78 years) with metastatic prostate cancerT, A4, and DHEA significantly decreased with both doses of spironolactone and of similar magnitude between doses. Influence more apparent after 2–3 weeks of treatment.Walsh & Siiteri (1975)
5 mg/kg/day for 1 week (275 mg/day for a 55 kg person) in 7 boys with delayed puberty (14–16 years)Significant increase in LH (+60%) and non-significant increase in FSH (+60%); individual responses for FSH variable. Increased P4 and 17α-OHP. T and E2 not actually reported.Santen et al. (1976)
Initially 400 mg/day for 12 weeks; dosage later decreased in some due to hypotension (range 150–400 mg/day) in 5 men and 5 women (3 premenopausal, 2 postmenopausal) with normal or low renin hypertensionP4 and 17α-OHP increased by 2 to 4 times compared to pre-treatment and post-treatment. T, E2, LH, FSH, PRL, and 17-KS all unchanged.Taylor et al. (1976)
100 mg/day for 4 weeks, then 0 mg/day for 4 weeks, then 400 mg/day for 4 weeks in 9 healthy men (18–39 years; mean 25 years)Dialyzable fraction of T increased significantly (+20%). LH, FSH, T, and E2 unchanged. LH and FSH responses to GnRH agonist unchanged.Caminos-Torres, Ma, & Snyder (1977)
400 mg/day for 24 weeks in 9 healthy men (21–28 years)No changes in LH, FSH, T, or E2.Caminos-Torres, Ma, & Snyder (1977)
200–400 mg/day for 4–13 months (mean 7 months) in 6 men with hypertension (35–61 years; mean 47 years) vs. 10 untreated male controls with hypertension (mean age 45 years)Significantly greater LH and E2 (30 pg/mL vs. 13 pg/mL; +130%), significantly lower T (440 ng/dL vs. 270 ng/dL; –38%), no difference in FSH. Also, significantly greater metabolic clearance rate of T, significantly greater rate of peripheral conversion (conversion ratio and transfer constant) of T into E2, non-significantly greater metabolic clearance rate of E2, no difference in blood production rate of T, and significantly greater blood production rate of E2.Rose et al. (1977)
200–400 mg/day (mean 330 mg/day) for 20–27 days in 5 gonadally intact men (50–76 years) with prostate cancerP4 increased significantly from 0.25 ± 0.10 ng/mL (mean ± SD) to maximum of 1.3 ± 0.31 ng/mL by 20 days (increase of 5.2-fold or 420%). T decreased significantly from 427 ± 74.3 ng/dL to 200 ± 80.3 ng/dL (–53.2%). No significant change in E2, LH, or FSH.Baba (1977); Baba et al. (1978)
200 mg/day for 21 days in 4 healthy men (26–35 years)No change in total T or E2. Unbound T and E2 slightly but significantly increased. Thought to be due to a direct interaction of spironolactone metabolites with the plasma protein binding of T and E2. But not due to binding to SHBG as T binding to SHBG was not significantly altered.Horth et al. (1977); Horth et al. (1979)
200 mg/day for 1 week in 6 normal men (23–40 years) (RCT)No changes in T, LH, or P4.Huffman et al. (1978)
100 mg/day for 10 months in 10 normal men (23–40 years) (RCT)No changes in T, E2, E3, LH, FSH, P4, or PRL. No change in metabolic clearance of A4 or T.Huffman et al. (1978)
100 mg/day for 2 months, then 200 mg/day for 8 months in 8 normal men (23–40 years) (RCT)No changes in T, E2, E3, LH, FSH, P4, or PRL. No change in metabolic clearance of A4 or T.Huffman et al. (1978)
75–150 mg/day for 12 weeks in 6 men with essential hypertension (28–64 years; mean 48 years)E1 significantly increased. E2 small, gradual, non-significant increase. T, LH, and PRL not significantly changed. PRL responses to TRH normal/not significantly changed.Miyatake et al. (1978)
150–300 mg/day for 40 weeks in 2 men with idiopathic hyperaldosteronism (23 and 44 years)E1 increased. E2 fluctuated. E2 increased by 10-fold in one person by 16 weeks and this was associated with gynecomastia. T, LH, and PRL not altered significantly.Miyatake et al. (1978)
200 mg/day for 10 days (n=5) vs. placebo (n=5) in 10 healthy men (18–31 years) (RCT)Significantly greater urinary A4, urinary EC, and urinary total E excretion. Differences in T, E2, LH, and FSH as well as urinary DHEA, LH, and FSH not significant. Examination of interaction between treatment and time showed significant changes in T, LH, and urinary DHEA. Concluded that there was a transient rise in T and urine DHEA for 2–4 days followed by increase in LH and normalization of T and DHEA excretion after 4–10 days.Tidd et al. (1978)
300 mg/day for 7 days (n=5) vs. 200 mg/day triamterene (n=5) in 10 normal young men with diet-induced hyperaldosteronism (14 days of a diet modifying electrolyte intake)P4, 17α-OHP, unchanged. T near-but-non-significantly decreased (704.6 ± 55.5 ng/dL (mean ± SEM) to 508.4 ± 45.9 ng/dL on day 6; p < 0.10). Also assessed endogenous corticosteroids.Abshagen et al. (1978); Spörl (1978/1979)
100 mg/day for 3 months in treatment group of 47 men (age 60–80 years) with BPH; control group of 58 healthy men without BPH (also age 60–80 years)In spiro/BPH group, T decreased from 650 ng/dL to 290 ng/dL and DHT decreased from 450 ng/dL to 150 ng/dL. In control/non-BPH group, T was 280 ng/dL and DHT was 90 ng/dL. P4, E2, and LH increased in spiro/BPH group. FSH also assessed. The authors stated that prostate gland can be a source of androgen production, implying that BPH can produce elevated androgen levels and that spironolactone can normalize elevated androgen levels in the condition.Zgliczynski, Baranowska, & Szymanowski (1981)
150 mg/m2/day for 5 days in 6 boys with irregular puberty (11–13 years)No significant changes in T or urinary 17-KS excretion, elevated LH (by 600%—likely typo of “60%” (?)), and slightly increased FSH (from 0.75 ng/mL to 0.86 ng/mL).Skorodok, Savchenko, & Liss (1983)
50–200 mg/day for 3 months in 17 males and 19 females (36 people total; 18–38 years, mean 24 years) with severe acneMales no significant changes in T, SHBG, DHT, or FAI.Goodfellow et al. (1984)
50 mg/day for 4 weeks in 13 males (28–60 years, mean 47 years) with rosaceaNo changes in T, A4, DHT, or DHEA-S. 17α-OHP significantly increased (from 1.0 ± 0.65 ng/mL (mean ± SD) to 1.7 ± 0.98 ng/mL; +70%). E2 non-significantly increased (from 61 ± 29 pg/mL to 77 ± 45 pg/mL; +26%).Aizawa & Niimura (1992)
25–400 mg/day (median 100 mg/day) for 12 months in 32 males (59%) of a group of 54 males (17–64 years; mean 44 years) with non-alcoholic liver disease requiring liver transplantation vs. 469 healthy male controls (mean 31 years) with normal liver functionSignificantly decreased T with spironolactone in men with moderate-severity liver disease but not with low- or high-severity liver disease. SHBG not influenced by spironolactone dosage. No influence on gonadotropin responses to GnRH stimulation.Handelsman et al. (1995)

Abbreviations: T = testosterone; E2 = estradiol; E1 = estrone; E3 = estriol; E = estrogen(s); P4 = progesterone; 17α-OHP = 17α-hydroxyprogesterone; A4 = androstenedione; EC = etiocholanolone; DHT = dihydrotestosterone; DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; 17-KS = 17-ketosteroids; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; PRL = prolactin; TRH = thyrotropin-releasing hormone; FAI = free androgen index; SHBG = sex hormone-binding globulin; BPH = benign prostatic hyperplasia; RCT = randomized controlled trial.

A few additional studies with the spironolactone-related drugs canrenone or potassium canrenoate (a prodrug of canrenone) (e.g., Soldactona) were also identified (Dymling, Nilsson, & Hökfelt, 1972; Dymling & Hökfelt, 1973; Erbler, 1974; Corvol et al., 1976; Dymling, 1978). These studies are notable as canrenone is a known active metabolite of spironolactone and as the studies consistently found decreased androgen levels with drugs delivering canrenone. In any case, the studies are excluded from the present review as they did not actually employ spironolactone.

Although the quality of these studies is limited, the findings of the studies, which are mixed but are overall more suggestive against spironolactone reducing testosterone levels than it doing so, are in notable contrast to similar studies of CPA and testosterone suppression in cisgender men that were published in the 1970s and 1980s. These studies consistently found that CPA suppressed testosterone levels by 40 to 70% on average (Aly, 2019). Subsequently, the findings were replicated in several more modern studies of CPA in cisgender men and transfeminine people, which likewise found that the drug given alone consistently suppressed testosterone levels by about 45 to 65% on average (Aly, 2019).

Spironolactone in Cisgender Women

Spironolactone has a long history of use in cisgender women in the treatment of androgen-dependent skin and hair conditions like acne, hirsutism, scalp hair loss, and hyperandrogenism (due to e.g. polycystic ovary syndrome (PCOS)). It has been used at similar doses for androgen-dependent conditions in cisgender women as it has in transfeminine people (e.g., 50–200 mg/day most typically). There are many dozens of studies of spironolactone as an antiandrogen in cisgender women (e.g., PubMed). Instead of attempting to individually review all of these studies, the present article will discuss the findings of several papers that have themselves reviewed substantial numbers of these studies and have summarized available findings on testosterone levels with spironolactone.

Callan (1988) reviewed the literature on spironolactone for treatment of acne and hirsutism in cisgender women and found that some clinical studies reported decreased levels of testosterone and/or other androgens with spironolactone (4 studies cited) whereas other studies reported no change in androgen levels (4 studies cited). The author cited several studies to support the claim that androgen receptor antagonism with spironolactone is more clinically important than any influence it has on androgen production (5 studies cited). For instance, clinical benefits against acne and hirsutism occurred with spironolactone both before androgen levels decrease as well as when androgen levels do not decrease.

McMullen & Van Herle (1993) reviewed 19 studies of spironolactone for treatment of androgen-dependent conditions in cisgender women, with a majority of these studies reporting long-term hormone levels. Most of the studies were open-label and uncontrolled, with only five studies having a control group and only two studies being double-blind placebo-controlled trials. Changes in hormone levels across studies were very heterogenous, with the majority of changes not reaching statistical significance. Only 1 of 7 (14%) studies found a decrease in DHEA-S levels. The review concluded that a clinically significant change in adrenal androgen levels with spironolactone in cisgender women was not supported. Conversely, testosterone levels were decreased with spironolactone in 13 of 16 (81%) of studies. However, in the only two RCTs, there were no differences in testosterone levels with spironolactone versus in the placebo control groups. As such, the review concluded that the decreased testosterone levels with spironolactone in cisgender women reported in many of the non-RCT studies may not actually be a real phenomenon. As with Callan (1988), the review noted that the major mechanism of action of spironolactone as an antiandrogen is likely to be androgen receptor blockade.

Bradstreet et al. (2007) cited and discussed a Cochrane review of spironolactone for treatment of acne and/or hirsutism in cisgender women (Farquhar et al., 2003). Cochrane reviews are rigorous high-quality systematic reviews of all of the available RCTs for a given medical intervention. The Cochrane review identified 19 RCTs, with 9 included in the review, 8 excluded due to methodological issues (e.g., with randomization), and two others which were described as “awaiting assessment” (Farquhar et al., 2003). Bradstreet and colleagues noted per the Cochrane review that spironolactone at a dosage of 100 mg/day had little influence on levels of DHEA, DHEA-S, or testosterone in the trials evaluated and said that this is because its mechanism of action as an antiandrogen is androgen receptor antagonism (Bradstreet et al., 2007). The Cochrane review itself did not discuss changes in androgen or testosterone levels with spironolactone in aggregate. An update of the Cochrane review was published in 2009, but with no new studies found and with the findings unchanged (Brown et al., 2009).

Layton et al. (2017) was a hybrid systematic review of spironolactone for acne in cisgender women. In a table discussing the mechanism of action of spironolactone and other antiandrogens for acne, the authors stated that “Data from over 50 articles reporting effects [of spironolactone] on serum androgens are equivocal” (i.e., ambiguous, uncertain, questionable) (Layton et al., 2017). The review further noted that inhibition of androgen synthesis by spironolactone in humans may be unlikely at therapeutic doses and may occur instead only at supraphysiological doses (with Menard et al. (1979) cited in support of these claims, presumably related to the very high doses required) (Layton et al., 2017).

Rozner et al. (2019) reviewed clinical studies of the endocrine effects of spironolactone in cisgender women to assess whether it is safe to use in women with past or present breast cancer receiving endocrine therapy. The review included 18 studies with 465 women (mostly having androgen-dependent conditions) assessing the influence of spironolactone on sex hormone levels. The assessed studies included retrospective cohort studies, case–control studies, and RCTs. Of the included studies, 10 (56%) studies (with 179 women) found no change in testosterone levels with spironolactone, 8 (44%) studies (with 253 women) found a decrease, and 1 (6%) study (with 33 women) found an increase in free but not total testosterone levels. Changes in levels of DHEA-S, androstenedione, and estrogen were also assessed and findings were similar, with no changes observed in majorities of studies for these hormones. The review concluded that there is no significant change in levels of androgens, estrogen, or gonadotropins with spironolactone in cisgender women.

Almalki et al. (2020) conducted a systematic review and network meta-analysis of RCTs on the comparative efficacy of several types of medications (statins, metformin, spironolactone, and combined birth control pills) on reducing testosterone levels in cisgender women specifically with PCOS. Nine RCTs including 613 women were included for all of the medications. The meta-analysis concluded that the statin atorvastatin was more effective than the other included medications in reducing testosterone levels. Only two of the included RCTs employed spironolactone, one of which was with spironolactone alone (n=34) versus metformin (n=35) (Ganie et al., 2004) and the other of which was with spironolactone plus metformin (n=62) versus spironolactone alone (n=51) versus metformin alone (n=56) (Ganie et al., 2013). Both of the included trials found that spironolactone alone significantly decreased testosterone levels in pre-treatment versus post-treatment comparisons (Ganie et al., 2004; Ganie et al., 2013). No trials of spironolactone versus placebo controls were included.

Taken together, the available studies of spironolactone and testosterone levels in cisgender women with androgen-dependent conditions are highly inconsistent and mixed, but with numerous studies finding no significant changes in testosterone levels. The reasons for the findings being so mixed are unclear, but may relate to study methodology and quality. Findings in this population seem particularly notable as regulation of the hypothalamic–pituitary–gonadal (HPG) axis by androgens in women is minimal to negligible, in turn making it such that androgen receptor antagonists will have little effect of upregulating gonadal sex hormone production as they can in cisgender men and transfeminine people. As a result, there is less homeostatic interference that could influence findings in evaluating the steroid synthesis inhibition of spironolactone in this sex, and hence these studies may provide a clearer picture of steroid synthesis inhibition as a possible clinical effect of spironolactone. However, as the findings are still so mixed, the results seem inconclusive. In any case, only a limited effect at best seems clear.

Spironolactone Alone in Transfeminine People

Only one study of spironolactone alone (without estrogen) and sex hormone levels in transfeminine people was identified (Table 2). It was conducted by Louis Gooren and colleagues of the Dutch Center of Expertise on Gender Dysphoria (CEGD) at the Vrije Universiteit Medical Center (VUMC) in Amsterdam, Netherlands in the 1980s. The study compared levels of testosterone, DHT, estradiol, LH, FSH, and prolactin before and after treatment with 200 mg/day spironolactone for 6 weeks in 6 young pre-hormone-therapy transfeminine people. It found slightly but significantly increased testosterone levels, increased prolactin levels, and no change in levels of estradiol, DHT, LH, or FSH.

Table 2: Studies of sex hormone levels with spironolactone alone in transfeminine people:

Treatment and subjectsFindingsSource(s)
200 mg/day for 6 weeks in 6 pre-hormone therapy transfeminine people (21–39 years)T (mean ± SEM) increased significantly from 17.2 ± 0.8 nmol/L (496 ± 20 ng/dL) to 20.6 ± 1.7 nmol/L (594 ± 50 ng/dL) (+19.8%). No change in E2 (90 ± 20 pmol/L [25 ± 5.0 pg/mL] vs. 100 ± 30 pmol/L [27 ± 8.2 pg/mL] or 80 ± 20 pmol/L [22 ± 5.4 pg/mL]) or DHT (1.7 ± 0.8 nmol/L [49 ± 20 ng/dL] vs. 1.8 ± 0.9 nmol/L [52 ± 30 ng/dL]). LH, FSH, and GnRH-stimulated LH and FSH unchanged. PRL and TRH-stimulated PRL increased.Gooren et al. (1984a); Gooren et al. (1984b)

Abbreviations: T = testosterone; E2 = estradiol; DHT = dihydrotestosterone; LH = luteinizing hormone; FSH = follicle-stimulating hormone; GnRH = gonadotropin-releasing hormone; PRL = prolactin; TRH = thyrotropin-releasing hormone.

The fact that this study was done by the CEGD is notable as this institute is among the most prolific research centers on transgender hormone therapy in the world (Bakker, 2021), and, while they evaluated spironolactone as well as nilutamide as antiandrogens in studies in transfeminine people in the 1980s and 1990s (Wiki), the group ultimately settled on using only CPA instead. This was probably related to the lack of testosterone suppression with spironolactone and pure androgen receptor antagonists like nilutamide, as the researchers have touched on in other publications (e.g., Gooren, 1999).

Estrogen Plus Spironolactone in Transfeminine People

Eleven studies of the combination of estrogen and spironolactone and sex hormone levels in transfeminine people were identified (Table 3). The first study was conducted by Jerilynn Prior and colleagues in Canada in the 1980s. Subsequent studies were conducted over 25 years later by groups in the United States, Australia, Israel, and Thailand. All of the studies were retrospective chart reviews or prospective non-randomized studies, with the exception of a single RCT.

Table 3: Studies of testosterone levels with estrogen plus spironolactone in transfeminine people:

Treatment and subjectsFindingsSource(s)
Oral CEEs (0.625–5 mg/day cyclically—3 of 4 weeks per month), oral MPA (10–20 mg/day cyclically—3 of 4 weeks per month—or continuously—”if gonadotrophins increased or to aid in T reduction or breast development”), and spironolactone (100–600 mg/day continuously) for 12 months in 27 transfeminine people who had been on “high-dose” E alone for an extended duration (Group 1) and 23 transfeminine people who were pre-hormone-therapy (Group 2), or 50 transfeminine people total, at Vancouver General Hospital.T decreased in Group 1 from mean 169 ng/dL to 87.4 ng/dL (–48.2%) and in Group 2 from mean 642 ng/dL to 49.2 ng/dL (–92.3%). In the groups combined, T following treatment would be mean 69.8 ng/dL. Per authors, spironolactone was intended to help reduce T and facilitate feminization while MPA was intended to help suppress gonadotropins and T and improve breast development. However, authors emphasized the decrease in T as being due to spironolactone despite inclusion of MPA, without data provided to substantiate this.Prior, Vigna, & Watson (1989); Prior et al. (1986)
Sublingual estradiol (4 mg/day—2 mg b.i.d.) (n=14), transdermal estradiol patch (100 μg/day) (n=1), or injectable estradiol valerate (20 mg/2 weeks) (n=1) with spironolactone (100–200 mg/day) for 6 months in 16 transfeminine people at an LGBT community health center in Los Angeles, California.T was median 405 ng/dL at baseline and 42 ng/dL after 6 months (–89.6%). Free T was median 11.4 ng/dL at baseline and 0.8 ng/dL at 6 months (–93.0%). 10 of 15 (66.7%) had total T in female range and 14 of 15 (93.3%) had free T in female range.Deutsch, Bhakri, & Kubicek (2015)
Oral E2 (1–8 mg/day) with or without spironolactone (200 mg/day) (n=61), finasteride (5 mg/day) (n=49), and/or MPA (2.5–10 mg/day) (n=38) for 0.3 to 10.5 years (mean 4.3 ± 3.1 years) in 156 transfeminine people at Albany Medical Center.Oral E2 dose-dependently and substantially but incompletely suppressed T. Relative to E2 alone (at equivalent E2 levels), E2 plus spironolactone had no significant influence on T (+10.6 ± 16 ng/dL (mean ± SE); p = 0.5) and no greater likelihood of achieving better T suppression (<100 ng/dL) (OR = 0.75; 95% CI = 0.44–1.29). T levels with E2 alone were mean ~80 ng/dL and with E2 plus spironolactone were mean ~95 ng/dL per own re-analysis. Finasteride was also associated with greater T levels. MPA helped with T suppression in some (71% of subjects). More discussion and re-analysis including graphs (Aly, 2019).Leinung, Feustel, & Joseph (2018); Leinung (2014)
Oral E2 (0.5–10 mg/day) (n=67) or oral CEEs (0.625–5 mg/day) (n=12) and spironolactone (25–400 mg/day; mean/median 145 mg/day) for 12 months in 98 transfeminine people at Boston Medical Center.Combined E and spironolactone decreased T from median 385 ng/dL to 130 ng/dL (–66.2%). E alone vs. E and spironolactone not reported. No significant influence of spironolactone dosage on T. Incomplete suppression of T (>50 ng/dL) in all but the lowest quartile (25%) of individuals.Liang et al. (2018); Bonzagni (2014)
Oral EV (4–6 mg/day; median 5–6 mg/day) (88.3%) or transdermal E2 (11.7%) alone or in combination with CPA (25–50 mg/day; median 50 mg/day) or spironolactone (87.5–200 mg/day; median 100 mg/day) for 0.9 to 2.6 years (median 1.5 years) in 80 transfeminine people at two gender clinics in Melbourne, Australia.T was median 10.5 nmol/L (303 ng/dL) with E2 only, 2.0 nmol/L (58 ng/dL) with E2 plus spironolactone, and 0.8 nmol/L (23 ng/dL) with E2 plus CPA. 90% of those on E2 plus CPA and 40% of those on E2 plus spironolactone had T of <2 nmol/L (<58 ng/dL). T significantly lower with E2 plus CPA compared to E2 plus spironolactone and E2 alone. T with E2 plus spironolactone lower than with E2 alone but non-significantly. No significant differences between groups in age, hormone therapy duration, or E2 dosage or levels. Graph that visually summarizes the results.Angus et al. (2019); Cheung et al. (2018)
Sublingual estradiol (2–12 mg/day) and spironolactone (100–200 mg/day) with or without sublingual MPA (5–10 mg/day) or injectable MPA (150 mg/3 months) for 3.4 ± 1.7 years in 92 transfeminine people at Rhode Island Hospital.T (mean ± SD) was 215 ± 29 ng/dL with E2 plus spironolactone and 79 ± 18 ng/dL with E2 plus spironolactone and MPA.Jain, Kwan, & Forcier (2019)
Oral E2 (2–8 mg/day) (84.2%) or other E forms (15.8%) with spironolactone (80.4%; n=107) or without spironolactone (19.6%) for more than 6 months in 133 transfeminine people at three clinics in Dallas, Texas.T decreased from median 367 ng/dL (95% range 175–731 ng/dL) (n=70) at baseline to median 55 ng/dL (95% range 3–709 ng/dL) (n=131) in whole group (80.4% taking spironolactone). 65 of 133 (49%) had adequate T suppression (presumably <50 or <60 ng/dL) in whole group. T with E2 plus spironolactone at 25–75 mg/day (n=15) was mean 129.4 ng/dL (range <3—611 ng/dL), at 100–175 mg/day (n=61) was mean 180.4 ng/dL (range <3–1137 ng/dL), and at 200–300 mg/day (n=31) was mean 170.1 ng/dL (range <3–798 ng/dL). In the whole E2 plus spironolactone group (n=107), T would be mean 170.3 ng/dL.SoRelle et al. (2019); Allen et al. (2021)
Oral E2 (2–8 mg/day), transdermal E2 gel (2.5–5 mg/day), or transdermal E2 patches (50–200 μg/day) plus spironolactone (50–200 mg/day) (n=16), CPA (10–100 mg/day) (n=41), or a GnRH agonist (n=10) for 12 months in 67 transfeminine people at Tel Aviv-Sourasky Medical Center in Israel.With spironolactone, T (mean ± SD) decreased from 15.2 ± 8.1 nmol/L (438 ± 230 ng/dL) at baseline to 10.2 ± 5.7 nmol/L (294 ± 164 ng/dL) at 3 months (–32.9%), 3.5 ± 1.2 nmol/L (100 ± 35 ng/dL) at 6 months (–77.0%), and 4 ± 7.1 nmol/L (120 ± 200 ng/dL) at 12 months (–73.7%). T was in the female range (<1.8 nmol/L [52 ng/dL]) at all follow-ups after baseline for both CPA and GnRH agonist (–92.0% to –96.4%).Sofer et al. (2020)
Oral EV 4 mg/day plus spironolactone (100 mg/day) (n=26) or CPA (25 mg/day) (n=26) for 12 weeks in 52 transfeminine people at two clinics in Bangkok, Thailand (RCT).With intention-to-treat analysis, T decreased with E2 plus spironolactone from median 645.0 ng/dL (IQR 466.7−1027.7 ng/dL) to 468.3 ng/dL (IQR 287.0−765.4 ng/dL) (–27.4%) and with E2 plus CPA from 655.5 ng/dL (402.6−872.7 ng/dL) to 9.3 ng/dL (IQR 5.5−310.4 ng/dL) (–98.6%). Adequate suppression of testosterone (<50 ng/dL) was achieved by 4 of 26 (15%) in the E2 plus spironolactone group and by 18 of 26 (69%) in the E2 plus CPA group. Study also assessed and reported E2, SHBG, and PRL levels.Burinkul et al. (2021)
E2 (sublingual, transdermal, or injectable) with spironolactone (n=39) or without spironolactone (n=37) for 12 months in 93 transfeminine people at two LGBTQ-oriented clinics in Seattle, Washington and Iowa City, Iowa.T was median 11 to 18 ng/dL in different estradiol groups without spironolactone and median 10 to 12 ng/dL in different estradiol groups with spironolactone. T was significantly lower with spironolactone only for sublingual E2 group (median 11 ng/dL (IQR 6–35 ng/dL) [n=27] vs. median 18 ng/dL (IQR 13–205 ng/dL) [n=16]) and not for transdermal or injectable E2 groups.Cirrincione et al. (2021)
Oral E2 (4–12 mg/day, median 6 mg/day) (n=27) or injectable EV (2–5 mg/week, median 4 mg/week) (n=6) with spironolactone (n=31) or without spironolactone (n=2) for median 6.2 months (range 0.6–28.2 months) (time on optimized E2 dose specifically) in 33 transfeminine people at Maine Medical Center.T was median 13.0 ng/dL (range 2.7–559 ng/dL) for whole group (93.9% taking spironolactone). 28 of 33 (84.8%) of whole group had female-range T (<50 ng/dL). However, in earlier studies by the same group, similar T suppression with E2 alone was reported (Reardon et al., 2013; Spratt et al., 2014).Pappas et al. (2021); Pappas et al. (2020); Stewart et al. (2018)

Abbreviations: E = estrogen; E2 = estradiol; EV = estradiol valerate; CEEs = conjugated [equine] estrogens; CPA = cyproterone acetate; MPA = medroxyprogesterone acetate; GnRH = gonadotropin-releasing hormone; T = testosterone; DHEA-S = dehydroepiandrosterone sulfate; LH = luteinizing hormone; FSH = follicle-stimulating hormone; PRL = prolactin.

The data on the testosterone levels with estrogen plus spironolactone in transfeminine people from the 11 studies in the table can be roughly summarized. Some studies reported mean testosterone levels and some reported median testosterone levels, so these cases must be considered separately. In terms of reported mean testosterone levels across studies (4 studies), the median value of these study averages would be about 171 ng/dL and the range of study averages would be about 95 to 215 ng/dL. In terms of reported median testosterone levels across studies (7 studies), the median value of these study medians would be about 55 ng/dL and the range of study medians would be about 11 to 468 ng/dL. One study had to be excluded due to concomitant use of the progestogen medroxyprogesterone acetate (MPA) in all individuals (Prior, Vigna, & Watson, 1989; Prior et al., 1986). Insights from the preceding results include large variability in testosterone levels across studies and mean testosterone levels being much higher than median testosterone levels. Limitations of the preceding values include lack of equivalent estrogen and spironolactone dosages and levels across studies, lack of equivalent durations of hormone therapy across studies, lack of equivalent testosterone blood-testing methodologies across studies, lack of equivalent transfeminine patient samples, and, in the case of the study median testosterone values, two of the studies notably having almost all but not all individuals on spironolactone (80 and 94% rather than 100%). These limitations likely underlie the large variability in reported values across studies. In any case, these results suggest that estrogen plus spironolactone results in variably inadequate testosterone suppression in most transfeminine people, which is in notable major contrast to testosterone suppression with estrogen plus CPA or a GnRH agonist in transfeminine people.

Individual findings of the studies include inadequate testosterone suppression with estradiol plus spironolactone in most transfeminine people (Leinung et al., 2018; Liang et al., 2018; Jain, Kwan, & Forcier, 2019; Sofer et al., 2020; Burinkul et al., 2021), no difference in testosterone suppression with spironolactone versus without spironolactone (Leinung et al., 2018), lack of notable influence of spironolactone dosage on testosterone suppression (Liang et al., 2018; SoRelle et al., 2019), and inferior testosterone suppression with estradiol plus spironolactone compared to estradiol plus CPA or a GnRH agonist in transfeminine people (Angus et al., 2019; Sofer et al., 2020; Burinkul et al., 2021). Conversely, some studies have found adequate or near-adequate testosterone suppression with estradiol plus spironolactone in most or almost all transfeminine people (Deutsch, Bhakri, & Kubicek, 2015; Angus et al., 2019; SoRelle et al., 2019; Cirrincione et al., 2021; Pappas et al., 2021), and some studies have found indications of greater testosterone suppression with spironolactone versus without spironolactone (Angus et al., 2019; Cirrincione et al., 2021). On the other hand, some studies using estradiol alone without any antiandrogen at physiological estradiol levels (<200 pg/mL) have reported adequate testosterone suppression similarly to the preceding estradiol plus spironolactone studies (Reardon et al., 2013; Spratt et al., 2014; Cirrincione et al., 2021). One study was confounded by the concomitant use of MPA, which is known to suppress testosterone levels on its own, and hence reliable conclusions cannot not be drawn from this study (Prior, Vigna, & Watson, 1989; Prior et al., 1986). Indeed, it is notable that this study found lower mean testosterone levels with estrogen and spironolactone than any other study did. A couple of studies found that testosterone levels progressively decline with time (particularly over the first 12 months) with estradiol plus spironolactone in most transfeminine people (Liang et al., 2018; Sofer et al., 2020). Whether the decreases in testosterone levels with time were more related to estradiol or to spironolactone is unclear, though estradiol seems more likely (e.g., Wiki).

Taken together, the findings of available studies on estradiol plus spironolactone and testosterone suppression in transfeminine people are highly variable and mixed, although overall more studies support spironolactone having poor or no testosterone-suppressing effectiveness. The reasons underlying the differences in findings on testosterone suppression between studies are unclear, but contributing factors may include varying estradiol doses, routes, and levels, durations of hormone therapy, differing laboratory assays of testosterone levels, and other differences in study methodologies, as well as limitations in study and evidence quality. In any case, the conflicting nature of the findings is in major contrast to the almost invariably strong to maximal testosterone suppression in studies of estradiol plus CPA and estradiol plus GnRH agonists in transfeminine people.

Spironolactone, Androgen Receptor Antagonism, and Clinical Antiandrogenic Effectiveness

The clinical antiandrogenic effectiveness of spironolactone in cisgender women with androgen-dependent skin and hair conditions, like acne, hirsutism, and scalp hair loss, is well-established (Brown et al., 2009; van Zuuren & Fedorowicz, 2016; Layton et al., 2017; Barrionuevo et al., 2018; James, Jamerson, & Aguh, 2022; Wang et al., 2023). Conversely, the clinical antiandrogenic efficacy of spironolactone in transfeminine people has been very limitedly assessed to date and is largely unknown (Angus et al., 2021). Spironolactone does not appear to be very effective for decreasing testosterone levels in either cisgender women or transfeminine people based on the findings of the present review. However, spironolactone is a competitive antagonist of the androgen receptor in addition to its actions a weak androgen synthesis inhibitor, and hence it also directly blocks androgens from mediating their effects in the body (Loriaux et al., 1976; McMullen & Van Herle, 1993). Based on studies in populations besides transfeminine people, for instance cisgender women (discussed above) and cisgender boys with gonadotropin-independent precocious puberty (e.g., Holland, 1991), in which spironolactone has not decreased testosterone levels but has nonetheless been effective as an antiandrogen, the androgen receptor blockade of spironolactone is likely to be its main mechanism of action as an antiandrogen and may account for most or all of its therapeutic antiandrogenic effectiveness.

However, while spironolactone is clearly effective as an androgen receptor antagonist, it appears to be a relatively weak androgen receptor blocker at typical doses used in cisgender women and transfeminine people. Numerous publications in the literature describe spironolactone as being only a weak androgen receptor antagonist (Wiki; Wiki). In relation to this, animal studies have found that spironolactone is a far less potent androgen receptor antagonist than other antiandrogens like CPA, flutamide, and bicalutamide (Bonne & Raynaud, 1974; Hecker, Hasan, & Neumann, 1980; Sivelle, Underwood, & Jelly, 1982; Weissmann et al., 1985; Labrie et al., 1987; Snyder, Winneker, & Batzold, 1989 [Table]; Yamasaki et al., 2004 [Graph]). Moreover, in cisgender women, the population in which spironolactone is most widely used as an antiandrogen, testosterone levels are relatively low, on average about 20-fold lower than in cisgender men (around 30 ng/dL on average compared to about 600 ng/dL on average, respectively) (Aly, 2018). However, many cisgender women with androgen-dependent conditions have PCOS, which is associated with limitedly elevated testosterone levels (e.g., perhaps around 60 ng/dL on average) (Aly, 2018). The typical therapeutic dose range of spironolactone in cisgender women with androgen-dependent conditions is 50 to 200 mg/day, in which its effectiveness may be assumed to be dose-dependent, and this is roughly the same general dosage range used in transfeminine people (though up to 300–400 mg/day may be used and are allowed for by guidelines) (Aly, 2018; Aly, 2020).

A relatively small amount of dose-ranging data on spironolactone in cisgender women with androgen-dependent conditions exists, but in any case substantiates its dose-dependent effectiveness across its clinically used dose range (partially reviewed in Hammerstein (1990) and Shaw (1996)). One study compared spironolactone at doses of 50 to 200 mg/day with placebo for treatment of acne in cisgender women and reported progressive increases in effectiveness with spironolactone up to the 200 mg/day dosage (Goodfellow et al., 1984). Similarly, another study found that progressively increasing the dosage of spironolactone from 100 mg/day, to 150 mg/day, and up to 200 mg/day, resulted in increased effectiveness in the treatment of acne in cisgender women (Charny, Choi, & James, 2017). Spironolactone has been reported to be effective in the treatment of hirsutism in cisgender women at a dosage of as low as 50 mg/day (Diamanti-Kandarakis, Tolis, & Duleba, 1995). However, even a dosage of 100 mg/day did not appear to be maximally effective for hirsutism in a study that compared different doses of spironolactone; effectiveness was near-significantly greater at a dosage of 100 mg/day relative to a dosage of 200 mg/day (19% ± 8% and 30% ± 3% (mean ± SEM) reduction in hair shaft diameter, respectively; p = 0.07) (Lobo et al., 1985). Levels of free testosterone in this study were unchanged, suggesting that the effects of spironolactone was purely due to androgen receptor blockade. Finally, a 2022 systematic review of spironolactone for treatment of androgen-related scalp hair loss in cisgender women reported that the drug was “largely ineffective” at doses of less than 100 mg/day, whereas doses of 100 to 200 mg/day were effective (James, Jamerson, & Aguh, 2022).

Aside from dose-ranging studies, the antiandrogenic efficacy of spironolactone can be evaluated by comparing it to more potent antiandrogenic regimens. A study found that spironolactone 100 mg/day was significantly inferior to flutamide, a substantially more potent androgen receptor antagonist, in improving androgen-dependent skin and hair symptoms in cisgender women (Cusan et al., 1994). However, in other studies, there were no significant differences between spironolactone 100 mg/day and flutamide for hirsutism (Erenus et al., 1994; Moghetti et al., 2000; Inal, Yildirim, & Taner, 2005; Karakurt et al., 2008). Spironolactone and flutamide were variably taken together with an ethinylestradiol-containing combined birth control pill in these studies, which is likely to have limited detection of differences in effectiveness. This is because these birth control pills considerably suppress total and free testosterone levels and hence have substantial antiandrogenic effects themselves (Zimmerman et al., 2014; Amiri et al., 2018). In a biochemical study, spironolactone 100 mg/day was numerically inferior to flutamide in reducing levels of prostate-specific antigen (PSA) in cisgender women (Negri et al., 2000). This is notable as PSA is a systemic biomarker of androgen action (Negri et al., 2000). However, the study had small sample sizes, and the differences between groups were not statistically significant (Negri et al., 2000). A case report of a cisgender woman with female pattern hair loss and normal androgen levels found that treatment with spironolactone 200 mg/day for 5 years failed to improve or halt progression of her hair loss, in spite of almost complete loss of secondary sexual hair, but switching to flutamide resulted in a considerable improvement in hair loss after 12 months (Yazdabadi & Sinclair, 2011 [Figure]). Besides comparison with flutamide, a study found that spironolactone 100 mg/day was inferior to spironolactone 100 mg/day plus finasteride, a 5α-reductase inhibitor and hence functional antiandrogen, for hirsutism in cisgender women (–36.6% vs. –51.3% in scores; p < 0.005) (Unlühizarci et al., 2002; Keleştimur et al., 2004).

The preceding findings suggest that the clinical antiandrogenic effectiveness of spironolactone in cisgender women is not maximal at a dosage of below at least 200 mg/day despite the relatively low testosterone levels in these individuals. Put another way, spironolactone at typical doses seems best-suited for blocking female-range levels of testosterone. As many transfeminine people do not achieve female-range testosterone levels with estradiol plus spironolactone therapy, and in fact often have testosterone levels well above the normal female range or even in the male range, spironolactone may not be fully effective as an antiandrogen at the typical doses used in transfeminine hormone therapy. Higher doses of spironolactone, like 300 to 400 mg/day, may be to some degree more effective.

Summary, Discussion, and Conclusions

Numerous studies have assessed the influence of spironolactone on testosterone levels in cisgender men, cisgender women, and transfeminine people. Although the quality of these studies has often been limited, the studies have revealed highly inconsistent influences of spironolactone on testosterone levels in these populations, with many studies finding no changes, some studies finding decreases, and a small number of studies finding increases. The findings of studies of spironolactone and testosterone levels are in notable contrast to those of studies with estrogens, progestogens like CPA, and GnRH agonists, which consistently show substantial decreases in testosterone levels. This has been the case even in studies of similarly low quality to those of some of the included spironolactone studies (e.g., many of those in cisgender men). The fact that in the available studies testosterone levels with spironolactone have usually been unchanged, but have sometimes been decreased and have rarely been decreased, seems to suggest that spironolactone may be a clinically significant inhibitor of steroid hormone synthesis, but that it is only a weakly efficacious one, and that its effects may be variable depending on the individual and other clinical circumstances. In any case, the conflicting findings warrant more research with higher-quality study designs, particularly RCTs that have with spironolactone versus without comparison groups.

The notion that spironolactone decreases testosterone levels in transfeminine people, and the use of spironolactone in transfeminine hormone therapy in general, appear to have originated from the papers on spironolactone in transfeminine people published by Dr. Jerilynn Prior and colleagues in the 1980s (Prior, Vigna, & Watson, 1989; Prior et al., 1986). In their study, transfeminine people who were either already on high-dose estrogen therapy with inadequate testosterone suppression or had not yet started hormone therapy were put on physiological-dose estrogen therapy in combination with 200 to 600 mg/day spironolactone. Cyclic or continuous administration of the progestogen MPA at an oral dose of 10 mg/day was also given to all of the individuals. The authors reported that despite the lower estrogen dosage, testosterone levels decreased, from 169 ng/dL to 87 ng/dL (–49%) in those who had already been on hormone therapy and to 49 ng/dL in those who were pre-hormone therapy. Prior and her colleagues concluded that spironolactone helps to decrease testosterone levels in transfeminine people and that it can be used as a safer alternative to high doses of estrogen for this purpose.

However, the concomitant use of MPA in the study is a major confounding factor in terms of their results. This is because MPA is a progestogen, and progestogens, like estrogens, are antigonadotropins which are able to robustly suppress testosterone levels on their own (Aly, 2018; Aly, 2019). Indeed, MPA alone has been shown to dose-dependently lower testosterone levels in cisgender men (Wiki), and at a dosage of 10 mg/day, has been shown to considerably suppress testosterone levels in transfeminine people when added to estradiol and spironolactone therapy (Jain, Kwan, & Forcier, 2019). Hence, MPA may have been, and likely was, responsible for the decreases in testosterone levels seen in the study, rather than spironolactone. This point was also notably raised by other researchers, who were unable to replicate Prior and colleagues’ results on spironolactone and testosterone levels in transfeminine people (Leinung et al., 2018). Strangely, Prior and colleagues concluded that spironolactone was responsible for the decreased testosterone levels in their study even though they noted in their papers that MPA was also given to help suppress testosterone levels (as well as to help improve breast development). The work of Prior and colleagues likely resulted in the prominent and long-standing, but poorly supported, notion that spironolactone decreases testosterone levels in transfeminine people. Subsequent studies assessing the hypothesis that spironolactone decreases testosterone levels in transfeminine people were not published until 25 years after Prior and colleagues’ studies, with several of these studies, though not all of them, failing to replicate the earlier findings of Prior and colleagues.

Many people do not realize the capacity of estradiol to substantially and even completely suppress testosterone, and many mistakenly assume that it is the antiandrogen—which is often spironolactone—that is mostly or fully responsible for the decrease in testosterone levels seen with estradiol and antiandrogen therapy in transfeminine people. It is certainly true that antiandrogens like CPA and GnRH agonists play an important role in testosterone suppression in transfeminine people. However, as evidenced by the present review of studies of testosterone suppression with spironolactone, it is not necessarily always the case that the antiandrogen plays a major role—or potentially even any role—in reducing testosterone levels. This is notably also not the case with certain other antiandrogens besides spironolactone, for instance pure androgen receptor antagonists like bicalutamide, which likewise do not decrease testosterone levels but instead can actually increase them (Aly, 2019; Wiki). Clinicians and transfeminine people attributing observations of testosterone decreases to spironolactone rather than to estradiol with estradiol and spironolactone therapy may also have played a role in the perception that spironolactone considerably decreases testosterone levels in transfeminine people.

Due to its relatively weak strength as an androgen receptor antagonist and its limited efficacy in lowering testosterone levels, spironolactone is likely to be a limitedly effective antiandrogen in transfeminine people. Additionally, spironolactone is likely to be less effective than other antiandrogenic approaches used in transfeminine hormone therapy which either more robustly block androgens or more substantially reduce testosterone levels, for instance CPA, other progestogens (e.g., MPA, non-oral progesterone), GnRH agonists (and antagonists), bicalutamide, and high-dose parenteral estradiol monotherapy. These approaches can be used in transfeminine people instead of or in addition to spironolactone, or could be considered when testosterone suppression is inadequate with estradiol and spironolactone.

More studies are needed to evaluate the influence of spironolactone on testosterone levels, especially RCTs that compare estradiol alone versus estradiol plus spironolactone in transfeminine people. More research is also needed to clarify why some studies find highly inadequate testosterone suppression with estradiol alone or estradiol plus spironolactone while other studies find excellent or satisfactory testosterone suppression with these regimens. In any case, available data overall suggest that spironolactone does not consistently suppress testosterone levels, and that estradiol plus spironolactone produces inadequate testosterone suppression in many transfeminine people. Moreover, available data suggest that spironolactone is a relatively weak androgen receptor antagonist at the typical clinical doses used in cisgender women and transfeminine people, and is able to block only relatively low or female-range testosterone levels. Hence, spironolactone may not be fully effective in blocking the testosterone it fails to suppress, and may be particularly unsuitable for transfeminine people with testosterone levels that are well above the normal female range. In any case, more research is similarly needed to assess the androgen receptor antagonism and clinical antiandrogenic effectiveness of spironolactone.

Updates

Update 1: Spironolactone for Adult Female Acne (SAFA) Trial

A large new phase 3 RCT, the Spironolactone for Adult Female Acne (SAFA) trial, was published in May 2023 and assessed the effectiveness of spironolactone in the treatment of acne in cisgender women:

  • Santer, M., Lawrence, M., Renz, S., Eminton, Z., Stuart, B., Sach, T. H., Pyne, S., Ridd, M. J., Francis, N., Soulsby, I., Thomas, K., Permyakova, N., Little, P., Muller, I., Nuttall, J., Griffiths, G., Thomas, K. S., & Layton, A. M. (2023). Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ, 381, e074349. [DOI:10.1136/bmj-2022-074349]

The trial included a total of 342 women, including 176 treated with spironolactone and 166 in the placebo control group. The dose of spironolactone employed was 50 mg/day for the first 6 weeks and then 100 mg/day thereafter. The trial was 24 weeks (5.5 months) in duration. Women who might become pregnant were required to use a hormonal or barrier method of contraception.

Spironolactone significantly outperformed placebo in terms of improvement in mean Acne-QoL symptom scores (higher is better). Significant improvement was apparent within 12 weeks of treatment (+45% in scores with spironolactone, +38% with placebo) and was highest at 24 weeks (+61% in scores with spironolactone, +35% with placebo). There was no difference in the rates of women who reported improvement in acne scores at 12 weeks (72% with spironolactone, 68% with placebo), but there was a significant difference at 24 weeks (82% with spironolactone, 63% with placebo). In terms of the Investigator’s Global Assessment (IGA), treatment success at 12 weeks was 19% with spironolactone and 6% with placebo. Rates of hormonal contraceptive use in the spironolactone and placebo groups were not reported. Testosterone levels were also not reported. A small subset of the women had PCOS (15% in the spironolactone group, 23% in the placebo group).

Adverse effects occurred only slightly more often with spironolactone than with placebo (64% vs. 51%, p = 0.01). The only side effect that occurred significantly more often with spironolactone than with placebo was headache (20% vs. 12%; p = 0.02). However, a few other side effects trended towards occurring significantly more frequently with spironolactone than with placebo: “other” (17% vs. 11%; p = 0.06), dizziness/vertigo/lightheadness (19% vs. 12%; p = 0.07), vomiting/being sick (2% vs. 1%; p = 0.16), and polyuria (urinary frequency) (31% vs. 25%; p = 0.18). Rates of other potentially relevant side effects, like abdominal pain, breast enlargement, breast tenderness, drowsiness/sleepiness, fatigue/tiredness, menstrual irregularity, and reduced libido, were all not different between spironolactone and placebo. There were no serious adverse reactions in the trial. Rates of compliance were similar between the spironolactone and placebo groups, suggesting that spironolactone was well-tolerated.

This trial is the largest and most rigorous RCT of spironolactone in the treatment of androgen-dependent skin and hair conditions in cisgender women that has been conducted to date. Although spironolactone was found to be effective in this study and was about twice as effective as placebo in terms of Acne-QoL symptom scores and three times as effective as placebo in terms of IGA treatment success rates, the effectiveness of spironolactone was seemingly less than in previous clinical studies of spironolactone for acne. This may be related to the relatively low doses of spironolactone used in this study (50–100 mg/day), to the more rigorous and less-risk-of-bias design of the study (large phase 3 RCT), to a possibly too-short treatment duration (24 weeks/5.5 months), and to concomitant hormonal contraceptive use possibly blunting the degree of potential improvement. The latter is relevant as hormonal contraceptives containing ethinylestradiol provide a considerable improvement in acne via functional antiandrogenic effects all on their own. A final possibility however is that spironolactone is simply a less effective antiandrogen even in cisgender women than has been previously thought. On the other hand, similarly to findings in previous clinical studies, spironolactone was well-tolerated and produced few side effects.

Update 2: New Spironolactone and Testosterone Suppression Studies

The following new studies have additionally assessed and found inadequate testosterone suppression in transfeminine people treated with estradiol and spironolactone:

  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (November 2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (November 2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
  • Miro, E., Rizzone, K., Ho, T., Mark, B., Sullivan, E., & Cushman, D. (2024). 2024 AMSSM Research Podium Presentations: Testosterone Levels Among Transgender Women on Gender-affirming Hormone Therapy. Clinical Journal of Sports Medicine, 34(2), 152–152. [DOI:10.1097/JSM.0000000000001212]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]

Angus et al. (2023) and Yang et al. (2024) compared estradiol plus spironolactone to estradiol plus CPA and are described in-depth in a section of a different article located here. Yang et al. (2024) found that in addition to spironolactone resulting in much less testosterone suppression than CPA, it was also less effective than CPA as an antiandrogen on multiple clinical measures of demasculinization.

References

  • Abshagen, U., Spörl, S., Schöneshöfer, M., L’age, M., & Oelkers, W. (1978). Interference of spironolactone therapy with adrenal steroid metabolism in secondary hyperaldosteronism. [Zum Einfluß einer Spironolaktonbehandlung auf den adrenalen Steroidstoffwechsel bei sekundärem Hyperaldosteronismus.] Klinische Wochenschrift, 56(7), 341–349. [DOI:10.1007/bf01477394]
  • Aizawa, H., & Niimura, M. (1992). Oral Spironolactone Therapy in Male Patients with Rosacea. The Journal of Dermatology, 19(5), 293–297. [DOI:10.1111/j.1346-8138.1992.tb03227.x]
  • Allen, A. N., Jiao, R., Day, P., Pagels, P., Gimpel, N., & SoRelle, J. A. (2020). Dynamic Impact of Hormone Therapy on Laboratory Values in Transgender Patients over Time. The Journal of Applied Laboratory Medicine, 6(1), 27–40. [DOI:10.1093/jalm/jfaa192]
  • Almalki, H. H., Alshibani, T. M., Alhifany, A. A., & Almohammed, O. A. (2020). Comparative efficacy of statins, metformin, spironolactone and combined oral contraceptives in reducing testosterone levels in women with polycystic ovary syndrome: a network meta-analysis of randomized clinical trials. BMC Women’s Health, 20(1), 68. [DOI:10.1186/s12905-020-00919-5]
  • Amiri, M., Kabir, A., Nahidi, F., Shekofteh, M., & Ramezani Tehrani, F. (2018). Effects of combined oral contraceptives on the clinical and biochemical parameters of hyperandrogenism in patients with polycystic ovary syndrome: a systematic review and meta-analysis. The European Journal of Contraception & Reproductive Health Care, 23(1), 64–77. [DOI:10.1080/13625187.2018.1435779]
  • Angus, L., Leemaqz, S., Ooi, O., Cundill, P., Silberstein, N., Locke, P., Zajac, J. D., & Cheung, A. S. (2019). Cyproterone acetate or spironolactone in lowering testosterone concentrations for transgender individuals receiving oestradiol therapy. Endocrine Connections, 8(7), 935–940. [DOI:10.1530/ec-19-0272]
  • Angus, L. M., Leemaqz, S., Zajac, J. D., & Cheung, A. S. (2023). A randomised controlled trial of spironolactone versus cyproterone in trans people commencing estradiol. AusPATH 2023 Symposium. [URL] [PDF] [Trans Health Research Blog Post]
  • Angus, L. M., Leemaqz, S. Y., Zajac, J. D., & Cheung, A. S. (2023). The effect of cyproterone and spironolactone on breast development in transgender women: a randomised controlled trial. ESA/SRB/ENSA 2023 ASM 26-29 November, Brisbane, 54–55 (abstract no. 132). [URL] [PDF] [Full Abstract Book] [Trans Health Research Blog Post]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2021). A systematic review of antiandrogens and feminization in transgender women. Clinical Endocrinology, 94(5), 743–752. [DOI:10.1111/cen.14329]
  • Baba, S. (1977). Antiandrogenic effect of spironolactone. The Japanese Journal of Urology, 68(12), 1184–1192. [DOI:10.5980/jpnjurol1928.68.12_1184]
  • Baba, S., Murai, M., Jitsukawa, S., Hata, M., & Tazaki, H. (1978). Antiandrogenic Effects of Spironolactone: Hormonal and Ultrastructural Studies in Dogs and Men. Journal of Urology, 119(3), 375–380. [DOI:10.1016/s0022-5347(17)57495-9]
  • Bakker, A. (2021). Een halve eeuw transgenderzorg aan de VU [Half a Century of Transgender Care at the VU]. Amsterdam: Boom. [Google Books] [WorldCat] [URL]
  • Barrionuevo, P., Nabhan, M., Altayar, O., Wang, Z., Erwin, P. J., Asi, N., Martin, K. A., & Murad, M. H. (2018). Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism, 103(4), 1258–1264. [DOI:10.1210/jc.2017-02052]
  • Bonne, C., & Raynaud, J. (1974). Mode of spironolactone anti-androgenic action: Inhibition of androstanolone binding to rat prostate androgen receptor. Molecular and Cellular Endocrinology, 2(1), 59–67. [DOI:10.1016/0303-7207(74)90012-4]
  • Bonzagni, A. F. (2014). Understanding the effects of long-term hormone therapy in transgender individuals being provided care at Boston Medical Center Endocrinology Clinic: a quality assurance project. (Doctoral dissertation, Boston University.) [Google Scholar] [URL] [PDF]
  • Bradstreet, J. J., Smith, S., Granpeesheh, D., El-Dahr, J. M., & Rossignol, D. (2007). Spironolactone might be a desirable immunologic and hormonal intervention in autism spectrum disorders. Medical Hypotheses, 68(5), 979–987. [DOI:10.1016/j.mehy.2006.10.015]
  • Brown, J., Farquhar, C., Lee, O., Toomath, R., & Jepson, R. G. (2003). Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews, 2003(4), CD000194. [DOI:10.1002/14651858.cd000194]
  • Brown, J., Farquhar, C., Lee, O., Toomath, R., & Jepson, R. G. (2009). Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews, 2009(2), CD000194. [DOI:10.1002/14651858.cd000194.pub2]
  • Burinkul, S., Panyakhamlerd, K., Suwan, A., Tuntiviriyapun, P., & Wainipitapong, S. (2021). Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. The Journal of Sexual Medicine, 18(7), 1299–1307. [DOI:10.1016/j.jsxm.2021.05.003] [PDF]
  • Callan, A. W. (1988). Spironolactone therapy in hirsutism and acne. Australasian Journal of Dermatology, 29(3), 135–139. [DOI:10.1111/j.1440-0960.1988.tb00385.x]
  • Caminos-Torres, R., MA, L., & Snyder, P. J. (1977). Gynecomastia and Semen Abnormalities Induced by Spironolactone in Normal Men. The Journal of Clinical Endocrinology & Metabolism, 45(2), 255–260. [DOI:10.1210/jcem-45-2-255]
  • Charny, J., Choi, J., & James, W. (2017). Spironolactone for the treatment of acne in women, a retrospective study of 110 patients. International Journal of Women’s Dermatology, 3(2), 111–115. [DOI:10.1016/j.ijwd.2016.12.002]
  • Cheung, A. S., Ooi, O., Davidoff, D., Leemaqz, S. Y., Cundill, P., Silberstein, N., Bretherton, I., Grossmann, M., & Zajac, J. D. (2018). Cyproterone vs spironolactone as anti-androgen therapy for transgender females receiving oestradiol therapy. Clinical Endocrinology, 89(S1) [Abstracts of the Endocrine Society of Australia’s Annual Scientific Meeting 2017], 14–14 (abstract no. 62). [Google Scholar] [DOI:10.1111/cen.13727] [URL 1] [URL 2] [PDF]
  • Cirrincione, L. R., Winston McPherson, G., Rongitsch, J., Sadilkova, K., Drees, J. C., Krasowski, M. D., Dickerson, J. A., & Greene, D. N. (2021). Sublingual Estradiol Is Associated with Higher Estrone Concentrations than Transdermal or Injectable Preparations in Transgender Women and Gender Nonbinary Adults. LGBT Health, 8(2), 125–132. [DOI:10.1089/lgbt.2020.0249]
  • Corvol, P., Mahoudeau, J. A., Valcke, J. C., Ménard, J., & Bricaire, H. (1976). Effets sexuels secondaires des spirolactones. Mécanismes possibles de l’action antiandrogène. [Sexual side-effects of spironolactones. Possible mechanisms of their anti-androgen action]. La Nouvelle Presse Medicale, 5(11), 691–694. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF]
  • Cusan, L., Dupont, A., Gomez, J., Tremblay, R. R., & Labrie, F. (1994). Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertility and Sterility, 61(2), 281–287. [DOI:10.1016/s0015-0282(16)56518-2]
  • Deutsch, M. B., Bhakri, V., & Kubicek, K. (2015). Effects of Cross-Sex Hormone Treatment on Transgender Women and Men. Obstetrics & Gynecology, 125(3), 605–610. [DOI:10.1097/aog.0000000000000692]
  • Diamanti-Kandarakis, E., Tolis, G., & Duleba, A. J. (1995). Androgens and Therapeutic Aspects of Antiandrogens in Women. Journal of the Society for Gynecologic Investigation, 2(4), 577–592. [DOI:10.1177/107155769500200401]
  • Dymling, J., Nilsson, K. O., & Hökfelt, B. (1972). The effect of Soldactona® (canrenoate potassium) on plasma testosterone and androstenedione and urinary 17-ketosteroids and 17-hydroxycorticosteroids. Acta Endocrinologica, 70(1), 104–112. [DOI:10.1530/acta.0.0700104]
  • Dymling, J. F., & Hökfelt, B. (1973). Reduced plasma testosterone following spirolactone in man. Acta Endocrinologica, 73(Suppl 177) [9th Acta Endocrinologica Congress], 53–53 (abstract no. 53). [Google Scholar] [PDF 1] [PDF 2]
  • Dymling, J. F. (1978). The effect of spirolactone and spironolactone on plasma testosterone in man. In Addison, G. M., Asmussen, N. W., Corvol, P., Kloppernborg, P. W. C., Norman, N., Schroder, R., & Robertson, J. I. C. (Eds.). Aldosterone Antagonists in Clinical Medicine: Proceedings of the Searle Symposium, Nice, April 13–15, 1978 (pp. 297–302). Amsterdam: Excerpta Medica. [Google Scholar] [Google Books] [WorldCat] [PDF 1] [PDF 2]
  • Erbler, H. C. (1974). Suppression by the spironolactone metabolite canrenone of plasma testosterone in man. Naunyn-Schmiedeberg’s Archives of Pharmacology, 285(4), 403–406. [DOI:10.1007/bf00501468]
  • Erenus, M., Gürbüz, O., Durmuşoğlu, F., Demirçay, Z., & Pekin, S. (1994). Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertility and Sterility, 61(4), 613–616. [DOI:10.1016/s0015-0282(16)56634-5]
  • Ganie, M. A., Khurana, M. L., Eunice, M., Gulati, M., Dwivedi, S. N., & Ammini, A. C. (2004). Comparison of Efficacy of Spironolactone with Metformin in the Management of Polycystic Ovary Syndrome: An Open-Labeled Study. The Journal of Clinical Endocrinology & Metabolism, 89(6), 2756–2762. [DOI:10.1210/jc.2003-031780]
  • Ganie, M. A., Khurana, M. L., Nisar, S., Shah, P. A., Shah, Z. A., Kulshrestha, B., Gupta, N., Zargar, M. A., Wani, T. A., Mudasir, S., Mir, F. A., & Taing, S. (2013). Improved Efficacy of Low-Dose Spironolactone and Metformin Combination Than Either Drug Alone in the Management of Women With Polycystic Ovary Syndrome (PCOS): A Six-Month, Open-Label Randomized Study. The Journal of Clinical Endocrinology & Metabolism, 98(9), 3599–3607. [DOI:10.1210/jc.2013-1040]
  • Goodfellow, A., Alaghband-Zadeh, J., Carter, G., Cream, J., Holland, S., Scully, J., & Wise, P. (1984). Oral spironolactone improves acne vulgaris and reduces sebum excretion. British Journal of Dermatology, 111(2), 209–214. [DOI:10.1111/j.1365-2133.1984.tb04045.x]
  • Gooren, L. J., Veen, E. A., Kessel, H., Harmsen-Louman, W., & Wiegel, A. R. (1984). Prolactin secretion in the human male is increased by endogenous oestrogens and decreased by exogenous/endogenous androgens. International Journal of Andrology, 7(1), 53–60. [DOI:10.1111/j.1365-2605.1984.tb00759.x]
  • Gooren, L., Veen, E., Kessel, H., Harmsen-Louman, W., & Wiegel, A. (1984). Androgens in the Feedback Regulation of Gonadotropin Secretion in Men: Effects of Administration of Dihydrotestosterone to Eugonadal and Agonadal Subjects and of Spironolactone to Eugonadal Subjects. Andrologia, 16(4), 289–298. [DOI:10.1111/j.1439-0272.1984.tb00286.x]
  • Gooren, L. J. G. (1999). Hormonal Sex Reassignment. International Journal of Transgenderism, 3(3), 1–7. [Google Scholar] [URL 1] [URL 2]
  • Hammerstein, J. (1990). Antiandrogens: Clinical Aspects. In Orfanos, C. E., & Happle, R. (Eds.). Hair and Hair Diseases (pp. 827–886). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-74612-3_35]
  • Handelsman, D. J., Strasser, S., McDonald, J. A., Conway, A. J., & McCaughan, G. W. (1995). Hypothalamic-pituitary-testicular function in end-stage non-alcoholic liver disease before and after liver transplantation. Clinical Endocrinology, 43(3), 331–337. [DOI:10.1111/j.1365-2265.1995.tb02040.x]
  • Hecker, A., Hasan, S. H., & Neumann, F. (1980). Disturbances in sexual differentiation of rat foetuses following spironolactone treatment. Acta Endocrinologica, 95(4), 540–545. [DOI:10.1530/acta.0.0950540]
  • Holland, F. J. (1991). Gonadotropin-lndependent Precocious Puberty. Endocrinology and Metabolism Clinics of North America, 20(1), 191–210. [DOI:10.1016/s0889-8529(18)30288-3]
  • Horth, C., Lobo, P., Shelton, J., Asbury, M., Clarke, J., & Venning, G. (1977). Effects of spironolaetone on the plasma binding and unbound levels of testosterone and oestradiol in healthy men. Journal of Steroid Biochemistry, 8(12), xx–xx. [DOI:10.1016/0022-4731(77)90178-9]
  • Horth, C. E., Lobo, P. J., Shelton, J. R., Asbury, M. J., Clarke, J. M., & Venning, G. R. (1979). Effects of spironolactone on the plasma binding and unbound levels of testosterone and oestradiol in healthy men. In Klopper, A., Lerner, L., van der Molen, H. J., & Sciarra, F. (Eds.). Research on Steroids: Proceedings of the International Study Group for Steroid Hormones, Volume 8 / Research on Steroids Transactions of the Eighth Meeting of the International Study Group for Steroid Hormones (Proceedings of the Serono Symposia, Volume 21) (pp. 313–315). London/New York/San Francisco: Academic Press. [Google Scholar]
  • Huffman, D. H., Kampmann, J. P., Hignite, C. E., & Azarnoff, D. L. (1978). Gynecomastia induced in normal males by spironolactone. Clinical Pharmacology & Therapeutics, 24(4), 465–473. [DOI:10.1002/cpt1978244465]
  • Inal, M. M., Yildirim, Y., & Taner, C. E. (2005). Comparison of the clinical efficacy of flutamide and spironolactone plus Diane 35 in the treatment of idiopathic hirsutism: a randomized controlled study. Fertility and Sterility, 84(6), 1693–1697. [DOI:10.1016/j.fertnstert.2005.05.051]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • James, J. F., Jamerson, T. A., & Aguh, C. (2022). Efficacy and safety profile of oral spironolactone use for androgenic alopecia: A systematic review. Journal of the American Academy of Dermatology, 86(2), 425–429. [DOI:10.1016/j.jaad.2021.07.048]
  • Karakurt, F., Sahin, I., Güler, S., Demirbas, B., Culha, C., Serter, R., Aral, Y., & Bavbek, N. (2008). Comparison of the clinical efficacy of flutamide and spironolactone plus ethinyloestradiol/cyproterone acetate in the treatment of hirsutism: A randomised controlled study. Advances in Therapy, 25(4), 321–328. [DOI:10.1007/s12325-008-0039-5]
  • Keleştimur, F., Everest, H., Unlühizarci, K., Bayram, F., & Șahin, Y. (2004). A comparison between spironolactone and spironolactone plus finasteride in the treatment of hirsutism. European Journal of Endocrinology, 150(3), 351–354. [DOI:10.1530/eje.0.1500351]
  • Labrie, C., Cusan, L., Plante, M., Lapointe, S., & Labrie, F. (1987). Analysis of the androgenic activity of synthetic “progestins” currently used for the treatment of prostate cancer. Journal of Steroid Biochemistry, 28(4), 379–384. [DOI:10.1016/0022-4731(87)91054-5]
  • Layton, A. M., Eady, E. A., Whitehouse, H., Del Rosso, J. Q., Fedorowicz, Z., & van Zuuren, E. J. (2017). Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. American Journal of Clinical Dermatology, 18(2), 169–191. [DOI:10.1007/s40257-016-0245-x]
  • Leinung, M. C. (2014). Variable Response to Oral Estradiol Therapy in Male to Female Transgender Patients. Endocrine Reviews, 35(Suppl 1) [Endocrine Society’s 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago], ?–? (abstract no. OR42-1). [Google Scholar] [DOI:10.1093/edrv/35.supp.1] [DOI:10.1210/endo-meetings.2014.RE.2.OR42-1] [URL] [MedPage Today]
  • Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
  • Liang, J. J., Jolly, D., Chan, K. J., & Safer, J. D. (2018). Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort. Endocrine Practice, 24(2), 135–142. [DOI:10.4158/ep-2017-0116]
  • Lobo, R. A., Shoupe, D., Serafini, P., Brinton, D., & Horton, R. (1985). The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertility and Sterility, 43(2), 200–205. [DOI:10.1016/s0015-0282(16)48373-1]
  • Loriaux, D. L. (1976). Spironolactone and Endocrine Dysfunction. Annals of Internal Medicine, 85(5), 630–630. [DOI:10.7326/0003-4819-85-5-630]
  • McMullen, G. R., & Van Herle, A. J. (1993). Hirsutism and the effectiveness of spironolactone in its management. Journal of Endocrinological Investigation, 16(11), 925–932. [DOI:10.1007/bf03348960]
  • Menard, R., Guenthner, T., Kon, H., & Gillette, J. (1979). Studies on the destruction of adrenal and testicular cytochrome P-450 by spironolactone. Requirement for the 7α-thio group and evidence for the loss of the heme and apoproteins of cytochrome P-450. Journal of Biological Chemistry, 254(5), 1726–1733. [DOI:10.1016/s0021-9258(17)37833-x]
  • Miro, E., Rizzone, K., Ho, T., Mark, B., Sullivan, E., & Cushman, D. (2024). 2024 AMSSM Research Podium Presentations: Testosterone Levels Among Transgender Women on Gender-affirming Hormone Therapy. Clinical Journal of Sports Medicine, 34(2), 152–152. [DOI:10.1097/JSM.0000000000001212]
  • Miyatake, A., Noma, K., Nakao, K., Morimoto, Y., & Yamamura, Y. (1978). Increased serum oestrone and oestradiol following spironolactone administration in hypertensive men. Clinical Endocrinology, 9(6), 523–533. [DOI:10.1111/j.1365-2265.1978.tb01510.x]
  • Moghetti, P., Tosi, F., Tosti, A., Negri, C., Misciali, C., Perrone, F., Caputo, M., Muggeo, M., & Castello, R. (2000). Comparison of Spironolactone, Flutamide, and Finasteride Efficacy in the Treatment of Hirsutism: A Randomized, Double Blind, Placebo-Controlled Trial. The Journal of Clinical Endocrinology & Metabolism, 85(1), 89–94. [DOI:10.1210/jcem.85.1.6245]
  • Negri, C., Tosi, F., Dorizzi, R., Fortunato, A., Spiazzi, G. G., Muggeo, M., Castello, R., & Moghetti, P. (2000). Antiandrogen Drugs Lower Serum Prostate-Specific Antigen (PSA) Levels in Hirsute Subjects: Evidence That Serum PSA Is a Marker of Androgen Action in Women. The Journal of Clinical Endocrinology & Metabolism, 85(1), 81–84. [DOI:10.1210/jcem.85.1.6230]
  • Pappas, I. I., Craig, W. Y., Spratt, L. V., & Spratt, D. I. (2020). Efficacy of Sex Steroid Therapy Without Progestin or GnRH Agonist for Gonadal Suppression in Adult Transgender Patients. The Journal of Clinical Endocrinology & Metabolism, 106(3), e1290–e1300. [DOI:10.1210/clinem/dgaa884]
  • Pappas, I. I., Craig, W., Spratt, L. V., & Spratt, D. I. (2020). Testosterone (T) and estradiol (E2) therapy alone can suppress gonadal function in transgender patients. Costas T. Lambrew Research Retreat 2020, 47. [Google Scholar] [URL] [PDF]
  • Pentikäinen, P. J., Pentikäinen, L. A., Huffman, D. H., & Azarnoff, D. L. (1974). The effect of spironolactone on plasma levels and excretion of testosterone and oestrogens in the urine in males. (A preliminary report). The Journal of International Medical Research, 2(6), 439–443. [Google Scholar] [PubMed] [PDF]
  • Prior, J. C., Vigna, Y. M., Watson, D., Diewold, P., & Robinow, O. (1986). Spironolactone in the presurgical therapy of male to female transsexuals: Philosophy and experience of the Vancouver Gender Dysphoria Clinic. Journal of Sex Information & Education Council of Canada, 1(1), 1–7. [Google Scholar] [PDF]
  • Prior, J. C., Vigna, Y. M., & Watson, D. (1989). Spironolactone with physiological female steroids for presurgical therapy of male-to-female transsexualism. Archives of Sexual Behavior, 18(1), 49–57. [DOI:10.1007/bf01579291]
  • Reardon, E., Farnell, P., Langzettel, J., & Spratt, D. (2013). Efficacy of single agent hormonal therapy in transgender patients to suppress endogenous hypothalamic-pituitary-gonadal (HPG) activity. Fertility and Sterility, 100(3 Suppl) [Scientific Program Supplement: Oral and Poster Session Abstracts 12 October 2013 - 17 October 2013], S333–S333 (abstract no. P-640). [Google Scholar] [DOI:10.1016/j.fertnstert.2013.07.914]
  • Rose, L. I. (1977). Pathophysiology of Spironolactone-Induced Gynecomastia. Annals of Internal Medicine, 87(4), 398–403. [DOI:10.7326/0003-4819-87-4-398]
  • Rozner, R. N., Freites-Martinez, A., Shapiro, J., Geer, E. B., Goldfarb, S., & Lacouture, M. E. (2018). Safety of 5α-reductase inhibitors and spironolactone in breast cancer patients receiving endocrine therapies. Breast Cancer Research and Treatment, 174(1), 15–26. [DOI:10.1007/s10549-018-4996-3]
  • Santen, R. J., Kulin, H. E., Loriaux, D. L., & Friend, J. (1976). Spironolactone Stimulation of Gonadotropin Secretion in Boys with Delayed Adolescence. The Journal of Clinical Endocrinology & Metabolism, 43(6), 1386–1390. [DOI:10.1210/jcem-43-6-1386]
  • Santer, M., Lawrence, M., Renz, S., Eminton, Z., Stuart, B., Sach, T. H., Pyne, S., Ridd, M. J., Francis, N., Soulsby, I., Thomas, K., Permyakova, N., Little, P., Muller, I., Nuttall, J., Griffiths, G., Thomas, K. S., & Layton, A. M. (2023). Effectiveness of spironolactone for women with acne vulgaris (SAFA) in England and Wales: pragmatic, multicentre, phase 3, double blind, randomised controlled trial. BMJ, 381, e074349. [DOI:10.1136/bmj-2022-074349]
  • Shaw, J. C. (1996). Antiandrogen and hormonal treatment of acne. Dermatologic Clinics, 14(4), 803–811. [DOI:10.1016/s0733-8635(05)70405-8]
  • Sivelle, P. C., Underwood, A. H., & Jelly, J. A. (1982). The effects of histamine H2 receptor antagonists on androgen action in vivo and dihydrotestosterone binding to the rat prostate androgen receptor in vitro. Biochemical Pharmacology, 31(5), 677–684. [DOI:10.1016/0006-2952(82)90449-x]
  • Skorodok, L. M., Savchenko, O. N., & Liss, V. L. (1983). Hypothalamo-hypophyseal-gonadal function in boys with irregular puberty. Neuroscience and Behavioral Physiology, 13(2), 141–145. [DOI:10.1007/bf01190800]
  • Snyder, B. W., Winneker, R. C., & Batzold, F. H. (1989). Endocrine profile of win 49596 in the rat: A novel androgen receptor antagonist. Journal of Steroid Biochemistry, 33(6), 1127–1132. [DOI:10.1016/0022-4731(89)90419-6]
  • Sofer, Y., Yaish, I., Yaron, M., Bach, M. Y., Stern, N., & Greenman, Y. (2020). Differential Endocrine and Metabolic Effects of Testosterone Suppressive Agents in Transgender Women. Endocrine Practice, 26(8), 883–890. [DOI:10.4158/ep-2020-0032]
  • SoRelle, J. A., Jiao, R., Gao, E., Veazey, J., Frame, I., Quinn, A. M., Day, P., Pagels, P., Gimpel, N., & Patel, K. (2019). Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clinical Chemistry, 65(1), 170–179. [DOI:10.1373/clinchem.2018.292730]
  • Spörl, S. (1978/1979). Über den Einfluß von Spironolacton (Aldactone®) auf den Stoffwechsel von Nebennierenrindenhormonen und von Testosteron bei Gesunden mit diätinduziertem Hyperaldosterismus. [On the influence of spironolactone (Aldactone®) on the metabolism of adrenocortical hormones and testosterone in healthy individuals with diet-induced hyperaldosteronism.] (Doctoral dissertation, Freie Universität, Berlin.) [Google Scholar] [Google Books] [WorldCat] [PDF]
  • Spratt, L. V., Reardon, E., Olshan, J. S., & Eimicke, T. (2014). Efficacy of Testosterone (T) or Estradiol (E2) Therapy without a GnRH Agonist or Progestin to Suppress Endogenous Gonadal Activity in Transsexual Patients. Endocrine Reviews, 35(Suppl 1) [Endocrine Society’s 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago], ?–? (abstract no. OR42-2). [DOI:10.1093/edrv/35.supp.1] [URL]
  • Stewart, I., Spratt, L., Craig, W., Olshan, J., & Spratt, D. (2018). The efficacy of testosterone or estradiol therapy without a GnRH agonist or progestin to suppress endogenous gonadal activity in transgender patients. Fertility and Sterility, 110(4 Suppl) [Scientific Congress Supplement: Oral and Poster Session Abstracts 06 October 2018 - 10 October 2018], e21–e21 (abstract no. O-44). [Google Scholar] [DOI:10.1016/j.fertnstert.2018.07.075]
  • Stripp, B., Taylor, A. A., Bartter, F. C., Gillette, J. R., Loriaux, D. L., Easley, R., & Menard, R. H. (1975). Effect of Spironolactone on Sex Hormones in Man. The Journal of Clinical Endocrinology & Metabolism, 41(4), 777–781. [DOI:10.1210/jcem-41-4-777]
  • Taylor, A. A., Rollins, D., Snodgrass, W., & Bartter, F. (1976). Effect of spironolactone (S) on adrenal and gonadal steroids in man. Clinical Research, 24(3), A279–A279. [Google Scholar] [PDF]
  • Unlühizarci, K., Everest, H., Bayram, F., & Keleştimur, F. (2002). Comparison of spironolactone and spironolactone plus finasteride in the treatment of hirsutism. Fertility and Sterility, 78(6), 1331–1333. [DOI:10.1016/s0015-0282(02)04294-2]
  • Tidd, M. J., Horth, C. E., Ramsay, L. E., Shelton, J. R., & Palmer, R. F. (1978). Endocrine effects of spironolactone in man. Clinical Endocrinology, 9(5), 389–399. [DOI:10.1111/j.1365-2265.1978.tb03578.x]
  • van Zuuren, E., & Fedorowicz, Z. (2016). Interventions for hirsutism excluding laser and photoepilation therapy alone: abridged Cochrane systematic review including GRADE assessments. British Journal of Dermatology, 175(1), 45–61. [DOI:10.1111/bjd.14486]
  • Walsh, P. C., & Siiteri, P. K. (1975). Suppression of Plasma Androgens by Spironolactone in Castrated Men with Carcinoma of the Prostate. Journal of Urology, 114(2), 254–256. [DOI:10.1016/s0022-5347(17)67001-0]
  • Wang, C., Du, Y., Bi, L., Lin, X., Zhao, M., & Fan, W. (2023). The Efficacy and Safety of Oral and Topical Spironolactone in Androgenetic Alopecia Treatment: A Systematic Review. Clinical, Cosmetic and Investigational Dermatology, 16, 603–612. [DOI:10.2147/ccid.s398950]
  • Weissmann, A. (1985). Antiandrogenic Effects of Topically Applied Spironolactone on the Hamster Flank Organ. Archives of Dermatology, 121(1), 57–62. [DOI:10.1001/archderm.1985.01660010061019]
  • Yamasaki, K., Sawaki, M., Noda, S., Muroi, T., Takakura, S., Mitoma, H., Sakamoto, S., Nakai, M., & Yakabe, Y. (2004). Comparison of the Hershberger assay and androgen receptor binding assay of twelve chemicals. Toxicology, 195(2–3), 177–186. [DOI:10.1016/j.tox.2003.09.012]
  • Yang, W., Hong, T., Chang, X., Han, M., Gao, H., Pan, B., Zhao, Z., & Liu, Y. (2024). The efficacy of and user satisfaction with different antiandrogens in Chinese transgender women. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2323514]
  • Yazdabadi, A., & Sinclair, R. (2011). Treatment of female pattern hair loss with the androgen receptor antagonist flutamide. The Australasian Journal of Dermatology, 52(2), 132–134. [DOI:10.1111/j.1440-0960.2010.00735.x]
  • Zgliczynski, S., Baranowska, B., & Szymanowski, J. (1981). L’influence du spironolactone sur la concentration des gonatrophines et des hormones gonadiques dans l’hypertrophie prostatique. [The influence of spironolactone on the concentration of gonadotrophins and gonadal hormones in prostatic hypertrophy]. Journal d’Urologie, 87(9), 635–638. [Google Scholar 1] [Google Scholar 2] [PubMed] [PDF] [Translation]
  • Zimmerman, Y., Eijkemans, M. J., Coelingh Bennink, H. J., Blankenstein, M. A., & Fauser, B. C. (2013). The effect of combined oral contraception on testosterone levels in healthy women: a systematic review and meta-analysis. Human Reproduction Update, 20(1), 76–105. [DOI:10.1093/humupd/dmt038]
\ No newline at end of file diff --git a/transfemscience.org/articles/transfem-intro/index.html b/transfemscience.org/articles/transfem-intro/index.html index 654366524..c10dfab51 100644 --- a/transfemscience.org/articles/transfem-intro/index.html +++ b/transfemscience.org/articles/transfem-intro/index.html @@ -1 +1 @@ -An Introduction to Hormone Therapy for Transfeminine People - Transfeminine Science Link

An Introduction to Hormone Therapy for Transfeminine People

By Aly | First published August 4, 2018 | Last modified June 17, 2023

Abstract / TL;DR

Sex hormones such as estrogen, testosterone, and progesterone are produced by the gonads. The sex hormones mediate the development of the secondary sexual characteristics. Testosterone causes masculinization, while estradiol causes feminization and breast development. Males have high amounts of testosterone, while females have low testosterone but high amounts of estradiol. These hormonal differences are responsible for the physical differences between males and females. Sex hormones and other hormonal medications are used in transfeminine people to shift the hormonal profile from a male-typical one to a female-typical profile. This causes feminization and demasculinization and allows for alleviation of gender dysphoria. The changes caused by transfeminine hormone therapy occur over a period of months to years. There are many different types and forms of hormonal medications, and these medications can be administered by a variety of different routes. Examples include as pills taken by mouth, as patches or gel applied to the skin, and as injections, among others. Different hormonal medications, routes, and doses have differences in efficacy, side effects, risks, costs, convenience, and availability. Hormone therapy should ideally be regularly monitored in transfeminine people with blood tests to ensure effectiveness and safety and to allow for adjustment as necessary.

The Sex Hormones

Types and Effects

The sex hormones include the estrogens (E), progestogens (P), and androgens. A person’s hormonal profile is a product of the type of gonads that they are born with. Natal males have testes while natal females have ovaries. Testes produce large amounts of androgens and small amounts of estrogens whereas ovaries produce high amounts of estrogens and progesterone and low amounts of androgens.

The major estrogen in the body is estradiol (E2), the main progestogen is progesterone (P4), and the major androgens are testosterone (T) and dihydrotestosterone (DHT). The sex hormones are responsible for and determine the secondary sex characteristics. They mediate their effects by acting as agonists (or activators) of receptors inside of cells. These receptors include the androgen receptor (AR), the estrogen receptors (ERs), and the progesterone receptors (PRs). Following their activation, these receptors modulate gene expression to influence cells and tissues.

Estrogens cause feminization. This includes breast development, softening of the skin, a feminine pattern of fat distribution (concentrated in the breasts, hips, thighs, and buttocks), widening of the hips (in those who are still of pubertal age), and other physical changes (Wiki).

Progestogens have essentially no known role in feminization or pubertal breast development. Rather than acting as mediators of feminization, progestogens have important effects in the female reproductive system and are essential hormones during pregnancy (Wiki). They also oppose the actions of estrogens in certain parts of the body, such as the uterus, vagina, and breasts (Wiki).

Androgens cause masculinization. This includes growth of the penis, broadening of the shoulders, expansion of the rib cage, muscle growth, voice deepening, a masculine pattern of fat distribution (concentrated in the stomach and waist), masculine changes in other soft tissues, and facial/body hair growth (Wiki). Androgens also cause a variety of generally undesirable skin and hair effects, including oily skin, acne, seborrhea, scalp hair loss, and body odor. They additionally oppose breast development and probably other aspects of feminization mediated by estrogens as well.

In addition to their effects on the body, sex hormones have actions in the brain. These actions influence cognition, emotions, and behavior. For instance, androgens produce pronounced sexual desire and arousal (including spontaneous erections) in men, while estrogens appear to be the major hormones responsible for sexual desire in women (Cappelletti & Wallen, 2016). Sex hormones also have important effects on health, which can be both positive and negative. For instance, estrogens maintain bone strength and likely protect against heart disease in cisgender women (NAMS, 2022), but also increase the risk of breast cancer (Aly, 2020) and can increase the risk of blood clots (Aly, 2020).

Estrogens, progestogens, and androgens also have antigonadotropic effects. That is, they inhibit the gonadotropin-releasing hormone (GnRH)-induced secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the pituitary gland in the brain. The gonadotropins signal the gonads to make sex hormones and to supply the sperm and egg cells necessary for fertility. Hence, lower levels of the gonadotropins will result in reduced gonadal sex hormone production and diminished fertility. If gonadotropin levels are sufficiently suppressed, the gonads will no longer make sex hormones at all and fertility will cease. The vast majorities of the quantities of estradiol, testosterone, and progesterone in the body are produced by the gonads. Most of the small remaining amounts of these hormones are produced via the adrenal glands of the kidneys.

Normal Hormone Levels

In cisgender females, the sex hormones are largely absent during childhood, gradually ramp up in production in late childhood and adolescence, are present in a cyclical manner during adulthood, and then largely stop being produced following the menopause. Hormone levels vary substantially but in a predictable manner during the normal menstrual cycle in adult premenopausal women. The menstrual cycle lasts about 28 days on average and consists of the following parts:

  1. Follicular phase—first half of the cycle or days 1–14
  2. Mid-cycle—middle of the cycle or days 12–16 or so
  3. Luteal phase—latter half of the cycle or days 14–28

Hormone levels during the menstrual cycle are shown in the following graph:

Figure 1: Median estradiol and progesterone levels throughout the menstrual cycle in premenopausal cisgender women (Stricker et al., 2006; Abbott, 2009). The horizontal dashed lines are the average levels over the spanned periods. Other figures available elsewhere show variation between individuals (Graph; Graph; Graph).

As can be seen in the graph, estradiol levels are relatively low and progesterone levels are very low during the follicular phase; estradiol but not progesterone levels briefly surge to very high levels and trigger ovulation during mid-cycle; and estradiol and progesterone levels both undergo a bump and are relatively high during the luteal phase (though estradiol is not as high as during the mid-cycle peak).

The table below shows the circulating levels and production rates of estradiol, progesterone, and testosterone in women and men and allows for comparison between them.

Table 1: Ranges for circulating levelsa and estimated production ratesb of the major sex hormones:

HormoneGroupTimeLevels (mass/vol)cLevels (mol/vol)cProduction rates
EstradiolWomendFollicular phase5–180 pg/mL20–660 pmol/L30–170 μg/daye
  Mid-cycle45–750 pg/mL170–2,750 pmol/L320–950 μg/daye
  Luteal phase20–300 pg/mL73–1100 pmol/L250–300 μg/daye
 Men–8–35 pg/mL30–130 pmol/L10–60 μg/day
ProgesteroneWomendFollicular phase≤0.3 ng/mL≤1.0 nmol/L0.75–5 mg/day
  Mid-cycle0.1–1.5 ng/mL0.3–4.8 nmol/L4 mg/day
  Luteal phase3.5–38 ng/mL11–120 nmol/L15–50 mg/dayf
 Men–≤0.5 ng/mL≤1.6 nmol/L0.75–3 mg/day
TestosteroneWomendMenstrual cycle5–55 ng/dL0.2–1.9 nmol/L190–260 μg/day
 Men–250–1100 ng/dL8.7–38 nmol/L5–7 mg/day

a Sources for hormone levels: Zhang & Stanczyk (2013); Nakamoto (2016); Styne (2016); LabCorp (2020). b Sources for production rates: Aufrère & Benson (1976); Powers et al. (1985); Lauritzen (1988); Carr (1993); O’Connell (1995); Kuhl (2003); Norman & Henry (2015a); Norman & Henry (2015b); Strauss & FitzGerald (2019). c With liquid chromatography–mass spectrometry (LC–MS) (state-of-the-art blood tests). d During the menstrual cycle in the adult premenopause (age ~18–50 years). e Average production rate of estradiol over the whole menstrual cycle is roughly 200 μg/day or 6 mg/month (Rosenfield, Cooke, & Radovich, 2021). f Average production rate of progesterone during the luteal phase of the menstrual cycle is about 25 mg/day (Carr, 1993).

Mean integrated estradiol levels are around 100 pg/mL (367 pmol/L) in premenopausal women and around 25 pg/mL (92 pmol/L) in men. The 95% range for mean estradiol levels in women is around 50 to 250 pg/mL (180–918 pmol/L) (e.g., Abbott, 2009 (Graph); Verdonk et al., 2019 (Graph)). The average production of estradiol by the ovaries in premenopausal women is about 6 mg over the course of one menstrual cycle (i.e., one month) (Rosenfield et al., 2008). This corresponds to a mean rate of about 200 μg/day. Estradiol levels increase slowly during normal female puberty, when breast development and feminization take place. Mean estradiol levels during the different stages of female puberty are quite low—less than about 50 to 60 pg/mL (180–220 pmol/L) until late puberty (Aly, 2020). In postmenopausal women, whose ovaries no longer produce considerable quantities of estrogens, estradiol levels are generally less than 10 to 20 pg/mL (37–73 pmol/L) (Nakamoto, 2016). Estradiol levels below 50 pg/mL (184 pmol/L) in adults are concentration-dependently associated with menopausal symptoms, including hot flashes, depressive mood changes, defeminization (e.g., breast atrophy, loss of feminine fat distribution), accelerated skin aging, and bone density loss with increased risk of bone fracture.

Mean testosterone levels are around 30 ng/dL (1.0 nmol/L) in women and 600 ng/dL (21 nmol/L) in men. Based on these values, testosterone levels are on average about 20-fold higher in men than in women. In men who have undergone gonadectomy (castration or surgical gonadal removal), testosterone levels are similar to those in women (<50 ng/dL [1.7 nmol/L]) (Nishiyama, 2014; Itty & Getzenberg, 2020). The mean or median levels of testosterone in women with polycystic ovary syndrome (PCOS), who often have clinically significant symptoms of androgen excess (e.g., excessive facial/body hair growth), range from 41 to 75 ng/dL (1.4–2.6 nmol/L) per different studies (Balen et al., 1995; Steinberger et al., 1998; Legro et al., 2010; Loh et al., 2020). Hence, it appears that even testosterone levels that are marginally elevated relative to normal female levels may produce undesirable androgenic effects.

It is important to be aware that measurement of hormone levels is subject to methodological limitations, and hormone levels vary significantly when quantified by different methods and laboratories on account of varying assay accuracy (Shackleton, 2010; Stanczyk & Clarke, 2010; Deutsch, 2016; Carmina, Stanczyk, & Lobo, 2019). Mass spectrometry (MS)-based assays, such as liquid chromatography–mass spectrometry (LC–MS), are regarded as more accurate and reliable than immunoassay (IA)-based assays, such as radioimmunoassays (RIA) and direct immunoassays like enzyme-linked immunosorbent assays (ELISA) (Stanczyk & Clarke, 2010; Carmina, Stanczyk, & Lobo, 2019). In relation to this, MS-based tests are gradually becoming the standard for laboratory testing of sex hormone levels. However, hormone levels vary between laboratories even with LC–MS, for instance due to differences in calibration of LC–MS instruments between laboratories (Carmina, Stanczyk, & Lobo, 2019). Whereas an accurate range for testosterone levels in cisgender women is 20 to 50 ng/dL (0.69–1.7 nmol/L), for instance with assays like RIA and LC–MS, the normal upper limit for direct immunoassays like ELISA may be 70 to 80 ng/dL (2.4–2.8 nmol/L) (Carmina, Stanczyk, & Lobo, 2019). When interpreting blood tests, care should be taken to compare sex hormone levels to same-laboratory reference ranges (Deutsch, 2016).

Overview of Hormone Therapy

The goal of hormone therapy for transfeminine people, otherwise known as feminizing hormone therapy (FHT) or (more in the past) as male-to-female (MtF) hormone replacement therapy (HRT), is to produce feminization and demasculinization of the body as well as alleviation of gender dysphoria. Medication therapy with sex hormones and other sex-hormonal medications is used to mediate these changes. Transfeminine people are given estrogens, progestogens, and antiandrogens (AAs) to supersede gonadal sex hormone production and shift the hormonal profile from male-typical to female-typical.

Transfeminine hormone therapy aims to achieve estradiol and testosterone levels within the normal female range. Commonly recommended ranges for transfeminine people in the literature are 100 to 200 pg/mL (367–734 pmol/L) for estradiol levels and less than 50 ng/dL (1.7 nmol/L) for testosterone levels (Table). However, higher estradiol levels of more than 200 pg/mL (734 pmol/L) can be useful in transfeminine hormone therapy to help suppress testosterone levels. Lower estradiol levels (≤50–60 pg/mL [≤180–220 pmol/L]) are recommended and more appropriate for pubertal and adolescent transfeminine individuals. Sex hormone levels in the blood can be measured with blood tests, in which blood is drawn from a vein using a needle and then analyzed in a laboratory. This is useful in transfeminine people to ensure that the hormonal profile has been satisfactorily altered in line with therapeutic goals—specifically that hormone levels are within female ranges.

Gonadal Suppression

At sufficiently high exposure, estrogens and androgens are able to completely suppress gonadal sex hormone production, while progestogens by themselves are able to partially but substantially suppress gonadal sex hormone production. More specifically, studies in cisgender men and transfeminine people have found that estradiol levels of around 200 pg/mL (734 pmol/L) generally suppress testosterone levels by about 90% (to ~50 ng/dL [1.7 nmol/L]), while estradiol levels of around 500 pg/mL (1,840 pmol/L) suppress testosterone levels by about 95% on average (to ~20–30 ng/dL [0.7–1.0 nmol/L]) (Wiki; Graphs). Estradiol levels of below 200 pg/mL (734 pmol/L) also suppress testosterone levels, although to a reduced extent compared to higher levels (Aly, 2019).

Figure 2: Estradiol and testosterone levels after a single injection of 320 mg polyestradiol phosphate (PEP) (a long-acting prodrug of estradiol) in men with prostate cancer (Stege et al., 1996). The maximal decrease in testosterone levels occurred with estradiol levels of greater than 200 pg/mL (734 pmol/L) and was about 90% (to roughly 50 ng/dL [1.7 nmol/L]). This figure demonstrates the ability of estradiol to concentration-dependently suppress gonadal testosterone production and circulating testosterone levels in people with testes.

Progestogens on their own are able to maximally suppress testosterone levels by about 50 to 70% (to ~150–300 ng/dL [5.2–10.4 nmol/L] on average) (Aly, 2019; Wiki). In combination with relatively small amounts of estrogen however, there is synergism in the antigonadotropic effect—the suppression of gonadal testosterone production with maximally effective doses of progestogens becomes complete, and testosterone levels are reduced by about 95% (to ~20–30 ng/dL [0.7–1.0 nmol/L]) (Aly, 2019). Hence, the combination of an estrogen and a progestogen can be used to achieve maximal testosterone suppression at lower doses than would be necessary if an estrogen or progestogen were used alone.

The antigonadotropic effects of estrogens and progestogens are taken advantage of in transfeminine hormone therapy to suppress gonadal testosterone production and attain testosterone levels that are more consistent with those in cisgender women. It should be noted that the preceding numbers on testosterone suppression with estrogens and progestogens are averages and there is significant variation between individuals in terms of testosterone suppression. In other words, some may need more or less in terms of hormonal dosages to achieve the same decrease in testosterone levels.

Timeline of Effects

During normal puberty in both males and females, sex hormone exposure increases slowly over a period of several years (Aly, 2020). In relation to this, sexual maturation occurs gradually during normal puberty. In non-adolescent transgender people, adult or higher amounts of hormones are generally administered right away, and this can result in changes in secondary sex characteristics happening more quickly. The table below is reproduced from literature sources with slight modification and is commonly cited as a timeline for the effects of hormone therapy in transfeminine people (Table). It is based on a mixture of anecdotal clinical experience, expert opinion, and available clinical studies of hormone therapy in transfeminine people. Due to limited research characterizing the effects of transfeminine hormone therapy at present, the table may or may not be completely accurate.

Table 2: Effects of hormone therapy at typical doses in adult transfeminine people (Wiki):

EffectOnsetaCompletionaPermanency
Breast development2–6 months2–3 yearsPermanent
Reduced and slowed growth of facial and body hair3–12 months>3 yearsbReversible
Cessation and reversal of scalp hair loss1–3 months1–2 yearsReversible
Softening of skin and decreased skin oiliness and acne3–6 monthsUnknownReversible
Redistribution of body fat in a feminine pattern3–6 months2–5 yearsReversible
Decreased muscle mass and strength3–6 months1–2 yearscReversible
Widening and rounding of the pelvisdUnknownUnknownPermanent
Changes in mood, emotionality, and behaviorImmediateUnknownReversible
Decreased sex drive and spontaneous erections1–3 months3–6 monthsReversible
Erectile dysfunction and decreased ejaculate volume1–3 monthsVariableReversible
Decreased sperm production and infertilityUnknown>3 yearsMixede
Decreased testicular volume3–6 months2–3 yearsUnknown
Voice changes (e.g., decreased pitch/resonance)NonefN/AN/A

a May vary significantly between individuals due to factors like genetics, diet/nutrition, hormone levels, etc. b Hormone therapy usually has little influence on facial hair density in transfeminine people. Complete removal of facial and body hair can be achieved with laser hair removal and electrolysis. Temporary hair removal can be achieved with shaving, epilating, waxing, and other methods. c May vary significantly depending on amount of physical exercise. d Occurs only in young individuals who have not yet completed growth plate closure (may not occur at all in post-adolescent people). e Only estrogens, particularly at high doses, seem to have the potential for long-lasting or irreversible infertility; impaired fertility caused by antiandrogens is usually readily reversible with discontinuation. f Voice training can be an effective means of feminizing the voice.

To see real-life photographic timelines of breast development and feminization with transfeminine hormone therapy, see the r/TransBreastTimelines community on the social media website Reddit.

Specific Hormonal Medications

The medications that are used in transfeminine hormone therapy include estrogens, progestogens, and antiandrogens. Estrogens produce feminization and testosterone suppression. Progestogens and antiandrogens do not mediate feminization themselves but further suppress and/or block testosterone. Testosterone suppression causes demasculinization and disinhibition of estrogen-mediated feminization. Androgens are sometimes used at low doses in transfeminine people who have low testosterone levels, although they are not required and benefits are uncertain. There are many different types of these hormonal medications available for transfeminine hormone therapy, with different benefits and risks.

Estrogens, progestogens, and antiandrogens are available in a variety of different formulations and for use by many different routes of administration in transfeminine people. The route of administration influences the absorption, distribution, metabolism, and elimination of the hormone in the body, resulting in significant differences between routes in terms of bioavailability, hormone levels in blood and specific tissues, and patterns of metabolites. These differences can have important therapeutic consequences.

Table 3: Major routes of administration of hormonal medications for transfeminine people:

RouteAbbr.DescriptionTypical forms
Oral administrationPOSwallowedTablet, capsule
Sublingual administrationSLHeld and absorbed under tongueTablet
Buccal administrationBUCHeld and absorbed in cheek or under lipsTablet
Transdermal administrationTDApplied to and absorbed through the skinPatch, gel, cream
Rectal administrationRECInserted into and absorbed by rectumSuppository
Intramuscular injectionIMInjected into muscle (e.g., buttocks, thigh, arm)Solution (vial/amp.)
Subcutaneous injectionSCInjected into fat under skinSolution (vial/amp.)
Subcutaneous implantSCiInsertion via surgical incision into fat under skinPellet

Vaginal administration is a major additional route of administration of hormonal medications in cisgender women. While vaginal administration via a natal vagina is of course not possible in transfeminine people, neovaginal administration is a possiblility in those who have undergone vaginoplasty. However, the lining of the neovagina is not the vaginal epithelium of natal females but instead is usually skin or colon—depending on the type of vaginoplasty performed (penile inversion or sigmoid colon vaginoplasty, respectively). For this reason, neovaginal administration in transfeminine people is likely more similar in its properties to transdermal and rectal administration—depending on the type of neovagina—than to vaginal administration in cisgender women. It is noteworthy that the vaginal and rectal routes are said to be similar in their properties for hormonal medications however (Goletiani, Keith, & Gorsky, 2007; Wiki). Moreover, absorption of estradiol via neovaginas constructed from peritoneum (internal abdominal lining)—a less commonly employed vaginoplasty approach in transfeminine people—was reported in one study to be similar to that with vaginal administration of estradiol in cisgender women (Willemsen et al., 1985). As such, neovaginal administration may be an additional possible route for certain transfeminine people depending on the circumstances. However, this route still remains to be more adequately characterized.

Estrogens

Estradiol, the primary bioidentical form normally found in the human body, is the main estrogen that is used in transfeminine hormone therapy. Estradiol hemihydrate (EH) is another form that is essentially identical to and interchangeable with estradiol. Estradiol esters are also sometimes used in place of estradiol. They are prodrugs of estradiol (i.e., are converted into estradiol in the body) and have essentially identical biological activity to estradiol. However, they have longer durations when used by injection due to slower absorption from the injection site, and this allows them to be administered less often. Some examples of major estradiol esters include estradiol valerate (EV; Progynova, Progynon Depot, Delestrogen) and estradiol cypionate (EC; Depo-Estradiol). Polyestradiol phosphate (PEP; Estradurin) is an injectable estradiol prodrug in the form of a polymer (i.e., linked chain of estradiol molecules) which is metabolized slowly and has a very long duration.

Non-bioidentical estrogens such as ethinylestradiol (EE; found in birth control pills), conjugated estrogens (CEEs; Premarin; used in menopausal hormone therapy), and diethylstilbestrol (DES; widely used previously but now abandoned) are resistant to metabolism in the liver and have disproportionate effects on estrogen-modulated liver synthesis when compared to bioidentical estrogens like estradiol (Aly, 2020). As a result, they have stronger influence on coagulation and greater risk of certain health problems like blood clots and associated cardiovascular issues (Aly, 2020). For this reason, as well as the fact that relatively high doses of estrogens may be needed for testosterone suppression, non-bioidentical estrogens should ideally never be used in transfeminine hormone therapy.

Physiological levels of estradiol are usually not sufficient to suppress testosterone levels into the female range in gonadally intact transfeminine people. As a result, estradiol is generally used in combination with an antiandrogen or progestogen in transfeminine hormone therapy. This results in partial suppression of testosterone levels by estradiol and further suppression or blockade of the remaining testosterone by the antiandrogen or progestogen. The addition of an antiandrogen or progestogen to estradiol therapy however also adds the side effects, risks, and costs of these medications. An alternative to the combination of estradiol with an antiandrogen or progestogen which may be used in transfeminine people is high-dose estradiol monotherapy. This is an approach in which estradiol is used alone at supraphysiological doses. These high doses can allow for greater testosterone suppression and reduction of testosterone levels into the female range with estradiol alone.

The feminizing effects of estradiol appear to be maximal at low levels in the absence of androgens. Higher doses of estradiol, aside from allowing for greater testosterone suppression, are not known to result in better feminization in transfeminine people (Deutsch, 2016; Nolan & Cheung, 2021). In fact, there is indication that higher estrogen doses early into hormone therapy could actually result in worse breast development. Hence, the therapeutic emphasis in transfeminine hormone therapy is more on testosterone suppression than on achieving a certain estradiol level. Higher doses of estrogens, including estradiol, also have a greater risk of adverse health effects such as blood clots and cardiovascular problems (Aly, 2020). As such, the use of physiological doses of estradiol is optimal. At the same time however, high estrogen doses can be useful for testosterone suppression. Moreover, the absolute risks in the case of non-oral bioidentical estradiol are low and are more important in people with specific risk factors. Examples of such risk factors include older age, physical inactivity, obesity, concomitant progestogen use, smoking, surgery, and rare thrombophilic abnormalities. In healthy young people without relevant risk factors, limitedly supraphysiological doses of non-oral estradiol for purposes of adequate testosterone suppression may be more acceptably safe (Aly, 2020).

Estradiol and estradiol esters are usually used orally, sublingually, transdermally, by injection (intramuscularly or subcutaneously), or by implant in transfeminine hormone therapy (Wiki).

Oral Estradiol

Estradiol is used orally in the form of tablets of estradiol (Wiki; Graphs). Alternatively, oral estradiol valerate tablets are used in some countries, for instance in many European countries. The only real differences between these oral estradiol forms is that estradiol valerate contains slightly less estradiol by weight (~76%) due to its ester component and hence requires somewhat higher doses (~1.3-fold) in comparison for equivalent estradiol levels (Wiki; Table). Oral estradiol has a duration suitable for once-daily administration. Oral administration of estradiol is a very convenient and inexpensive route, which makes it the most popular and widely used form of estradiol in transfeminine people. Oral estradiol has relatively low bioavailability (~5%), and there is substantial variability between people in terms of estradiol levels achieved with the same dose. Hence, in some transfeminine people estradiol levels may be low with oral estradiol, and testosterone suppression may be inadequate depending on the antiandrogen.

A major drawback of oral estradiol is that it results in excessive levels of estradiol in the liver due to the first pass that occurs with oral administration and has a disproportionate impact on estrogen-modulated liver synthesis (Aly, 2020). This in turn increases coagulation and the risk of associated health complications like blood clots and cardiovascular problems (Aly, 2020). These particular health concerns are largely allayed if estradiol is taken non-orally at reasonable and non-excessive doses. Hence non-oral forms of estradiol, like transdermal estradiol, although less convenient and often more expensive than oral estradiol, are preferable in transfeminine hormone therapy. It is recommended that all transfeminine people who are over 40 to 45 years of age use non-oral routes due to the greater risk of blood clots and cardiovascular problems that occurs with age (Aly, 2020; Coleman et al., 2022). Oral estradiol is not a good choice for high-dose estradiol monotherapy in transfeminine people due to the high estradiol levels required and the greater risks than with non-oral routes. In addition to its disproportionate liver impact, oral estradiol results in unphysiological levels of estradiol metabolites like estrone and estrone sulfate when compared to non-oral forms. The clinical implications of this, if any, are unknown. Oral and non-oral estradiol have in any case been found to have similar effectiveness in terms of feminization and breast development in transfeminine people in available studies (Sam, 2020).

Sublingual Estradiol

Oral estradiol tablets can be taken sublingually instead of orally. Sublingual use of estradiol tablets has several-fold higher bioavailability relative to oral administration and hence achieves much higher overall estradiol levels in comparison (Sam, 2021; Wiki; Graphs). Sublingual use of oral estradiol tablets can be employed instead of oral administration to reduce doses and hence medication costs or to produce higher estradiol levels for the purpose of achieving better testosterone suppression when needed. However, sublingual estradiol is very spiky in terms of estradiol levels when compared to oral estradiol and has a short duration of highly elevated estradiol levels. As such, it may be advisable for sublingual estradiol to be used in divided doses multiple times throughout the day in order to maintain at least somewhat steadier estradiol levels. The therapeutic implications for transfeminine people of the spikiness of sublingual estradiol, for instance in terms of testosterone suppression and health risks, have been little-studied and are mostly unknown. Oral estradiol valerate tablets can be taken sublingually instead of orally similarly to estradiol and are likewise highly effective when used in this way (Aly, 2019; Wiki). Due to partial swallowing of tablets, sublingual estradiol may in practice be a mixture of sublingual and oral administration and may have some of the same health risks of oral estradiol (Wiki). Buccal administration of estradiol appears to have similar properties as sublingual administration but is much less researched in comparison and is not used as often in transfeminine people (Wiki).

Transdermal Estradiol

Transdermal estradiol is available in the form of patches, gel, emulsions, and sprays (Wiki). These forms are usually applied to skin areas such as the arms, abdomen, or buttocks. Gel, emulsions, and sprays are applied and left to dry for a short period, whereas patches are applied and remain adhesed to the skin for a specified amount of time. Due to rate-limited absorption through the skin, there is a depot effect with transdermal estradiol and this route has a long duration with very steady estradiol levels. As a result, estradiol gel, emulsions, and sprays are all suitable for once-daily use. Patches stay applied and continuously deliver estradiol for either 3–4 days or 7 days depending on the patch brand (Table). Transdermal estradiol is more expensive than oral estradiol. Gel, emulsions, and sprays may be less convenient than oral administration, but patches can be more convenient due to their infrequent application. However, patches can sometimes cause application site problems like redness and irritation and can occasionally come off prematurely due to adhesive failure. As with oral estradiol, there is substantial variability in estradiol levels with transdermal estradiol, and some transfeminine people may have poor absorption, low estradiol levels, and inadequate testosterone suppression with this route. Estradiol sprays, such as Lenzetto, have been found to achieve very low estradiol levels that are probably not therapeutically adequate for use in transfeminine hormone therapy (Aly, 2020; Graph).

Transdermal estradiol is the form of estradiol most commonly used in transfeminine people who are over 40 years of age due to its lower health risks relative to oral estradiol. Transdermal estradiol gel is not a favorable option for high-dose estradiol monotherapy as it has difficulty achieving the high estradiol levels needed for adequate testosterone suppression (Aly, 2019). On the other hand, transdermal estradiol patches can be an effective option for high-dose estradiol monotherapy if multiple 100 μg/day patches are used (Wiki). Different skin sites absorb transdermal estradiol to different extents (Wiki). Genital application of transdermal estradiol, specifically to the scrotum or neolabia, is particularly better-absorbed than conventional skin sites and can result in much higher estradiol levels than usual (Aly, 2019). This can be useful for reducing doses and hence medication costs or for achieving higher estradiol levels for better testosterone suppression when needed. Transdermal estradiol should not be applied to the breasts as this is not known to result in improved breast development and the potential health consequences of doing so are unknown (e.g., influence on breast cancer risk).

Injectable Estradiol

Injectable estradiol preparations can be administered via either intramuscular or subcutaneous injection (Wiki; Wiki; Graphs). There is a depot effect with injection of estradiol esters such that they are slowly absorbed from the injection site and have a prolonged duration. This ranges from days to months depending on the ester. Commonly used injectable estradiol esters, which all have short to moderate durations, include estradiol valerate (EV), estradiol cypionate (EC), estradiol enanthate (EEn), and estradiol benzoate (EB). Longer-acting injectable estradiol esters, such as estradiol undecylate (EU) and polyestradiol phosphate (PEP), have been discontinued and are no longer pharmaceutically available. In the case of intramuscular injection, common injection sites include the deltoid muscle (upper arm), vastus lateralis and rectus femoris muscles (thigh), and ventrogluteal muscle (buttocks). Subcutaneous injection of estradiol injectables, while less commonly used, has comparable pharmacokinetics to intramuscular injection, and is easier, less painful, and more convenient in comparison (Wiki). However, the maximum volume that can be safely and comfortably injected subcutaneously is less than that which can be injected intramuscularly (depending on the site up to 1.5–3 mL and up to 2–5 mL, respectively) (Hopkins, & Arias, 2013; Usach et al., 2019). Injectable estradiol tends to be fairly inexpensive, but may be less convenient than other routes due to the need for regular injections. There may also be a risk of internal scar tissue build-up long-term. Estradiol injectables have been discontinued in many parts of the world (e.g., most of Europe), and their availability is limited. In recent years, many transfeminine people have turned to black market homebrewed injectable estradiol preparations to use this route.

Injectable estradiol preparations are typically used at higher doses than other forms of estradiol, and can easily achieve very high levels of estradiol. This can be useful for testosterone suppression, making this form of estradiol likely the best choice for high-dose estradiol monotherapy in transfeminine people. However, the high doses that are possible with injectable estradiol preparations can also easily lead to overdosage and unnecessarily increased risks (e.g., Aly, 2020). Resources are available on this site for guiding selection of appropriate doses and intervals of injectable estradiol esters in transfeminine people. This includes a simulator and informal meta-analysis of estradiol levels with these preparations (Aly, 2021; Aly, 2021) and a table providing approximate equivalent doses between injectable estradiol esters and other estradiol routes and forms (Aly, 2020). It is notable and unfortunate that currently recommended doses and intervals for injectable estradiol esters by transgender care guidelines (e.g., 10–40 mg/2 weeks estradiol valerate) appear to be highly excessive and too widely spaced, and are likely to be therapeutically inadvisable (Aly, 2021). Doses and intervals of injectable estradiol esters recommended by the present author for use as a means of high-dose estradiol monotherapy, targeting mean estradiol levels of around 300 pg/mL (1,100 pmol/L), are provided below (Table 4).

Table 4: Recommended doses and intervals of injectable estradiol esters for high-dose estradiol monotherapy (targeting estradiol levels of around 300 pg/mL [1,100 pmol/L]):

Estradiol EsterShortMediumLongSimulation
Estradiol benzoate0.67 mg/1 day1.33 mg/2 days2 mg/3 daysGraph
Estradiol valerate2 mg/3 days3.5 mg/5 days5 mg/7 daysGraph
Estradiol cypionate (in oil)5 mg/7 days7 mg/10 days10 mg/14 daysGraph
Estradiol cypionate (suspension)2 mg/3 days3.5 mg/5 days5 mg/7 daysGraph
Estradiol enanthate5 mg/7 days7 mg/10 days10 mg/14 daysGraph
Estradiol undecylatea10 mg/14 days20 mg/28 days30 mg/42 daysGraph
Polyestradiol phosphate160 mg/30 days240 mg/45 days320 mg/60 daysGraph

a Doses and intervals for estradiol undecylate are extrapolated and hypothetical (Aly, 2021).

These doses and intervals should be considered a starting point, and should be fine-tuned as necessary based on blood tests. In terms of injection intervals, the shorter interval, the more stable the estradiol levels, but the more often that injections need to be done. Doses may be increased if estradiol levels are too low and testosterone suppression is inadequate, and doses may be decreased if estradiol levels are too high so long as adequate testosterone suppression is maintained. Doses should be lower (targeting mean estradiol levels of 100–200 pg/mL [367–734 pmol/L]) if combined with an antiandrogen or progestogen as these agents will help with testosterone suppression. Similarly, doses should be lower following surgical gonadal removal as testosterone suppression will no longer be necessary.

Estradiol Pellets

Estradiol implants are pellets of pure crystalline hormone and are surgically placed into subcutaneous fat by a physician (Wiki). They are slowly absorbed by the body following implantation, and new implants are given once every 4 to 6 months. Due to the need for minor surgery, their high cost, and limited availability, estradiol implants are not as commonly used as other estradiol routes. Notably, almost all pharmaceutical estradiol implants throughout the world have been discontinued, and the implants that remain available are almost exclusively compounded products provided by compounding pharmacies. Dosage adjustment with estradiol implants is also more difficult than with other estradiol routes. Despite their various practical limitations however, estradiol implants allow for very steady estradiol levels, and their very long duration can allow for unusual convenience among available estradiol forms.

Additional Notes

Table 5: Available forms and recommended doses of estradiol for adulta transfeminine people:

MedicationRouteFormDosage
EstradiolOralTablets2–8 mg/day
 Sublingual or buccalTablets0.5–6 mg/dayb
 TransdermalPatches50–400 μg/day
  Gel1.5–6 mg/day
  SpraysNot recommendedc
 SC implantPellet25–150 mg/6 months
Estradiol valerateOralTablets3–10 mg/dayd
 Sublingual or buccalTablets1–8 mg/dayb,d
 IM or SC injectionOil solution0.75–4 mg/5 days; or
1–6 mg/7 days; or
1.5–9 mg/10 days
Estradiol cypionateIM or SC injectionOil solution1–6 mg/7 days; or
1.5–9 mg/10 days; or
2–12 mg/14 days
  Aqueous suspension0.75–4 mg/5 days; or
1–6 mg/7 days; or
1.5–9 mg/10 days
Estradiol enanthateIM or SC injectionOil solution1–6 mg/7 days; or
1.5–9 mg/10 days; or
2–12 mg/14 days
Estradiol benzoateIM or SC injectionOil solution0.15–0.75 mg/day; or
0.3–1.5 mg/2 days; or
0.45–2.25 mg/3 days
Estradiol undecylateeIM or SC injectionOil solution2–12 mg/14 days; or
4–24 mg/28 days; or
6–36 mg/42 days
Polyestradiol phosphateIM injectionWater solution40–160 mg/monthf

a Estradiol doses in pubertal adolescent transfeminine people should be lower to mimic estradiol exposure during normal female puberty (Aly, 2020). b May be advisable to use divided doses 2 to 4 times per day (i.e., once every 6 to 12 hours) instead of once per day (Sam, 2021). c This estradiol form achieves very low estradiol levels at typical doses that don’t appear to be well-suited for transfeminine hormone therapy (Aly, 2020; Graph). d Estradiol valerate contains about 75% of the same amount of estradiol as estradiol so doses are about 1.3-fold higher for the same estradiol levels (Aly, 2019; Sam, 2021). e Doses and intervals for estradiol undecylate are extrapolated and hypothetical (Aly, 2021). f A higher initial loading dose of e.g., 240 or 320 mg polyestradiol phosphate can be used for the first one or two injections to reach steady-state estradiol levels more quickly. However, this preparation has recently been discontinued and appears to no longer be available.

Additional informational resources are available in terms of estradiol levels (Wiki; Table) and approximate equivalent doses (Aly, 2020) with different forms, routes, and doses of estradiol.

There is high variability between individuals in the levels of estradiol achieved during estradiol therapy. That is, estradiol levels during treatment with the same dosage of estradiol can differ substantially between individuals. This variability is greatest with oral and transdermal estradiol but is also considerable even with injectable estradiol preparations and other estradiol forms. As such, estradiol doses are not absolute and should be individualized on a case-by-case basis in conjunction with blood work as a guide. It should also be noted that due to fluctuations in estradiol concentrations with certain routes, levels of estradiol can vary considerably from one blood test to another. This is most notable with sublingual estradiol and injectable estradiol. The fluctuations in estradiol levels with these routes are predictable and must be understood when interpreting blood work results. Differences in blood test results can be minimized with informed and consistent timing of blood draws.

If or when the gonads are surgically removed, testosterone suppression is no longer needed in transfeminine people. As a result, estradiol doses, if they are high or supraphysiological, can be lowered to more closely approximate normal physiological levels in cisgender women.

Progestogens

Progestogens include progesterone and progestins. Progestins are synthetic progestogens derived from structural modification of progesterone or testosterone. There are dozens of different progestins and these progestins can be divided into a variety of different structural classes with varying properties (Table). Examples of some major progestins of different classes include the 17α-hydroxyprogesterone derivative medroxyprogesterone acetate (MPA; Provera, Depo-Provera), the 19-nortestosterone derivative norethisterone (NET; many brand names), the retroprogesterone derivative dydrogesterone (Duphaston), and the 17α-spirolactone derivative drospirenone (Slynd, Yasmin). Progestins were developed because they have a more favorable disposition in the body than progesterone for use as medications. Only a few clinically used progestins have been used in transfeminine hormone therapy. However, progestogens largely produce the same progestogenic effects, with a few exceptions, and theoretically almost any progestogen could be employed.

Progestogens have antigonadotropic effects via their progestogenic activity and dose-dependently suppress the secretion of the gonadotropins from the pituitary gland. This in turn results in a reduction of gonadotropin-mediated gonadal stimulation and a decrease in sex hormone production as well as fertility. The dose-dependent testosterone-suppressing effects of a variety of different progestogens have been characterized in clinical studies in cisgender men and transfeminine people (Nieschlag, Zitzmann, & Kamischke, 2003; Nieschlag, 2010; Nieschlag & Behre, 2012; Zitzmann et al., 2017; Aly, 2019). Some notable examples of this include cyproterone acetate (CPA) (Aly, 2019; Wiki), MPA (Wiki), NET (Wiki) and its ester norethisterone acetate (NETA) (Wiki), levonorgestrel (LNG) (Zitzmann et al., 2017; Wiki), desogestrel (DSG) (Wu et al., 1999; Wiki), dienogest (DNG) (Meriggiola et al., 2002; Wiki), and progesterone (Wiki), among others. High doses of progestogens by themselves are able to maximally suppress testosterone levels by about 50 to 70% on average (Aly, 2019; Zitzmann et al., 2017 (Graph)). In combination with estrogen however, this increases to about 95%, with testosterone levels suppressed into the normal female range (Aly, 2019). Progestogens seem to usually achieve their maximal testosterone-suppressing capacity at a dose of around 5 to 10 times their ovulation-inhibiting dosage in cisgender women (Aly, 2019). Due to low potency or atypicality, oral progesterone and dydrogesterone are exceptions among progestogens which do not have significant antigonadotropic effects and which would not be expected to suppress testosterone levels (Aly, 2018; Wiki; Wiki).

Besides helping with testosterone suppression, progestogens are of no clear or known benefit for feminization or breast development in transfeminine people. While some transfeminine people anecdotally claim to experience improved breast development with progestogens, an involvement of progestogens in improving breast size or shape is controversial and is not supported by theory nor evidence at present (Wiki; Aly, 2020). It is possible that premature introduction of progestogens, particularly at high doses, could actually have an unfavorable influence on breast development (Aly, 2020). Many transfeminine people have also anecdotally claimed that progestogens have a beneficial effect on their sexual desire. However, a review of the literature by the present author found that neither progesterone nor progestins positively influence sexual desire in humans (Aly, 2020). Instead, the available evidence suggests either a neutral influence or an inhibitory effect of progestogens on sexual desire, although the latter may be specific only to high doses of progestogens (Aly, 2020). Claims have been made that progesterone may have beneficial effects on mood in transfeminine people as well, but clinical support for such notions is likewise lacking at this time (Coleman et al., 2022; Nolan et al., 2022). It is notable that progesterone at luteal-phase levels, due to its neurosteroid metabolites like allopregnanolone, actually appears to worsen mood in around 30% of cisgender women, and produces more overt negative reactions, which constitute the diagnoses of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), in around 2 to 10% of women (Bäckström et al., 2011; Edler Schiller, Schmidt, & Rubinow, 2014; Sundström-Poromaa et al., 2020). More research is needed to evaluate the possible beneficial effects of progestogens in transfeminine people.

Most clinically used progestogens have off-target activities in addition to their progestogenic activity, and these activities may be desirable or undesirable depending on the action in question (Kuhl, 2005; Stanczyk et al., 2013; Wiki; Table). Progesterone has a variety of neurosteroid as well as other activities that can result in central nervous system effects among others which are not shared by progestins. MPA as well as NET and its derivatives have weak androgenic activity, which is unfavorable in the context of transfeminine hormone therapy. NET and certain related progestins produce ethinylestradiol as a metabolite at high doses and hence can produce ethinylestradiol-like estrogenic effects, including increased risk of blood clots and associated cardiovascular problems. Other off-target actions of progestogens include antiandrogenic, glucocorticoid, and antimineralocorticoid activities. These actions can result in differences in therapeutic effectiveness (e.g., androgen suppression or blockade) as well as side effects and health risks. Some notable progestins without undesirable off-target activities (i.e., androgenic or glucocorticoid activity) include low-dose CPA, drospirenone (DRSP), dienogest, nomegestrol acetate (NOMAC), dydrogesterone, and hydroxyprogesterone caproate (OHPC). However, of these progestins, only CPA has been considerably used and studied in transfeminine people.

The addition of progestogens to estrogen therapy has been associated with a number of unfavorable health effects. These include increased risk of blood clots (Wiki; Aly, 2020), coronary heart disease (Wiki), and breast cancer (Wiki; Aly, 2020). High doses of progestogens are also associated with increased risk of certain non-cancerous brain tumors including meningiomas and prolactinomas (Wiki; Aly, 2020). The coronary heart disease risk may be due to changes in blood lipids caused by the weak androgenic activity of certain progestogens, but the rest of the aforementioned risks are probably due to their progestogenic activity (Stanczyk et al., 2013; Jiang & Tian, 2017). Aside from health risks, progestogens have also been associated with adverse mood changes (Wiki; Wiki). However, besides the case of progesterone and its neurosteroid metabolites, these effects of progestogens are controversial and are not well-supported by evidence (Wiki; Wiki). Progestogens are otherwise generally well-tolerated and are regarded as producing little in the way of side effects.

In contrast to certain progestins, progesterone has no unfavorable off-target activities. Due to its lack of androgenic activity, progesterone has no adverse influence on blood lipids and is not expected to raise the risk of coronary heart disease. The addition of oral progesterone to estrogen therapy notably has not been associated with increased risk of blood clots (Wiki). In addition, oral progesterone seems to have less risk of breast cancer than progestins with short-term therapy, although this is notably not the case with longer-term exposure (Wiki; Aly, 2020). Consequently, it has been suggested that progesterone, for reasons that have yet to be fully elucidated, may be a safer progestogen than progestins and that it should be the preferred progestogen for hormone therapy in cisgender women and transfeminine people. However, there are also theoretical arguments against such notions. Oral progesterone is known to produce very low progesterone levels and to have only weak progestogenic effects at typical doses (Aly, 2018; Wiki). The seemingly better safety of oral progesterone may simply be an artifact of the low progesterone levels that occur with it, and hence of progestogenic dosage. Non-oral progesterone, at doses resulting in physiological and full progestogenic strength, has never been properly evaluated in terms of health outcomes, and may have similar risks as progestins (Aly, 2018; Wiki).

Due to their lack of known influence on feminization and breast development and their known and possible adverse effects and risks, progestogens are not routinely used in transfeminine hormone therapy at present. Major transgender health guidelines note the limitations of the available evidence on progestogens for transfeminine people and have mixed attitudes on their use, either explictly recommending against their use (Coleman et al., 2022—WPATH SOC8), taking a more neutral stance (Hembree et al., 2017—Endocrine Society guidelines), or being permissive of their use (Deutsch, 2016—UCSF guidelines). There is however a very major exception to the preceding in the form of CPA, an antiandrogen which is widely used in transfeminine hormone therapy to suppress testosterone production and which happens to be a powerful progestogen at the typical doses used in transfeminine people. CPA will be described below in the section on antiandrogens. Although progestogens have various health risks, cisgender women of course have progesterone, and the absolute risks of progestogens are very low in healthy young people. Risks like breast cancer also are exposure-dependent and take many years to develop. The testosterone suppression provided by progestogens can furthermore be very useful in transfeminine people, as is widely taken advantage of with CPA. Given these considerations, a limited duration of progestogen therapy in transfeminine people, for instance a few years to help suppress testosterone levels before surgical gonadal removal, may be considered quite acceptable.

Progesterone can be used in transfeminine people by oral administration, sublingual administration, rectal administration, or by intramuscular or subcutaneous injection (Wiki). Progestins are usually used via oral administration, but certain progestins are also available in injectable formulations (Wiki).

Oral Progesterone

Progesterone is most commonly taken orally. It is used by this route in the form of oil-filled capsules containing 100 or 200 mg micronized progesterone under brand names such as Prometrium, Utrogestan, and Microgest (Wiki). Despite its widespread use, levels of progesterone via oral administration have been found using state-of-the-art assays (LC–MS) to be very low (<2 ng/mL [<6.4 nmol/L] at 100 mg/day) and inadequate for satisfactory progestogenic effects in various areas (Aly, 2018; Wiki). In relation to this, even high doses of oral progesterone (400 mg/day) showed no antigonadotropic effect or testosterone suppression in cisgender men (Aly, 2018; Wiki). This is in major contrast to non-oral forms of progesterone and to progestins, which produce dose-dependent and robust testosterone suppression (Aly, 2019; Wiki). In addition to its low progestogenic potency, oral progesterone is excessively converted into neurosteroid metabolites like allopregnanolone and pregnanolone. These metabolites act as potent GABAA receptor positive allosteric modulators, and can produce undesirable alcohol-like side effects such as sedation, cognitive, memory, and motor impairment, and mood changes (Wiki; Wiki). As such, while inconvenient, non-oral routes are greatly preferable for progesterone.

Sublingual Progesterone

Sublingual progesterone tablets exist and are marketed under the brand name Luteina but today are only available in Poland and Ukraine (Wiki). Oral progesterone could theoretically be taken sublingually, analogously to sublingual use of oral estradiol. However, because oral progesterone is formulated as oil-filled capsules, this makes it difficult and unpleasant to use by sublingual administration. Buccal progesterone, which would be expected to have similar characteristics to those of sublingual progesterone, has been used in medicine in the past, but is no longer marketed today (Wiki).

Rectal Progesterone

Progesterone is approved for use by rectal administration in the form of suppositories under the brand name Cyclogest (Wiki). This product is marketed in only a limited number of countries however, although it is available in the United Kingdom (Wiki). While not approved for use by rectal administration, oral progesterone capsules can be taken rectally instead of orally, and using them in this way may allow for much higher progesterone levels than would be achieved by oral administration due to avoidance of most first-pass metabolism. Rectal administration of oral progesterone capsules has not been formally studied, but oral progesterone capsules have been administered vaginally in cisgender women with success (Miles et al., 1994; Wang et al., 2019), and the vaginal and rectal routes are said to have similar pharmacokinetics in general (Goletiani, Keith, & Gorsky, 2007; Wiki). Hence, there is good theoretical basis for rectal administration of oral progesterone capsules being an effective route of administration of progesterone. Whereas oral progesterone achieves very low levels of progesterone, rectal progesterone can readily achieve normal luteal-phase levels of progesterone (Wiki). Although inconvenient, rectal administration may be the overall best route of administration of progesterone for transfeminine people.

Injectable Progesterone

Progesterone by injection is available as an oil solution for intramuscular injection under brand names such as Proluton, Progestaject, and Gestone (Wiki) and as an aqueous solution for subcutaneous injection under the brand name Prolutex (Wiki). Oil solutions of progesterone for intramuscular injection are widely available, whereas the aqueous solution of progesterone for subcutaneous injection is available only in some European countries (Wiki). Injectable progesterone, regardless of route, has a relatively short duration and must be injected once every one to three days (Wiki; Wiki). This makes it too inconvenient to use for most people. Unlike with estradiol, progesterone esters with longer durations than progesterone itself by injection are not chemically possible as progesterone has no hydroxyl groups available for esterification (Wiki). Injectable aqueous suspensions of microcrystalline progesterone were previously marketed and had a duration of 1 to 2 weeks, but these preparations were associated with pain at the injection site and were eventually discontinued (Aly, 2019; Wiki).

Other Progesterone Routes

Other progesterone routes, such as transdermal progesterone and subcutaneous progesterone pellets, are also known, but are not available as pharmaceutical drugs and are little-used medically (Wiki). This is related to the low potency of progesterone and difficulty achieving progesterone levels high enough for adequate therapeutic effects with these routes (Wiki; Wiki). In addition, progesterone pellets tend to be extruded at high rates (Wiki). In any case, certain compounding pharmacies may make forms of progesterone that could be used by these routes.

Oral and Injectable Progestins

Most progestins are taken orally in the form of solid tablets (Wiki). In contrast to progesterone, progestins, owing to their synthetic nature, are resistant to metabolism in the intestines and liver and have high oral bioavailability. In addition, unlike the case of the estrogen receptors, the progesterone receptors are expressed minimally or not at all in the liver, and there is no known first pass influence of progestogenic activity on liver synthesis (Lax, 1987; Stanczyk, Mathews, & Cortessis, 2017). As a result, there are no apparent problems with oral administration in the case of purely progestogenic progestins. However, some progestins have liver-impacting off-target hormonal actions, such as androgenic, estrogenic, and/or glucocorticoid activity, and this can result in adverse effects like unfavorable lipid changes or procoagulation—which may be augmented by the first pass with oral administration.

A selection of progestins are available in injectable formulations, including for intramuscular or subcutaneous injection (Wiki). Some of the more notable ones include medroxyprogesterone acetate (MPA), norethisterone enanthate (NETE), hydroxyprogesterone caproate (OHPC), and algestone acetophenide (dihydroxyprogesterone acetophenide; DHPA) (Wiki). In addition to being used alone, injectable progestins are used together with estradiol esters in combined injectable contraceptives (Wiki). These preparations are often used as a means of hormone therapy by transfeminine people in Latin America. Whereas injectable progesterone has a duration measured in days, injectable progestins have durations ranging from weeks to months, and can be injected much less often in comparison (Table).

Additional Notes

Table 6: Available forms and recommended doses of progestogens for transfeminine people:

MedicationRouteFormDosage
ProgesteroneOralOil-filled capsules100–300 mg 1–2x/day
 RectalSuppositories; Oil-filled capsules100–200 mg 1–2x/day
 IM injectionOil solution25–75 mg/1–3 days
 SC injectionWater solution25 mg/day
ProgestinsOral; IM or SC injectionTablets; Oil solution; Water solutionVarious

For progesterone levels with different forms, routes, and doses of progesterone, see the table here (only LC–MS and IA + CS assays for oral progesterone) and the graphs here.

As with estradiol, there is high variability between individuals in progesterone levels. Conversely, there is less variability between individuals in the case of progestins.

After removal of the gonads, progestogen doses can be lowered or adjusted to approximate normal female physiological exposure or they can be discontinued entirely.

Antiandrogens

Aside from estrogens and progestogens, there is another class of hormonal medications used in transfeminine hormone therapy known as antiandrogens (AAs). These medications reduce the effects of androgens in the body by either decreasing androgen production and thereby lowering androgen levels or by directly blocking the actions of androgens. They work via a variety of different mechanisms of action, and include androgen receptor antagonists, antigonadotropins, and androgen synthesis inhibitors.

Androgen receptor antagonists act by directly blocking the effects of androgens, including testosterone, DHT, and other androgens, at the level of their biological target. They bind to the androgen receptor without activating it, thereby displacing androgens from the receptor. Due to the nature of their mechanism of action as competitive blockers of androgens, the antiandrogenic efficacy of androgen receptor antagonists is both highly dose-dependent and fundamentally dependent on testosterone levels. They do not act by lowering testosterone levels, although some androgen receptor antagonists may have additional antiandrogenic actions that result in decreased testosterone levels. Because androgen receptor antagonists do not work by lowering testosterone levels, blood work can be less informative for them compared to antiandrogens that suppress testosterone levels. Androgen receptor antagonists include steroidal antiandrogens (SAAs) like spironolactone (Aldactone) and cyproterone acetate (CPA; Androcur) and nonsteroidal antiandrogens (NSAAs) like bicalutamide (Casodex).

Antigonadotropins suppress the gonadal production of androgens by inhibiting the GnRH-mediated secretion of gonadotropins from the pituitary gland. They include estrogens and progestogens. In addition, GnRH agonists such as leuprorelin (Lupron) and GnRH antagonists such as elagolix (Orilissa) act similarly and could likewise be described as antigonadotropins.

Androgen synthesis inhibitors inhibit the enzyme-mediated synthesis of androgens. They include 5α-reductase inhibitors (5α-RIs) like finasteride (Propecia) and dutasteride (Avodart). There are also other types of androgen synthesis inhibitors, for instance potent 17α-hydroxylase/17,20-lyase inhibitors like ketoconazole (Nizoral) and abiraterone acetate (Zytiga). However, these agents have limitations (e.g., toxicity, high cost, and lack of experience) and have not been used in transfeminine hormone therapy.

Although antigonadotropins and androgen synthesis inhibitors have antiandrogenic effects secondary to decreased androgen levels, they are not usually referred to as “antiandrogens”. Instead, this term is most commonly reserved to refer specifically to androgen receptor antagonists. However, antigonadotropins and androgen synthesis inhibitors may nonetheless be described as antiandrogens as well.

After removal of the gonads, antiandrogens can be discontinued. If unwanted androgen-dependent symptoms, such as acne, seborrhea, or scalp hair loss, persist despite full suppression or ablation of gonadal testosterone, then a lower dose of an androgen receptor antagonist, such as 100 to 200 mg/day spironolactone or 12.5 to 25 mg/day bicalutamide, can be continued to treat these symptoms.

Table 7: Available forms and recommended doses of antiandrogens for transfeminine people:

MedicationTypeRouteFormDosage
Cyproterone acetateProgestogen; Androgen receptor antagonistOralTablets2.5–12.5 mg/daya
SpironolactoneAndrogen receptor antagonist; Weak androgen synthesis inhibitorOralTablets100–400 mg/dayb,c
BicalutamideAndrogen receptor antagonistOralTablets12.5–50 mg/dayb

a For CPA, this dose range is specifically one-quarter of a 10-mg tablet to one full 10-mg tablet per day (2.5–10 mg/day) or a quarter of a 50-mg tablet every other day or every 2 to 3 days (4.2–12.5 mg/day). A dosage of 5–10 mg/day or 6.25–12.5 mg/day is likely to ensure maximal testosterone suppression, while lower doses may be less effective (Aly, 2019). b For spironolactone and bicalutamide, it is assumed that testosterone levels are substantially suppressed (≤200 ng/dL [<6.9 nmol/L]). If testosterone levels are not suppressed to this range, then higher doses may be warranted. c Spironolactone and its metabolites have relatively short half-lives, and twice-daily administration in divided doses (e.g., 100–200 mg twice per day) is recommended.

Figure 3: Suppression of gonadal testosterone production and circulating testosterone levels (ng/dL) with estradiol in combination with different antiandrogens over one year of hormone therapy in transfeminine people (Sofer et al., 2020). The estradiol forms included oral tablets 2–8 mg/day, transdermal gel 2.5–5 mg/day, and transdermal patches 50–200 μg/day. The antiandrogens included spironolactone 50–200 mg/day (n=16), cyproterone acetate (n=41), and GnRH agonists (specifically triptorelin 3.75 mg/month or goserelin 3.6 mg/month by injection) (n=10) (Sofer et al., 2020). It should be noted that lower doses of cyproterone acetate (10–12.5 mg/day) show equal testosterone suppression to higher doses (25–100 mg/day) and higher doses should no longer be used (Aly, 2019). The dashed horizontal line corresponds to the upper limit of the normal female range for testosterone levels.

Cyproterone Acetate

Cyproterone acetate (CPA; Androcur) is a progestogen and antiandrogen. It is widely used as a progestogen in cisgender women, including in hormonal birth control and menopausal hormone therapy. CPA is also widely used as an antiandrogen in the treatment of androgen-dependent conditions in cisgender women and cisgender men. In cisgender women, it is used to treat acne, hirsutism (excessive facial/body hair growth), scalp hair loss, and hyperandrogenism (high androgen levels) due to polycystic ovary syndrome (PCOS). In cisgender men, it is used to treat prostate cancer and to lower sex drive in the management of sexual problems such as paraphilias, hypersexuality, and sex offenses. Besides cisgender people, CPA is widely used as a component of hormone therapy—specifically as an antiandrogen—in transfeminine people. The medication is notably not marketed in the United States, where spironolactone is most commonly used instead. However, CPA is widely available throughout the rest of the world, and is the most frequently used antiandrogen in transfeminine people in Europe and probably the whole world overall (T’Sjoen et al., 2019; Glintborg et al., 2021; Coleman et al., 2022).

As an antiandrogen, CPA has a dual mechanism of action of suppressing testosterone levels via its progestogenic and hence antigonadotropic activity and of acting as an androgen receptor antagonist (Aly, 2019). The progestogenic activity of CPA is of far greater potency than its androgen receptor antagonism however (Aly, 2019). The dose of CPA used as a progestogen in cisgender women is about 2 mg per day, which produces similar progestogenic effects to those of physiological luteal-phase levels of progesterone (e.g., suppression of gonadotropin secretion, ovulation inhibition, and endometrial transformation and protection) (Aly, 2019). Conversely, much higher doses of CPA of 50 to 300 mg/day have typically been used for androgen-dependent indications (Aly, 2019). These high doses of CPA result in profound progestogenic overdosage and associated side effects and risks (Aly, 2019). In transfeminine people, CPA has historically been used at doses of 50 to 150 mg/day (Aly, 2019). However, CPA doses have dramatically fallen in recent years, and today doses of no more than 10 to 12.5 mg/day are recommended (Aly, 2019; Coleman et al., 2022—WPATH SOC8). These lower doses of CPA still produce strong progestogenic effects, and in combination with estradiol, are equally effective as higher doses in suppressing testosterone levels (Aly, 2019; Meyer et al., 2020; Even Zohar et al., 2021; Kuijpers et al., 2021; Coleman et al., 2022). Even lower doses of CPA, for instance 5 to 6.25 mg/day, are currently being studied, and may still be fully effective (Aly, 2019).

Given by itself without estrogen, CPA typically suppresses testosterone levels in people with testes by about 50 to 70%, down to about 150 to 300 ng/dL (5.2–10.4 nmol/L) (Meriggiola et al., 2002; Toorians et al., 2003; Giltay et al., 2004; T’Sjoen et al., 2005; Tack et al., 2017; Zitzmann et al., 2017; Aly, 2019). Lower doses of CPA alone (e.g., 10 mg/day) show the same degree of testosterone suppression as higher doses of CPA alone (e.g., 50–100 mg/day), indicating that the antigonadotropic effects of CPA are maximal at relatively low therapeutic doses of this medication (Aly, 2019). This is on the order of about 5 to 10 times the ovulation-inhibiting dosage of CPA in cisgender women, a dose–response relationship that has also been observed with a number of other progestogens (Aly, 2019). Per the preceding, CPA alone, regardless of dosage, is unable to reduce testosterone levels into the normal female range (<50 ng/dL [<1.7 nmol/L]). But when CPA is combined with estradiol, even at relatively small doses of estradiol, it consistently suppresses testosterone levels into the normal female range (Aly, 2019; Angus et al., 2019; Gava et al., 2020; Sofer et al., 2020; Collet et al., 2022). However, it appears that a certain minimum level of estradiol, perhaps around 60 pg/mL (220 pmol/L) on average, is required for this to occur (Aly, 2019). Estradiol levels lower than this threshold in those taking CPA, which can occasionally be encountered in transfeminine people due to estradiol being dosed too low, have the potential to compromise full testosterone suppression (Aly, 2019).

In addition to testosterone suppression, CPA can dose-dependently block the androgen receptor (Aly, 2019). However, relatively high doses of CPA are needed to considerably antagonize the androgen receptor (e.g., 50–300 mg/day), and lower doses (e.g., ≤12.5 mg/day) may not be able to do this to a meaningful degree (Aly, 2019). As such, lower doses of CPA may essentially be purely progestogenic, with minimal or no androgen receptor antagonism. In this regard, referring to CPA at such doses as an “antiandrogen”—rather than as a “progestogen”—may be considered somewhat of a misnomer. Higher doses of CPA (>12.5 mg/day) can no longer be considered safe due to the massive progestogenic overdosage that occurs with them, and should no longer be used in transfeminine people. Moreover, as testosterone levels are usually suppressed into the normal female range in transfeminine people taking estradiol plus CPA, there is no actual need for any additional androgen receptor blockade (Aly, 2019).

CPA has been reported to produce various side effects. Some of these side effects include fatigue and a degree of weight gain (Belisle & Love, 1986; Hammerstein, 1990; Martinez-Martin et al., 2022). CPA might be able to produce a magnitude of sexual dysfunction (e.g., reduced sexual desire) beyond that expected with testosterone suppression alone (Wiki; Aly, 2019). It may also have a small risk of depressive mood changes (Wiki). In transfeminine people, CPA has been documented to produce pregnancy-like breast changes (i.e., lobuloalveolar development of the mammary glands) (Kanhai et al., 2000). In relation to this, CPA sometimes causes lactation as a side effect (Gooren, Harmsen-Louman, & van Kessel, 1985; Schlatterer et al., 1998; Bazarra-Castro, 2009). Concerns have been raised about premature introduction of progestogens—particularly at high doses like with CPA—and possible adverse influence on breast development (Aly, 2020). However, little data exists in humans to substantiate such concerns at present. The side effects of CPA are assumed to be dose-dependent, and using the lowest effective doses is expected to minimize its side effects.

As CPA is a progestogen, it is associated with increased risks of breast cancer (Fournier, Berrino, & Clavel-Chapelon, 2008; CGHFBC, 2019; de Blok et al., 2019; Aly, 2020; Wiki) and blood clots (Seaman et al., 2007; Connors & Middeldorp, 2019; Aly, 2020; Wiki) even at very low doses (e.g., 2 mg/day). Higher doses of CPA, likewise presumed to be due to its progestogenic activity, are additionally associated with elevated prolactin levels (Sofer et al., 2020; Wilson et al., 2020; Wiki) as well as with certain generally non-cancerous brain tumors including prolactinomas (McFarlane, Zajac, & Cheung, 2018; Nota et al., 2018; Wiki) and meningiomas (McFarlane, Zajac, & Cheung, 2018; Nota et al., 2018; Millward et al., 2021; Weill et al., 2021; Aly, 2020; Wiki). These risks appear to be dose-dependent, and thus are likely to be minimized with lower doses of CPA. Besides risks related to its progestogenic activity, CPA at high doses has shown weak but significant androgenic effects in the liver and has been associated with an unfavorable influence on lipid profile, for instance decreased HDL (“good”) cholesterol levels (Coleman et al., 2022; Wiki). Long-term, this could result in an increase in the risk of coronary heart disease. Other potential adverse effects of CPA at high doses with unclear mechanisms may include increased blood pressure and heightened insulin resistance (Martinez-Martin et al., 2022). Additionally, CPA has been associated with abnormal liver function tests and rare cases of liver toxicity, including at doses used in transfeminine people of 25 to 50 mg/day (Heinemann et al., 1997; Bessone et al., 2016; Kumar et al., 2021; Wiki; Table). The likelihood of abnormal liver function tests with CPA, and probably of liver toxicity, appears to be much lower at doses of less than 20 mg/day (Wiki). More than 100 cases of clinically significant liver toxicity have been reported with CPA, but only two cases have been reported with CPA at doses of 50 mg/day or less (Wiki; Table). Monitoring of prolactin levels to detect prolactinomas, and monitoring of liver function to detect liver toxicity, may both be advisable in people taking CPA. Regular magnetic resonance imaging (MRI) scans have also been recommended to monitor for meningiomas in people taking CPA (at ≥10 mg/day) (Aly, 2020).

CPA is usually taken orally in the form of tablets (e.g., 10, 50, and 100 mg) (Wiki). Under the brand name Androcur Depot, it is also available as a long-lasting 300 mg depot injectable in some countries (Wiki). However, this formulation is not commonly used in transfeminine people, and happens to correspond to very high doses in terms of CPA exposure. A pill cutter (Amazon) can be used to split CPA tablets and achieve lower doses (e.g., 12.5 mg doses with 50-mg tablets). CPA has a relatively long elimination half-life of about 1.6 to 4.3 days (Wiki; Aly, 2019). As such, it can be taken once daily, or even as infrequently as once every 2 or 3 days, if needed (Aly, 2019). In addition to splitting of CPA tablets, dosing CPA once every 2 or 3 days can also be useful for achieving lower doses (Aly, 2019).

As already described, CPA is a powerful progestogen even at the relatively low doses now used in transfeminine people (e.g., 5–12.5 mg/day). As such, there is no need, nor point, in adding another progestogen, for instance progesterone, in those who are taking CPA—at least if the goal of doing so is to produce progestogenic effects. This is something that is often overlooked in people taking CPA, and can result in increased costs, side effects, and inconvenience without any expected benefit.

Spironolactone

Spironolactone (Aldactone) is an antiandrogen and antimineralocorticoid. It is widely used as an antiandrogen in cisgender women for treatment of androgen-dependent hair and skin conditions like acne, hirsutism (excessive facial/body hair growth), and scalp hair loss, in cisgender women for treatment of hyperandrogenism (high androgen levels) due to polycystic ovary syndrome (PCOS), and in transfeminine people as a component of hormone therapy. Spironolactone is particularly widely used in transfeminine people in the United States, where it is the most commonly used antiandrogen in this population. As an antimineralocorticoid, the original and primary use of spironolactone in medicine, it is used to treat heart failure, high blood pressure, high mineralocorticoid levels, low potassium levels, and conditions of excess fluid retention like nephrotic syndrome and ascites, among others (Wiki). In terms of its antiandrogenic actions, spironolactone is a relatively weak androgen receptor antagonist as well as a weak androgen synthesis inhibitor (Wiki). The androgen synthesis inhibition of spironolactone is mediated specifically via inhibition of 17α-hydroxylase and 17,20-lyase (Wiki). Spironolactone does not appear to have meaningful progestogenic activity, 5α-reductase inhibition, or direct estrogenic activity (Wiki). However, indirect estrogenic effects secondary to its antiandrogenic activity (e.g., breast development and feminization) can occur with it at sufficiently high doses (Wiki).

Spironolactone shows limited and highly inconsistent effects on testosterone levels in clinical studies in cisgender men, cisgender women, and transfeminine people, with most studies finding no change in levels, some studies finding a decrease in levels, and a small number even finding an increase in levels (Aly, 2018). In spite of this, studies commonly find that spironolactone still produces antiandrogenic effects even when androgen levels remain unchanged. Hence, the primary mechanism of action of spironolactone as an antiandrogen appears to be androgen receptor blockade. In relation to this, in transfeminine people taking spironolactone as an antiandrogen, the estrogen component of the regimen is likely to be the main or possibly sole agent suppressing testosterone production. This is in part based on studies in transfeminine people comparing estradiol plus spironolactone to estradiol alone (e.g., Leinung, 2014; Leinung, Feustel, & Joseph, 2018; Angus et al., 2019) and on studies comparing testosterone levels with different doses of spironolactone (e.g., Liang et al., 2018; SoRelle et al., 2019; Allen et al., 2021). Due to the minimal influence of spironolactone on testosterone production, testosterone levels are not usually suppressed into the female range in transfeminine people taking estradiol plus spironolactone, with testosterone levels often remaining well above this range (e.g., 50–450 ng/dL [1.7–15.6 nmol/L] on average) (Leinung, 2014; Leinung, Feustel, & Joseph, 2018; Liang et al., 2018; Angus et al., 2019; Jain, Kwan, & Forcier, 2019; SoRelle et al., 2019; Sofer et al., 2020; Burinkul et al., 2021). However, testosterone levels do tend to decline gradually over time in transfeminine people on this regimen (e.g., Liang et al., 2018; Sofer et al., 2020 (Graph); Allen et al., 2021).

Due to its relatively weak androgen receptor antagonism, spironolactone is likely best-suited for blocking female-range or somewhat-higher testosterone levels (e.g., <100 ng/dL [<3.5 nmol/L]) (Aly, 2018). This is based on clinical dose-ranging studies of spironolactone (typically using 50–200 mg/day) in healthy cisgender women and cisgender women with PCOS (Goodfellow et al., 1984; Lobo et al., 1985; Hammerstein, 1990; James, Jamerson, & Aguh, 2022) as well as comparative studies of spironolactone against the more-potent antiandrogen flutamide (Cusan et al., 1994; Erenus et al., 1994; Shaw, 1996). The clinical antiandrogenic efficacy of spironolactone has been very limitedly assessed in transfeminine people to date, and is largely unknown (Angus et al., 2021). In any case, the antiandrogenic efficacy of spironolactone in cisgender women with androgen-dependent hair and skin conditions is well-established, and the medication thus does appear to be effective so long as testosterone levels are not too high (Brown et al., 2009; van Zuuren & Fedorowicz, 2016; Layton et al., 2017; Barrionuevo et al., 2018; James, Jamerson, & Aguh, 2022). In addition, higher doses of spironolactone (e.g., 300–400 mg/day) may be more useful for blocking higher testosterone levels in transfeminine people, and are allowed for by transgender care guidelines (Aly, 2020).

Consequent to spironolactone’s limited and inconsistent influence on testosterone levels and its relatively weak androgen receptor antagonism, estradiol plus spironolactone regimens will likely not be fully effective in terms of testosterone suppression for many transfeminine people. This is liable to result in suboptimal demasculinization, feminization, and breast development in these individuals. Other antiandrogenic approaches, such as bicalutamide, CPA, GnRH modulators, and high-dose estradiol monotherapy, will likely be more effective in these cases owing either to their ability to more potently block androgens or their capacity to reliably reduce testosterone levels into the female range. If testosterone levels are still too high with estradiol plus spironolactone, a switch to a different antiandrogen, increasing to a higher dosage of estradiol, or addition of a clinically antigonadotropic progestogen (e.g., non-oral progesterone or a progestin) should be considered.

Spironolactone is a strong antimineralocorticoid, or antagonist of the mineralocorticoid receptor, the biological target of the mineralocorticoid steroid hormones aldosterone and 11-deoxycorticosterone. This is an action that spironolactone shares with progesterone, although spironolactone is a much more potent antimineralocorticoid than progesterone. The mineralocorticoid receptor is involved in regulating electrolyte and fluid balances, among other roles. Spironolactone is associated with modestly lowered blood pressure, which may be considered a beneficial effect of its antimineralocorticoid activity (Martinez-Martin et al., 2022). Although spironolactone is usually well-tolerated, it can sometimes produce antimineralocorticoid side effects such as excessively lowered blood pressure, dizziness, fatigue, urinary frequency, and increased cortisol levels, among others (Kellner & Wiedemann, 2008; Kim & Del Rosso, 2012; Zaenglein et al., 2016; Layton et al., 2017; James, Jamerson, & Aguh, 2022). It has been argued by some in the online transgender community that spironolactone, via its antimineralocorticoid activity and increased cortisol levels, may increase visceral fat in transfeminine people (Aly, 2020). However, evidence does not support this hypothetical side effect at present (Aly, 2020). Available data also do not support spironolactone stunting breast development in transfeminine people or producing serious neuropsychiatric side effects, such as prominent depressive mood changes.

The most important risk of spironolactone, which is consequent to its antimineralocorticoid activity, is hyperkalemia (high potassium levels) (Wiki). This complication is rare and is mostly limited to those who have specific risk factors for it, but is serious and can result in hospitalization or death. Monitoring of blood potassium levels during spironolactone therapy is advisable in those with risk factors for hyperkalemia, but does not appear to be necessary in people without such risk factors (Plovanich, Weng, & Mostaghimi, 2015; Zaenglein et al., 2016; Layton et al., 2017; Millington, Liu, & Chan, 2019; Wang & Lipner, 2020; Gupta et al., 2022; Hayes et al., 2022). Risk factors for hyperkalemia include older age (>45 years), reduced kidney function, concomitant use of other potassium-elevating drugs, and intake of potassium supplements or potassium-containing salt substitutes. Other notable potassium-elevating drugs include other potassium-sparing diuretics (e.g., amiloride (Midamor), triamterene (Dyrenium), other antimineralocorticoids), ACE inhibitors, angiotensin II receptor blockers, and the antibiotic trimethoprim (Bactrim), among others (Kim & Rosso, 2012; Salem et al., 2014). As an example drug interaction, serious hyperkalemia and sudden death can occur in elderly people (>65 years of age) concomitantly taking spironolactone and trimethoprim (Antoniou et al., 2011; Antoniou et al., 2015).

In people who are at-risk for hyperkalemia, dietary restriction to limit intake of potassium-rich foods is often recommended (Roscioni et al., 2012; Cupisti et al., 2018). This is often encountered in transgender health as transfeminine people being told “not to eat bananas”, which are said to be high in potassium. However, limiting dietary potassium with spironolactone to avoid hyperkalemia is theoretical and not actually evidence-based, with data so far contradicting its efficacy (St-Jules, Goldfarb, & Sevick, 2016; St-Jules & Fouque, 2021; Babich, Kalantar-Zadeh, & Joshi, 2022; St-Jules & Fouque, 2022). As such, routine restriction of dietary potassium with spironolactone is probably not warranted.

Aside from its antimineralocorticoid activity, spironolactone has been reported to increase levels of LDL (“bad”) cholesterol levels and to decrease levels of HDL (“good”) cholesterol in women with PCOS (Nakhjavani et al., 2009). However, findings appear to be conflicting, with other studies not finding unfavorable influences on cholesterol levels with spironolactone (Polyzos et al., 2011). Long-term, adverse effects on cholesterol levels could result in an increase in the risk of coronary heart disease.

Spironolactone is taken orally in the form of tablets (e.g., 25, 50, and 100 mg) (Wiki). It is a prodrug of several active metabolites, including 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone, and canrenone (7α-desthioacetyl-δ6-spironolactone) (Wiki). Spironolactone and these active metabolites have elimination half-lives of 1.4 hours, 13.8 hours, 15.0 hours, and 16.5 hours, respectively (Wiki). Due to the relatively short duration of elevated drug levels with spironolactone and its active metabolites (Graph), twice-daily administration of spironolactone in divided doses may be more optimal than once-daily intake and is advised (Reiter et al., 2010).

Bicalutamide

Bicalutamide (Casodex) is a nonsteroidal antiandrogen (NSAA) which acts as a potent and highly selective androgen receptor antagonist (Wiki). It is primarily used in the treatment of prostate cancer in cisgender men. Prostate cancer is an androgen-dependent cancer which antiandrogens can help to slow the progression of, and this use constitutes the vast majority of prescriptions for bicalutamide (Wiki). In addition to prostate cancer, although to a much lesser extent, bicalutamide has been used in the treatment of hirsutism (excessive facial/body hair growth), scalp hair loss, and polycystic ovary syndrome (PCOS) in cisgender women, peripheral or gonadotropin-independent precocious puberty (a rare form of precocious puberty in which antigonadotropins such as GnRH agonists are not effective) in cisgender boys, and priapism in cisgender men (Wiki). Bicalutamide is also becoming increasingly adopted for use as an antiandrogen in transfeminine people (Aly, 2020; Wiki). However, its use in transgender health is still very limited, and well-regarded transgender care guidelines either recommend against its use (Deutsch, 2016—UCSF guidelines; Coleman et al., 2022—WPATH SOC8) or are only cautiously permissive of its use (Thompson et al., 2021—Fenway Health guidelines). This is due to a lack of studies of bicalutamide in transfeminine people and its potential risks. Nonetheless, a small but growing number of clinicians are using bicalutamide in transfeminine people or are willing to prescribe it, with these clinicians located particularly in the United States. A single small clinical study has assessed bicalutamide in transfeminine people so far, specifically as a puberty blocker in 13 transfeminine adolescents who were denied insurance coverage for GnRH agonists (Neyman, Fuqua, & Eugster, 2019).

Bicalutamide is a much more potent androgen receptor antagonist than either spironolactone or CPA (Wiki; Neyman, Fuqua, & Eugster, 2019). It is typically used in transfeminine people at a dosage of 25 to 50 mg/day, although this dosage has been arbitrarily selected and is not based on clinical data. Nonetheless, due to its relatively high potency as an androgen receptor antagonist and concomitant suppression of testosterone levels by estradiol, these doses may be adequate for testosterone blockade for many transfeminine people. At higher doses (>50 mg/day), bicalutamide is able to substantially block male-range testosterone levels (>300 ng/dL [>10.4 nmol/L]) based on studies of bicalutamide monotherapy in cisgender men with prostate cancer (Wiki). This is something that spironolactone and CPA are not capable of in the same way. Owing to its selectivity for the androgen receptor, bicalutamide has no off-target hormonal activity and produces almost no side effects in women (Wiki; Erem, 2013; Moretti et al., 2018). The only apparent side effect of bicalutamide in a rigorous clinical trial of the drug for hirsutism in cisgender women was significantly increased total and LDL (“bad”) cholesterol levels (Moretti et al., 2018). Hence, bicalutamide tends to be very well-tolerated. The relative lack of side effects with bicalutamide is contrast to other antiandrogens like spironolactone and CPA, which are not pure androgen receptor antagonists and have off-target hormonal actions like antimineralocorticoid activity or strong progestogenic activity with consequent side effects and risks.

As a selective androgen receptor antagonist, bicalutamide taken by itself does not decrease testosterone production or levels but rather increases them (Wiki). This is due to a loss of androgen receptor-mediated negative feedback on gonadotropin secretion and a consequent compensatory upregulation of gonadal testosterone production (Wiki). Bicalutamide more than blocks the effects of any increase in testosterone it causes, and in fact fundamentally cannot increase testosterone levels more than it can block them (Wiki). In addition, increases in testosterone levels with bicalutamide will be blunted or abolished if it is combined with an adequate dose of an antigonadotropin such as estradiol (Wiki; Wiki). Since estradiol is made from testosterone in the body, bicalutamide taken alone also preserves and increases estradiol production and levels (Wiki). Because of this, although bicalutamide has no other important intrinsic hormonal activity besides its antiandrogenic activity, it produces robust indirect estrogenic effects including feminization and breast development even when it is not combined with estrogen (Wiki; Wiki; Neyman, Fuqua, & Eugster, 2019). This has important implications for the use of bicalutamide as a puberty blocker in transfeminine adolescents, as bicalutamide does not actually block puberty like conventional puberty blockers (GnRH agonists) but instead has the effect of dose-dependently converting male puberty into female puberty (Wiki; Neyman, Fuqua, & Eugster, 2019).

Bicalutamide has certain health risks, which has been a major reason that it has not been more readily adopted in transfeminine hormone therapy (Aly, 2020). It has a small risk of liver toxicity (Wiki; Aly, 2020) and of lung toxicity (Wiki). Abnormal liver function tests (LFTs), such as elevated liver enzymes and elevated bilirubin, occurred in about 3.4% of men with bicalutamide monotherapy plus standard care versus 1.9% of men with placebo plus standard care in the Early Prostate Trial (EPC) clinical programme after 3.0 years of follow-up (Wiki). In clinical trials, treatment with bicalutamide had to be discontinued in about 0.3 to 1.5% of men due to LFTs that became too highly elevated and could have progressed to serious liver toxicity (Wiki). To date, there are around 10 published case reports of serious liver toxicity, including cases of death, with bicalutamide, all of which have been in men with prostate cancer (Wiki; Table; Aly, 2020). There have also been a few unpublished reports of serious liver toxicity including deaths with bicalutamide in transfeminine people (Aly, 2020). However, these reports have not been confirmed, and they may or may not be reliable. In addition to the preceding reports, hundreds of additional instances of liver complications in people taking bicalutamide exist in the United States FDA Adverse Event Reporting System (FAERS) database (Wiki; FDA). Abnormal LFTs with bicalutamide usually occur within the first 3 to 6 months of treatment (Kolvenbag & Blackledge, 1996; Casodex FDA Label), and all case reports of liver toxicity with bicalutamide have had an onset of less than 6 months (Table). The liver toxicity of bicalutamide is not known to be dose-dependent across its clinically used dose range (Wiki). Abnormal LFTs have occurred with bicalutamide (at rates of 2.9% to 11.4%) even at relatively low doses in cisgender women (e.g., 10–50 mg/day) (de Melo Carvalho, 2022). Due to its risk of liver toxicity, periodic liver monitoring is strongly advised with bicalutamide, especially within the first 6 months of treatment. Possible signs of liver toxicity include nausea, vomiting, abdominal pain, fatigue, appetite loss, flu-like symptoms, dark urine, and jaundice (yellowing of the skin/eyes) (Wiki).

In terms of its lung toxicity risk, bicalutamide has been associated rarely with interstitial pneumonitis, which can lead to pulmonary fibrosis and can be fatal, and also less often with eosinophilic lung disease (Wiki; Table). As of writing, 15 published case reports of interstitial pneumonitis and 2 case reports of eosinophilic lung disease in association with bicalutamide therapy exist, likewise all in men with prostate cancer (Table). As with liver toxicity, hundreds of additional cases of interstitial pneumonitis in people taking bicalutamide exist in the United States FAERS database (Wiki; FDA). It has been estimated that interstitial pneumonitis with bicalutamide occurs at a rate of around 1 in 10,000 people, although this may be an underestimate due to under-reporting (Wiki; Ahmad & Graham, 2003). Asian people may be especially likely to experience lung toxicity with bicalutamide and other NSAAs, as much higher incidences have been observed in this population (Mahler et al., 1996; Wu et al., 2022). There is no laboratory test for routine monitoring of lung changes with bicalutamide. Possible signs of relevant lung toxicity include dyspnea (difficulty breathing or shortness of breath), coughing, and pharyngitis (inflammation of the throat, typically manifesting as sore throat) (Wiki).

Aside from liver and lung toxicity, bicalutamide monotherapy has been found in cisgender men with prostate cancer to increase the risk of death due to causes other than prostate cancer (Iversen et al., 2004; Iversen et al., 2006; Wellington & Keam, 2006; Jia & Spratt, 2022; Wiki). This led to marketing authorization of bicalutamide for treatment of the earliest stage of prostate cancer being revoked and to the drug being abandoned for this use (Wiki). Bicalutamide remains approved and used for treatment of later stages of prostate cancer, as the antiandrogenic benefits of bicalutamide against prostate cancer outweigh any adverse influence it has on non-prostate-cancer mortality in these more severe stages. The mechanisms underlying the increase in risk of death with bicalutamide in men are unknown (Wiki). It is also unclear whether bicalutamide could likewise increase the risk of death in transfeminine people. Limitations of generalizing these studies to transfeminine people include the men in the trials being relatively old and ill, a relatively high dosage of bicalutamide (150 mg/day) being used in the trials for an extended duration (e.g., 5 years), the question of whether the risks were due to androgen deprivation or to specific drug-related toxicity of bicalutamide, and estradiol levels with bicalutamide monotherapy in men with prostate cancer being only about 30 to 50 pg/mL (110–184 pmol/L) (Wiki). The preceding estradiol levels are well above castrate levels and are sufficient for a substantial degree of estrogenic effect, but are nonetheless below those recommended for transfeminine people and potentially needed for full sex-hormone replacement (which are ≥50 pg/mL [≥184 pmol/L]). In any case, as the specific mechanisms underlying the increased mortality risk with bicalutamide seen in men with prostate cancer are uncertain, and as clinical safety data showing that the risk does not generalize do not exist, it remains a possibility that bicalutamide could also increase the risk of death in transfeminine people.

Bicalutamide is taken orally in the form of tablets (e.g., 50 and 150 mg) (Wiki). Due to saturation of absorption in the gastrointestinal tract, the oral bioavailability of bicalutamide progressively starts to decrease above a dosage of about 150 mg/day, and there is no further increase in bicalutamide levels above 300 mg/day (Wiki; Graph). Bicalutamide has a very long elimination half-life of about 6 to 10 days (Wiki; Graphs). As a result, it does not necessarily have to be taken daily, and can be dosed less often (in proportionally higher doses)—for instance twice weekly or even once weekly—if this is more convenient or otherwise desired. Due to its long half-life, bicalutamide requires about 4 to 12 weeks to fully reach steady-state levels (Wiki; Graph; Wiki). However, about 50% of steady state is reached within 1 week of administration of bicalutamide, and about 80 to 90% of steady state is reached after 3 to 4 weeks (Wiki; Graph; Wiki). Loading doses of bicalutamide can be taken to reach steady state more quickly if desired. Animal studies originally suggested that bicalutamide did not cross the blood–brain barrier and hence was peripherally selective (i.e., did not block androgen receptors in the brain) (Wiki). However, subsequent clinical studies found that this was not similarly the case in humans, in whom bicalutamide shows clear and robust centrally mediated antiandrogenic effects (Wiki).

Older NSAAs related to bicalutamide like flutamide (Eulexin) and nilutamide (Anandron, Nilandron) have much greater risks in comparison to bicalutamide and should not be used in transfeminine people. Nilutamide was previously characterized as an antiandrogen in transfeminine people in several studies, but was not further pursued probably due to its very high incidence of lung toxicity and other side effects (Aly, 2020; Wiki; Wiki). Flutamide has been used limitedly as an antiandrogen in transfeminine people in the past, but should no longer be used due to a much higher risk of liver toxicity than bicalutamide as well as other side effects and drawbacks (Aly, 2020; Wiki). Other newer and more-potent NSAAs like enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) also have risks and have been studied and used little outside of prostate cancer to date.

5α-Reductase Inhibitors

Testosterone is converted into DHT within certain tissues in the body (Swerdloff et al., 2017). DHT is an androgen metabolite of testosterone with several-fold higher activity than testosterone. The transformation of testosterone into DHT is mediated by the enzyme 5α-reductase. The tissues in which 5α-reductase is present and testosterone is converted into DHT are limited but most importantly include the skin, hair follicles, and prostate gland. Although DHT is more potent than testosterone, it is thought to have minimal biological role as a circulating hormone (Horton, 1992; Swerdloff et al., 2017). Instead, testosterone serves as the main circulating androgen, and the role of DHT is thought to be mainly via local metabolism and potentiation of testosterone into DHT within certain tissues.

5α-Reductase inhibitors (5α-RIs), such as finasteride (Proscar, Propecia) and dutasteride (Avodart), inhibit 5α-reductase and thereby block the conversion of testosterone into DHT. This results in marked decreases in circulating and within-tissue levels of DHT. Due to the primary role of DHT as a mediator in tissues rather than as circulating hormone, the antiandrogenic efficacy of 5α-RIs is limited. This is evidenced by the fact that they are well-tolerated in cisgender men and do not cause notable demasculinization in these individuals (Hirshburg, 2016). The medical use of 5α-RIs is mainly restricted to the treatment of scalp hair loss in men and women, hirsutism (excessive facial/body hair) in women, and prostate enlargement in men. They might also be useful for acne in women, but evidence of this is very limited (Wiki). Due to their specificity, 5α-RIs are inappropriate as general antiandrogens in transfeminine people. Moreover, DHT levels decrease in tandem with testosterone levels with suppression of testosterone production in transfeminine hormone therapy, and routine use of 5α-RIs in transfeminine people with testosterone levels within the female range is of limited usefulness and can be considered unnecessary (Gooren et al., 2016; Irwig, 2020; Prince & Safer, 2020; Glintborg et al., 2021). In any case, 5α-RIs may be useful in transfeminine people on hormone therapy who have persistent body hair growth or scalp hair loss—as they have been shown to be in cisgender women (Barrionuevo et al., 2018; Prince & Safer, 2020). However, it is notable that evidence of effectiveness in cisgender women is better for androgen receptor antagonists for such indications (van Zuuren et al., 2015). This is intuitive as androgen receptor antagonists block both testosterone and DHT whereas 5α-RIs only prevent conversion of testosterone into DHT. Hence, although 5α-RIs strongly reduce or eliminate DHT and their net effect is antiandrogenic, they do not decrease testosterone levels and in fact increase them.

There are three subtypes of 5α-reductase. Dutasteride inhibits all three subtypes of 5α-reductase whereas finasteride only inhibits two of the subtypes. As a result of this, dutasteride is a more complete 5α-RI than finasteride. Dutasteride decreases DHT levels in the blood by up to 98% while finasteride can only decrease them by around 65 to 70%. As nearly all circulating DHT originates from synthesis in peripheral tissues, these decreases indicate parallel reductions in tissue DHT production (Horton, 1992). In accordance with these findings, dutasteride has been found to be more effective than finasteride in the treatment of scalp hair loss in men (Zhou et al., 2018; Dhurat et al., 2020; Wiki). For these reasons, although both finasteride and dutasteride are effective 5α-RIs, dutasteride may be the preferable choice if a 5α-RI is used (Zhou et al., 2018; Dhurat et al., 2020).

A potentially undesirable effect of 5α-RIs in transfeminine people is that they may increase circulating testosterone levels to a degree in those in whom testosterone production isn’t fully suppressed (Leinung, Feustel, & Joseph, 2018; Aly, 2019; Traish et al., 2019; Irwig, 2020; Glintborg et al., 2021). It appears that DHT adds significantly to negative feedback on gonadotropin secretion in the pituitary gland in people with testes who have low testosterone levels relative to the normal male range (Traish et al., 2019). The therapeutic implications of this for transfeminine people, if any, are uncertain.

Another potentially undesirable action of 5α-RIs is that they inhibit not only the production of DHT but also of certain neurosteroids. Neurosteroids are steroids that act on the nervous system—most notably the brain. Examples of neurosteroids that 5α-RIs inhibit the synthesis of include allopregnanolone, which is formed from progesterone, and 3α-androstanediol, which is derived from testosterone and DHT. Research suggests that these neurosteroids have significant biological modulatory roles in mood, anxiety, stress, and other cognitive/emotional processes (King, 2013). Possibly in relation to this, 5α-RIs have been associated with a small risk of depression (Welk et al., 2018; Deng et al., 2020; Dyson, Cantrell, & Lund, 2020; Nguyen et al., 2020; Wiki). Claims of other, more significant and persistent side effects with 5α-RIs, which are termed “post-finasteride syndrome” (PFS) in the case of finasteride, also exist (Traish, 2020). However, they are based on low-quality reports and are controversial (Fertig et al., 2016; Rezende, Dias, & Trüeb, 2018). The nocebo effect is likely to worsen perceptions of side effects with 5α-RIs (Kuhl & Wiegratz, 2017; Maksym et al., 2019).

Clinical dose-ranging studies have found that lower doses of finasteride and dutasteride than are typically used still provide substantial or near-maximal 5α-reductase inhibition (Gormley et al., 1990; Vermeulen et al., 1991; Sudduth & Koronkowski, 1993; Drake et al., 1999; Roberts et al., 1999; Clark et al., 2004; Frye, 2006; Olsen et al., 2006; Harcha et al., 2014; Kuhl & Wiegratz, 2017). In one study with finasteride for instance, DHT levels decreased by 49.5% at 0.05 mg/day, 68.6% at 0.2 mg/day, 71.4% at 1 mg/day, and 72.2% at 5 mg/day (Drake et al., 1999). Parallel reductions in DHT levels were seen locally in the scalp (Drake et al., 1999). In a study with dutasteride, DHT levels were decreased by 52.9% at 0.05 mg/day, 94.7% at 0.5 mg/day, 97.7% at 2.5 mg/day, and 98.4% at 5 mg/day (Clark et al., 2004). Based on these findings, 5α-RIs can potentially be taken at lower doses to help reduce medication costs if needed. Finasteride tablets can be split to achieve smaller doses. Conversely, dutasteride cannot be split as it is formulated as an oil capsule. However, dutasteride has a long half-life, and instead of dividing pills, it can be taken less frequently (e.g., once every few days) as a means of reducing dosage.

5α-Reductase inhibitors are taken orally in the form of tablets and capsules. Compounded topical formulations of finasteride also exist (Marks et al., 2020). However, caution is advised with these preparations as they have been found to be excessively dosed and to produce equivalent systemic DHT suppression as oral finasteride formulations (Marks et al., 2020). Lower-concentration formulations of topical finsteride on the other hand may be more locally selective (Marks et al., 2020).

Table 8: Available forms and recommended doses of 5α-reductase inhibitors for transfeminine people:

MedicationRouteFormDosage
DutasterideOralCapsules0.05–2.5 mg/day
FinasterideOralTablets0.05–5 mg/day

GnRH Agonists and Antagonists

GnRH agonists and antagonists (GnRHa), also known as GnRH receptor agonists and antagonists or GnRH modulators, are antiandrogens which work by preventing the effects of GnRH in the pituitary gland and thereby suppressing LH and FSH secretion. Receptor agonists normally activate receptors while receptor antagonists block and thereby inhibit the activation of receptors. Due to a physiological quirk however, GnRH agonists and antagonists have the same effects in the pituitary gland. This is because GnRH is secreted in pulses under normal physiological circumstances, and when the GnRH receptor is unnaturally activated in a continuous manner, as with exogenous GnRH agonists, the GnRH receptor in the pituitary gland is strongly desensitized to the point of becoming inactive. Consequently, both GnRH agonists and GnRH antagonists have the effect of abolishing gonadal sex hormone production. This, in turn, reduces testosterone levels into the castrate or normal female range (both <50 ng/dL or <1.7 nmol/L) in people with testes. GnRHa are like a reversible gonadectomy, and for this reason, are also sometimes referred to as “medical castration”. Provided that an estrogen is taken in combination with a GnRHa to prevent sex hormone deficiency, these medications have essentially no known side effects or risks. For these reasons, GnRHa are the ideal antiandrogens for use in transfeminine people.

GnRHa are widely used to suppess puberty in adolescent transgender individuals. Unfortunately however, they are very expensive (e.g., ~US$10,000 per year) and medical insurance does not usually cover them for adult transgender people. Consequently, GnRHa are not commonly used in adult transfeminine people at this time. An exception is in the United Kingdom, where GnRH agonists are covered for all adult transgender people by the National Health Service (NHS). Another exception is buserelin (Suprefact), which has become available very inexpensively in its nasal spray form from certain Eastern European online pharmacies in recent years (Aly, 2018).

GnRH agonists cause a brief flare in testosterone levels at the start of therapy prior to the GnRH receptors in the pituitary gland becoming desensitized (Wiki). Testosterone levels increase by up to about 1.5- to 2-fold for about 1 week and then decrease thereafter (Wiki). Castrate or female-range levels of testosterone are generally reached within 2 to 4 weeks (Wiki). In contrast to GnRH agonists, there is no testosterone flare with GnRH antagonists and testosterone levels start decreasing immediately, reaching castrate levels within a few days (Wiki; Graph). This is because GnRH antagonists work by blocking the GnRH receptor without initially activating it, and hence desensitization of the receptor is not necessary for their action. If desired, the testosterone flare at the initiation of GnRH agonist therapy can be prevented or blunted with the use of antigonadotropins, for instance estrogens and progestogens, as well as with potent androgen receptor antagonists such as bicalutamide (Wiki).

GnRH agonists must be injected subcutaneously or intramuscularly once per day or once every one to six months depending on the formulation employed (buserelin, goserelin, leuprorelin, triptorelin). Alternatively, they can be surgically implanted once a year (histrelin, leuprorelin) or used as a nasal spray two to three times per day (buserelin, nafarelin). The first GnRH antagonists were developed for use by once-monthly intramuscular or subcutaneous injection (abarelix, degarelix). More recently, orally administered GnRH antagonists such as elagolix and relugolix have been introduced for medical use. They are taken in the form of tablets once or twice daily.

Table 9: Available forms and recommended doses of GnRH agonists for transfeminine people:

MedicationBrand nameRouteFormDosage
BuserelinSuprefact, othersSC injectionSolution200 μg/daya
   Implant6.3 mg/2 months
    9.45 mg/3 months
  IntranasalNasal spray400 µg 3x/dayb,c
GoserelinZoladexSC injectionImplant3.6 mg/month
    10.8 mg/3 months
HistrelinSupprelin LA, VantasSC implantImplant50 mg/year
LeuprorelinLupron, othersIM injectionSolution1 mg/day
 Eligard, Lupron Depot, othersIM/SC injectionSuspension3.75–7.5 mg/month
    11.25–22.5 mg/3 months
    30 mg/4 months
    45 mg/6 months
 ViadurSC implantImplant65 mg/year
NafarelinSynarelIntranasalNasal spray400–600 μg 2–3x/day
TriptorelinDecapeptyl, Trelstar Depot/LAIM injectionSuspension3.75 mg/month
    11.25 mg/3 months

a 500 μg 3x/day for the first week then 200 μg/day. b 800 μg 3x/day for the first week then 400 μg 3x/day. c 500 μg 2x/day can be used instead of 400 μg 3x/day but is less effective (70% decrease in testosterone levels (to ~180 ng/dL [6.2 nmol/L]) instead of 90% decrease (to ~50 ng/dL [1.7 nmol/L]) per available studies of buserelin in men with prostate cancer) (Aly, 2018; Wiki).

Table 10: Available forms and recommended doses of GnRH antagonists for transfeminine people:

MedicationBrand nameRouteFormDosage
AbarelixPlenaxisIM injectionSuspension113 mg/month
DegarelixFirmagonSC injectionSolution80 mg/montha
ElagolixOrilissaOralTablets150–200 mg 1–2x/dayb
RelugolixReluminaOralTablets20–120 mg/dayc

a First month is 240 mg then 80 mg per month thereafter. b 150 mg 1x/day is less effective than 200 mg 2x/day (which provides full gonadal sex-hormone suppression in cisgender women) (Wiki). c 80–120 mg/day for full gonadal sex-hormone suppression and 20–40 mg/day for substantial but partial gonadal sex-hormone suppression (MacLean et al., 2015; DailyMed).

Other Hormonal Medications

Androgens and Anabolic Steroids

In addition to estrogens, progestogens, and antiandrogens, androgens/anabolic steroids (AAS) are sometimes added to transfeminine hormone therapy. This is when testosterone levels are low (e.g., below the female average of 30 ng/dL [1.0 nmol/L]) and androgen replacement is desired. It has been proposed that adequate levels of testosterone may provide benefits such as increased sexual desire, improved mood and energy, positive effects on skin health and cellulite (Avram, 2004), and increased muscle size and strength (Huang & Basaria, 2017). However, there is insufficient clinical evidence to support such benefits at present, and androgens can produce adverse effects in cisgender women and transfeminine people, for instance acne, hirsutism, scalp hair loss, and masculinization (Wiki). For transfeminine people who nonetheless desire androgen replacement therapy, possible options for androgen medications include testosterone and its esters, dehydroepiandrosterone (DHEA; prasterone), and nandrolone esters such as nandrolone decanoate (ND) (Aly, 2020; Table), among others.

Monitoring of Therapy

Transfeminine people on hormone therapy should undergo regular laboratory monitoring in the form of blood work to assess efficacy and monitor for safety. Total estradiol levels and total testosterone levels should be measured to assess the effectiveness of therapy—that is, whether hormone levels are in appropriate ranges for cisgender females—and determine whether medication adjustments may be necessary. Levels of free testosterone, free estradiol, estrone (E1), dihydrotestosterone (DHT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) can also be measured to provide further information although they’re not absolutely necessary. If progesterone is used as a part of hormone therapy, progesterone levels can be measured to provide insight on the degree of progesterone exposure. In addition to hormone blood tests, transfeminine people can monitor their physical changes with hormone therapy, such as breast development and other aspects of feminization, using various physical and digital measurement methods (e.g., Aly, 2020).

In transfeminine people taking bicalutamide or high doses of CPA (≥20 mg/day), liver function tests (LFTs), such as aspartate transaminase (AST) and alanine transaminase (ALT) levels, should be regularly performed to monitor for liver toxicity. In those who are taking spironolactone and have relevant risk factors for hyperkalemia (high potassium levels), such as older age, reduced kidney function, or concomitant use of potassium-elevating medications or potassium supplements, potassium levels should be regularly monitored to assess for hyperkalemia. Conversely, in healthy young people without such risk factors who are taking spironolactone, potassium monitoring seems to be of limited usefulness (Plovanich, Weng, & Mostaghimi, 2015; Zaenglein et al., 2016; Layton et al., 2017; Millington, Liu, & Chan, 2019; Wang & Lipner, 2020; Gupta et al., 2022; Hayes et al., 2022). In transfeminine people taking high doses of estrogens or progestogens—particularly CPA—prolactin levels should be regularly measured to monitor for hyperprolactinemia (high prolactin levels) and prolactinoma (Callen-Lorde, 2018; Iwamoto et al., 2019). In people taking high doses of CPA (>12.5 mg/day), periodic magnetic resonance imaging (MRI) exams should be performed to monitor for development of meningiomas (Aly, 2020). If the preceding tests come back abnormal, depending on the situation and its severity, medication doses should be reduced or specific medications should be discontinued or replaced with alternatives.

Certain therapeutic situations can result in inaccurate lab blood work results. Monitoring of progesterone levels with oral progesterone using immunoassay-based blood tests can result in falsely high readings for progesterone levels due to cross-reactivity with high levels of progesterone metabolites such as allopregnanolone (Aly, 2018; Wiki). Instead of immunoassay-based tests, mass spectrometry-based tests should be used to determine progesterone levels with oral progesterone (Aly, 2018; Wiki). Conversely, either type of test may be used to measure progesterone levels with non-oral progesterone therapy. High-dose biotin (vitamin B7) supplements can interfere with the accuracy of immunoassay-based hormone blood tests, causing falsely low or falsely high readings (Samarasinghe et al., 2017; Avery, 2019; Bowen et al., 2019; FDA, 2019; Luong, Male, & Glennon, 2019). Transdermal estradiol formulations applied to the arm can result in contamination of blood draws taken from the same arm and can result in falsely high readings for estradiol levels (Vihtamäkia, Luukkaala, & Tuimala, 2004).

Certain cancers are known to be hormone-sensitive and their incidence can be influenced by hormone therapy. Screening for breast and prostate cancer is recommended in transfeminine people (Sterling & Garcia, 2020; Iwamoto et al., 2021). The risk of breast cancer appears to be dramatically increased with transfeminine hormone therapy, perhaps especially with progestogens (Aly, 2020). However, the risk still remains lower than in cisgender women (Aly, 2020). The incidence of prostate cancer is greatly decreased with hormone therapy in transfeminine people as a consequence of androgen deprivation, but the risk is not abolished and prostate cancer can still occur (de Nie et al., 2020). The prostate gland is not removed with vaginoplasty, so transfeminine people who have undergone vaginoplasty will also require monitoring for prostate cancer still. Testicular cancer is not known to be a hormone-dependent cancer and its incidence does not appear to be increased with hormone therapy in transfeminine people (Bensley et al., 2021; de Nie et al., 2021; Jacoby et al., 2021).

References

  • Abbott Laboratories. (2009). Estradiol. Architect System. Abbott Park, Illinois/Wiesbaden, Germany: Abbott Laboratories. [PDF]
  • Ahmad, S. R., & Graham, D. J. (2003). Pneumonitis with Antiandrogens. Annals of Internal Medicine, 139(6), 528–529. [DOI:10.7326/0003-4819-139-6-200309160-00023]
  • Allen, A. N., Jiao, R., Day, P., Pagels, P., Gimpel, N., & SoRelle, J. A. (2020). Dynamic Impact of Hormone Therapy on Laboratory Values in Transgender Patients over Time. The Journal of Applied Laboratory Medicine, 6(1), 27–40. [DOI:10.1093/jalm/jfaa192]
  • Angus, L., Leemaqz, S., Ooi, O., Cundill, P., Silberstein, N., Locke, P., Zajac, J. D., & Cheung, A. S. (2019). Cyproterone acetate or spironolactone in lowering testosterone concentrations for transgender individuals receiving oestradiol therapy. Endocrine Connections, 8(7), 935–940. [DOI:10.1530/ec-19-0272]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2020). A systematic review of antiandrogens and feminization in transgender women. Clinical Endocrinology, 94(5), 743–752. [DOI:10.1111/cen.14329]
  • Antoniou, T., Gomes, T., Mamdani, M. M., Yao, Z., Hellings, C., Garg, A. X., Weir, M. A., & Juurlink, D. N. (2011). Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study. BMJ, 343, d5228. [DOI:10.1136/bmj.d5228]
  • Antoniou, T., Hollands, S., Macdonald, E. M., Gomes, T., Mamdani, M. M., & Juurlink, D. N. (2015). Trimethoprim–sulfamethoxazole and risk of sudden death among patients taking spironolactone. Canadian Medical Association Journal, 187(4), E138–E143. [DOI:10.1503/cmaj.140816]
  • Aufrère, M. B., & Benson, H. (1976). Progesterone: An overview and recent advances. Journal of Pharmaceutical Sciences, 65(6), 783–800. [DOI:10.1002/jps.2600650602]
  • Avery, G. (2019). Biotin interference in immunoassay: a review for the laboratory scientist. Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, 56(4), 424–430. [DOI:10.1177/0004563219842231]
  • Avram, M. M. (2004). Cellulite: a review of its physiology and treatment. Journal of Cosmetic and Laser Therapy, 6(4), 181–185. [DOI:10.1080/14764170410003057]
  • Babich, J. S., Kalantar-Zadeh, K., & Joshi, S. (2022). Taking the Kale out of Hyperkalemia: Plant Foods and Serum Potassium in Patients With Kidney Disease. Journal of Renal Nutrition, 32(6), 641–649. [DOI:10.1053/j.jrn.2022.01.013]
  • Bäckström, T., Haage, D., Löfgren, M., Johansson, I., Strömberg, J., Nyberg, S., Andréen, L., Ossewaarde, L., van Wingen, G., Turkmen, S., & Bengtsson, S. (2011). Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons. Neuroscience, 191, 46–54. [DOI:10.1016/j.neuroscience.2011.03.061]
  • Barrionuevo, P., Nabhan, M., Altayar, O., Wang, Z., Erwin, P. J., Asi, N., Martin, K. A., & Murad, M. H. (2018). Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism, 103(4), 1258–1264. [DOI:10.1210/jc.2017-02052]
  • Bazarra-Castro, M. A. (2009). Etiological aspects, therapy regimes, side effects and treatment satisfaction of transsexual patients. (Doctoral dissertation, Ludwig Maximilian University of Munich.) [DOI:10.5282/edoc.9984] [URN:urn:nbn:de:bvb:19-99840] [PDF]
  • Belisle, S., & Love, E. J. (1986). Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study. Fertility and Sterility, 46(6), 1015–1020. [DOI:10.1016/s0015-0282(16)49873-0]
  • Ben Salem, C., Badreddine, A., Fathallah, N., Slim, R., & Hmouda, H. (2014). Drug-Induced Hyperkalemia. Drug Safety, 37(9), 677–692. [DOI:10.1007/s40264-014-0196-1]
  • Bensley, J. G., Cheung, A. S., Grossmann, M., & Papa, N. (2022). Testicular Cancer in Trans People Using Feminising Hormone Therapy–A Brief Review. Urology, 160, 1–4. [DOI:10.1016/j.urology.2021.11.014]
  • Bessone, F., Lucena, M., Roma, M. G., Stephens, C., Medina-Cáliz, I., Frider, B., Tsariktsian, G., Hernández, N., Bruguera, M., Gualano, G., Fassio, E., Montero, J., Reggiardo, M. V., Ferretti, S., Colombato, L., Tanno, F., Ferrer, J., Zeno, L., Tanno, H., & Andrade, R. J. (2015). Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases. Liver International, 36(2), 302–310. [DOI:10.1111/liv.12899]
  • Bowen, R., Benavides, R., Colón-Franco, J. M., Katzman, B. M., Muthukumar, A., Sadrzadeh, H., Straseski, J., Klause, U., & Tran, N. (2019). Best practices in mitigating the risk of biotin interference with laboratory testing. Clinical Biochemistry, 74, 1–11. [DOI:10.1016/j.clinbiochem.2019.08.012]
  • Brown, J., Farquhar, C., Lee, O., Toomath, R., & Jepson, R. G. (2009). Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews, 2009(2), CD000194. [DOI:10.1002/14651858.cd000194.pub2]
  • Burinkul, S., Panyakhamlerd, K., Suwan, A., Tuntiviriyapun, P., & Wainipitapong, S. (2021). Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. The Journal of Sexual Medicine, 18(7), 1299–1307. [DOI:10.1016/j.jsxm.2021.05.003] [PDF]
  • Callen-Lorde Community Health Center. (2018). Protocols for the Provision of Hormone Therapy. New York City: Callen-Lorde Community Health Center. [URL] [PDF]
  • Cappelletti, M., & Wallen, K. (2016). Increasing women’s sexual desire: The comparative effectiveness of estrogens and androgens. Hormones and Behavior, 78, 178–193. [DOI:10.1016/j.yhbeh.2015.11.003]
  • Carmina, E., Stanczyk, F. Z., & Lobo, R. A. (2019). Evaluation of Hormonal Status. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 887–915.e4). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-47912-7.00034-2]
  • Carr, B. R. (1993). The Ovary. In Carr, B. R., & Blackwell, R. E. (Eds.). Textbook of Reproductive Medicine, 1st Edition (pp. 183–207). Norwalk, Connecticut: Appleton & Lange. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org—2nd edition]
  • Carvalho, R. d., Santos, L. D., Ramos, P. M., Machado, C. J., Acioly, P., Frattini, S. C., Barcaui, C. B., Donda, A. L., & Melo, D. F. (2022). Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know. Journal of Cosmetic Dermatology, 21(10), 4171–4175. [DOI:10.1111/jocd.14773]
  • Clark, R. V., Hermann, D. J., Cunningham, G. R., Wilson, T. H., Morrill, B. B., & Hobbs, S. (2004). Marked Suppression of Dihydrotestosterone in Men with Benign Prostatic Hyperplasia by Dutasteride, a Dual 5α-Reductase Inhibitor. The Journal of Clinical Endocrinology & Metabolism, 89(5), 2179–2184. [DOI:10.1210/jc.2003-030330]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Collaborative Group on Hormonal Factors in Breast Cancer. (2019). Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. The Lancet, 394(10204), 1159–1168. [DOI:10.1016/s0140-6736(19)31709-x]
  • Collet, S., Gieles, N. C., Wiepjes, C. M., Heijboer, A. C., Reyns, T., Fiers, T., Lapauw, B., den Heijer, M., & T’Sjoen, G. (2022). Changes in Serum Testosterone and Adrenal Androgen Levels in Transgender Women With and Without Gonadectomy. The Journal of Clinical Endocrinology & Metabolism, 108(2), 331–338. [DOI:10.1210/clinem/dgac576]
  • Connors, J. M., & Middeldorp, S. (2019). Transgender patients and the role of the coagulation clinician. Journal of Thrombosis and Haemostasis, 17(11), 1790–1797. [DOI:10.1111/jth.14626]
  • Cupisti, A., Kovesdy, C., D’Alessandro, C., & Kalantar-Zadeh, K. (2018). Dietary Approach to Recurrent or Chronic Hyperkalaemia in Patients with Decreased Kidney Function. Nutrients, 10(3), 261–261. [DOI:10.3390/nu10030261]
  • Cusan, L., Dupont, A., Gomez, J., Tremblay, R. R., & Labrie, F. (1994). Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertility and Sterility, 61(2), 281–287. [DOI:10.1016/s0015-0282(16)56518-2]
  • de Blok, C. J., Wiepjes, C. M., Nota, N. M., van Engelen, K., Adank, M. A., Dreijerink, K. M., Barbé, E., Konings, I. R., & den Heijer, M. (2019). Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ, 365, l1652. [DOI:10.1136/bmj.l1652]
  • de Nie, I., de Blok, C. J., van der Sluis, T. M., Barbé, E., Pigot, G. L., Wiepjes, C. M., Nota, N. M., van Mello, N. M., Valkenburg, N. E., Huirne, J., Gooren, L. J., van Moorselaar, R. J., Dreijerink, K. M., & den Heijer, M. (2020). Prostate Cancer Incidence under Androgen Deprivation: Nationwide Cohort Study in Trans Women Receiving Hormone Treatment. The Journal of Clinical Endocrinology & Metabolism, 105(9), e3293–e3299. [DOI:10.1210/clinem/dgaa412]
  • Deng, T., Duan, X., He, Z., Zhao, Z., & Zeng, G. (2020). Association Between 5-Alpha Reductase Inhibitor Use and The Risk of Depression: A Meta-Analysis. Urology Journal, 18(2), 144–150. [DOI:10.22037/uj.v16i7.5866]
  • Deutsch, M. B. (2016). Overview of feminizing hormone therapy. In Deutsch, M. B. (Ed.). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition (pp. 26–48). San Francisco: University of California, San Francisco/UCSF Transgender Care. [URL] [PDF]
  • Dhurat, R., Sharma, A., Rudnicka, L., Kroumpouzos, G., Kassir, M., Galadari, H., Wollina, U., Lotti, T., Golubovic, M., Binic, I., Grabbe, S., & Goldust, M. (2020). 5‐Alpha reductase inhibitors in androgenetic alopecia: Shifting paradigms, current concepts, comparative efficacy, and safety. Dermatologic Therapy, 33(3), e13379. [DOI:10.1111/dth.13379]
  • Drake, L., Hordinsky, M., Fiedler, V., Swinehart, J., Unger, W. P., Cotterill, P. C., Thiboutot, D. M., Lowe, N., Jacobson, C., Whiting, D., Stieglitz, S., Kraus, S. J., Griffin, E. I., Weiss, D., Carrington, P., Gencheff, C., Cole, G. W., Pariser, D. M., Epstein, E. S., Tanaka, W., Dallob, A., Vandormael, K., Geissler, L., & Waldsteicher, J. (1999). The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. Journal of the American Academy of Dermatology, 41(4), 550–554. [DOI:10.1016/s0190-9622(99)80051-6]
  • Dyson, T. E., Cantrell, M. A., & Lund, B. C. (2020). Lack of Association between 5α-Reductase Inhibitors and Depression. Journal of Urology, 204(4), 793–798. [DOI:10.1097/ju.0000000000001079]
  • Erem, C. (2013). Update on idiopathic hirsutism: diagnosis and treatment. Acta Clinica Belgica, 68(4), 268–274. [DOI:10.2143/acb.3267]
  • Erenus, M., Gürbüz, O., Durmuşoğlu, F., Demirçay, Z., & Pekin, S. (1994). Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertility and Sterility, 61(4), 613–616. [DOI:10.1016/s0015-0282(16)56634-5]
  • Esoterix/LabCorp. (2020). Endocrinology Expected Values and S.I. Unit Conversion Tables. LabCorp/Endocrine Sciences. [PDF]
  • Even Zohar, N., Sofer, Y., Yaish, I., Serebro, M., Tordjman, K., & Greenman, Y. (2021). Low-Dose Cyproterone Acetate Treatment for Transgender Women. The Journal of Sexual Medicine, 18(7), 1292–1298. [DOI:10.1016/j.jsxm.2021.04.008]
  • Fertig, R., Shapiro, J., Bergfeld, W., & Tosti, A. (2016). Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome. Skin Appendage Disorders, 2(3–4), 120–129. [DOI:10.1159/000450617]
  • Food and Drug Administration. (2019). UPDATE: The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety Communication. Food and Drug Administration. [URL]
  • Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2007). Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Research and Treatment, 107(1), 103–111. [DOI:10.1007/s10549-007-9523-x]
  • Frye, S. (2006). Discovery and Clinical Development of Dutasteride, a Potent Dual 5α-Reductase Inhibitor. Current Topics in Medicinal Chemistry, 6(5), 405–421. [DOI:10.2174/156802606776743101]
  • Gava, G., Mancini, I., Alvisi, S., Seracchioli, R., & Meriggiola, M. C. (2020). A comparison of 5-year administration of cyproterone acetate or leuprolide acetate in combination with estradiol in transwomen. European Journal of Endocrinology, 183(6), 561–569. [DOI:10.1530/eje-20-0370]
  • Getzenberg, R., & Itty, S. (2020). How do we define “castration” in men on androgen deprivation therapy? Asian Journal of Andrology, 22(5), 441–446. [DOI:10.4103/aja.aja_139_19]
  • Giltay, E. J., Gooren, L. J., Toorians, A. W., Katan, M. B., & Zock, P. L. (2004). Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. The American Journal of Clinical Nutrition, 80(5), 1167–1174. [DOI:10.1093/ajcn/80.5.1167]
  • Glintborg, D., T’Sjoen, G., Ravn, P., & Andersen, M. S. (2021). MANAGEMENT OF ENDOCRINE DISEASE: Optimal feminizing hormone treatment in transgender people. European Journal of Endocrinology, 185(2), R49–R63. [DOI:10.1530/eje-21-0059]
  • Goletiani, N. V., Keith, D. R., & Gorsky, S. J. (2007). Progesterone: Review of safety for clinical studies. Experimental and Clinical Psychopharmacology, 15(5), 427–444. [DOI:10.1037/1064-1297.15.5.427]
  • Goodfellow, A., Alaghband-Zadeh, J., Carter, G., Cream, J., Holland, S., Scully, J., & Wise, P. (1984). Oral spironolactone improves acne vulgaris and reduces sebum excretion. British Journal of Dermatology, 111(2), 209–214. [DOI:10.1111/j.1365-2133.1984.tb04045.x]
  • Gooren, L. J., Harmsen-Louman, W., & Kessel, H. (1985). Follow-up of prolactin levels in long-term oestrogen-treated male-to-female transsexuals with regard to prolactinoma induction. Clinical Endocrinology, 22(2), 201–207. [DOI:10.1111/j.1365-2265.1985.tb01081.x]
  • Gooren, L. J. (2016). The Endocrinology of Sexual Behavior and Gender Identity. In Jameson, J. L., & De Groot, L. J. (Eds.). Endocrinology: Adult and Pediatric, 7th Edition, Volume 2 (pp. 2163–2176.e4). Philadelphia: Saunders/Elsevier. [Google Books] [DOI:10.1016/B978-0-323-18907-1.00124-4]
  • Gormley, G. J., Stoner, E., Rittmaster, R. S., Gregg, H., Thompson, D. L., Lasseter, K. C., Vlasses, P. H., & Stein, E. A. (1990). Effects of Finasteride (MK-906), a 5α-Reductase Inhibitor, on Circulating Androgens in Male Volunteers. The Journal of Clinical Endocrinology & Metabolism, 70(4), 1136–1141. [DOI:10.1210/jcem-70-4-1136]
  • Gubelin Harcha, W., Barboza Martínez, J., Tsai, T., Katsuoka, K., Kawashima, M., Tsuboi, R., Barnes, A., Ferron-Brady, G., & Chetty, D. (2014). A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. Journal of the American Academy of Dermatology, 70(3), 489–498.e3. [DOI:10.1016/j.jaad.2013.10.049]
  • Gupta, P., Suppakitjanusant, P., Stevenson, M., Goodman, M., & Tangpricha, V. (2022). Potassium Concentrations in Transgender Women Using Spironolactone: A Retrospective Chart Review. Endocrine Practice, 28(11), 1113–1117. [DOI:10.1016/j.eprac.2022.08.007]
  • Hammerstein, J. (1990). Antiandrogens: Clinical Aspects. In Orfanos, C. E., & Happle, R. (Eds.). Hair and Hair Diseases (pp. 827–886). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-74612-3_35]
  • Hayes, H., Russell, R., Haugen, A., Nagavally, S., & Sarvaideo, J. (2022). The Utility of Monitoring Potassium in Transgender, Gender Diverse, and Nonbinary Individuals on Spironolactone. Journal of the Endocrine Society, 6(11), bvac133. [DOI:10.1210/jendso/bvac133]
  • Heinemann, L. A., Will-Shahab, L., van Kesteren, P., Gooren, L. J., & (1997). Safety of Cyproterone Acetate: Report of Active Surveillance. Pharmacoepidemiology and Drug Safety, 6(3), 169–178. [DOI:10.1002/(sici)1099-1557(199705)6:3<169::aid-pds263>3.0.co;2-3]
  • Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., Rosenthal, S. M., Safer, J. D., Tangpricha, V., & T’Sjoen, G. G. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism, 102(11), 3869–3903. [DOI:10.1210/jc.2017-01658] [PDF]
  • Hirshburg, J. M., Kelsey, P. A., Therrien, C. A., Gavino, A. C., & Reichenberg, J. S. (2016). Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. The Journal of Clinical and Aesthetic Dermatology, 9(7), 56–62. [PubMed] [PubMed Central]
  • Hopkins, U., & Arias, C. Y. (2013). Large-volume IM injections: a review of best practices. Oncology Nurse Advisor, 4(1), 32–37. [Google Scholar] [URL] [PDF]
  • Horton, R. (1992). Dihydrotestosterone Is a Peripheral Paracrine Hormone. Journal of Andrology, 13(1), 23–27. [DOI:10.1002/j.1939-4640.1992.tb01621.x]
  • Huang, G., & Basaria, S. (2017). The Case for Androgens in Menopausal Women: When and How? In Pal, L., & Sayegh, R. A. (Eds.). Essentials of Menopause Management: A Case-Based Approach (pp. 173–196). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-42451-4_10]
  • Irwig, M. S. (2020). Is there a role for 5α‐reductase inhibitors in transgender individuals? Andrology, 9(6), 1729–1731. [DOI:10.1111/andr.12881]
  • Iversen, P., Johansson, J. E., Lodding, P., Lukkarinen, O., Lundmo, P., Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T., Carroll, K., & Scandinavian Prostatic Cancer Group. (2004). Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. The Journal of Urology, 172(5 Part 1), 1871–1876. [DOI:10.1097/01.ju.0000139719.99825.54]
  • Iversen, P., Johansson, J., Lodding, P., Kylmälä, T., Lundmo, P., Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T., Armstrong, J., & (2006). Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer Updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years. Scandinavian Journal of Urology and Nephrology, 40(6), 441–452. [DOI:10.1080/00365590601017329]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 204201881987116. [DOI:10.1177/2042018819871166]
  • Iwamoto, S. J., Grimstad, F., Irwig, M. S., & Rothman, M. S. (2021). Routine Screening for Transgender and Gender Diverse Adults Taking Gender-Affirming Hormone Therapy: a Narrative Review. Journal of General Internal Medicine, 36(5), 1380–1389. [DOI:10.1007/s11606-021-06634-7]
  • Jacoby, A., Rifkin, W., Zhao, L. C., & Bluebond-Langner, R. (2020). Incidence of Cancer and Premalignant Lesions in Surgical Specimens of Transgender Patients. Plastic & Reconstructive Surgery, 147(1), 194–198. [DOI:10.1097/prs.0000000000007452]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • James, J. F., Jamerson, T. A., & Aguh, C. (2022). Efficacy and safety profile of oral spironolactone use for androgenic alopecia: A systematic review. Journal of the American Academy of Dermatology, 86(2), 425–429. [DOI:10.1016/j.jaad.2021.07.048]
  • Jia, A. Y., & Spratt, D. E. (2022). Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative. International Journal of Radiation Oncology*Biology*Physics, 113(2), 316–319. [DOI:10.1016/j.ijrobp.2022.01.037]
  • Jiang, Y., & Tian, W. (2017). The effects of progesterones on blood lipids in hormone replacement therapy. Lipids in Health and Disease, 16(1), 219. [DOI:10.1186/s12944-017-0612-5]
  • Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E., & Mulder, J. W. (2000). Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men. The American Journal of Surgical Pathology, 24(1), 74–80. [DOI:10.1097/00000478-200001000-00009]
  • Kellner, M., & Wiedemann, K. (2008). Mineralocorticoid receptors in brain, in health and disease: Possibilities for new pharmacotherapy. European Journal of Pharmacology, 583(2–3), 372–378. [DOI:10.1016/j.ejphar.2007.07.072]
  • Kim, G. K., & Del Rosso, J. Q. (2012). Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris: Practical Considerations for the Clinician Based on Current Data and Clinical Experience. The Journal of Clinical and Aesthetic Dermatology, 5(3), 37–50. [PubMed] [PubMed Central]
  • King, S. R. (2012). Neurosteroids and the Nervous System. In King, S. R. Neurosteroids and the Nervous System (pp. 1–122). New York: Springer New York. [DOI:10.1007/978-1-4614-5559-2_1]
  • Kolvenbag, G. J., & Blackledge, G. R. (1996). Worldwide activity and safety of bicalutamide: a summary review. Urology, 47(1), 70–79. [DOI:10.1016/s0090-4295(96)80012-4]
  • Kuhl, H. (2003). Östrogene für den Mann? [Estrogen for men?] Blickpunkt der Mann, 1(3), 6–12. [Google Scholar] [URL] [PDF]
  • Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(Suppl 1), 3–63. [DOI:10.1080/13697130500148875] [PDF]
  • Kuhl, H., & Wiegratz, I. (2017). Das Post-Finasterid-Syndrom. [Post Finasteride Syndrome.] Gynäkologische Endokrinologie, 15(2), 153–163. [DOI:10.1007/s10304-017-0126-2]
  • Kuijpers, S. M., Wiepjes, C. M., Conemans, E. B., Fisher, A. D., T’Sjoen, G., & den Heijer, M. (2021). Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study. The Journal of Clinical Endocrinology & Metabolism, 106(10), e3936–e3945. [DOI:10.1210/clinem/dgab427]
  • Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., & Rao, P. N. (2021). Cyproterone Acetate–Induced Acute Liver Failure: A Case Report and Review of the Literature. Journal of Clinical and Experimental Hepatology, 11(6), 739–741. [DOI:10.1016/j.jceh.2021.01.003]
  • Lauritzen, C. (1988). Natürliche und synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien. [Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles.] In Lauritzen, C., Schneider, H. P. G., & Nieschlag, E. (Eds.). Grundlagen und Klinik der Menschlichen Fortpflanzung [Foundations and Clinic of Human Reproduction] (pp. 229–306). Berlin: de Gruyter. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [PDF] [Translation]
  • Lax, E. (1987). Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver. Journal of Steroid Biochemistry, 27(4–6), 1119–1128. [DOI:10.1016/0022-4731(87)90198-1]
  • Layton, A. M., Eady, E. A., Whitehouse, H., Del Rosso, J. Q., Fedorowicz, Z., & van Zuuren, E. J. (2017). Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. American Journal of Clinical Dermatology, 18(2), 169–191. [DOI:10.1007/s40257-016-0245-x]
  • Legro, R. S., Schlaff, W. D., Diamond, M. P., Coutifaris, C., Casson, P. R., Brzyski, R. G., Christman, G. M., Trussell, J. C., Krawetz, S. A., Snyder, P. J., Ohl, D., Carson, S. A., Steinkampf, M. P., Carr, B. R., McGovern, P. G., Cataldo, N. A., Gosman, G. G., Nestler, J. E., Myers, E. R., Santoro, N., Eisenberg, E., Zhang, M., & Zhang, H. (2010). Total Testosterone Assays in Women with Polycystic Ovary Syndrome: Precision and Correlation with Hirsutism. The Journal of Clinical Endocrinology & Metabolism, 95(12), 5305–5313. [DOI:10.1210/jc.2010-1123]
  • Leinung, M. C. (2014). Variable Response to Oral Estradiol Therapy in Male to Female Transgender Patients. Endocrine Reviews, 35(Suppl 1) [Endocrine Society’s 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago], ?–? (abstract no. OR42-1). [Google Scholar] [DOI:10.1093/edrv/35.supp.1] [DOI:10.1210/endo-meetings.2014.RE.2.OR42-1] [URL] [MedPage Today]
  • Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
  • Liang, J. J., Jolly, D., Chan, K. J., & Safer, J. D. (2018). Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort. Endocrine Practice, 24(2), 135–142. [DOI:10.4158/ep-2017-0116]
  • Lobo, R. A., Shoupe, D., Serafini, P., Brinton, D., & Horton, R. (1985). The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertility and Sterility, 43(2), 200–205. [DOI:10.1016/s0015-0282(16)48373-1]
  • Loh, H. H., Yee, A., Loh, H. S., Kanagasundram, S., Francis, B., & Lim, L. (2020). Sexual dysfunction in polycystic ovary syndrome: a systematic review and meta-analysis. Hormones, 19(3), 413–423. [DOI:10.1007/s42000-020-00210-0]
  • Luong, J. H., Male, K. B., & Glennon, J. D. (2019). Biotin interference in immunoassays based on biotin-strept(avidin) chemistry: An emerging threat. Biotechnology Advances, 37(5), 634–641. [DOI:10.1016/j.biotechadv.2019.03.007]
  • MacLean, D. B., Shi, H., Faessel, H. M., & Saad, F. (2015). Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males. The Journal of Clinical Endocrinology & Metabolism, 100(12), 4579–4587. [DOI:10.1210/jc.2015-2770]
  • Mahler, C. (1996). A Review of the Clinical Studies with Nilutamide. In Denis, L. (Ed.). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment (ESO Monographs) (pp. 105–111). Berlin/Heidelberg: Springer Berlin Heidelberg. [DOI:10.1007/978-3-642-45745-6_10]
  • Maksym, R. B., Kajdy, A., & Rabijewski, M. (2019). Post-finasteride syndrome – does it really exist? The Aging Male, 22(4), 250–259. [DOI:10.1080/13685538.2018.1548589]
  • Marks, D. H., Prasad, S., De Souza, B., Burns, L. J., & Senna, M. M. (2019). Topical Antiandrogen Therapies for Androgenetic Alopecia and Acne Vulgaris. American Journal of Clinical Dermatology, 21(2), 245–254. [DOI:10.1007/s40257-019-00493-z]
  • Martinez-Martin, F. J., Kuzior, A., Hernandez-Lazaro, A., de Leon-Durango, R. J., Rios-Gomez, C., Santana-Ojeda, B., Perez-Rivero, J. M., Fernandez-Trujillo-Comenge, P. M., Gonzalez-Diaz, P., Arnas-Leon, C., Acosta-Calero, C., Perdomo-Herrera, E., Tocino-Hernandez, A. L., del Sol Sanchez-Bacaicoa, M., & del Pino Perez-Garcia, M. (2022). Incidence of hypertension in young transgender people after a 5-year follow-up: association with gender-affirming hormonal therapy. Hypertension Research, 46(1), 219–225. [DOI:10.1038/s41440-022-01067-z]
  • McFarlane, T., Zajac, J. D., & Cheung, A. S. (2018). Gender-affirming hormone therapy and the risk of sex hormone-dependent tumours in transgender individuals—A systematic review. Clinical Endocrinology, 89(6), 700–711. [DOI:10.1111/cen.13835]
  • Meriggiola, M. C., Bremner, W. J., Costantino, A., Bertaccini, A., Morselli-Labate, A. M., Huebler, D., Kaufmann, G., Oettel, M., & Flamigni, C. (2002). Twenty-One Day Administration of Dienogest Reversibly Suppresses Gonadotropins and Testosterone in Normal Men. The Journal of Clinical Endocrinology & Metabolism, 87(5), 2107–2113. [DOI:10.1210/jcem.87.5.8514]
  • Meyer, G., Mayer, M., Mondorf, A., Flügel, A. K., Herrmann, E., & Bojunga, J. (2020). Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. European Journal of Endocrinology, 182(2), 149–156. [DOI:10.1530/eje-19-0463]
  • Miles, R. A., Paulson, R. J., Lobo, R. A., Press, M. F., Dahmoush, L., & Sauer, M. V. (1994). Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertility and Sterility, 62(3), 485–490. [DOI:10.1016/s0015-0282(16)56935-0]
  • Millington, K., Liu, E., & Chan, Y. (2019). The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone. Journal of the Endocrine Society, 3(5), 1031–1038. [DOI:10.1210/js.2019-00030]
  • Millward, C. P., Keshwara, S. M., Islim, A. I., Jenkinson, M. D., Alalade, A. F., & Gilkes, C. E. (2022). Development and Growth of Intracranial Meningiomas in Transgender Women Taking Cyproterone Acetate as Gender-Affirming Progestogen Therapy: A Systematic Review. Transgender Health, 7(6), 473–483. [DOI:10.1089/trgh.2021.0025]
  • Moretti, C., Guccione, L., Di Giacinto, P., Simonelli, I., Exacoustos, C., Toscano, V., Motta, C., De Leo, V., Petraglia, F., & Lenzi, A. (2017). Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial. The Journal of Clinical Endocrinology & Metabolism, 103(3), 824–838. [DOI:10.1210/jc.2017-01186]
  • Nakamoto, J. (2016). Endocrine Testing. In Jameson, J. L., & De Groot, L. J. (Eds.). Endocrinology: Adult and Pediatric, 7th Edition (pp. 2655–2688.e1). Philadelphia: Saunders/Elsevier. [DOI:10.1016/B978-0-323-18907-1.00154-2]
  • Nakhjavani, M., Hamidi, S., Esteghamati, A., Abbasi, M., Nosratian-Jahromi, S., & Pasalar, P. (2009). Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism. British Journal of Clinical Pharmacology, 68(4), 634–637. [DOI:10.1111/j.1365-2125.2009.03483.x]
  • Neyman, A., Fuqua, J. S., & Eugster, E. A. (2019). Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents. Journal of Adolescent Health, 64(4), 544–546. [DOI:10.1016/j.jadohealth.2018.10.296]
  • Nguyen, D., Marchese, M., Cone, E. B., Paciotti, M., Basaria, S., Bhojani, N., & Trinh, Q. (2021). Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride. JAMA Dermatology, 157(1), 35–42. [DOI:10.1001/jamadermatol.2020.3385]
  • Nie, I., Wiepjes, C. M., Blok, C. J., Moorselaar, R. J., Pigot, G. L., Sluis, T. M., Barbé, E., Voorn, P., Mello, N. M., Huirne, J., & Heijer, M. (2021). Incidence of testicular cancer in trans women using gender‐affirming hormonal treatment: a nationwide cohort study. BJU International, 129(4), 491–497. [DOI:10.1111/bju.15575]
  • Nieschlag, E., Zitzmann, M., & Kamischke, A. (2003). Use of progestins in male contraception. Steroids, 68(10–13), 965–972. [DOI:10.1016/s0039-128x(03)00135-1]
  • Nieschlag, E. (2010). Clinical trials in male hormonal contraception. Contraception, 82(5), 457–470. [DOI:10.1016/j.contraception.2010.03.020]
  • Nieschlag, E., & Behre, H. M. (2012). The essential role of testosterone in hormonal male contraception. In Nieschlag, E., Behre, H. M., & Nieschlag, S. (Eds.). Testosterone: Action · Deficiency · Substitution, 4th Edition (pp. 470–493). Cambridge/New York: Cambridge University Press. [DOI:10.1017/cbo9781139003353.023]
  • Nishiyama, T. (2014). Serum testosterone levels after medical or surgical androgen deprivation: A comprehensive review of the literature. Urologic Oncology: Seminars and Original Investigations, 32(1), 38.e17–38.e28. [DOI:10.1016/j.urolonc.2013.03.007]
  • Nolan, B. J., & Cheung, A. S. (2021). Relationship Between Serum Estradiol Concentrations and Clinical Outcomes in Transgender Individuals Undergoing Feminizing Hormone Therapy: A Narrative Review. Transgender Health, 6(3), 125–131. [DOI:10.1089/trgh.2020.0077]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study. Endocrine Connections, 11(5), e220170. [DOI:10.1530/EC-22-0170]
  • Norman, A. W., & Henry, H. L. (2015). Androgens. In Norman, A. W., & Henry, H. L. Hormones, 3rd Edition (pp. 255–273). London: Academic Press/Elsevier. [DOI:10.1016/b978-0-08-091906-5.00012-4]
  • Norman, A. W., & Henry, H. L. (2015). Estrogens and Progestins. In Norman, A. W., & Henry, H. L. Hormones, 3rd Edition (pp. 275–296). London: Academic Press/Elsevier. [DOI:10.1016/b978-0-08-091906-5.00013-6]
  • Nota, N. M., Wiepjes, C. M., de Blok, C. J., Gooren, L. J., Peerdeman, S. M., Kreukels, B. P., & den Heijer, M. (2018). The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment. Brain, 141(7), 2047–2054. [DOI:10.1093/brain/awy108]
  • North American Menopause Society. (2022). The 2022 hormone therapy position statement of The North American Menopause Society. Menopause, 29(7), 767–794. [DOI:10.1097/gme.0000000000002028]
  • O’Connell, M. B. (1995). Pharmacokinetic and Pharmacologic Variation Between Different Estrogen Products. The Journal of Clinical Pharmacology, 35(9S), 18S–24S. [DOI:10.1002/j.1552-4604.1995.tb04143.x]
  • Olsen, E. A., Hordinsky, M., Whiting, D., Stough, D., Hobbs, S., Ellis, M. L., Wilson, T., & Rittmaster, R. S. (2006). The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss: Results of a randomized placebo-controlled study of dutasteride versus finasteride. Journal of the American Academy of Dermatology, 55(6), 1014–1023. [DOI:10.1016/j.jaad.2006.05.007]
  • Plovanich, M., Weng, Q. Y., & Mostaghimi, A. (2015). Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatology, 151(9), 941–944. [DOI:10.1001/jamadermatol.2015.34]
  • Polyzos, S. A., Kountouras, J., Zavos, C., & Deretzi, G. (2011). Spironolactone Revisited. The Journal of Clinical Hypertension, 13(10), 783–784. [DOI:10.1111/j.1751-7176.2011.00484.x]
  • Powers, M. S., Schenkel, L., Darley, P. E., Good, W. R., Balestra, J. C., & Place, V. A. (1985). Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: Comparison with conventional oral estrogens used for hormone replacement. American Journal of Obstetrics and Gynecology, 152(8), 1099–1106. [DOI:10.1016/0002-9378(85)90569-1]
  • Prince, J. C., & Safer, J. D. (2020). Endocrine treatment of transgender individuals: current guidelines and strategies. Expert Review of Endocrinology & Metabolism, 15(6), 395–403. [DOI:10.1080/17446651.2020.1825075]
  • Reiter, E. O., Mauras, N., McCormick, K., Kulshreshtha, B., Amrhein, J., De Luca, F., O’Brien, S., Armstrong, J., & Melezinkova, H. (2010). Bicalutamide plus Anastrozole for the Treatment of Gonadotropin-Independent Precocious Puberty in Boys with Testotoxicosis: A Phase II, Open-Label Pilot Study (BATT). Journal of Pediatric Endocrinology and Metabolism, 23(10), 999–1009. [DOI:10.1515/jpem.2010.161]
  • Rezende, H. D., Dias, M. F. R. G., & Trüeb, R. M. (2018). A Comment on the Post-Finasteride Syndrome. International Journal of Trichology, 10(6), 255–261. [PubMed] [PubMed Central] [DOI:10.4103/ijt.ijt_61_18]
  • Roberts, J. L., Fiedler, V., Imperato-McGinley, J., Whiting, D., Olsen, E., Shupack, J., Stough, D., DeVillez, R., Rietschel, R., Savin, R., Bergfeld, W., Swinehart, J., Funicella, T., Hordinsky, M., Lowe, N., Katz, I., Lucky, A., Drake, L., Price, V. H., Weiss, D., Whitmore, E., Millikan, L., Muller, S., Gencheff, C., Carrington, P., Binkowitz, B., Kotey, P., He, W., Bruno, K., Jacobsen, C., Terranella, L., Gormley, G. J., & Kaufman, K. D. (1999). Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss. Journal of the American Academy of Dermatology, 41(4), 555–563. [DOI:10.1016/s0190-9622(99)80052-8]
  • Roscioni, S. S., de Zeeuw, D., Bakker, S. J., & Lambers Heerspink, H. J. (2012). Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy. Nature Reviews Nephrology, 8(12), 691–699. [DOI:10.1038/nrneph.2012.217]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2008). Puberty and its disorders in the female. In Sperling, M. A. (Ed.). Pediatric Endocrinology, 3rd Edition (pp. 530–609). Philadelphia: Saunders. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2021). Puberty in the Female and Its Disorders. In Sperling, M. A., Majzoub, J. A., Menon, R. K., & Stratakis, C. A. (Eds.). Sperling Pediatric Endocrinology, 5th Edition (pp. 528–626). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-62520-3.00016-6]
  • Samarasinghe, S., Meah, F., Singh, V., Basit, A., Emanuele, N., Emanuele, M. A., Mazhari, A., & Holmes, E. W. (2017). Biotin Interference with Routine Clinical Immunoassays: Understand the Causes and Mitigate the Risks. Endocrine Practice, 23(8), 989–998. [DOI:10.4158/ep171761.ra]
  • Schiller, C. E., Schmidt, P. J., & Rubinow, D. R. (2014). Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology, 231(17), 3557–3567. [DOI:10.1007/s00213-014-3599-x]
  • Schlatterer, K., Yassouridis, A., Werder, K. V., Poland, D., Kemper, J., & Stalla, G. K. (1998). Archives of Sexual Behavior, 27(5), 475–492. [DOI:10.1023/a:1018704630036]
  • Seaman, H. E., Langley, S. E., Farmer, R. D., & de Vries, C. S. (2007). Venous thromboembolism and cyproterone acetate in men with prostate cancer: a study using the General Practice Research Database. BJU International, 99(6), 1398–1403. [DOI:10.1111/j.1464-410x.2007.06859.x]
  • Shackleton, C. (2010). Clinical steroid mass spectrometry: A 45-year history culminating in HPLC–MS/MS becoming an essential tool for patient diagnosis. The Journal of Steroid Biochemistry and Molecular Biology, 121(3–5), 481–490. [DOI:10.1016/j.jsbmb.2010.02.017]
  • Shaw, J. C. (1996). Antiandrogen and hormonal treatment of acne. Dermatologic Clinics, 14(4), 803–811. [DOI:10.1016/s0733-8635(05)70405-8]
  • Sofer, Y., Yaish, I., Yaron, M., Bach, M. Y., Stern, N., & Greenman, Y. (2020). Differential Endocrine and Metabolic Effects of Testosterone Suppressive Agents in Transgender Women. Endocrine Practice, 26(8), 883–890. [DOI:10.4158/ep-2020-0032] [PDF]
  • SoRelle, J. A., Jiao, R., Gao, E., Veazey, J., Frame, I., Quinn, A. M., Day, P., Pagels, P., Gimpel, N., & Patel, K. (2019). Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clinical Chemistry, 65(1), 170–179. [DOI:10.1373/clinchem.2018.292730]
  • St-Jules, D. E., Goldfarb, D. S., & Sevick, M. A. (2016). Nutrient Non-equivalence: Does Restricting High-Potassium Plant Foods Help to Prevent Hyperkalemia in Hemodialysis Patients? Journal of Renal Nutrition, 26(5), 282–287. [DOI:10.1053/j.jrn.2016.02.005]
  • St-Jules, D. E., & Fouque, D. (2020). Is it time to abandon the nutrient-based renal diet model? Nephrology Dialysis Transplantation, 36(4), 574–577. [DOI:10.1093/ndt/gfaa257]
  • St-Jules, D. E., & Fouque, D. (2022). Etiology-based dietary approach for managing hyperkalemia in people with chronic kidney disease. Nutrition Reviews, 80(11), 2198–2205. [DOI:10.1093/nutrit/nuac026]
  • Stanczyk, F. Z., & Clarke, N. J. (2010). Advantages and challenges of mass spectrometry assays for steroid hormones. The Journal of Steroid Biochemistry and Molecular Biology, 121(3–5), 491–495. [DOI:10.1016/j.jsbmb.2010.05.001]
  • Stanczyk, F. Z., Hapgood, J. P., Winer, S., & Mishell, D. R. (2012). Progestogens Used in Postmenopausal Hormone Therapy: Differences in Their Pharmacological Properties, Intracellular Actions, and Clinical Effects. Endocrine Reviews, 34(2), 171–208. [DOI:10.1210/er.2012-1008]
  • Stanczyk, F. Z., Mathews, B. W., & Cortessis, V. K. (2017). Does the type of progestin influence the production of clotting factors? Contraception, 95(2), 113–116. [DOI:10.1016/j.contraception.2016.07.007]
  • Stege, R., Gunnarsson, P. O., Johansson, C., Olsson, P., Pousette, Å., & Carlström, K. (1996). Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin®) in prostatic cancer patients. The Prostate, 28(5), 307–310. [DOI:10.1002/(sici)1097-0045(199605)28:5<307::aid-pros6>3.0.co;2-8]
  • Steinberger, E., Ayala, C., Hsi, B., Smith, K. D., Rodriguez-Rigau, L. J., Weidman, E. R., & Reimondo, G. G. (1998). Utilization of Commercial Laboratory Results in Management of Hyperandrogenism in Women. Endocrine Practice, 4(1), 1–10. [DOI:10.4158/ep.4.1.1]
  • Sterling, J., & Garcia, M. M. (2020). Cancer screening in the transgender population: a review of current guidelines, best practices, and a proposed care model. Translational Andrology and Urology, 9(6), 2771–2785. [DOI:10.21037/tau-20-954]
  • Strauss, J. F., & FitzGerald, G. A. (2019). Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 75–114.e7). Philadelphia: Elsevier. [Google Books] [DOI:10.1016/b978-0-323-47912-7.00004-4]
  • Stricker, R., Eberhart, R., Chevailler, M., Quinn, F. A., Bischof, P., & Stricker, R. (2006). Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT® analyzer. Clinical Chemistry and Laboratory Medicine (CCLM), 44(7), 883–887. [DOI:10.1515/cclm.2006.160]
  • Styne, D. M. (2016). Laboratory Values for Pediatric Endocrinology. In Styne, D. M. Pediatric Endocrinology: A Clinical Handbook (pp. 385–434). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-18371-8_16]
  • Sudduth, S. L., & Koronkowski, M. J. (1993). Finasteride: The First 5α-Reductase Inhibitor. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 13(4), 309–329. [DOI:10.1002/j.1875-9114.1993.tb02739.x]
  • Sundström-Poromaa, I., Comasco, E., Sumner, R., & Luders, E. (2020). Progesterone – Friend or foe? Frontiers in Neuroendocrinology, 59, 100856. [DOI:10.1016/j.yfrne.2020.100856]
  • Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C., & Salameh, W. A. (2017). Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocrine Reviews, 38(3), 220–254. [DOI:10.1210/er.2016-1067]
  • T’Sjoen, G. G., Beguin, Y., Feyen, E., Rubens, R., Kaufman, J., & Gooren, L. (2005). Influence of exogenous oestrogen or (anti-) androgen administration on soluble transferrin receptor in human plasma. Journal of Endocrinology, 186(1), 61–67. [DOI:10.1677/joe.1.06112]
  • T’Sjoen, G., Arcelus, J., Gooren, L., Klink, D. T., & Tangpricha, V. (2018). Endocrinology of Transgender Medicine. Endocrine Reviews, 40(1), 97–117. [DOI:10.1210/er.2018-00011]
  • Tack, L. J., Heyse, R., Craen, M., Dhondt, K., Bossche, H. V., Laridaen, J., & Cools, M. (2017). Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents. The Journal of Sexual Medicine, 14(5), 747–757. [DOI:10.1016/j.jsxm.2017.03.251]
  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
  • Toorians, A. W., Thomassen, M. C., Zweegman, S., Magdeleyns, E. J., Tans, G., Gooren, L. J., & Rosing, J. (2003). Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People. The Journal of Clinical Endocrinology & Metabolism, 88(12), 5723–5729. [DOI:10.1210/jc.2003-030520]
  • Traish, A. M., Krakowsky, Y., Doros, G., & Morgentaler, A. (2019). Do 5α-Reductase Inhibitors Raise Circulating Serum Testosterone Levels? A Comprehensive Review and Meta-Analysis to Explaining Paradoxical Results. Sexual Medicine Reviews, 7(1), 95–114. [DOI:10.1016/j.sxmr.2018.06.002]
  • Traish, A. M. (2020). Post-finasteride syndrome: a surmountable challenge for clinicians. Fertility and Sterility, 113(1), 21–50. [DOI:10.1016/j.fertnstert.2019.11.030]
  • Usach, I., Martinez, R., Festini, T., & Peris, J. (2019). Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Advances in Therapy, 36(11), 2986–2996. [DOI:10.1007/s12325-019-01101-6]
  • van Zuuren, E. J., Fedorowicz, Z., Carter, B., & Pandis, N. (2015). Interventions for hirsutism (excluding laser and photoepilation therapy alone). Cochrane Database of Systematic Reviews, 2015, CD010334. [DOI:10.1002/14651858.cd010334.pub2]
  • Verdonk, S. J., Vesper, H. W., Martens, F., Sluss, P. M., Hillebrand, J. J., & Heijboer, A. C. (2019). Estradiol reference intervals in women during the menstrual cycle, postmenopausal women and men using an LC-MS/MS method. Clinica Chimica Acta, 495, 198–204. [DOI:10.1016/j.cca.2019.04.062]
  • Vermeulen, A., Giagulli, V., De Schepper, P., & Buntinx, A. (1991). Hormonal Effects of a 5α-Reductase Inhibitor (Finasteride) onHormonal Levels in Normal Men and in Patients withBenign Prostatic Hyperplasia. European Urology, 20(1), 82–86. [DOI:10.1159/000471752]
  • Vihtamäki, T., Luukkaala, T., & Tuimala, R. (2004). Skin contamination by oestradiol gel—a remarkable source of error in plasma oestradiol measurements during percutaneous hormone replacement therapy. Maturitas, 48(4), 347–353. [DOI:10.1016/s0378-5122(03)00043-4]
  • Wang, H., Liu, M., Fu, Q., & Deng, C. (2019). Pharmacokinetics of hard micronized progesterone capsules via vaginal or oral route compared with soft micronized capsules in healthy postmenopausal women: a randomized open-label clinical study. Drug Design, Development and Therapy, 13, 2475–2482. [DOI:10.2147/dddt.s204624]
  • Wang, Y., & Lipner, S. R. (2020). Retrospective analysis of adverse events with spironolactone in females reported to the United States Food and Drug Administration. International Journal of Women’s Dermatology, 6(4), 272–276. [DOI:10.1016/j.ijwd.2020.05.002]
  • Weill, A., Nguyen, P., Labidi, M., Cadier, B., Passeri, T., Duranteau, L., Bernat, A., Yoldjian, I., Fontanel, S., Froelich, S., & Coste, J. (2021). Use of High Dose Cyproterone Acetate and Risk of Intracranial Meningioma in Women: Cohort Study. BMJ, 372, n37. [DOI:10.1136/bmj.n37]
  • Welk, B., McArthur, E., Ordon, M., Anderson, K. K., Hayward, J., & Dixon, S. (2017). Association of Suicidality and Depression With 5α-Reductase Inhibitors. JAMA Internal Medicine, 177(5), 683–691. [DOI:10.1001/jamainternmed.2017.0089]
  • Wellington, K., & Keam, S. J. (2006). Bicalutamide 150mg: A Review of its Use in the Treatment of Locally Advanced Prostate Cancer. Drugs, 66(6), 837–850. [DOI:10.2165/00003495-200666060-00007]
  • Willemsen, W. N., Mastboom, J. L., Thomas, C. M., & Rolland, R. (1985). Absorption of 17β-estradiol in a neovagina constructed from the peritoneum. European Journal of Obstetrics & Gynecology and Reproductive Biology, 19(4), 247–253. [DOI:10.1016/0028-2243(85)90036-x]
  • Wilson, L. M., Baker, K. E., Sharma, R., Dukhanin, V., McArthur, K., & Robinson, K. A. (2020). Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review. International Journal of Transgender Health, 21(4), 391–402. [DOI:10.1080/15532739.2020.1819505]
  • Wu, B., Shen, P., Yin, X., Yu, L., Wu, F., Chen, C., Li, J., & Xu, T. (2022). Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System. British Journal of Clinical Pharmacology, 89(2), 440–448. [DOI:10.1111/bcp.15336]
  • Wu, F. C., Balasubramanian, R., Mulders, T. M., & Coelingh-Bennink, H. J. (1999). Oral Progestogen Combined with Testosterone as a Potential Male Contraceptive: Additive Effects between Desogestrel and Testosterone Enanthate in Suppression of Spermatogenesis, Pituitary-Testicular Axis, and Lipid Metabolism. The Journal of Clinical Endocrinology & Metabolism, 84(1), 112–122. [DOI:10.1210/jcem.84.1.5412]
  • Zaenglein, A. L., Pathy, A. L., Schlosser, B. J., Alikhan, A., Baldwin, H. E., Berson, D. S., Bowe, W. P., Graber, E. M., Harper, J. C., Kang, S., Keri, J. E., Leyden, J. J., Reynolds, R. V., Silverberg, N. B., Stein Gold, L. F., Tollefson, M. M., Weiss, J. S., Dolan, N. C., Sagan, A. A., Stern, M., Boyer, K. M., & Bhushan, R. (2016). Guidelines of care for the management of acne vulgaris. Journal of the American Academy of Dermatology, 74(5), 945–973.e33. [DOI:10.1016/j.jaad.2015.12.037]
  • Zhang, J., & Stanczyk, F. Z. (2013). LC-MS Bioanalysis of Steroids. In Li, W., Zhang, J., & Tse, F. L. S. (Eds.). Handbook of LC-MS Bioanalysis: Best Practices, Experimental Protocols, and Regulations (pp. 573–590). Hoboken, New Jersey: John Wiley & Sons. [DOI:10.1002/9781118671276.ch45]
  • Zhou, Z., Song, S., Gao, Z., Wu, J., Ma, J., & Cui, Y. (2019). The efficacy and safety of dutasteride compared with finasteride in treating men with androgenetic alopecia: a systematic review and meta-analysis. Clinical Interventions in Aging, 14, 399–406. [DOI:10.2147/cia.s192435]
  • Zitzmann, M., Rohayem, J., Raidt, J., Kliesch, S., Kumar, N., Sitruk-Ware, R., & Nieschlag, E. (2017). Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial. Andrology, 5(3), 516–526. [DOI:10.1111/andr.12328]
  • Zuuren, E., & Fedorowicz, Z. (2016). Interventions for hirsutism excluding laser and photoepilation therapy alone: abridged Cochrane systematic review including GRADE assessments. British Journal of Dermatology, 175(1), 45–61. [DOI:10.1111/bjd.14486]
\ No newline at end of file +An Introduction to Hormone Therapy for Transfeminine People - Transfeminine Science Link

An Introduction to Hormone Therapy for Transfeminine People

By Aly | First published August 4, 2018 | Last modified April 10, 2024

Abstract / TL;DR

Sex hormones such as estrogen, testosterone, and progesterone are produced by the gonads. The sex hormones mediate the development of the secondary sexual characteristics. Testosterone causes masculinization, while estradiol causes feminization and breast development. Males have high amounts of testosterone, while females have low testosterone but high amounts of estradiol. These hormonal differences are responsible for the physical differences between males and females. Sex hormones and other hormonal medications are used in transfeminine people to shift the hormonal profile from a male-typical one to a female-typical profile. This causes feminization and demasculinization and allows for alleviation of gender dysphoria. The changes caused by transfeminine hormone therapy occur over a period of months to years. There are many different types and forms of hormonal medications, and these medications can be administered by a variety of different routes. Examples include as pills taken by mouth, as patches or gel applied to the skin, and as injections, among others. Different hormonal medications, routes, and doses have differences in efficacy, side effects, risks, costs, convenience, and availability. Hormone therapy should ideally be regularly monitored in transfeminine people with blood tests to ensure effectiveness and safety and to allow for adjustment as necessary.

The Sex Hormones

Types and Effects

The sex hormones include the estrogens (E), progestogens (P), and androgens. A person’s hormonal profile is a product of the type of gonads that they are born with. Natal males have testes while natal females have ovaries. Testes produce large amounts of androgens and small amounts of estrogens whereas ovaries produce high amounts of estrogens and progesterone and low amounts of androgens.

The major estrogen in the body is estradiol (E2), the main progestogen is progesterone (P4), and the major androgens are testosterone (T) and dihydrotestosterone (DHT). The sex hormones are responsible for and determine the secondary sex characteristics. They mediate their effects by acting as agonists (or activators) of receptors inside of cells. These receptors include the androgen receptor (AR), the estrogen receptors (ERs), and the progesterone receptors (PRs). Following their activation, these receptors modulate gene expression to influence cells and tissues.

Estrogens cause feminization. This includes breast development, softening of the skin, a feminine pattern of fat distribution (concentrated in the breasts, hips, thighs, and buttocks), widening of the hips (in those who are still of pubertal age), and other physical changes (Wiki).

Progestogens have essentially no known role in feminization or pubertal breast development. Rather than acting as mediators of feminization, progestogens have important effects in the female reproductive system and are essential hormones during pregnancy (Wiki). They also oppose the actions of estrogens in certain parts of the body, such as the uterus, vagina, and breasts (Wiki).

Androgens cause masculinization. This includes growth of the penis, broadening of the shoulders, expansion of the rib cage, muscle growth, voice deepening, a masculine pattern of fat distribution (concentrated in the stomach and waist), masculine changes in other soft tissues, and facial/body hair growth (Wiki). Androgens also cause a variety of generally undesirable skin and hair effects, including oily skin, acne, seborrhea, scalp hair loss, and body odor. They additionally oppose breast development and probably other aspects of feminization mediated by estrogens as well.

In addition to their effects on the body, sex hormones have actions in the brain. These actions influence cognition, emotions, and behavior. For instance, androgens produce pronounced sexual desire and arousal (including spontaneous erections) in men, while estrogens appear to be the major hormones responsible for sexual desire in women (Cappelletti & Wallen, 2016). As another example, testosterone levels have been negatively associated with agreeableness, whereas estrogen levels have been positively associated with this characteristic (Treleaven et al., 2013). Sex hormones also have important effects on health, which can be both positive and negative. For instance, estrogens maintain bone strength and likely protect against heart disease in cisgender women (NAMS, 2022), but also increase the risk of breast cancer (Aly, 2020) and can increase the risk of blood clots (Aly, 2020).

Estrogens, progestogens, and androgens also have antigonadotropic effects. That is, they inhibit the gonadotropin-releasing hormone (GnRH)-induced secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), from the pituitary gland in the brain. The gonadotropins signal the gonads to make sex hormones and to supply the sperm and egg cells necessary for fertility. Hence, lower levels of the gonadotropins will result in reduced gonadal sex hormone production and diminished fertility. If gonadotropin levels are sufficiently suppressed, the gonads will no longer make sex hormones at all and fertility will cease. The vast majorities of the quantities of estradiol, testosterone, and progesterone in the body are produced by the gonads. Most of the small remaining amounts of these hormones are produced via the adrenal glands of the kidneys.

Normal Hormone Levels

In cisgender females, the sex hormones are largely absent during childhood, gradually ramp up in production in late childhood and adolescence, are present in a cyclical manner during adulthood, and then largely stop being produced following the menopause. Hormone levels vary substantially but in a predictable manner during the normal menstrual cycle in adult premenopausal women. The menstrual cycle lasts about 28 days on average and consists of the following parts:

  1. Follicular phase—first half of the cycle or days 1–14
  2. Mid-cycle—middle of the cycle or days 12–16 or so
  3. Luteal phase—latter half of the cycle or days 14–28

Hormone levels during the menstrual cycle are shown in the following graph:

Figure 1: Median estradiol and progesterone levels throughout the menstrual cycle in premenopausal cisgender women (Stricker et al., 2006; Abbott, 2009). The horizontal dashed lines are the average levels over the spanned periods. Other figures available elsewhere show variation between individuals (Graph; Graph; Graph).

As can be seen in the graph, estradiol levels are relatively low and progesterone levels are very low during the follicular phase; estradiol but not progesterone levels briefly surge to very high levels and trigger ovulation during mid-cycle; and estradiol and progesterone levels both undergo a bump and are relatively high during the luteal phase (though estradiol is not as high as during the mid-cycle peak).

The table below shows the circulating levels and production rates of estradiol, progesterone, and testosterone in women and men and allows for comparison between them.

Table 1: Ranges for circulating levelsa and estimated production ratesb of the major sex hormones:

HormoneGroupTimeLevels (mass/vol)cLevels (mol/vol)cProduction rates
EstradiolWomendFollicular phase5–180 pg/mL20–660 pmol/L30–170 μg/daye
  Mid-cycle45–750 pg/mL170–2,750 pmol/L320–950 μg/daye
  Luteal phase20–300 pg/mL73–1100 pmol/L250–300 μg/daye
 Men–8–35 pg/mL30–130 pmol/L10–60 μg/day
ProgesteroneWomendFollicular phase≤0.3 ng/mL≤1.0 nmol/L0.75–5 mg/day
  Mid-cycle0.1–1.5 ng/mL0.3–4.8 nmol/L4 mg/day
  Luteal phase3.5–38 ng/mL11–120 nmol/L15–50 mg/dayf
 Men–≤0.5 ng/mL≤1.6 nmol/L0.75–3 mg/day
TestosteroneWomendMenstrual cycle5–55 ng/dL0.2–1.9 nmol/L190–260 μg/day
 Men–250–1100 ng/dL8.7–38 nmol/L5–7 mg/day

a Sources for hormone levels: Zhang & Stanczyk (2013); Nakamoto (2016); Styne (2016); LabCorp (2020). b Sources for production rates: Aufrère & Benson (1976); Powers et al. (1985); Lauritzen (1988); Carr (1993); O’Connell (1995); Kuhl (2003); Norman & Henry (2015a); Norman & Henry (2015b); Strauss & FitzGerald (2019). c With liquid chromatography–mass spectrometry (LC–MS) (state-of-the-art blood tests). d During the menstrual cycle in the adult premenopause (age ~18–50 years). e Average production rate of estradiol over the whole menstrual cycle is roughly 200 μg/day or 6 mg/month (Rosenfield, Cooke, & Radovich, 2021). f Average production rate of progesterone during the luteal phase of the menstrual cycle is about 25 mg/day (Carr, 1993).

Mean integrated estradiol levels are around 100 pg/mL (367 pmol/L) in premenopausal women and around 25 pg/mL (92 pmol/L) in men. The 95% range for mean estradiol levels in women is around 50 to 250 pg/mL (180–918 pmol/L) (e.g., Abbott, 2009 (Graph); Verdonk et al., 2019 (Graph)). The average production of estradiol by the ovaries in premenopausal women is about 6 mg over the course of one menstrual cycle (i.e., one month) (Rosenfield et al., 2008). This corresponds to a mean rate of about 200 μg/day. Estradiol levels increase slowly during normal female puberty, when breast development and feminization take place. Mean estradiol levels during the different stages of female puberty are quite low—less than about 50 to 60 pg/mL (180–220 pmol/L) until late puberty (Aly, 2020). In postmenopausal women, whose ovaries no longer produce considerable quantities of estrogens, estradiol levels are generally less than 10 to 20 pg/mL (37–73 pmol/L) (Nakamoto, 2016). Estradiol levels below 50 pg/mL (184 pmol/L) in adults are concentration-dependently associated with menopausal symptoms, including hot flashes, depressive mood changes, defeminization (e.g., breast atrophy, loss of feminine fat distribution), accelerated skin aging, and bone density loss with increased risk of bone fracture.

Mean testosterone levels are around 30 ng/dL (1.0 nmol/L) in women and 600 ng/dL (21 nmol/L) in men. Based on these values, testosterone levels are on average about 20-fold higher in men than in women. In men who have undergone gonadectomy (castration or surgical gonadal removal), testosterone levels are similar to those in women (<50 ng/dL [1.7 nmol/L]) (Nishiyama, 2014; Itty & Getzenberg, 2020). The mean or median levels of testosterone in women with polycystic ovary syndrome (PCOS), who often have clinically significant symptoms of androgen excess (e.g., excessive facial/body hair growth), range from 41 to 75 ng/dL (1.4–2.6 nmol/L) per different studies (Balen et al., 1995; Steinberger et al., 1998; Legro et al., 2010; Loh et al., 2020). Hence, it appears that even testosterone levels that are marginally elevated relative to normal female levels may produce undesirable androgenic effects.

It is important to be aware that measurement of hormone levels is subject to methodological limitations, and hormone levels vary significantly when quantified by different methods and laboratories on account of varying assay accuracy (Shackleton, 2010; Stanczyk & Clarke, 2010; Deutsch, 2016; Carmina, Stanczyk, & Lobo, 2019). Mass spectrometry (MS)-based assays, such as liquid chromatography–mass spectrometry (LC–MS), are regarded as more accurate and reliable than immunoassay (IA)-based assays, such as radioimmunoassays (RIA) and direct immunoassays like enzyme-linked immunosorbent assays (ELISA) (Stanczyk & Clarke, 2010; Carmina, Stanczyk, & Lobo, 2019). In relation to this, MS-based tests are gradually becoming the standard for laboratory testing of sex hormone levels. However, hormone levels vary between laboratories even with LC–MS, for instance due to differences in calibration of LC–MS instruments between laboratories (Carmina, Stanczyk, & Lobo, 2019). Whereas an accurate range for testosterone levels in cisgender women is 20 to 50 ng/dL (0.69–1.7 nmol/L), for instance with assays like RIA and LC–MS, the normal upper limit for direct immunoassays like ELISA may be 70 to 80 ng/dL (2.4–2.8 nmol/L) (Carmina, Stanczyk, & Lobo, 2019). When interpreting blood tests, care should be taken to compare sex hormone levels to same-laboratory reference ranges (Deutsch, 2016).

Overview of Hormone Therapy

The goal of hormone therapy for transfeminine people, otherwise known as feminizing hormone therapy (FHT) or (more in the past) as male-to-female (MtF) hormone replacement therapy (HRT), is to produce feminization and demasculinization of the body as well as alleviation of gender dysphoria. Medication therapy with sex hormones and other sex-hormonal medications is used to mediate these changes. Transfeminine people are given estrogens, progestogens, and antiandrogens (AAs) to supersede gonadal sex hormone production and shift the hormonal profile from male-typical to female-typical.

Transfeminine hormone therapy aims to achieve estradiol and testosterone levels within the normal female range. Commonly recommended ranges for transfeminine people in the literature are 100 to 200 pg/mL (367–734 pmol/L) for estradiol levels and less than 50 ng/dL (1.7 nmol/L) for testosterone levels (Table). However, higher estradiol levels of more than 200 pg/mL (734 pmol/L) can be useful in transfeminine hormone therapy to help suppress testosterone levels. Lower estradiol levels (≤50–60 pg/mL [≤180–220 pmol/L]) are recommended and more appropriate for pubertal and adolescent transfeminine individuals. Sex hormone levels in the blood can be measured with blood tests, in which blood is drawn from a vein using a needle and then analyzed in a laboratory. This is useful in transfeminine people to ensure that the hormonal profile has been satisfactorily altered in line with therapeutic goals—specifically that hormone levels are within female ranges.

Gonadal Suppression

At sufficiently high exposure, estrogens and androgens are able to completely suppress gonadal sex hormone production, while progestogens by themselves are able to partially but substantially suppress gonadal sex hormone production. More specifically, studies in cisgender men and transfeminine people have found that estradiol levels of around 200 pg/mL (734 pmol/L) suppress testosterone levels by about 90% on average (to ~50 ng/dL [1.7 nmol/L]), while estradiol levels of around 500 pg/mL (1,840 pmol/L) suppress testosterone levels by about 95% on average (to ~20–30 ng/dL [0.7–1.0 nmol/L]) (Gooren et al., 1984 [Graph]; Herndon et al., 2023 [Discussion]; Wiki; Graphs). Estradiol levels of below 200 pg/mL (734 pmol/L) also suppress testosterone levels, although to a reduced extent compared to higher levels (Aly, 2019; Krishnamurthy et al., 2023; Slack et al., 2023). In one large study in transfeminine people, the rates of adequate testosterone suppression (to testosterone levels of <50 ng/dL or <1.7 nmol/L) were 24% of individuals at estradiol levels of <100 pg/mL (367 pmol/L), 58% at 100 to 200 pg/mL (367–734 pmol/L), and 77% at >200 pg/mL (>734 pmol/L) (Krishnamurthy et al., 2023).

Figure 2: Estradiol and testosterone levels after a single injection of 320 mg polyestradiol phosphate (PEP) (a long-acting prodrug of estradiol) in men with prostate cancer (Stege et al., 1996). The maximal decrease in testosterone levels occurred with estradiol levels of greater than 200 pg/mL (734 pmol/L) and was about 90% (to roughly 50 ng/dL [1.7 nmol/L]). This figure demonstrates the ability of estradiol to concentration-dependently suppress gonadal testosterone production and circulating testosterone levels in people with testes.

Progestogens on their own are able to maximally suppress testosterone levels by about 50 to 70% (to ~150–300 ng/dL [5.2–10.4 nmol/L] on average) (Aly, 2019; Wiki). In combination with relatively small amounts of estrogen however, there is synergism in the antigonadotropic effect—the suppression of gonadal testosterone production with maximally effective doses of progestogens becomes complete, and testosterone levels are reduced by about 95% (to ~20–30 ng/dL [0.7–1.0 nmol/L]) (Aly, 2019). Hence, the combination of an estrogen and a progestogen can be used to achieve maximal testosterone suppression at lower doses than would be necessary if an estrogen or progestogen were used alone.

The antigonadotropic effects of estrogens and progestogens are taken advantage of in transfeminine hormone therapy to suppress gonadal testosterone production and attain testosterone levels that are more consistent with those in cisgender women. It should be noted that the preceding numbers on testosterone suppression with estrogens and progestogens are averages and there is significant variation between individuals in terms of testosterone suppression. In other words, some may need more or less in terms of hormonal dosages to achieve the same decrease in testosterone levels.

Timeline of Effects

During normal puberty in both males and females, sex hormone exposure increases slowly over a period of several years (Aly, 2020). In relation to this, sexual maturation occurs gradually during normal puberty. In non-adolescent transgender people, adult or higher amounts of hormones are generally administered right away, and this can result in changes in secondary sex characteristics happening more quickly. The table below is reproduced from literature sources with slight modification and is commonly cited as a timeline for the effects of hormone therapy in transfeminine people (Table). It is based on a mixture of anecdotal clinical experience, expert opinion, and available clinical studies of hormone therapy in transfeminine people. Due to limited research characterizing the effects of transfeminine hormone therapy at present, the table may or may not be completely accurate.

Table 2: Effects of hormone therapy at typical doses in adult transfeminine people (Wiki):

EffectOnsetaCompletionaPermanency
Breast development2–6 months2–3 yearsPermanent
Reduced and slowed growth of facial and body hair3–12 months>3 yearsbReversible
Cessation and reversal of scalp hair loss1–3 months1–2 yearsReversible
Softening of skin and decreased skin oiliness and acne3–6 monthsUnknownReversible
Redistribution of body fat in a feminine pattern3–6 months2–5 yearsReversible
Decreased muscle mass and strength3–6 months1–2 yearscReversible
Widening and rounding of the pelvisdUnknownUnknownPermanent
Changes in mood, emotionality, and behaviorImmediateUnknownReversible
Decreased sex drive and spontaneous erections1–3 months3–6 monthsReversible
Erectile dysfunction and decreased ejaculate volume1–3 monthsVariableReversible
Decreased sperm production and infertilityUnknown>3 yearsMixede
Decreased testicular volume3–6 months2–3 yearsUnknown
Voice changes (e.g., decreased pitch/resonance)NonefN/AN/A

a May vary significantly between individuals due to factors like genetics, diet/nutrition, hormone levels, etc. b Hormone therapy usually has little influence on facial hair density in transfeminine people. Complete removal of facial and body hair can be achieved with laser hair removal and electrolysis. Temporary hair removal can be achieved with shaving, epilating, waxing, and other methods. c May vary significantly depending on amount of physical exercise. d Occurs only in young individuals who have not yet completed growth plate closure (may not occur at all in post-adolescent people). e Only estrogens, particularly at high doses, seem to have the potential for long-lasting or irreversible infertility; impaired fertility caused by antiandrogens is usually readily reversible with discontinuation. f Voice training can be an effective means of feminizing the voice.

Breast development is one of the most anticipated effects of feminizing hormone therapy in transfeminine people (Masumori et al., 2021; Grock et al., 2024). Some review content on breast development in transfeminine people exists on this site (e.g., Aly, 2020). Breast growth can notably be measured and tracked with a variety of methods (Wiki; Aly, 2020). For see real-life photographic timelines of breast development (as well as feminization in general) with feminizing hormone therapy in transfeminine people, see the r/TransBreastTimelines community on the social media website Reddit.

Specific Hormonal Medications

The medications that are used in transfeminine hormone therapy include estrogens, progestogens, and antiandrogens. Estrogens produce feminization and testosterone suppression. Progestogens and antiandrogens do not mediate feminization themselves but further suppress and/or block testosterone. Testosterone suppression causes demasculinization and disinhibition of estrogen-mediated feminization. Androgens are sometimes used at low doses in transfeminine people who have low testosterone levels, although they are not required and benefits are uncertain. There are many different types of these hormonal medications available for transfeminine hormone therapy, with different benefits and risks.

Estrogens, progestogens, and antiandrogens are available in a variety of different formulations and for use by many different routes of administration in transfeminine people. The route of administration influences the absorption, distribution, metabolism, and elimination of the hormone in the body, resulting in significant differences between routes in terms of bioavailability, hormone levels in blood and specific tissues, and patterns of metabolites. These differences can have important therapeutic consequences.

Table 3: Major routes of administration of hormonal medications for transfeminine people:

RouteAbbr.DescriptionTypical forms
Oral administrationPOSwallowedTablet, capsule
Sublingual administrationSLHeld and absorbed under tongueTablet
Buccal administrationBUCHeld and absorbed in cheek or under lipsTablet
Transdermal administrationTDApplied to and absorbed through the skinPatch, gel, cream
Rectal administrationRECInserted into and absorbed by rectumSuppository
Intramuscular injectionIMInjected into muscle (e.g., buttocks, thigh, arm)Solution (vial/amp.)
Subcutaneous injectionSCInjected into fat under skinSolution (vial/amp.)
Subcutaneous implantSCiInsertion via surgical incision into fat under skinPellet

Vaginal administration is a major additional route of administration of hormonal medications in cisgender women. While vaginal administration via a natal vagina is of course not possible in transfeminine people, neovaginal administration is a possiblility in those who have undergone vaginoplasty. However, the lining of the neovagina is not the vaginal epithelium of natal females but instead is usually skin or colon—depending on the type of vaginoplasty performed (penile inversion or sigmoid colon vaginoplasty, respectively). For this reason, neovaginal administration in transfeminine people is likely more similar in its properties to transdermal and rectal administration—depending on the type of neovagina—than to vaginal administration in cisgender women. It is noteworthy that the vaginal and rectal routes are said to be similar in their properties for hormonal medications however (Goletiani, Keith, & Gorsky, 2007; Wiki). Moreover, absorption of estradiol via neovaginas constructed from peritoneum (internal abdominal lining)—a less commonly employed vaginoplasty approach in transfeminine people—was reported in one study to be similar to that with vaginal administration of estradiol in cisgender women (Willemsen et al., 1985). As such, neovaginal administration may be an additional possible route for certain transfeminine people depending on the circumstances. However, this route still remains to be more adequately characterized.

Estrogens

Estradiol, the primary bioidentical form normally found in the human body, is the main estrogen that is used in transfeminine hormone therapy. Estradiol hemihydrate (EH) is another form that is essentially identical to and interchangeable with estradiol. Estradiol esters are also sometimes used in place of estradiol. They are prodrugs of estradiol (i.e., are converted into estradiol in the body) and have essentially identical biological activity to estradiol. However, they have longer durations when used by injection due to slower absorption from the injection site, and this allows them to be administered less often. Some examples of major estradiol esters include estradiol valerate (EV; Progynova, Progynon Depot, Delestrogen) and estradiol cypionate (EC; Depo-Estradiol). Polyestradiol phosphate (PEP; Estradurin) is an injectable estradiol prodrug in the form of a polymer (i.e., linked chain of estradiol molecules) which is metabolized slowly and has a very long duration.

Non-bioidentical estrogens such as ethinylestradiol (EE; found in birth control pills), conjugated estrogens (CEEs; Premarin; used in menopausal hormone therapy), and diethylstilbestrol (DES; widely used previously but now abandoned) are resistant to metabolism in the liver and have disproportionate effects on estrogen-modulated liver synthesis when compared to bioidentical estrogens like estradiol (Aly, 2020). As a result, they have stronger influence on coagulation and greater risk of certain health problems like blood clots and associated cardiovascular issues (Aly, 2020). For this reason, as well as the fact that relatively high doses of estrogens may be needed for testosterone suppression, non-bioidentical estrogens should ideally never be used in transfeminine hormone therapy.

Estradiol dose-dependently suppresses testosterone levels in people with testes. Physiological and guideline-based levels of estradiol (<200 pg/mL or <734 pmol/L) are often not sufficient to suppress testosterone levels into the female range in transfeminine people who have not had their gonads removed (e.g., Liang et al., 2018; Krishnamurthy et al., 2023; Slack et al., 2023). As a result, estradiol is generally used in combination with an antiandrogen or progestogen in transfeminine hormone therapy (Hembree et al., 2017; Coleman et al., 2022; Rose et al., 2023). This results in partial suppression of testosterone levels by estradiol and further suppression or blockade of the remaining testosterone by the antiandrogen or progestogen. While combination therapy can be effective in fully suppressing or blocking testosterone (e.g., Aly, 2019; Aly, 2020), testosterone suppression can also still remain incomplete with antiandrogens and progestogens in certain forms (e.g., Aly, 2018; Jain, Kwan, & Forcier, 2019). In contrast to physiological estradiol levels, supraphysiological levels of estradiol are able to consistently and fully suppress testosterone levels into the normal female range with estradiol alone in transfeminine people (e.g., Gooren et al., 1984 [Graph]; Igo & Visram, 2021; Herndon et al., 2023 [Discussion]). This alternative approach, often referred to as high-dose estradiol monotherapy, has the advantage of avoiding the side effects, risks, and costs of antiandrogens and progestogens. However, it has the disadvantage of exposure to supraphysiological estradiol levels that are above those recommended by guidelines and that may have greater health risks. Physiological estradiol doses and combination therapy are more often used in transfeminine people treated by clinicians, whereas high-dose estradiol monotherapy is more frequently encountered in transfeminine people on DIY hormone therapy.

The feminizing effects of estradiol appear to be maximal at relatively low levels in the absence of androgens. Higher doses of estradiol and supraphysiological estradiol levels, aside from allowing for greater testosterone suppression, are not known to result in better feminization in transfeminine people (Deutsch, 2016; Nolan & Cheung, 2021). In fact, there is some indication that higher estrogen doses early into hormone therapy could actually result in worse breast development. Hence, the therapeutic emphasis in transfeminine hormone therapy is more on testosterone suppression than on achieving a specific estradiol level, at least above a certain low threshold level. Higher doses of estrogens, including of estradiol, also have a greater risk of adverse health effects such as blood clots and cardiovascular problems (Aly, 2020). As such, the use of physiological doses of estradiol is optimal in transfeminine people. At the same time however, high estrogen doses can be useful for improving testosterone suppression when it is inadequate, and the absolute risks, in the case of non-oral bioidentical estradiol, are low and are more important in people with specific risk factors (e.g., older age, physical inactivity, obesity, concomitant progestogen use, smoking, surgery, and rare thrombophilic abnormalities). If more adequate testosterone suppression is necessary, limitedly supraphysiological doses of non-oral estradiol may have a reasonable ratio of benefit to risk in this context, at least in those without relevant risk factors for estrogen-related complications (e.g., many healthy young people) (Aly, 2020).

Estradiol and estradiol esters are usually used orally, sublingually, transdermally, by injection (intramuscularly or subcutaneously), or by implant in transfeminine hormone therapy (Wiki).

Oral Estradiol

Estradiol is used orally in the form of tablets of estradiol (Wiki; Graphs). Alternatively, oral estradiol valerate tablets are used in some countries, for instance in many European countries. The only real differences between these oral estradiol forms is that estradiol valerate contains slightly less estradiol by weight (~76%) due to its ester component and hence requires somewhat higher doses (~1.3-fold) in comparison for equivalent estradiol levels (Wiki; Table). Oral estradiol has a duration suitable for once-daily administration. Oral administration of estradiol is a very convenient and inexpensive route, which makes it the most popular and widely used form of estradiol in transfeminine people. Oral estradiol has relatively low bioavailability (~5%), and there is substantial variability between people in terms of estradiol levels achieved with the same dose. Hence, in some transfeminine people estradiol levels may be low with oral estradiol, and testosterone suppression may be inadequate depending on the antiandrogen.

A major drawback of oral estradiol is that it results in excessive levels of estradiol in the liver due to the first pass that occurs with oral administration and has a disproportionate impact on estrogen-modulated liver synthesis (Aly, 2020). This in turn increases coagulation and the risk of associated health complications like blood clots and cardiovascular problems (Aly, 2020). These particular health concerns are largely allayed if estradiol is taken non-orally at reasonable and non-excessive doses. Hence non-oral forms of estradiol, like transdermal estradiol, although less convenient and often more expensive than oral estradiol, are preferable in transfeminine hormone therapy. It is recommended that all transfeminine people who are over 40 to 45 years of age use non-oral routes due to the greater risk of blood clots and cardiovascular problems that occurs with age (Aly, 2020; Coleman et al., 2022). Oral estradiol is not a good choice for high-dose estradiol monotherapy in transfeminine people due to the high estradiol levels required and the greater risks than with non-oral routes. In addition to its disproportionate liver impact, oral estradiol results in unphysiological levels of estradiol metabolites like estrone and estrone sulfate when compared to non-oral forms. The clinical implications of this, if any, are unknown. Oral and non-oral estradiol have in any case been found to have similar effectiveness in terms of feminization and breast development in transfeminine people in available studies (Sam, 2020).

Sublingual Estradiol

Oral estradiol tablets can be taken sublingually instead of orally. Sublingual use of estradiol tablets has several-fold higher bioavailability relative to oral administration and hence achieves much higher overall estradiol levels in comparison (Sam, 2021; Wiki; Graphs). Sublingual use of oral estradiol tablets can be employed instead of oral administration to reduce doses and hence medication costs or to produce higher estradiol levels for the purpose of achieving better testosterone suppression when needed. However, sublingual estradiol is very spiky in terms of estradiol levels when compared to oral estradiol and has a short duration of highly elevated estradiol levels. As such, it may be advisable for sublingual estradiol to be used in divided doses multiple times throughout the day in order to maintain at least somewhat steadier estradiol levels. The therapeutic implications for transfeminine people of the spikiness of sublingual estradiol, for instance in terms of testosterone suppression and health risks, have been little-studied and are mostly unknown. In any case, when used as a form of high-dose estradiol monotherapy and taken multiple times per day, strong though still incomplete testosterone suppression has been observed (Yaish et al., 2023). Oral estradiol valerate tablets can be taken sublingually instead of orally similarly to estradiol and are likewise highly effective when used in this way (Aly, 2019; Wiki). Due to partial swallowing of tablets, sublingual estradiol may in practice be a mixture of sublingual and oral administration and may have some of the same health risks of oral estradiol (Wiki). Buccal administration of estradiol appears to have similar properties as sublingual administration but is much less researched in comparison and is not used as often in transfeminine people (Wiki).

Transdermal Estradiol

Transdermal estradiol is available in the form of patches, gel, emulsions, and sprays (Wiki). These forms are usually applied to skin areas such as the arms, abdomen, or buttocks. Gel, emulsions, and sprays are applied and left to dry for a short period, whereas patches are applied and remain adhesed to the skin for a specified amount of time. Due to rate-limited absorption through the skin, there is a depot effect with transdermal estradiol and this route has a long duration with very steady estradiol levels. As a result, estradiol gel, emulsions, and sprays are all suitable for once-daily use. Patches stay applied and continuously deliver estradiol for either 3–4 days or 7 days depending on the patch brand (Table). Transdermal estradiol is more expensive than oral estradiol. Gel, emulsions, and sprays may be less convenient than oral administration, but patches can be more convenient due to their infrequent application. However, patches can sometimes cause application site problems like redness and irritation and can occasionally come off prematurely due to adhesive failure. As with oral estradiol, there is substantial variability in estradiol levels with transdermal estradiol, and some transfeminine people may have poor absorption, low estradiol levels, and inadequate testosterone suppression with this route. Estradiol sprays, such as Lenzetto, have been found to achieve very low estradiol levels that are probably not therapeutically adequate for use in transfeminine hormone therapy (Aly, 2020; Graph).

Transdermal estradiol is the form of estradiol most commonly used in transfeminine people who are over 40 years of age due to its lower health risks relative to oral estradiol. Transdermal estradiol gel is not a favorable option for high-dose estradiol monotherapy as it has difficulty achieving the high estradiol levels needed for adequate testosterone suppression (Aly, 2019). On the other hand, transdermal estradiol patches can be an effective option for high-dose estradiol monotherapy if multiple 100 μg/day patches are used, although this can require the use of many patches and can be expensive (Wiki). Different skin sites absorb transdermal estradiol to different extents (Wiki). Genital application of transdermal estradiol, specifically to the scrotum or neolabia, is particularly better-absorbed than conventional skin sites and can result in much higher estradiol levels than usual (Aly, 2019). This can be useful for reducing doses and hence medication costs or for achieving higher estradiol levels for better testosterone suppression when needed, for instance in the context of high-dose estradiol monotherapy. Transdermal estradiol should not be applied to the breasts as this is not known to result in improved breast development and the potential health consequences of doing so are unknown (e.g., influence on breast cancer risk).

Injectable Estradiol

Injectable estradiol preparations can be administered via either intramuscular or subcutaneous injection (Wiki; Wiki; Graphs). There is a depot effect with injection of estradiol esters such that they are slowly absorbed from the injection site and have a prolonged duration. This ranges from days to months depending on the ester. Commonly used injectable estradiol esters, which all have short to moderate durations, include estradiol valerate (EV), estradiol cypionate (EC), estradiol enanthate (EEn), and estradiol benzoate (EB). Longer-acting injectable estradiol esters, such as estradiol undecylate (EU) and polyestradiol phosphate (PEP), have been discontinued and are no longer pharmaceutically available. In the case of intramuscular injection, common injection sites include the deltoid muscle (upper arm), vastus lateralis and rectus femoris muscles (thigh), and ventrogluteal muscle (buttocks). Subcutaneous injection of estradiol injectables, while less commonly used, has comparable pharmacokinetics to intramuscular injection, and is easier, less painful, and more convenient in comparison (Wiki). However, the maximum volume that can be safely and comfortably injected subcutaneously is less than that which can be injected intramuscularly (depending on the site up to 1.5–3 mL and up to 2–5 mL, respectively) (Hopkins, & Arias, 2013; Usach et al., 2019). Injectable estradiol tends to be fairly inexpensive, but may be less convenient than other routes due to the need for regular injections. There may also be a risk of internal scar tissue build-up long-term. Estradiol injectables have been discontinued in many parts of the world (e.g., most of Europe), and their availability is limited. In recent years, many transfeminine people have turned to black market homebrewed injectable estradiol preparations to use this route.

Injectable estradiol preparations are typically used at higher doses than other forms of estradiol, and can easily achieve very high levels of estradiol. This can be useful for testosterone suppression, making this form of estradiol likely the best choice for high-dose estradiol monotherapy in transfeminine people. However, the high doses that are possible with injectable estradiol preparations can also easily lead to overdosage and unnecessarily increased risks (e.g., Aly, 2020). Resources are available on this site for guiding selection of appropriate doses and intervals of injectable estradiol esters in transfeminine people. This includes a simulator and informal meta-analysis of estradiol levels with these preparations (Aly, 2021; Aly, 2021) and a table providing approximate equivalent doses between injectable estradiol esters and other estradiol routes and forms (Aly, 2020). It is notable and unfortunate that currently recommended doses and intervals for injectable estradiol esters by transgender care guidelines (e.g., 10–40 mg/2 weeks estradiol valerate) appear to be highly excessive and too widely spaced, and are likely to be therapeutically inadvisable (Aly, 2021). Doses and intervals of injectable estradiol esters recommended by the present author for use as a means of high-dose estradiol monotherapy, targeting mean estradiol levels of around 300 pg/mL (1,100 pmol/L), are provided below (Table 4).

Table 4: Recommended doses and intervals of injectable estradiol esters for high-dose estradiol monotherapy (targeting estradiol levels of around 300 pg/mL [1,100 pmol/L]):

Estradiol EsterShortMediumLongSimulation
Estradiol benzoate0.67 mg/1 day1.33 mg/2 days2 mg/3 daysGraph
Estradiol valerate2 mg/3 days3.5 mg/5 days5 mg/7 daysGraph
Estradiol cypionate (in oil)5 mg/7 days7 mg/10 days10 mg/14 daysGraph
Estradiol cypionate (suspension)2 mg/3 days3.5 mg/5 days5 mg/7 daysGraph
Estradiol enanthate5 mg/7 days7 mg/10 days10 mg/14 daysGraph
Estradiol undecylatea10 mg/14 days20 mg/28 days30 mg/42 daysGraph
Polyestradiol phosphate160 mg/30 days240 mg/45 days320 mg/60 daysGraph

a Doses and intervals for estradiol undecylate are extrapolated and hypothetical (Aly, 2021).

These doses and intervals should be considered a starting point, and should be fine-tuned as necessary based on blood tests. In terms of injection intervals, the shorter interval, the more stable the estradiol levels, but the more often that injections need to be done. Doses may be increased if estradiol levels are too low and testosterone suppression is inadequate, and doses may be decreased if estradiol levels are too high so long as adequate testosterone suppression is maintained. Doses should be lower (targeting mean estradiol levels of 100–200 pg/mL [367–734 pmol/L]) if combined with an antiandrogen or progestogen as these agents will help with testosterone suppression. Similarly, doses should be lower following surgical gonadal removal as testosterone suppression will no longer be necessary.

Estradiol Pellets

Estradiol implants are pellets of pure crystalline hormone and are surgically placed into subcutaneous fat by a physician (Wiki). They are slowly absorbed by the body following implantation, and new implants are given once every 4 to 6 months. Due to the need for minor surgery, their high cost, and limited availability, estradiol implants are not as commonly used as other estradiol routes. Notably, almost all pharmaceutical estradiol implants throughout the world have been discontinued, and the implants that remain available are almost exclusively compounded products provided by compounding pharmacies. Dosage adjustment with estradiol implants is also more difficult than with other estradiol routes. Despite their various practical limitations however, estradiol implants allow for very steady estradiol levels, and their very long duration can allow for unusual convenience among available estradiol forms.

Additional Notes

Table 5: Available forms and recommended doses of estradiol for adulta transfeminine people:

MedicationRouteFormDosage
EstradiolOralTablets2–8 mg/day
 Sublingual or buccalTablets0.5–6 mg/dayb
 TransdermalPatches50–400 μg/day
  Gel1.5–6 mg/day
  SpraysNot recommendedc
 SC implantPellet25–150 mg/6 months
Estradiol valerateOralTablets3–10 mg/dayd
 Sublingual or buccalTablets1–8 mg/dayb,d
 IM or SC injectionOil solution0.75–4 mg/5 days; or
1–6 mg/7 days; or
1.5–9 mg/10 days
Estradiol cypionateIM or SC injectionOil solution1–6 mg/7 days; or
1.5–9 mg/10 days; or
2–12 mg/14 days
  Aqueous suspension0.75–4 mg/5 days; or
1–6 mg/7 days; or
1.5–9 mg/10 days
Estradiol enanthateIM or SC injectionOil solution1–6 mg/7 days; or
1.5–9 mg/10 days; or
2–12 mg/14 days
Estradiol benzoateIM or SC injectionOil solution0.15–0.75 mg/day; or
0.3–1.5 mg/2 days; or
0.45–2.25 mg/3 days
Estradiol undecylateeIM or SC injectionOil solution2–12 mg/14 days; or
4–24 mg/28 days; or
6–36 mg/42 days
Polyestradiol phosphateIM injectionWater solution40–160 mg/monthf

a Estradiol doses in pubertal adolescent transfeminine people should be lower to mimic estradiol exposure during normal female puberty (Aly, 2020). b May be advisable to use divided doses 2 to 4 times per day (i.e., once every 6 to 12 hours) instead of once per day (Sam, 2021). c This estradiol form achieves very low estradiol levels at typical doses that don’t appear to be well-suited for transfeminine hormone therapy (Aly, 2020; Graph). d Estradiol valerate contains about 75% of the same amount of estradiol as estradiol so doses are about 1.3-fold higher for the same estradiol levels (Aly, 2019; Sam, 2021). e Doses and intervals for estradiol undecylate are extrapolated and hypothetical (Aly, 2021). f A higher initial loading dose of e.g., 240 or 320 mg polyestradiol phosphate can be used for the first one or two injections to reach steady-state estradiol levels more quickly. However, this preparation has recently been discontinued and appears to no longer be available.

Additional informational resources are available in terms of estradiol levels (Wiki; Table) and approximate equivalent doses (Aly, 2020) with different forms, routes, and doses of estradiol.

There is high variability between individuals in the levels of estradiol achieved during estradiol therapy. That is, estradiol levels during treatment with the same dosage of estradiol can differ substantially between individuals. This variability is greatest with oral and transdermal estradiol but is also considerable even with injectable estradiol preparations and other estradiol forms. As such, estradiol doses are not absolute and should be individualized on a case-by-case basis in conjunction with blood work as a guide. It should also be noted that due to fluctuations in estradiol concentrations with certain routes, levels of estradiol can vary considerably from one blood test to another. This is most notable with sublingual estradiol and injectable estradiol. The fluctuations in estradiol levels with these routes are predictable and must be understood when interpreting blood work results. Differences in blood test results can be minimized with informed and consistent timing of blood draws.

If or when the gonads are surgically removed, testosterone suppression is no longer needed in transfeminine people. As a result, estradiol doses, if they are high or supraphysiological, can be lowered to more closely approximate normal physiological levels in cisgender women.

Progestogens

Progestogens include progesterone and progestins. Progestins are synthetic progestogens derived from structural modification of progesterone or testosterone. There are dozens of different progestins and these progestins can be divided into a variety of different structural classes with varying properties (Table). Examples of some major progestins of different classes include the 17α-hydroxyprogesterone derivative medroxyprogesterone acetate (MPA; Provera, Depo-Provera), the 19-nortestosterone derivative norethisterone (NET; many brand names), the retroprogesterone derivative dydrogesterone (Duphaston), and the 17α-spirolactone derivative drospirenone (Slynd, Yasmin). Progestins were developed because they have a more favorable disposition in the body than progesterone for use as medications. Only a few clinically used progestins have been used in transfeminine hormone therapy. However, progestogens largely produce the same progestogenic effects, with a few exceptions, and theoretically almost any progestogen could be employed.

Progestogens have antigonadotropic effects via their progestogenic activity and dose-dependently suppress the secretion of the gonadotropins from the pituitary gland. This in turn results in a reduction of gonadotropin-mediated gonadal stimulation and a decrease in sex hormone production as well as fertility. The dose-dependent testosterone-suppressing effects of a variety of different progestogens have been characterized in clinical studies in cisgender men and transfeminine people (Nieschlag, Zitzmann, & Kamischke, 2003; Nieschlag, 2010; Nieschlag & Behre, 2012; Zitzmann et al., 2017; Aly, 2019). Some notable examples of this include cyproterone acetate (CPA) (Aly, 2019; Wiki), MPA (Wiki), NET (Wiki) and its ester norethisterone acetate (NETA) (Wiki), levonorgestrel (LNG) (Zitzmann et al., 2017; Wiki), desogestrel (DSG) (Wu et al., 1999; Wiki), dienogest (DNG) (Meriggiola et al., 2002; Wiki), and progesterone (Wiki), among others. High doses of progestogens by themselves are able to maximally suppress testosterone levels by about 50 to 70% on average (Aly, 2019; Zitzmann et al., 2017 (Graph)). In combination with estrogen however, this increases to about 95%, with testosterone levels suppressed into the normal female range (Aly, 2019). Progestogens seem to usually achieve their maximal testosterone-suppressing capacity at a dose of around 5 to 10 times their ovulation-inhibiting dosage in cisgender women (Aly, 2019). Due to low potency or atypicality, oral progesterone and dydrogesterone are exceptions among progestogens which do not have significant antigonadotropic effects and which would not be expected to suppress testosterone levels (Aly, 2018; Wiki; Wiki).

Besides helping with testosterone suppression, progestogens are of no clear or known benefit for feminization or breast development in transfeminine people. While some transfeminine people anecdotally claim to experience improved breast development with progestogens, an involvement of progestogens in improving breast size or shape is controversial and is not supported by theory nor evidence at present (Wiki; Aly, 2020). It is possible that premature introduction of progestogens, particularly at high doses, could actually have an unfavorable influence on breast development (Aly, 2020). Many transfeminine people have also anecdotally claimed that progestogens have a beneficial effect on their sexual desire. However, a review of the literature by the present author found that neither progesterone nor progestins positively influence sexual desire in humans (Aly, 2020). Instead, the available evidence suggests either a neutral influence or an inhibitory effect of progestogens on sexual desire, although the latter may be specific only to high doses of progestogens (Aly, 2020). Claims have been made that progesterone may have beneficial effects on mood in transfeminine people as well, but clinical support for such notions is likewise lacking at this time (Coleman et al., 2022; Nolan et al., 2022). It is notable that progesterone at luteal-phase levels, due to its neurosteroid metabolites like allopregnanolone, actually appears to worsen mood in around 30% of cisgender women, and produces more overt negative reactions, which constitute the diagnoses of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD), in around 2 to 10% of women (Bäckström et al., 2011; Edler Schiller, Schmidt, & Rubinow, 2014; Sundström-Poromaa et al., 2020). More research is needed to evaluate the possible beneficial effects of progestogens in transfeminine people.

Most clinically used progestogens have off-target activities in addition to their progestogenic activity, and these activities may be desirable or undesirable depending on the action in question (Kuhl, 2005; Stanczyk et al., 2013; Wiki; Table). Progesterone has a variety of neurosteroid as well as other activities that can result in central nervous system effects among others which are not shared by progestins. MPA as well as NET and its derivatives have weak androgenic activity, which is unfavorable in the context of transfeminine hormone therapy. NET and certain related progestins produce ethinylestradiol as a metabolite at high doses and hence can produce ethinylestradiol-like estrogenic effects, including increased risk of blood clots and associated cardiovascular problems. Other off-target actions of progestogens include antiandrogenic, glucocorticoid, and antimineralocorticoid activities. These actions can result in differences in therapeutic effectiveness (e.g., androgen suppression or blockade) as well as side effects and health risks. Some notable progestins without undesirable off-target activities (i.e., androgenic or glucocorticoid activity) include low-dose CPA, drospirenone (DRSP), dienogest, nomegestrol acetate (NOMAC), dydrogesterone, and hydroxyprogesterone caproate (OHPC). However, of these progestins, only CPA has been considerably used and studied in transfeminine people.

The addition of progestogens to estrogen therapy has been associated with a number of unfavorable health effects. These include increased risk of blood clots (Wiki; Aly, 2020), coronary heart disease (Wiki), and breast cancer (Wiki; Aly, 2020). High doses of progestogens are also associated with increased risk of certain non-cancerous brain tumors including meningiomas and prolactinomas (Wiki; Aly, 2020). The coronary heart disease risk may be due to changes in blood lipids caused by the weak androgenic activity of certain progestogens, but the rest of the aforementioned risks are probably due to their progestogenic activity (Stanczyk et al., 2013; Jiang & Tian, 2017). Aside from health risks, progestogens have also been associated with adverse mood changes (Wiki; Wiki). However, besides the case of progesterone and its neurosteroid metabolites, these effects of progestogens are controversial and are not well-supported by evidence (Wiki; Wiki). Progestogens are otherwise generally well-tolerated and are regarded as producing little in the way of side effects.

In contrast to certain progestins, progesterone has no unfavorable off-target activities. Due to its lack of androgenic activity, progesterone has no adverse influence on blood lipids and is not expected to raise the risk of coronary heart disease. The addition of oral progesterone to estrogen therapy notably has not been associated with increased risk of blood clots (Wiki). In addition, oral progesterone seems to have less risk of breast cancer than progestins with short-term therapy, although this is notably not the case with longer-term exposure (Wiki; Aly, 2020). Consequently, it has been suggested that progesterone, for reasons that have yet to be fully elucidated, may be a safer progestogen than progestins and that it should be the preferred progestogen for hormone therapy in cisgender women and transfeminine people. However, there are also theoretical arguments against such notions. Oral progesterone is known to produce very low progesterone levels and to have only weak progestogenic effects at typical doses (Aly, 2018; Wiki). The seemingly better safety of oral progesterone may simply be an artifact of the low progesterone levels that occur with it, and hence of progestogenic dosage. Non-oral progesterone, at doses resulting in physiological and full progestogenic strength, has never been properly evaluated in terms of health outcomes, and may have similar risks as progestins (Aly, 2018; Wiki).

Due to their lack of known influence on feminization and breast development and their known and possible adverse effects and risks, progestogens are not routinely used in transfeminine hormone therapy at present. Major transgender health guidelines note the limitations of the available evidence on progestogens for transfeminine people and have mixed attitudes on their use, either explictly recommending against their use (Coleman et al., 2022—WPATH SOC8), taking a more neutral stance (Hembree et al., 2017—Endocrine Society guidelines), or being permissive of their use (Deutsch, 2016—UCSF guidelines). There is however a very major exception to the preceding in the form of CPA, an antiandrogen which is widely used in transfeminine hormone therapy to suppress testosterone production and which happens to be a powerful progestogen at the typical doses used in transfeminine people. CPA will be described below in the section on antiandrogens. Although progestogens have various health risks, cisgender women of course have progesterone, and the absolute risks of progestogens are very low in healthy young people. Risks like breast cancer also are exposure-dependent and take many years to develop. The testosterone suppression provided by progestogens can furthermore be very useful in transfeminine people, as is widely taken advantage of with CPA. Given these considerations, a limited duration of progestogen therapy in transfeminine people, for instance a few years to help suppress testosterone levels before surgical gonadal removal, may be considered quite acceptable.

Progesterone can be used in transfeminine people by oral administration, sublingual administration, rectal administration, or by intramuscular or subcutaneous injection (Wiki). Progestins are usually used via oral administration, but certain progestins are also available in injectable formulations (Wiki).

Oral Progesterone

Progesterone is most commonly taken orally. It is used by this route in the form of oil-filled capsules containing 100 or 200 mg micronized progesterone under brand names such as Prometrium, Utrogestan, and Microgest (Wiki). Despite its widespread use, levels of progesterone via oral administration have been found using state-of-the-art assays (LC–MS) to be very low (<2 ng/mL [<6.4 nmol/L] at 100 mg/day) and inadequate for satisfactory progestogenic effects in various areas (Aly, 2018; Wiki). In relation to this, even high doses of oral progesterone (400 mg/day) showed no antigonadotropic effect or testosterone suppression in cisgender men (Aly, 2018; Wiki). This is in major contrast to non-oral forms of progesterone and to progestins, which produce dose-dependent and robust testosterone suppression (Aly, 2019; Wiki). In addition to its low progestogenic potency, oral progesterone is excessively converted into neurosteroid metabolites like allopregnanolone and pregnanolone. These metabolites act as potent GABAA receptor positive allosteric modulators, and can produce undesirable alcohol-like side effects such as sedation, cognitive, memory, and motor impairment, and mood changes (Wiki; Wiki). As such, while inconvenient, non-oral routes are greatly preferable for progesterone.

Sublingual Progesterone

Sublingual progesterone tablets exist and are marketed under the brand name Luteina but today are only available in Poland and Ukraine (Wiki). Oral progesterone could theoretically be taken sublingually, analogously to sublingual use of oral estradiol. However, because oral progesterone is formulated as oil-filled capsules, this makes it difficult and unpleasant to use by sublingual administration. Buccal progesterone, which would be expected to have similar characteristics to those of sublingual progesterone, has been used in medicine in the past, but is no longer marketed today (Wiki).

Rectal Progesterone

Progesterone is approved for use by rectal administration in the form of suppositories under the brand name Cyclogest (Wiki). This product is marketed in only a limited number of countries however, although it is available in the United Kingdom (Wiki). While not approved for use by rectal administration, oral progesterone capsules can be taken rectally instead of orally, and using them in this way may allow for much higher progesterone levels than would be achieved by oral administration due to avoidance of most first-pass metabolism. Rectal administration of oral progesterone capsules has not been formally studied, but oral progesterone capsules have been administered vaginally in cisgender women with success (Miles et al., 1994; Wang et al., 2019), and the vaginal and rectal routes are said to have similar pharmacokinetics in general (Goletiani, Keith, & Gorsky, 2007; Wiki). Hence, there is good theoretical basis for rectal administration of oral progesterone capsules being an effective route of administration of progesterone. Whereas oral progesterone achieves very low levels of progesterone, rectal progesterone can readily achieve normal luteal-phase levels of progesterone (Wiki). Although inconvenient, rectal administration may be the overall best route of administration of progesterone for transfeminine people.

Injectable Progesterone

Progesterone by injection is available as an oil solution for intramuscular injection under brand names such as Proluton, Progestaject, and Gestone (Wiki) and as an aqueous solution for subcutaneous injection under the brand name Prolutex (Wiki). Oil solutions of progesterone for intramuscular injection are widely available, whereas the aqueous solution of progesterone for subcutaneous injection is available only in some European countries (Wiki). Injectable progesterone, regardless of route, has a relatively short duration and must be injected once every one to three days (Wiki; Wiki). This makes it too inconvenient to use for most people. Unlike with estradiol, progesterone esters with longer durations than progesterone itself by injection are not chemically possible as progesterone has no hydroxyl groups available for esterification (Wiki). Injectable aqueous suspensions of microcrystalline progesterone were previously marketed and had a duration of 1 to 2 weeks, but these preparations were associated with pain at the injection site and were eventually discontinued (Aly, 2019; Wiki).

Other Progesterone Routes

Other progesterone routes, such as transdermal progesterone and subcutaneous progesterone pellets, are also known, but are not available as pharmaceutical drugs and are little-used medically (Wiki). This is related to the low potency of progesterone and difficulty achieving progesterone levels high enough for adequate therapeutic effects with these routes (Wiki; Wiki). In addition, progesterone pellets tend to be extruded at high rates (Wiki). In any case, certain compounding pharmacies may make forms of progesterone that could be used by these routes.

Oral and Injectable Progestins

Most progestins are taken orally in the form of solid tablets (Wiki). In contrast to progesterone, progestins, owing to their synthetic nature, are resistant to metabolism in the intestines and liver and have high oral bioavailability. In addition, unlike the case of the estrogen receptors, the progesterone receptors are expressed minimally or not at all in the liver, and there is no known first pass influence of progestogenic activity on liver synthesis (Lax, 1987; Stanczyk, Mathews, & Cortessis, 2017). As a result, there are no apparent problems with oral administration in the case of purely progestogenic progestins. However, some progestins have liver-impacting off-target hormonal actions, such as androgenic, estrogenic, and/or glucocorticoid activity, and this can result in adverse effects like unfavorable lipid changes or procoagulation—which may be augmented by the first pass with oral administration.

A selection of progestins are available in injectable formulations, including for intramuscular or subcutaneous injection (Wiki). Some of the more notable ones include medroxyprogesterone acetate (MPA), norethisterone enanthate (NETE), hydroxyprogesterone caproate (OHPC), and algestone acetophenide (dihydroxyprogesterone acetophenide; DHPA) (Wiki). In addition to being used alone, injectable progestins are used together with estradiol esters in combined injectable contraceptives (Wiki). These preparations are often used as a means of hormone therapy by transfeminine people in Latin America. Whereas injectable progesterone has a duration measured in days, injectable progestins have durations ranging from weeks to months, and can be injected much less often in comparison (Table).

Additional Notes

Table 6: Available forms and recommended doses of progestogens for transfeminine people:

MedicationRouteFormDosage
ProgesteroneOralOil-filled capsules100–300 mg 1–2x/day
 RectalSuppositories; Oil-filled capsules100–200 mg 1–2x/day
 IM injectionOil solution25–75 mg/1–3 days
 SC injectionWater solution25 mg/day
ProgestinsOral; IM or SC injectionTablets; Oil solution; Water solutionVarious

For progesterone levels with different forms, routes, and doses of progesterone, see the table here (only LC–MS and IA + CS assays for oral progesterone) and the graphs here.

As with estradiol, there is high variability between individuals in progesterone levels. Conversely, there is less variability between individuals in the case of progestins.

After removal of the gonads, progestogen doses can be lowered or adjusted to approximate normal female physiological exposure or they can be discontinued entirely.

Antiandrogens

Aside from estrogens and progestogens, there is another class of hormonal medications used in transfeminine hormone therapy known as antiandrogens (AAs). These medications reduce the effects of androgens in the body by either decreasing androgen production and thereby lowering androgen levels or by directly blocking the actions of androgens. They work via a variety of different mechanisms of action, and include androgen receptor antagonists, antigonadotropins, and androgen synthesis inhibitors.

Androgen receptor antagonists act by directly blocking the effects of androgens, including testosterone, DHT, and other androgens, at the level of their biological target. They bind to the androgen receptor without activating it, thereby displacing androgens from the receptor. Due to the nature of their mechanism of action as competitive blockers of androgens, the antiandrogenic efficacy of androgen receptor antagonists is both highly dose-dependent and fundamentally dependent on testosterone levels. They do not act by lowering testosterone levels, although some androgen receptor antagonists may have additional antiandrogenic actions that result in decreased testosterone levels. Because androgen receptor antagonists do not work by lowering testosterone levels, blood work can be less informative for them compared to antiandrogens that suppress testosterone levels. Androgen receptor antagonists include steroidal antiandrogens (SAAs) like spironolactone (Aldactone) and cyproterone acetate (CPA; Androcur) and nonsteroidal antiandrogens (NSAAs) like bicalutamide (Casodex).

Antigonadotropins suppress the gonadal production of androgens by inhibiting the GnRH-mediated secretion of gonadotropins from the pituitary gland. They include estrogens and progestogens. In addition, GnRH agonists such as leuprorelin (Lupron) and GnRH antagonists such as elagolix (Orilissa) act similarly and could likewise be described as antigonadotropins.

Androgen synthesis inhibitors inhibit the enzyme-mediated synthesis of androgens. They include 5α-reductase inhibitors (5α-RIs) like finasteride (Propecia) and dutasteride (Avodart). There are also other types of androgen synthesis inhibitors, for instance potent 17α-hydroxylase/17,20-lyase inhibitors like ketoconazole (Nizoral) and abiraterone acetate (Zytiga). However, these agents have limitations (e.g., toxicity, high cost, and lack of experience) and have not been used in transfeminine hormone therapy.

Although antigonadotropins and androgen synthesis inhibitors have antiandrogenic effects secondary to decreased androgen levels, they are not usually referred to as “antiandrogens”. Instead, this term is most commonly reserved to refer specifically to androgen receptor antagonists. However, antigonadotropins and androgen synthesis inhibitors may nonetheless be described as antiandrogens as well.

After removal of the gonads, antiandrogens can be discontinued. If unwanted androgen-dependent symptoms, such as acne, seborrhea, or scalp hair loss, persist despite full suppression or ablation of gonadal testosterone, then a lower dose of an androgen receptor antagonist, such as 100 to 200 mg/day spironolactone or 12.5 to 25 mg/day bicalutamide, can be continued to treat these symptoms.

Table 7: Available forms and recommended doses of antiandrogens for transfeminine people:

MedicationTypeRouteFormDosage
Cyproterone acetateProgestogen; Androgen receptor antagonistOralTablets2.5–12.5 mg/daya
SpironolactoneAndrogen receptor antagonist; Weak androgen synthesis inhibitorOralTablets100–400 mg/dayb,c
BicalutamideAndrogen receptor antagonistOralTablets12.5–50 mg/dayb

a For CPA, this dose range is specifically one-quarter of a 10-mg tablet to one full 10-mg tablet per day (2.5–10 mg/day) or a quarter of a 50-mg tablet every other day or every 2 to 3 days (4.2–12.5 mg/day). A dosage of 5–10 mg/day or 6.25–12.5 mg/day is likely to ensure maximal testosterone suppression, while lower doses may be less effective (Aly, 2019). b For spironolactone and bicalutamide, it is assumed that testosterone levels are substantially suppressed (≤200 ng/dL [<6.9 nmol/L]). If testosterone levels are not suppressed to this range, then higher doses may be warranted. c Spironolactone and its metabolites have relatively short half-lives, and twice-daily administration in divided doses (e.g., 100–200 mg twice per day) is recommended.

Figure 3: Suppression of gonadal testosterone production and circulating testosterone levels (ng/dL) with estradiol in combination with different antiandrogens over one year of hormone therapy in transfeminine people (Sofer et al., 2020). The estradiol forms included oral tablets 2–8 mg/day, transdermal gel 2.5–5 mg/day, and transdermal patches 50–200 μg/day. The antiandrogens included spironolactone 50–200 mg/day (n=16), cyproterone acetate (n=41), and GnRH agonists (specifically triptorelin 3.75 mg/month or goserelin 3.6 mg/month by injection) (n=10) (Sofer et al., 2020). It should be noted that lower doses of cyproterone acetate (10–12.5 mg/day) show equal testosterone suppression to higher doses (25–100 mg/day) and higher doses should no longer be used (Aly, 2019). The dashed horizontal line corresponds to the upper limit of the normal female range for testosterone levels.

Cyproterone Acetate

Cyproterone acetate (CPA; Androcur) is a progestogen and antiandrogen. It is widely used as a progestogen in cisgender women, including in hormonal birth control and menopausal hormone therapy. CPA is also widely used as an antiandrogen in the treatment of androgen-dependent conditions in cisgender women and cisgender men. In cisgender women, it is used to treat acne, hirsutism (excessive facial/body hair growth), scalp hair loss, and hyperandrogenism (high androgen levels) due to polycystic ovary syndrome (PCOS). In cisgender men, it is used to treat prostate cancer and to lower sex drive in the management of sexual problems such as paraphilias, hypersexuality, and sex offenses. Besides cisgender people, CPA is widely used as a component of hormone therapy—specifically as an antiandrogen—in transfeminine people. The medication is notably not marketed in the United States, where spironolactone is most commonly used instead. However, CPA is widely available throughout the rest of the world, and is the most frequently used antiandrogen in transfeminine people in Europe and probably the whole world overall (T’Sjoen et al., 2019; Glintborg et al., 2021; Coleman et al., 2022).

As an antiandrogen, CPA has a dual mechanism of action of suppressing testosterone levels via its progestogenic and hence antigonadotropic activity and of acting as an androgen receptor antagonist (Aly, 2019). The progestogenic activity of CPA is of far greater potency than its androgen receptor antagonism however (Aly, 2019). The dose of CPA used as a progestogen in cisgender women is about 2 mg per day, which produces similar progestogenic effects to those of physiological luteal-phase levels of progesterone (e.g., suppression of gonadotropin secretion, ovulation inhibition, and endometrial transformation and protection) (Aly, 2019). Conversely, much higher doses of CPA of 50 to 300 mg/day have typically been used for androgen-dependent indications (Aly, 2019). These high doses of CPA result in profound progestogenic overdosage and associated side effects and risks (Aly, 2019). In transfeminine people, CPA has historically been used at doses of 50 to 150 mg/day (Aly, 2019). However, CPA doses have dramatically fallen in recent years, and today doses of no more than 10 to 12.5 mg/day are recommended (Aly, 2019; Coleman et al., 2022—WPATH SOC8). These lower doses of CPA still produce strong progestogenic effects, and in combination with estradiol, are equally effective as higher doses in suppressing testosterone levels (Aly, 2019; Meyer et al., 2020; Even Zohar et al., 2021; Kuijpers et al., 2021; Coleman et al., 2022). Even lower doses of CPA, for instance 5 to 6.25 mg/day, are currently being studied, and may still be fully effective (Aly, 2019).

Given by itself without estrogen, CPA typically suppresses testosterone levels in people with testes by about 50 to 70%, down to about 150 to 300 ng/dL (5.2–10.4 nmol/L) (Meriggiola et al., 2002; Toorians et al., 2003; Giltay et al., 2004; T’Sjoen et al., 2005; Tack et al., 2017; Zitzmann et al., 2017; Aly, 2019). Lower doses of CPA alone (e.g., 10 mg/day) show the same degree of testosterone suppression as higher doses of CPA alone (e.g., 50–100 mg/day), indicating that the antigonadotropic effects of CPA are maximal at relatively low therapeutic doses of this medication (Aly, 2019). This is on the order of about 5 to 10 times the ovulation-inhibiting dosage of CPA in cisgender women, a dose–response relationship that has also been observed with a number of other progestogens (Aly, 2019). Per the preceding, CPA alone, regardless of dosage, is unable to reduce testosterone levels into the normal female range (<50 ng/dL [<1.7 nmol/L]). But when CPA is combined with estradiol, even at relatively small doses of estradiol, it consistently suppresses testosterone levels into the normal female range (Aly, 2019; Angus et al., 2019; Gava et al., 2020; Sofer et al., 2020; Collet et al., 2022). However, it appears that a certain minimum level of estradiol, perhaps around 60 pg/mL (220 pmol/L) on average, is required for this to occur (Aly, 2019). Estradiol levels lower than this threshold in those taking CPA, which can occasionally be encountered in transfeminine people due to estradiol being dosed too low, have the potential to compromise full testosterone suppression (Aly, 2019).

In addition to testosterone suppression, CPA can dose-dependently block the androgen receptor (Aly, 2019). However, relatively high doses of CPA are needed to considerably antagonize the androgen receptor (e.g., 50–300 mg/day), and lower doses (e.g., ≤12.5 mg/day) may not be able to do this to a meaningful degree (Aly, 2019). As such, lower doses of CPA may essentially be purely progestogenic, with minimal or no androgen receptor antagonism. In this regard, referring to CPA at such doses as an “antiandrogen”—rather than as a “progestogen”—may be considered somewhat of a misnomer. Higher doses of CPA (>12.5 mg/day) can no longer be considered safe due to the massive progestogenic overdosage that occurs with them, and should no longer be used in transfeminine people. Moreover, as testosterone levels are usually suppressed into the normal female range in transfeminine people taking estradiol plus CPA, there is no actual need for any additional androgen receptor blockade (Aly, 2019).

CPA has been reported to produce various side effects. Some of these side effects include fatigue and a degree of weight gain (Belisle & Love, 1986; Hammerstein, 1990; Martinez-Martin et al., 2022). CPA might be able to produce a magnitude of sexual dysfunction (e.g., reduced sexual desire) beyond that expected with testosterone suppression alone (Wiki; Aly, 2019). It may also have a small risk of depressive mood changes (Wiki). In transfeminine people, CPA has been documented to produce pregnancy-like breast changes (i.e., lobuloalveolar development of the mammary glands) (Kanhai et al., 2000). In relation to this, CPA sometimes causes lactation as a side effect (Gooren, Harmsen-Louman, & van Kessel, 1985; Schlatterer et al., 1998; Bazarra-Castro, 2009). Concerns have been raised about premature introduction of progestogens—particularly at high doses like with CPA—and possible adverse influence on breast development (Aly, 2020). However, little data exists in humans to substantiate such concerns at present. The side effects of CPA are assumed to be dose-dependent, and using the lowest effective doses is expected to minimize its side effects.

As CPA is a progestogen, it is associated with increased risks of breast cancer (Fournier, Berrino, & Clavel-Chapelon, 2008; CGHFBC, 2019; de Blok et al., 2019; Aly, 2020; Wiki) and blood clots (Seaman et al., 2007; Connors & Middeldorp, 2019; Aly, 2020; Wiki) even at very low doses (e.g., 2 mg/day). Higher doses of CPA, likewise presumed to be due to its progestogenic activity, are additionally associated with elevated prolactin levels (Sofer et al., 2020; Wilson et al., 2020; Wiki) as well as with certain generally non-cancerous brain tumors including prolactinomas (McFarlane, Zajac, & Cheung, 2018; Nota et al., 2018; Wiki) and meningiomas (McFarlane, Zajac, & Cheung, 2018; Nota et al., 2018; Millward et al., 2021; Weill et al., 2021; Aly, 2020; Wiki). These risks appear to be dose-dependent, and thus are likely to be minimized with lower doses of CPA. Besides risks related to its progestogenic activity, CPA at high doses has shown weak but significant androgenic effects in the liver and has been associated with an unfavorable influence on lipid profile, for instance decreased HDL (“good”) cholesterol levels (Coleman et al., 2022; Wiki). Long-term, this could result in an increase in the risk of coronary heart disease. Other potential adverse effects of CPA at high doses with unclear mechanisms may include increased blood pressure and heightened insulin resistance (Martinez-Martin et al., 2022). Additionally, CPA has been associated with abnormal liver function tests and rare cases of liver toxicity, including at doses used in transfeminine people of 25 to 50 mg/day (Heinemann et al., 1997; Bessone et al., 2016; Kumar et al., 2021; Wiki; Table). The likelihood of abnormal liver function tests with CPA, and probably of liver toxicity, appears to be much lower at doses of less than 20 mg/day (Wiki). More than 100 cases of clinically significant liver toxicity have been reported with CPA, but only two cases have been reported with CPA at doses of 50 mg/day or less (Wiki; Table). Monitoring of prolactin levels to detect prolactinomas, and monitoring of liver function to detect liver toxicity, may both be advisable in people taking CPA. Regular magnetic resonance imaging (MRI) scans have also been recommended to monitor for meningiomas in people taking CPA (at ≥10 mg/day) (Aly, 2020).

CPA is usually taken orally in the form of tablets (e.g., 10, 50, and 100 mg) (Wiki). Under the brand name Androcur Depot, it is also available as a long-lasting 300 mg depot injectable in some countries (Wiki). However, this formulation is not commonly used in transfeminine people, and happens to correspond to very high doses in terms of CPA exposure. A pill cutter (Amazon) can be used to split CPA tablets and achieve lower doses (e.g., 12.5 mg doses with 50-mg tablets). CPA has a relatively long elimination half-life of about 1.6 to 4.3 days (Wiki; Aly, 2019). As such, it can be taken once daily, or even as infrequently as once every 2 or 3 days, if needed (Aly, 2019). In addition to splitting of CPA tablets, dosing CPA once every 2 or 3 days can also be useful for achieving lower doses (Aly, 2019).

As already described, CPA is a powerful progestogen even at the relatively low doses now used in transfeminine people (e.g., 5–12.5 mg/day). As such, there is no need, nor point, in adding another progestogen, for instance progesterone, in those who are taking CPA—at least if the goal of doing so is to produce progestogenic effects. This is something that is often overlooked in people taking CPA, and can result in increased costs, side effects, and inconvenience without any expected benefit.

Spironolactone

Spironolactone (Aldactone) is an antiandrogen and antimineralocorticoid. It is widely used as an antiandrogen in cisgender women for treatment of androgen-dependent hair and skin conditions like acne, hirsutism (excessive facial/body hair growth), and scalp hair loss, in cisgender women for treatment of hyperandrogenism (high androgen levels) due to polycystic ovary syndrome (PCOS), and in transfeminine people as a component of hormone therapy. Spironolactone is particularly widely used in transfeminine people in the United States, where it is the most commonly used antiandrogen in this population. As an antimineralocorticoid, the original and primary use of spironolactone in medicine, it is used to treat heart failure, high blood pressure, high mineralocorticoid levels, low potassium levels, and conditions of excess fluid retention like nephrotic syndrome and ascites, among others (Wiki). In terms of its antiandrogenic actions, spironolactone is a relatively weak androgen receptor antagonist as well as a weak androgen synthesis inhibitor (Wiki). The androgen synthesis inhibition of spironolactone is mediated specifically via inhibition of 17α-hydroxylase and 17,20-lyase (Wiki). Spironolactone does not appear to have meaningful progestogenic activity, 5α-reductase inhibition, or direct estrogenic activity (Wiki). However, indirect estrogenic effects secondary to its antiandrogenic activity (e.g., breast development and feminization) can occur with it at sufficiently high doses (Wiki).

Spironolactone shows limited and highly inconsistent effects on testosterone levels in clinical studies in cisgender men, cisgender women, and transfeminine people, with most studies finding no change in levels, some studies finding a decrease in levels, and a small number even finding an increase in levels (Aly, 2018). In spite of this, studies commonly find that spironolactone still produces antiandrogenic effects even when androgen levels remain unchanged. Hence, the primary mechanism of action of spironolactone as an antiandrogen appears to be androgen receptor blockade. In relation to this, in transfeminine people taking spironolactone as an antiandrogen, the estrogen component of the regimen is likely to be the main or possibly sole agent suppressing testosterone production. This is in part based on studies in transfeminine people comparing estradiol plus spironolactone to estradiol alone (e.g., Leinung, 2014; Leinung, Feustel, & Joseph, 2018; Angus et al., 2019) and on studies comparing testosterone levels with different doses of spironolactone (e.g., Liang et al., 2018; SoRelle et al., 2019; Allen et al., 2021). Due to the minimal influence of spironolactone on testosterone production, testosterone levels are not usually suppressed into the female range in transfeminine people taking estradiol plus spironolactone, with testosterone levels often remaining well above this range (e.g., 50–450 ng/dL [1.7–15.6 nmol/L] on average) (Leinung, 2014; Leinung, Feustel, & Joseph, 2018; Liang et al., 2018; Angus et al., 2019; Jain, Kwan, & Forcier, 2019; SoRelle et al., 2019; Sofer et al., 2020; Burinkul et al., 2021). However, testosterone levels do tend to decline gradually over time in transfeminine people on this regimen (e.g., Liang et al., 2018; Sofer et al., 2020 (Graph); Allen et al., 2021).

Due to its relatively weak androgen receptor antagonism, spironolactone is likely best-suited for blocking female-range or somewhat-higher testosterone levels (e.g., <100 ng/dL [<3.5 nmol/L]) (Aly, 2018). This is based on clinical dose-ranging studies of spironolactone (typically using 50–200 mg/day) in healthy cisgender women and cisgender women with PCOS (Goodfellow et al., 1984; Lobo et al., 1985; Hammerstein, 1990; James, Jamerson, & Aguh, 2022) as well as comparative studies of spironolactone against the more-potent antiandrogen flutamide (Cusan et al., 1994; Erenus et al., 1994; Shaw, 1996). The clinical antiandrogenic efficacy of spironolactone has been very limitedly assessed in transfeminine people to date, and is largely unknown (Angus et al., 2021). In any case, the antiandrogenic efficacy of spironolactone in cisgender women with androgen-dependent hair and skin conditions is well-established, and the medication thus does appear to be effective so long as testosterone levels are not too high (Brown et al., 2009; van Zuuren & Fedorowicz, 2016; Layton et al., 2017; Barrionuevo et al., 2018; James, Jamerson, & Aguh, 2022). In addition, higher doses of spironolactone (e.g., 300–400 mg/day) may be more useful for blocking higher testosterone levels in transfeminine people, and are allowed for by transgender care guidelines (Aly, 2020).

Consequent to spironolactone’s limited and inconsistent influence on testosterone levels and its relatively weak androgen receptor antagonism, estradiol plus spironolactone regimens will likely not be fully effective in terms of testosterone suppression for many transfeminine people. This is liable to result in suboptimal demasculinization, feminization, and breast development in these individuals. Other antiandrogenic approaches, such as bicalutamide, CPA, GnRH modulators, and high-dose estradiol monotherapy, will likely be more effective in these cases owing either to their ability to more potently block androgens or their capacity to reliably reduce testosterone levels into the female range. If testosterone levels are still too high with estradiol plus spironolactone, a switch to a different antiandrogen, increasing to a higher dosage of estradiol, or addition of a clinically antigonadotropic progestogen (e.g., non-oral progesterone or a progestin) should be considered.

Spironolactone is a strong antimineralocorticoid, or antagonist of the mineralocorticoid receptor, the biological target of the mineralocorticoid steroid hormones aldosterone and 11-deoxycorticosterone. This is an action that spironolactone shares with progesterone, although spironolactone is a much more potent antimineralocorticoid than progesterone. The mineralocorticoid receptor is involved in regulating electrolyte and fluid balances, among other roles. Spironolactone is associated with modestly lowered blood pressure, which may be considered a beneficial effect of its antimineralocorticoid activity (Martinez-Martin et al., 2022). Although spironolactone is usually well-tolerated, it can sometimes produce antimineralocorticoid side effects such as excessively lowered blood pressure, dizziness, fatigue, urinary frequency, and increased cortisol levels, among others (Kellner & Wiedemann, 2008; Kim & Del Rosso, 2012; Zaenglein et al., 2016; Layton et al., 2017; James, Jamerson, & Aguh, 2022). It has been argued by some in the online transgender community that spironolactone, via its antimineralocorticoid activity and increased cortisol levels, may increase visceral fat in transfeminine people (Aly, 2020). However, evidence does not support this hypothetical side effect at present (Aly, 2020). Available data also do not support spironolactone stunting breast development in transfeminine people or producing serious neuropsychiatric side effects, such as prominent depressive mood changes.

The most important risk of spironolactone, which is consequent to its antimineralocorticoid activity, is hyperkalemia (high potassium levels) (Wiki). This complication is rare and is mostly limited to those who have specific risk factors for it, but is serious and can result in hospitalization or death. Monitoring of blood potassium levels during spironolactone therapy is advisable in those with risk factors for hyperkalemia, but does not appear to be necessary in people without such risk factors (Plovanich, Weng, & Mostaghimi, 2015; Zaenglein et al., 2016; Layton et al., 2017; Millington, Liu, & Chan, 2019; Wang & Lipner, 2020; Gupta et al., 2022; Hayes et al., 2022). Risk factors for hyperkalemia include older age (>45 years), reduced kidney function, concomitant use of other potassium-elevating drugs, and intake of potassium supplements or potassium-containing salt substitutes. Other notable potassium-elevating drugs include other potassium-sparing diuretics (e.g., amiloride (Midamor), triamterene (Dyrenium), other antimineralocorticoids), ACE inhibitors, angiotensin II receptor blockers, and the antibiotic trimethoprim (Bactrim), among others (Kim & Rosso, 2012; Salem et al., 2014). As an example drug interaction, serious hyperkalemia and sudden death can occur in elderly people (>65 years of age) concomitantly taking spironolactone and trimethoprim (Antoniou et al., 2011; Antoniou et al., 2015).

In people who are at-risk for hyperkalemia, dietary restriction to limit intake of potassium-rich foods is often recommended (Roscioni et al., 2012; Cupisti et al., 2018). This is often encountered in transgender health as transfeminine people being told “not to eat bananas”, which are said to be high in potassium. However, limiting dietary potassium with spironolactone to avoid hyperkalemia is theoretical and not actually evidence-based, with data so far contradicting its efficacy (St-Jules, Goldfarb, & Sevick, 2016; St-Jules & Fouque, 2021; Babich, Kalantar-Zadeh, & Joshi, 2022; St-Jules & Fouque, 2022). As such, routine restriction of dietary potassium with spironolactone may not be warranted.

Aside from its antimineralocorticoid activity, spironolactone has been reported to increase levels of LDL (“bad”) cholesterol levels and to decrease levels of HDL (“good”) cholesterol in women with PCOS (Nakhjavani et al., 2009). However, findings appear to be conflicting, with other studies not finding unfavorable influences on cholesterol levels with spironolactone (Polyzos et al., 2011). Long-term, adverse effects on cholesterol levels could result in an increase in the risk of coronary heart disease.

Spironolactone is taken orally in the form of tablets (e.g., 25, 50, and 100 mg) (Wiki). It is a prodrug of several active metabolites, including 7α-thiomethylspironolactone, 6β-hydroxy-7α-thiomethylspironolactone, and canrenone (7α-desthioacetyl-δ6-spironolactone) (Wiki). Spironolactone and these active metabolites have elimination half-lives of 1.4 hours, 13.8 hours, 15.0 hours, and 16.5 hours, respectively (Wiki). Due to the relatively short duration of elevated drug levels with spironolactone and its active metabolites (Graph), twice-daily administration of spironolactone in divided doses may be more optimal than once-daily intake and is advised (Reiter et al., 2010).

Bicalutamide

Bicalutamide (Casodex) is a nonsteroidal antiandrogen (NSAA) which acts as a potent and highly selective androgen receptor antagonist (Wiki). It is primarily used in the treatment of prostate cancer in cisgender men. Prostate cancer is an androgen-dependent cancer which antiandrogens can help to slow the progression of, and this use constitutes the vast majority of prescriptions for bicalutamide (Wiki). In addition to prostate cancer, although to a much lesser extent, bicalutamide has been used in the treatment of hirsutism (excessive facial/body hair growth), scalp hair loss, and polycystic ovary syndrome (PCOS) in cisgender women, peripheral or gonadotropin-independent precocious puberty (a rare form of precocious puberty in which antigonadotropins such as GnRH agonists are not effective) in cisgender boys, and priapism in cisgender men (Wiki). Bicalutamide is also becoming increasingly adopted for use as an antiandrogen in transfeminine people (Aly, 2020; Wiki). However, its use in transgender health is still very limited, and well-regarded transgender care guidelines either recommend against its use (Deutsch, 2016—UCSF guidelines; Coleman et al., 2022—WPATH SOC8) or are only cautiously permissive of its use (Thompson et al., 2021—Fenway Health guidelines). This is due to a lack of studies of bicalutamide in transfeminine people and its potential risks. Nonetheless, a small but growing number of clinicians are using bicalutamide in transfeminine people or are willing to prescribe it, with these clinicians located particularly in the United States. A single small clinical study has assessed bicalutamide in transfeminine people so far, specifically as a puberty blocker in 13 transfeminine adolescents who were denied insurance coverage for GnRH agonists (Neyman, Fuqua, & Eugster, 2019). (Update: More studies of bicalutamide in transfeminine people have since been published, see Aly (2020).)

Bicalutamide is a much more potent androgen receptor antagonist than either spironolactone or CPA (Wiki; Neyman, Fuqua, & Eugster, 2019). It is typically used in transfeminine people at a dosage of 25 to 50 mg/day, although this dosage has been arbitrarily selected and is not based on clinical data. Nonetheless, due to its relatively high potency as an androgen receptor antagonist and concomitant suppression of testosterone levels by estradiol, these doses may be adequate for testosterone blockade for many transfeminine people. At higher doses (>50 mg/day), bicalutamide is able to substantially block male-range testosterone levels (>300 ng/dL [>10.4 nmol/L]) based on studies of bicalutamide monotherapy in cisgender men with prostate cancer (Wiki). This is something that spironolactone and CPA are not capable of in the same way. Owing to its selectivity for the androgen receptor, bicalutamide has no off-target hormonal activity and produces almost no side effects in women (Wiki; Erem, 2013; Moretti et al., 2018). The only apparent side effect of bicalutamide in a rigorous clinical trial of the drug for hirsutism in cisgender women was significantly increased total and LDL (“bad”) cholesterol levels (Moretti et al., 2018). Hence, bicalutamide tends to be very well-tolerated. The relative lack of side effects with bicalutamide is contrast to other antiandrogens like spironolactone and CPA, which are not pure androgen receptor antagonists and have off-target hormonal actions like antimineralocorticoid activity or strong progestogenic activity with consequent side effects and risks.

As a selective androgen receptor antagonist, bicalutamide taken by itself does not decrease testosterone production or levels but rather increases them (Wiki). This is due to a loss of androgen receptor-mediated negative feedback on gonadotropin secretion and a consequent compensatory upregulation of gonadal testosterone production (Wiki). Bicalutamide more than blocks the effects of any increase in testosterone it causes, and in fact fundamentally cannot increase testosterone levels more than it can block them (Wiki). In addition, increases in testosterone levels with bicalutamide will be blunted or abolished if it is combined with an adequate dose of an antigonadotropin such as estradiol (Wiki; Wiki). Since estradiol is made from testosterone in the body, bicalutamide taken alone also preserves and increases estradiol production and levels (Wiki). Because of this, although bicalutamide has no other important intrinsic hormonal activity besides its antiandrogenic activity, it produces robust indirect estrogenic effects including feminization and breast development even when it is not combined with estrogen (Wiki; Wiki; Neyman, Fuqua, & Eugster, 2019). This has important implications for the use of bicalutamide as a puberty blocker in transfeminine adolescents, as bicalutamide does not actually block puberty like conventional puberty blockers (GnRH agonists) but instead has the effect of dose-dependently converting male puberty into female puberty (Wiki; Neyman, Fuqua, & Eugster, 2019).

Bicalutamide has certain health risks, which has been a major reason that it has not been more readily adopted in transfeminine hormone therapy (Aly, 2020). It has a small risk of liver toxicity (Wiki; Aly, 2020) and of lung toxicity (Wiki). Abnormal liver function tests (LFTs), such as elevated liver enzymes and elevated bilirubin, occurred in about 3.4% of men with bicalutamide monotherapy plus standard care versus 1.9% of men with placebo plus standard care in the Early Prostate Trial (EPC) clinical programme after 3.0 years of follow-up (Wiki). In clinical trials, treatment with bicalutamide had to be discontinued in about 0.3 to 1.5% of men due to LFTs that became too highly elevated and could have progressed to serious liver toxicity (Wiki). To date, there are around 10 published case reports of serious liver toxicity, including cases of death, with bicalutamide, all of which have been in men with prostate cancer (Wiki; Table; Aly, 2020). There have also been a few unpublished reports of serious liver toxicity including deaths with bicalutamide in transfeminine people (Aly, 2020). However, these reports have not been confirmed, and they may or may not be reliable. In addition to the preceding reports, hundreds of additional instances of liver complications in people taking bicalutamide exist in the United States FDA Adverse Event Reporting System (FAERS) database (Wiki; FDA). Abnormal LFTs with bicalutamide usually occur within the first 3 to 6 months of treatment (Kolvenbag & Blackledge, 1996; Casodex FDA Label), and all case reports of liver toxicity with bicalutamide have had an onset of less than 6 months (Table). The liver toxicity of bicalutamide is not known to be dose-dependent across its clinically used dose range (Wiki). Abnormal LFTs have occurred with bicalutamide (at rates of 2.9% to 11.4%) even at relatively low doses in cisgender women (e.g., 10–50 mg/day) (de Melo Carvalho, 2022). Due to its risk of liver toxicity, periodic liver monitoring is strongly advised with bicalutamide, especially within the first 6 months of treatment. Possible signs of liver toxicity include nausea, vomiting, abdominal pain, fatigue, appetite loss, flu-like symptoms, dark urine, and jaundice (yellowing of the skin/eyes) (Wiki).

In terms of its lung toxicity risk, bicalutamide has been associated rarely with interstitial pneumonitis, which can lead to pulmonary fibrosis and can be fatal, and also less often with eosinophilic lung disease (Wiki; Table). As of writing, 15 published case reports of interstitial pneumonitis and 2 case reports of eosinophilic lung disease in association with bicalutamide therapy exist, likewise all in men with prostate cancer (Table). As with liver toxicity, hundreds of additional cases of interstitial pneumonitis in people taking bicalutamide exist in the United States FAERS database (Wiki; FDA). It has been estimated that interstitial pneumonitis with bicalutamide occurs at a rate of around 1 in 10,000 people, although this may be an underestimate due to under-reporting (Wiki; Ahmad & Graham, 2003). Asian people may be especially likely to experience lung toxicity with bicalutamide and other NSAAs, as much higher incidences have been observed in this population (Mahler et al., 1996; Wu et al., 2022). There is no laboratory test for routine monitoring of lung changes with bicalutamide. Possible signs of relevant lung toxicity include dyspnea (difficulty breathing or shortness of breath), coughing, and pharyngitis (inflammation of the throat, typically manifesting as sore throat) (Wiki).

Aside from liver and lung toxicity, bicalutamide monotherapy has been found in cisgender men with prostate cancer to increase the risk of death due to causes other than prostate cancer (Iversen et al., 2004; Iversen et al., 2006; Wellington & Keam, 2006; Jia & Spratt, 2022; Wiki). This led to marketing authorization of bicalutamide for treatment of the earliest stage of prostate cancer being revoked and to the drug being abandoned for this use (Wiki). Bicalutamide remains approved and used for treatment of later stages of prostate cancer, as the antiandrogenic benefits of bicalutamide against prostate cancer outweigh any adverse influence it has on non-prostate-cancer mortality in these more severe stages. The mechanisms underlying the increase in risk of death with bicalutamide in men are unknown (Wiki). It is also unclear whether bicalutamide could likewise increase the risk of death in transfeminine people. Limitations of generalizing these studies to transfeminine people include the men in the trials being relatively old and ill, a relatively high dosage of bicalutamide (150 mg/day) being used in the trials for an extended duration (e.g., 5 years), the question of whether the risks were due to androgen deprivation or to specific drug-related toxicity of bicalutamide, and estradiol levels with bicalutamide monotherapy in men with prostate cancer being only about 30 to 50 pg/mL (110–184 pmol/L) (Wiki). The preceding estradiol levels are well above castrate levels and are sufficient for a substantial degree of estrogenic effect, but are nonetheless below those recommended for transfeminine people and potentially needed for full sex-hormone replacement (which are ≥50 pg/mL [≥184 pmol/L]). In any case, as the specific mechanisms underlying the increased mortality risk with bicalutamide seen in men with prostate cancer are uncertain, and as clinical safety data showing that the risk does not generalize do not exist, it remains a possibility that bicalutamide could also increase the risk of death in transfeminine people.

Bicalutamide is taken orally in the form of tablets (e.g., 50 and 150 mg) (Wiki). Due to saturation of absorption in the gastrointestinal tract, the oral bioavailability of bicalutamide progressively starts to decrease above a dosage of about 150 mg/day, and there is no further increase in bicalutamide levels above 300 mg/day (Wiki; Graph). Bicalutamide has a very long elimination half-life of about 6 to 10 days (Wiki; Graphs). As a result, it does not necessarily have to be taken daily, and can be dosed less often (in proportionally higher doses)—for instance twice weekly or even once weekly—if this is more convenient or otherwise desired. Due to its long half-life, bicalutamide requires about 4 to 12 weeks to fully reach steady-state levels (Wiki; Graph; Wiki). However, about 50% of steady state is reached within 1 week of administration of bicalutamide, and about 80 to 90% of steady state is reached after 3 to 4 weeks (Wiki; Graph; Wiki). Loading doses of bicalutamide can be taken to reach steady state more quickly if desired. Animal studies originally suggested that bicalutamide did not cross the blood–brain barrier and hence was peripherally selective (i.e., did not block androgen receptors in the brain) (Wiki). However, subsequent clinical studies found that this was not similarly the case in humans, in whom bicalutamide shows clear and robust centrally mediated antiandrogenic effects (Wiki).

Older NSAAs related to bicalutamide like flutamide (Eulexin) and nilutamide (Anandron, Nilandron) have much greater risks in comparison to bicalutamide and should not be used in transfeminine people. Nilutamide was previously characterized as an antiandrogen in transfeminine people in several studies, but was not further pursued probably due to its very high incidence of lung toxicity and other side effects (Aly, 2020; Wiki; Wiki). Flutamide has been used limitedly as an antiandrogen in transfeminine people in the past, but should no longer be used due to a much higher risk of liver toxicity than bicalutamide as well as other side effects and drawbacks (Aly, 2020; Wiki). Other newer and more-potent NSAAs like enzalutamide (Xtandi), apalutamide (Erleada), and darolutamide (Nubeqa) also have risks and have been studied and used little outside of prostate cancer to date.

5α-Reductase Inhibitors

Testosterone is converted into DHT within certain tissues in the body (Swerdloff et al., 2017). DHT is an androgen metabolite of testosterone with several-fold higher activity than testosterone. The transformation of testosterone into DHT is mediated by the enzyme 5α-reductase. The tissues in which 5α-reductase is present and testosterone is converted into DHT are limited but most importantly include the skin, hair follicles, and prostate gland. Although DHT is more potent than testosterone, it is thought to have minimal biological role as a circulating hormone (Horton, 1992; Swerdloff et al., 2017). Instead, testosterone serves as the main circulating androgen, and the role of DHT is thought to be mainly via local metabolism and potentiation of testosterone into DHT within certain tissues.

5α-Reductase inhibitors (5α-RIs), such as finasteride (Proscar, Propecia) and dutasteride (Avodart), inhibit 5α-reductase and thereby block the conversion of testosterone into DHT. This results in marked decreases in circulating and within-tissue levels of DHT. Due to the primary role of DHT as a mediator in tissues rather than as circulating hormone, the antiandrogenic efficacy of 5α-RIs is limited. This is evidenced by the fact that they are well-tolerated in cisgender men and do not cause notable demasculinization in these individuals (Hirshburg, 2016). The medical use of 5α-RIs is mainly restricted to the treatment of scalp hair loss in men and women, hirsutism (excessive facial/body hair) in women, and prostate enlargement in men. They might also be useful for acne in women, but evidence of this is very limited (Wiki). Due to their specificity, 5α-RIs are inappropriate as general antiandrogens in transfeminine people. Moreover, DHT levels decrease in tandem with testosterone levels with suppression of testosterone production in transfeminine hormone therapy, and routine use of 5α-RIs in transfeminine people with testosterone levels within the female range is of limited usefulness and can be considered unnecessary (Gooren et al., 2016; Irwig, 2020; Prince & Safer, 2020; Glintborg et al., 2021). In any case, 5α-RIs may be useful in transfeminine people on hormone therapy who have persistent body hair growth or scalp hair loss—as they have been shown to be in cisgender women (Barrionuevo et al., 2018; Prince & Safer, 2020). However, it is notable that evidence of effectiveness in cisgender women is better for androgen receptor antagonists for such indications (van Zuuren et al., 2015). This is intuitive as androgen receptor antagonists block both testosterone and DHT whereas 5α-RIs only prevent conversion of testosterone into DHT. Hence, although 5α-RIs strongly reduce or eliminate DHT and their net effect is antiandrogenic, they do not decrease testosterone levels and in fact increase them.

There are three subtypes of 5α-reductase. Dutasteride inhibits all three subtypes of 5α-reductase whereas finasteride only inhibits two of the subtypes. As a result of this, dutasteride is a more complete 5α-RI than finasteride. Dutasteride decreases DHT levels in the blood by up to 98% while finasteride can only decrease them by around 65 to 70%. As nearly all circulating DHT originates from synthesis in peripheral tissues, these decreases indicate parallel reductions in tissue DHT production (Horton, 1992). In accordance with these findings, dutasteride has been found to be more effective than finasteride in the treatment of scalp hair loss in men (Zhou et al., 2018; Dhurat et al., 2020; Wiki). For these reasons, although both finasteride and dutasteride are effective 5α-RIs, dutasteride may be the preferable choice if a 5α-RI is used (Zhou et al., 2018; Dhurat et al., 2020).

A potentially undesirable effect of 5α-RIs in transfeminine people is that they may increase circulating testosterone levels to a degree in those in whom testosterone production isn’t fully suppressed (Leinung, Feustel, & Joseph, 2018; Aly, 2019; Traish et al., 2019; Irwig, 2020; Glintborg et al., 2021). It appears that DHT adds significantly to negative feedback on gonadotropin secretion in the pituitary gland in people with testes who have low testosterone levels relative to the normal male range (Traish et al., 2019). The therapeutic implications of this for transfeminine people, if any, are uncertain.

Another potentially undesirable action of 5α-RIs is that they inhibit not only the production of DHT but also of certain neurosteroids. Neurosteroids are steroids that act on the nervous system—most notably the brain. Examples of neurosteroids that 5α-RIs inhibit the synthesis of include allopregnanolone, which is formed from progesterone, and 3α-androstanediol, which is derived from testosterone and DHT. Research suggests that these neurosteroids have significant biological modulatory roles in mood, anxiety, stress, and other cognitive/emotional processes (King, 2013). Possibly in relation to this, 5α-RIs have been associated with a small risk of depression (Welk et al., 2018; Deng et al., 2020; Dyson, Cantrell, & Lund, 2020; Nguyen et al., 2020; Wiki). Claims of other, more significant and persistent side effects with 5α-RIs, which are termed “post-finasteride syndrome” (PFS) in the case of finasteride, also exist (Traish, 2020). However, they are based on low-quality reports and are controversial (Fertig et al., 2016; Rezende, Dias, & Trüeb, 2018). The nocebo effect is likely to worsen perceptions of side effects with 5α-RIs (Kuhl & Wiegratz, 2017; Maksym et al., 2019).

Clinical dose-ranging studies have found that lower doses of finasteride and dutasteride than are typically used still provide substantial or near-maximal 5α-reductase inhibition (Gormley et al., 1990; Vermeulen et al., 1991; Sudduth & Koronkowski, 1993; Drake et al., 1999; Roberts et al., 1999; Clark et al., 2004; Frye, 2006; Olsen et al., 2006; Harcha et al., 2014; Kuhl & Wiegratz, 2017). In one study with finasteride for instance, DHT levels decreased by 49.5% at 0.05 mg/day, 68.6% at 0.2 mg/day, 71.4% at 1 mg/day, and 72.2% at 5 mg/day (Drake et al., 1999). Parallel reductions in DHT levels were seen locally in the scalp (Drake et al., 1999). In a study with dutasteride, DHT levels were decreased by 52.9% at 0.05 mg/day, 94.7% at 0.5 mg/day, 97.7% at 2.5 mg/day, and 98.4% at 5 mg/day (Clark et al., 2004). Based on these findings, 5α-RIs can potentially be taken at lower doses to help reduce medication costs if needed. Finasteride tablets can be split to achieve smaller doses. Conversely, dutasteride cannot be split as it is formulated as an oil capsule. However, dutasteride has a long half-life, and instead of dividing pills, it can be taken less frequently (e.g., once every few days) as a means of reducing dosage.

5α-Reductase inhibitors are taken orally in the form of tablets and capsules. Compounded topical formulations of finasteride also exist (Marks et al., 2020). However, caution is advised with these preparations as they have been found to be excessively dosed and to produce equivalent systemic DHT suppression as oral finasteride formulations (Marks et al., 2020). Lower-concentration formulations of topical finsteride on the other hand may be more locally selective (Marks et al., 2020).

Table 8: Available forms and recommended doses of 5α-reductase inhibitors for transfeminine people:

MedicationRouteFormDosage
DutasterideOralCapsules0.05–2.5 mg/day
FinasterideOralTablets0.05–5 mg/day

GnRH Agonists and Antagonists

GnRH agonists and antagonists (GnRHa), also known as GnRH receptor agonists and antagonists or GnRH modulators, are antiandrogens which work by preventing the effects of GnRH in the pituitary gland and thereby suppressing LH and FSH secretion. Receptor agonists normally activate receptors while receptor antagonists block and thereby inhibit the activation of receptors. Due to a physiological quirk however, GnRH agonists and antagonists have the same effects in the pituitary gland. This is because GnRH is secreted in pulses under normal physiological circumstances, and when the GnRH receptor is unnaturally activated in a continuous manner, as with exogenous GnRH agonists, the GnRH receptor in the pituitary gland is strongly desensitized to the point of becoming inactive. Consequently, both GnRH agonists and GnRH antagonists have the effect of abolishing gonadal sex hormone production. This, in turn, reduces testosterone levels into the castrate or normal female range (both <50 ng/dL or <1.7 nmol/L) in people with testes. GnRHa are like a reversible gonadectomy, and for this reason, are also sometimes referred to as “medical castration”. Provided that an estrogen is taken in combination with a GnRHa to prevent sex hormone deficiency, these medications have essentially no known side effects or risks. For these reasons, GnRHa are the ideal antiandrogens for use in transfeminine people.

GnRHa are widely used to suppess puberty in adolescent transgender individuals. Unfortunately however, they are very expensive (e.g., ~US$10,000 per year) and medical insurance does not usually cover them for adult transgender people. Consequently, GnRHa are not commonly used in adult transfeminine people at this time. An exception is in the United Kingdom, where GnRH agonists are covered for all adult transgender people by the National Health Service (NHS). Another exception is buserelin (Suprefact), which has become available very inexpensively in its nasal spray form from certain Eastern European online pharmacies in recent years (Aly, 2018).

GnRH agonists cause a brief flare in testosterone levels at the start of therapy prior to the GnRH receptors in the pituitary gland becoming desensitized (Wiki). Testosterone levels increase by up to about 1.5- to 2-fold for about 1 week and then decrease thereafter (Wiki). Castrate or female-range levels of testosterone are generally reached within 2 to 4 weeks (Wiki). In contrast to GnRH agonists, there is no testosterone flare with GnRH antagonists and testosterone levels start decreasing immediately, reaching castrate levels within a few days (Wiki; Graph). This is because GnRH antagonists work by blocking the GnRH receptor without initially activating it, and hence desensitization of the receptor is not necessary for their action. If desired, the testosterone flare at the initiation of GnRH agonist therapy can be prevented or blunted with the use of antigonadotropins, for instance estrogens and progestogens, as well as with potent androgen receptor antagonists such as bicalutamide (Wiki).

GnRH agonists must be injected subcutaneously or intramuscularly once per day or once every one to six months depending on the formulation employed (buserelin, goserelin, leuprorelin, triptorelin). Alternatively, they can be surgically implanted once a year (histrelin, leuprorelin) or used as a nasal spray two to three times per day (buserelin, nafarelin). The first GnRH antagonists were developed for use by once-monthly intramuscular or subcutaneous injection (abarelix, degarelix). More recently, orally administered GnRH antagonists such as elagolix and relugolix have been introduced for medical use. They are taken in the form of tablets once or twice daily.

Table 9: Available forms and recommended doses of GnRH agonists for transfeminine people:

MedicationBrand nameRouteFormDosage
BuserelinSuprefact, othersSC injectionSolution200 μg/daya
   Implant6.3 mg/2 months
    9.45 mg/3 months
  IntranasalNasal spray400 µg 3x/dayb,c
GoserelinZoladexSC injectionImplant3.6 mg/month
    10.8 mg/3 months
HistrelinSupprelin LA, VantasSC implantImplant50 mg/year
LeuprorelinLupron, othersIM injectionSolution1 mg/day
 Eligard, Lupron Depot, othersIM/SC injectionSuspension3.75–7.5 mg/month
    11.25–22.5 mg/3 months
    30 mg/4 months
    45 mg/6 months
 ViadurSC implantImplant65 mg/year
NafarelinSynarelIntranasalNasal spray400–600 μg 2–3x/day
TriptorelinDecapeptyl, Trelstar Depot/LAIM injectionSuspension3.75 mg/month
    11.25 mg/3 months

a 500 μg 3x/day for the first week then 200 μg/day. b 800 μg 3x/day for the first week then 400 μg 3x/day. c 500 μg 2x/day can be used instead of 400 μg 3x/day but is less effective (70% decrease in testosterone levels (to ~180 ng/dL [6.2 nmol/L]) instead of 90% decrease (to ~50 ng/dL [1.7 nmol/L]) per available studies of buserelin in men with prostate cancer) (Aly, 2018; Wiki).

Table 10: Available forms and recommended doses of GnRH antagonists for transfeminine people:

MedicationBrand nameRouteFormDosage
AbarelixPlenaxisIM injectionSuspension113 mg/month
DegarelixFirmagonSC injectionSolution80 mg/montha
ElagolixOrilissaOralTablets150–200 mg 1–2x/dayb
RelugolixReluminaOralTablets20–120 mg/dayc

a First month is 240 mg then 80 mg per month thereafter. b 150 mg 1x/day is less effective than 200 mg 2x/day (which provides full gonadal sex-hormone suppression in cisgender women) (Wiki). c 80–120 mg/day for full gonadal sex-hormone suppression and 20–40 mg/day for substantial but partial gonadal sex-hormone suppression (MacLean et al., 2015; DailyMed).

Other Hormonal Medications

Androgens and Anabolic Steroids

In addition to estrogens, progestogens, and antiandrogens, androgens/anabolic steroids (AAS) are sometimes added to transfeminine hormone therapy. This is when testosterone levels are low (e.g., below the female average of 30 ng/dL [1.0 nmol/L]) and androgen replacement is desired. It has been proposed that adequate levels of testosterone may provide benefits such as increased sexual desire, improved mood and energy, positive effects on skin health and cellulite (Avram, 2004), and increased muscle size and strength (Huang & Basaria, 2017). However, there is insufficient clinical evidence to support such benefits at present, and androgens can produce adverse effects in cisgender women and transfeminine people, for instance acne, hirsutism, scalp hair loss, and masculinization (Wiki). For transfeminine people who nonetheless desire androgen replacement therapy, possible options for androgen medications include testosterone and its esters, dehydroepiandrosterone (DHEA; prasterone), and nandrolone esters such as nandrolone decanoate (ND) (Aly, 2020; Table), among others.

Monitoring of Therapy

Transfeminine people on hormone therapy should undergo regular laboratory monitoring in the form of blood work to assess efficacy and monitor for safety. Total estradiol levels and total testosterone levels should be measured to assess the effectiveness of therapy—that is, whether hormone levels are in appropriate ranges for cisgender females—and determine whether medication adjustments may be necessary. Levels of free testosterone, free estradiol, estrone (E1), dihydrotestosterone (DHT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and sex hormone-binding globulin (SHBG) can also be measured to provide further information although they’re not absolutely necessary. If progesterone is used as a part of hormone therapy, progesterone levels can be measured to provide insight on the degree of progesterone exposure. In addition to hormone blood tests, transfeminine people can monitor their physical changes with hormone therapy, such as breast development and other aspects of feminization, using various physical and digital measurement methods (e.g., Wiki; Aly, 2020).

In transfeminine people taking bicalutamide or high doses of CPA (≥20 mg/day), liver function tests (LFTs), such as aspartate transaminase (AST) and alanine transaminase (ALT) levels, should be regularly performed to monitor for liver toxicity. In those who are taking spironolactone and have relevant risk factors for hyperkalemia (high potassium levels), such as older age, reduced kidney function, or concomitant use of potassium-elevating medications or potassium supplements, potassium levels should be regularly monitored to assess for hyperkalemia. Conversely, in healthy young people without such risk factors who are taking spironolactone, potassium monitoring seems to be of limited usefulness (Plovanich, Weng, & Mostaghimi, 2015; Zaenglein et al., 2016; Layton et al., 2017; Millington, Liu, & Chan, 2019; Wang & Lipner, 2020; Gupta et al., 2022; Hayes et al., 2022). In transfeminine people taking high doses of estrogens or progestogens—particularly CPA—prolactin levels should be regularly measured to monitor for hyperprolactinemia (high prolactin levels) and prolactinoma (Callen-Lorde, 2018; Iwamoto et al., 2019). In people taking high doses of CPA (>12.5 mg/day), periodic magnetic resonance imaging (MRI) exams should be performed to monitor for development of meningiomas (Aly, 2020). If the preceding tests come back abnormal, depending on the situation and its severity, medication doses should be reduced or specific medications should be discontinued or replaced with alternatives.

Certain therapeutic situations can result in inaccurate lab blood work results. Monitoring of progesterone levels with oral progesterone using immunoassay-based blood tests can result in falsely high readings for progesterone levels due to cross-reactivity with high levels of progesterone metabolites such as allopregnanolone (Aly, 2018; Wiki). Instead of immunoassay-based tests, mass spectrometry-based tests should be used to determine progesterone levels with oral progesterone (Aly, 2018; Wiki). Conversely, either type of test may be used to measure progesterone levels with non-oral progesterone therapy. High-dose biotin (vitamin B7) supplements can interfere with the accuracy of immunoassay-based hormone blood tests, causing falsely low or falsely high readings (Samarasinghe et al., 2017; Avery, 2019; Bowen et al., 2019; FDA, 2019; Luong, Male, & Glennon, 2019). Transdermal estradiol formulations applied to the arm can result in contamination of blood draws taken from the same arm and can result in falsely high readings for estradiol levels (Vihtamäkia, Luukkaala, & Tuimala, 2004).

Certain cancers are known to be hormone-sensitive and their incidence can be influenced by hormone therapy. Screening for breast and prostate cancer is recommended in transfeminine people (Sterling & Garcia, 2020; Iwamoto et al., 2021). The risk of breast cancer appears to be dramatically increased with transfeminine hormone therapy, perhaps especially with progestogens (Aly, 2020). However, the risk still remains lower than in cisgender women (Aly, 2020). The incidence of prostate cancer is greatly decreased with hormone therapy in transfeminine people as a consequence of androgen deprivation, but the risk is not abolished and prostate cancer can still occur (de Nie et al., 2020). The prostate gland is not removed with vaginoplasty, so transfeminine people who have undergone vaginoplasty will also require monitoring for prostate cancer still. Testicular cancer is not known to be a hormone-dependent cancer and its incidence does not appear to be increased with hormone therapy in transfeminine people (Bensley et al., 2021; de Nie et al., 2021; Jacoby et al., 2021).

References

  • Abbott Laboratories. (2009). Estradiol. Architect System. Abbott Park, Illinois/Wiesbaden, Germany: Abbott Laboratories. [PDF]
  • Ahmad, S. R., & Graham, D. J. (2003). Pneumonitis with Antiandrogens. Annals of Internal Medicine, 139(6), 528–529. [DOI:10.7326/0003-4819-139-6-200309160-00023]
  • Allen, A. N., Jiao, R., Day, P., Pagels, P., Gimpel, N., & SoRelle, J. A. (2020). Dynamic Impact of Hormone Therapy on Laboratory Values in Transgender Patients over Time. The Journal of Applied Laboratory Medicine, 6(1), 27–40. [DOI:10.1093/jalm/jfaa192]
  • Angus, L., Leemaqz, S., Ooi, O., Cundill, P., Silberstein, N., Locke, P., Zajac, J. D., & Cheung, A. S. (2019). Cyproterone acetate or spironolactone in lowering testosterone concentrations for transgender individuals receiving oestradiol therapy. Endocrine Connections, 8(7), 935–940. [DOI:10.1530/ec-19-0272]
  • Angus, L. M., Nolan, B. J., Zajac, J. D., & Cheung, A. S. (2020). A systematic review of antiandrogens and feminization in transgender women. Clinical Endocrinology, 94(5), 743–752. [DOI:10.1111/cen.14329]
  • Antoniou, T., Gomes, T., Mamdani, M. M., Yao, Z., Hellings, C., Garg, A. X., Weir, M. A., & Juurlink, D. N. (2011). Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study. BMJ, 343, d5228. [DOI:10.1136/bmj.d5228]
  • Antoniou, T., Hollands, S., Macdonald, E. M., Gomes, T., Mamdani, M. M., & Juurlink, D. N. (2015). Trimethoprim–sulfamethoxazole and risk of sudden death among patients taking spironolactone. Canadian Medical Association Journal, 187(4), E138–E143. [DOI:10.1503/cmaj.140816]
  • Aufrère, M. B., & Benson, H. (1976). Progesterone: An overview and recent advances. Journal of Pharmaceutical Sciences, 65(6), 783–800. [DOI:10.1002/jps.2600650602]
  • Avery, G. (2019). Biotin interference in immunoassay: a review for the laboratory scientist. Annals of Clinical Biochemistry: International Journal of Laboratory Medicine, 56(4), 424–430. [DOI:10.1177/0004563219842231]
  • Avram, M. M. (2004). Cellulite: a review of its physiology and treatment. Journal of Cosmetic and Laser Therapy, 6(4), 181–185. [DOI:10.1080/14764170410003057]
  • Babich, J. S., Kalantar-Zadeh, K., & Joshi, S. (2022). Taking the Kale out of Hyperkalemia: Plant Foods and Serum Potassium in Patients With Kidney Disease. Journal of Renal Nutrition, 32(6), 641–649. [DOI:10.1053/j.jrn.2022.01.013]
  • Bäckström, T., Haage, D., Löfgren, M., Johansson, I., Strömberg, J., Nyberg, S., Andréen, L., Ossewaarde, L., van Wingen, G., Turkmen, S., & Bengtsson, S. (2011). Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons. Neuroscience, 191, 46–54. [DOI:10.1016/j.neuroscience.2011.03.061]
  • Barrionuevo, P., Nabhan, M., Altayar, O., Wang, Z., Erwin, P. J., Asi, N., Martin, K. A., & Murad, M. H. (2018). Treatment Options for Hirsutism: A Systematic Review and Network Meta-Analysis. The Journal of Clinical Endocrinology & Metabolism, 103(4), 1258–1264. [DOI:10.1210/jc.2017-02052]
  • Bazarra-Castro, M. A. (2009). Etiological aspects, therapy regimes, side effects and treatment satisfaction of transsexual patients. (Doctoral dissertation, Ludwig Maximilian University of Munich.) [DOI:10.5282/edoc.9984] [URN:urn:nbn:de:bvb:19-99840] [PDF]
  • Belisle, S., & Love, E. J. (1986). Clinical efficacy and safety of cyproterone acetate in severe hirsutism: results of a multicentered Canadian study. Fertility and Sterility, 46(6), 1015–1020. [DOI:10.1016/s0015-0282(16)49873-0]
  • Ben Salem, C., Badreddine, A., Fathallah, N., Slim, R., & Hmouda, H. (2014). Drug-Induced Hyperkalemia. Drug Safety, 37(9), 677–692. [DOI:10.1007/s40264-014-0196-1]
  • Bensley, J. G., Cheung, A. S., Grossmann, M., & Papa, N. (2022). Testicular Cancer in Trans People Using Feminising Hormone Therapy–A Brief Review. Urology, 160, 1–4. [DOI:10.1016/j.urology.2021.11.014]
  • Bessone, F., Lucena, M., Roma, M. G., Stephens, C., Medina-Cáliz, I., Frider, B., Tsariktsian, G., Hernández, N., Bruguera, M., Gualano, G., Fassio, E., Montero, J., Reggiardo, M. V., Ferretti, S., Colombato, L., Tanno, F., Ferrer, J., Zeno, L., Tanno, H., & Andrade, R. J. (2015). Cyproterone acetate induces a wide spectrum of acute liver damage including corticosteroid-responsive hepatitis: report of 22 cases. Liver International, 36(2), 302–310. [DOI:10.1111/liv.12899]
  • Bowen, R., Benavides, R., Colón-Franco, J. M., Katzman, B. M., Muthukumar, A., Sadrzadeh, H., Straseski, J., Klause, U., & Tran, N. (2019). Best practices in mitigating the risk of biotin interference with laboratory testing. Clinical Biochemistry, 74, 1–11. [DOI:10.1016/j.clinbiochem.2019.08.012]
  • Brown, J., Farquhar, C., Lee, O., Toomath, R., & Jepson, R. G. (2009). Spironolactone versus placebo or in combination with steroids for hirsutism and/or acne. Cochrane Database of Systematic Reviews, 2009(2), CD000194. [DOI:10.1002/14651858.cd000194.pub2]
  • Burinkul, S., Panyakhamlerd, K., Suwan, A., Tuntiviriyapun, P., & Wainipitapong, S. (2021). Anti-Androgenic Effects Comparison Between Cyproterone Acetate and Spironolactone in Transgender Women: A Randomized Controlled Trial. The Journal of Sexual Medicine, 18(7), 1299–1307. [DOI:10.1016/j.jsxm.2021.05.003] [PDF]
  • Callen-Lorde Community Health Center. (2018). Protocols for the Provision of Hormone Therapy. New York City: Callen-Lorde Community Health Center. [URL] [PDF]
  • Cappelletti, M., & Wallen, K. (2016). Increasing women’s sexual desire: The comparative effectiveness of estrogens and androgens. Hormones and Behavior, 78, 178–193. [DOI:10.1016/j.yhbeh.2015.11.003]
  • Carmina, E., Stanczyk, F. Z., & Lobo, R. A. (2019). Evaluation of Hormonal Status. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 887–915.e4). Philadelphia: Elsevier. [DOI:10.1016/b978-0-323-47912-7.00034-2]
  • Carr, B. R. (1993). The Ovary. In Carr, B. R., & Blackwell, R. E. (Eds.). Textbook of Reproductive Medicine, 1st Edition (pp. 183–207). Norwalk, Connecticut: Appleton & Lange. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [Archive.org—2nd edition]
  • Carvalho, R. d., Santos, L. D., Ramos, P. M., Machado, C. J., Acioly, P., Frattini, S. C., Barcaui, C. B., Donda, A. L., & Melo, D. F. (2022). Bicalutamide and the new perspectives for female pattern hair loss treatment: What dermatologists should know. Journal of Cosmetic Dermatology, 21(10), 4171–4175. [DOI:10.1111/jocd.14773]
  • Clark, R. V., Hermann, D. J., Cunningham, G. R., Wilson, T. H., Morrill, B. B., & Hobbs, S. (2004). Marked Suppression of Dihydrotestosterone in Men with Benign Prostatic Hyperplasia by Dutasteride, a Dual 5α-Reductase Inhibitor. The Journal of Clinical Endocrinology & Metabolism, 89(5), 2179–2184. [DOI:10.1210/jc.2003-030330]
  • Coleman, E., Radix, A. E., Bouman, W. P., Brown, G. R., de Vries, A. L., Deutsch, M. B., Ettner, R., Fraser, L., Goodman, M., Green, J., Hancock, A. B., Johnson, T. W., Karasic, D. H., Knudson, G. A., Leibowitz, S. F., Meyer-Bahlburg, H. F., Monstrey, S. J., Motmans, J., Nahata, L., … & Arcelus, J. (2022). [World Professional Association for Transgender Health (WPATH)] Standards of Care for the Health of Transgender and Gender Diverse People, Version 8. International Journal of Transgender Health, 23(Suppl 1), S1–S259. [DOI:10.1080/26895269.2022.2100644] [URL] [PDF]
  • Collaborative Group on Hormonal Factors in Breast Cancer. (2019). Type and timing of menopausal hormone therapy and breast cancer risk: individual participant meta-analysis of the worldwide epidemiological evidence. The Lancet, 394(10204), 1159–1168. [DOI:10.1016/s0140-6736(19)31709-x]
  • Collet, S., Gieles, N. C., Wiepjes, C. M., Heijboer, A. C., Reyns, T., Fiers, T., Lapauw, B., den Heijer, M., & T’Sjoen, G. (2022). Changes in Serum Testosterone and Adrenal Androgen Levels in Transgender Women With and Without Gonadectomy. The Journal of Clinical Endocrinology & Metabolism, 108(2), 331–338. [DOI:10.1210/clinem/dgac576]
  • Connors, J. M., & Middeldorp, S. (2019). Transgender patients and the role of the coagulation clinician. Journal of Thrombosis and Haemostasis, 17(11), 1790–1797. [DOI:10.1111/jth.14626]
  • Cupisti, A., Kovesdy, C., D’Alessandro, C., & Kalantar-Zadeh, K. (2018). Dietary Approach to Recurrent or Chronic Hyperkalaemia in Patients with Decreased Kidney Function. Nutrients, 10(3), 261–261. [DOI:10.3390/nu10030261]
  • Cusan, L., Dupont, A., Gomez, J., Tremblay, R. R., & Labrie, F. (1994). Comparison of flutamide and spironolactone in the treatment of hirsutism: a randomized controlled trial. Fertility and Sterility, 61(2), 281–287. [DOI:10.1016/s0015-0282(16)56518-2]
  • de Blok, C. J., Wiepjes, C. M., Nota, N. M., van Engelen, K., Adank, M. A., Dreijerink, K. M., Barbé, E., Konings, I. R., & den Heijer, M. (2019). Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ, 365, l1652. [DOI:10.1136/bmj.l1652]
  • de Nie, I., de Blok, C. J., van der Sluis, T. M., Barbé, E., Pigot, G. L., Wiepjes, C. M., Nota, N. M., van Mello, N. M., Valkenburg, N. E., Huirne, J., Gooren, L. J., van Moorselaar, R. J., Dreijerink, K. M., & den Heijer, M. (2020). Prostate Cancer Incidence under Androgen Deprivation: Nationwide Cohort Study in Trans Women Receiving Hormone Treatment. The Journal of Clinical Endocrinology & Metabolism, 105(9), e3293–e3299. [DOI:10.1210/clinem/dgaa412]
  • Deng, T., Duan, X., He, Z., Zhao, Z., & Zeng, G. (2020). Association Between 5-Alpha Reductase Inhibitor Use and The Risk of Depression: A Meta-Analysis. Urology Journal, 18(2), 144–150. [DOI:10.22037/uj.v16i7.5866]
  • Deutsch, M. B. (2016). Overview of feminizing hormone therapy. In Deutsch, M. B. (Ed.). Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People, 2nd Edition (pp. 26–48). San Francisco: University of California, San Francisco/UCSF Transgender Care. [URL] [PDF]
  • Dhurat, R., Sharma, A., Rudnicka, L., Kroumpouzos, G., Kassir, M., Galadari, H., Wollina, U., Lotti, T., Golubovic, M., Binic, I., Grabbe, S., & Goldust, M. (2020). 5‐Alpha reductase inhibitors in androgenetic alopecia: Shifting paradigms, current concepts, comparative efficacy, and safety. Dermatologic Therapy, 33(3), e13379. [DOI:10.1111/dth.13379]
  • Drake, L., Hordinsky, M., Fiedler, V., Swinehart, J., Unger, W. P., Cotterill, P. C., Thiboutot, D. M., Lowe, N., Jacobson, C., Whiting, D., Stieglitz, S., Kraus, S. J., Griffin, E. I., Weiss, D., Carrington, P., Gencheff, C., Cole, G. W., Pariser, D. M., Epstein, E. S., Tanaka, W., Dallob, A., Vandormael, K., Geissler, L., & Waldsteicher, J. (1999). The effects of finasteride on scalp skin and serum androgen levels in men with androgenetic alopecia. Journal of the American Academy of Dermatology, 41(4), 550–554. [DOI:10.1016/s0190-9622(99)80051-6]
  • Dyson, T. E., Cantrell, M. A., & Lund, B. C. (2020). Lack of Association between 5α-Reductase Inhibitors and Depression. Journal of Urology, 204(4), 793–798. [DOI:10.1097/ju.0000000000001079]
  • Erem, C. (2013). Update on idiopathic hirsutism: diagnosis and treatment. Acta Clinica Belgica, 68(4), 268–274. [DOI:10.2143/acb.3267]
  • Erenus, M., Gürbüz, O., Durmuşoğlu, F., Demirçay, Z., & Pekin, S. (1994). Comparison of the efficacy of spironolactone versus flutamide in the treatment of hirsutism. Fertility and Sterility, 61(4), 613–616. [DOI:10.1016/s0015-0282(16)56634-5]
  • Esoterix/LabCorp. (2020). Endocrinology Expected Values and S.I. Unit Conversion Tables. LabCorp/Endocrine Sciences. [PDF]
  • Even Zohar, N., Sofer, Y., Yaish, I., Serebro, M., Tordjman, K., & Greenman, Y. (2021). Low-Dose Cyproterone Acetate Treatment for Transgender Women. The Journal of Sexual Medicine, 18(7), 1292–1298. [DOI:10.1016/j.jsxm.2021.04.008]
  • Fertig, R., Shapiro, J., Bergfeld, W., & Tosti, A. (2016). Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome. Skin Appendage Disorders, 2(3–4), 120–129. [DOI:10.1159/000450617]
  • Food and Drug Administration. (2019). UPDATE: The FDA Warns that Biotin May Interfere with Lab Tests: FDA Safety Communication. Food and Drug Administration. [URL]
  • Fournier, A., Berrino, F., & Clavel-Chapelon, F. (2007). Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Research and Treatment, 107(1), 103–111. [DOI:10.1007/s10549-007-9523-x]
  • Frye, S. (2006). Discovery and Clinical Development of Dutasteride, a Potent Dual 5α-Reductase Inhibitor. Current Topics in Medicinal Chemistry, 6(5), 405–421. [DOI:10.2174/156802606776743101]
  • Gava, G., Mancini, I., Alvisi, S., Seracchioli, R., & Meriggiola, M. C. (2020). A comparison of 5-year administration of cyproterone acetate or leuprolide acetate in combination with estradiol in transwomen. European Journal of Endocrinology, 183(6), 561–569. [DOI:10.1530/eje-20-0370]
  • Getzenberg, R., & Itty, S. (2020). How do we define “castration” in men on androgen deprivation therapy? Asian Journal of Andrology, 22(5), 441–446. [DOI:10.4103/aja.aja_139_19]
  • Giltay, E. J., Gooren, L. J., Toorians, A. W., Katan, M. B., & Zock, P. L. (2004). Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. The American Journal of Clinical Nutrition, 80(5), 1167–1174. [DOI:10.1093/ajcn/80.5.1167]
  • Glintborg, D., T’Sjoen, G., Ravn, P., & Andersen, M. S. (2021). MANAGEMENT OF ENDOCRINE DISEASE: Optimal feminizing hormone treatment in transgender people. European Journal of Endocrinology, 185(2), R49–R63. [DOI:10.1530/eje-21-0059]
  • Goletiani, N. V., Keith, D. R., & Gorsky, S. J. (2007). Progesterone: Review of safety for clinical studies. Experimental and Clinical Psychopharmacology, 15(5), 427–444. [DOI:10.1037/1064-1297.15.5.427]
  • Goodfellow, A., Alaghband-Zadeh, J., Carter, G., Cream, J., Holland, S., Scully, J., & Wise, P. (1984). Oral spironolactone improves acne vulgaris and reduces sebum excretion. British Journal of Dermatology, 111(2), 209–214. [DOI:10.1111/j.1365-2133.1984.tb04045.x]
  • Gooren, L. J. (2016). The Endocrinology of Sexual Behavior and Gender Identity. In Jameson, J. L., & De Groot, L. J. (Eds.). Endocrinology: Adult and Pediatric, 7th Edition, Volume 2 (pp. 2163–2176.e4). Philadelphia: Saunders/Elsevier. [Google Books] [DOI:10.1016/B978-0-323-18907-1.00124-4]
  • Gooren, L. J., Harmsen-Louman, W., & Kessel, H. (1985). Follow-up of prolactin levels in long-term oestrogen-treated male-to-female transsexuals with regard to prolactinoma induction. Clinical Endocrinology, 22(2), 201–207. [DOI:10.1111/j.1365-2265.1985.tb01081.x]
  • Gooren, L., Rao, B., van Kessel, H., & Harmsen-Louman, W. (1984). Estrogen positive feedback on LH secretion in transsexuality. Psychoneuroendocrinology, 9(3), 249–259. [DOI:10.1016/0306-4530(84)90004-0]
  • Gormley, G. J., Stoner, E., Rittmaster, R. S., Gregg, H., Thompson, D. L., Lasseter, K. C., Vlasses, P. H., & Stein, E. A. (1990). Effects of Finasteride (MK-906), a 5α-Reductase Inhibitor, on Circulating Androgens in Male Volunteers. The Journal of Clinical Endocrinology & Metabolism, 70(4), 1136–1141. [DOI:10.1210/jcem-70-4-1136]
  • Grock, S., Weinreb, J., Williams, K. C., Weimer, A., Fadich, S., Patel, R., Geft, A., & Korenman, S. (2024). Priorities for efficacy trials of gender-affirming hormone therapy with estrogen: collaborative design and results of a community survey. Hormones, online ahead of print. [DOI:10.1007/s42000-024-00532-3]
  • Gubelin Harcha, W., Barboza Martínez, J., Tsai, T., Katsuoka, K., Kawashima, M., Tsuboi, R., Barnes, A., Ferron-Brady, G., & Chetty, D. (2014). A randomized, active- and placebo-controlled study of the efficacy and safety of different doses of dutasteride versus placebo and finasteride in the treatment of male subjects with androgenetic alopecia. Journal of the American Academy of Dermatology, 70(3), 489–498.e3. [DOI:10.1016/j.jaad.2013.10.049]
  • Gupta, P., Suppakitjanusant, P., Stevenson, M., Goodman, M., & Tangpricha, V. (2022). Potassium Concentrations in Transgender Women Using Spironolactone: A Retrospective Chart Review. Endocrine Practice, 28(11), 1113–1117. [DOI:10.1016/j.eprac.2022.08.007]
  • Hammerstein, J. (1990). Antiandrogens: Clinical Aspects. In Orfanos, C. E., & Happle, R. (Eds.). Hair and Hair Diseases (pp. 827–886). Berlin/Heidelberg: Springer. [DOI:10.1007/978-3-642-74612-3_35]
  • Hayes, H., Russell, R., Haugen, A., Nagavally, S., & Sarvaideo, J. (2022). The Utility of Monitoring Potassium in Transgender, Gender Diverse, and Nonbinary Individuals on Spironolactone. Journal of the Endocrine Society, 6(11), bvac133. [DOI:10.1210/jendso/bvac133]
  • Heinemann, L. A., Will-Shahab, L., van Kesteren, P., Gooren, L. J., & (1997). Safety of Cyproterone Acetate: Report of Active Surveillance. Pharmacoepidemiology and Drug Safety, 6(3), 169–178. [DOI:10.1002/(sici)1099-1557(199705)6:3<169::aid-pds263>3.0.co;2-3]
  • Hembree, W. C., Cohen-Kettenis, P. T., Gooren, L., Hannema, S. E., Meyer, W. J., Murad, M. H., Rosenthal, S. M., Safer, J. D., Tangpricha, V., & T’Sjoen, G. G. (2017). Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline. The Journal of Clinical Endocrinology and Metabolism, 102(11), 3869–3903. [DOI:10.1210/jc.2017-01658] [PDF]
  • Herndon, J. S., Maheshwari, A. K., Nippoldt, T. B., Carlson, S. J., Davidge-Pitts, C. J., & Chang, A. Y. (2023). Comparison of the Subcutaneous and Intramuscular Estradiol Regimens as Part of Gender-Affirming Hormone Therapy. Endocrine Practice, 29(5), 356–361. [DOI:10.1016/j.eprac.2023.02.006]
  • Hirshburg, J. M., Kelsey, P. A., Therrien, C. A., Gavino, A. C., & Reichenberg, J. S. (2016). Adverse Effects and Safety of 5-alpha Reductase Inhibitors (Finasteride, Dutasteride): A Systematic Review. The Journal of Clinical and Aesthetic Dermatology, 9(7), 56–62. [PubMed] [PubMed Central]
  • Hopkins, U., & Arias, C. Y. (2013). Large-volume IM injections: a review of best practices. Oncology Nurse Advisor, 4(1), 32–37. [Google Scholar] [URL] [PDF]
  • Horton, R. (1992). Dihydrotestosterone Is a Peripheral Paracrine Hormone. Journal of Andrology, 13(1), 23–27. [DOI:10.1002/j.1939-4640.1992.tb01621.x]
  • Huang, G., & Basaria, S. (2017). The Case for Androgens in Menopausal Women: When and How? In Pal, L., & Sayegh, R. A. (Eds.). Essentials of Menopause Management: A Case-Based Approach (pp. 173–196). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-42451-4_10]
  • Igo, J., & Visram, H. (2021). Testosterone Suppression With Injectable Estrogen Therapy Alone in Male to Female Transgender Patients. Canadian Journal of Diabetes, 45(7 Suppl), S40–S40 (abstract no. 114). [DOI:10.1016/j.jcjd.2021.09.124] [URL] [PDF]
  • Irwig, M. S. (2020). Is there a role for 5α‐reductase inhibitors in transgender individuals? Andrology, 9(6), 1729–1731. [DOI:10.1111/andr.12881]
  • Iversen, P., Johansson, J. E., Lodding, P., Lukkarinen, O., Lundmo, P., Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T., Carroll, K., & Scandinavian Prostatic Cancer Group. (2004). Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6. The Journal of Urology, 172(5 Part 1), 1871–1876. [DOI:10.1097/01.ju.0000139719.99825.54]
  • Iversen, P., Johansson, J., Lodding, P., Kylmälä, T., Lundmo, P., Klarskov, P., Tammela, T. L., Tasdemir, I., Morris, T., Armstrong, J., & (2006). Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer Updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years. Scandinavian Journal of Urology and Nephrology, 40(6), 441–452. [DOI:10.1080/00365590601017329]
  • Iwamoto, S. J., Defreyne, J., Rothman, M. S., Van Schuylenbergh, J., Van de Bruaene, L., Motmans, J., & T’Sjoen, G. (2019). Health considerations for transgender women and remaining unknowns: a narrative review. Therapeutic Advances in Endocrinology and Metabolism, 10, 204201881987116. [DOI:10.1177/2042018819871166]
  • Iwamoto, S. J., Grimstad, F., Irwig, M. S., & Rothman, M. S. (2021). Routine Screening for Transgender and Gender Diverse Adults Taking Gender-Affirming Hormone Therapy: a Narrative Review. Journal of General Internal Medicine, 36(5), 1380–1389. [DOI:10.1007/s11606-021-06634-7]
  • Jacoby, A., Rifkin, W., Zhao, L. C., & Bluebond-Langner, R. (2020). Incidence of Cancer and Premalignant Lesions in Surgical Specimens of Transgender Patients. Plastic & Reconstructive Surgery, 147(1), 194–198. [DOI:10.1097/prs.0000000000007452]
  • Jain, J., Kwan, D., & Forcier, M. (2019). Medroxyprogesterone Acetate in Gender-Affirming Therapy for Transwomen: Results From a Retrospective Study. The Journal of Clinical Endocrinology & Metabolism, 104(11), 5148–5156. [DOI:10.1210/jc.2018-02253]
  • James, J. F., Jamerson, T. A., & Aguh, C. (2022). Efficacy and safety profile of oral spironolactone use for androgenic alopecia: A systematic review. Journal of the American Academy of Dermatology, 86(2), 425–429. [DOI:10.1016/j.jaad.2021.07.048]
  • Jia, A. Y., & Spratt, D. E. (2022). Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative. International Journal of Radiation Oncology*Biology*Physics, 113(2), 316–319. [DOI:10.1016/j.ijrobp.2022.01.037]
  • Jiang, Y., & Tian, W. (2017). The effects of progesterones on blood lipids in hormone replacement therapy. Lipids in Health and Disease, 16(1), 219. [DOI:10.1186/s12944-017-0612-5]
  • Kanhai, R. C., Hage, J. J., van Diest, P. J., Bloemena, E., & Mulder, J. W. (2000). Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men. The American Journal of Surgical Pathology, 24(1), 74–80. [DOI:10.1097/00000478-200001000-00009]
  • Kellner, M., & Wiedemann, K. (2008). Mineralocorticoid receptors in brain, in health and disease: Possibilities for new pharmacotherapy. European Journal of Pharmacology, 583(2–3), 372–378. [DOI:10.1016/j.ejphar.2007.07.072]
  • Kim, G. K., & Del Rosso, J. Q. (2012). Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris: Practical Considerations for the Clinician Based on Current Data and Clinical Experience. The Journal of Clinical and Aesthetic Dermatology, 5(3), 37–50. [PubMed] [PubMed Central]
  • King, S. R. (2012). Neurosteroids and the Nervous System. In King, S. R. Neurosteroids and the Nervous System (pp. 1–122). New York: Springer New York. [DOI:10.1007/978-1-4614-5559-2_1]
  • Krishnamurthy, N., Slack, D., Kyweluk, M., Kirkley, J., Trakhtenberg, E., Contreras-Castro, F., & Safer, J. (2023). Not All Transfeminine Individuals on Estradiol Can Reach Both Target Testosterone and Target Estradiol Levels—Time to Revisit Treatment Guidelines? USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 94–94 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Kolvenbag, G. J., & Blackledge, G. R. (1996). Worldwide activity and safety of bicalutamide: a summary review. Urology, 47(1), 70–79. [DOI:10.1016/s0090-4295(96)80012-4]
  • Kuhl, H. (2003). Östrogene für den Mann? [Estrogen for men?] Blickpunkt der Mann, 1(3), 6–12. [Google Scholar] [URL] [PDF]
  • Kuhl, H. (2005). Pharmacology of estrogens and progestogens: influence of different routes of administration. Climacteric, 8(Suppl 1), 3–63. [DOI:10.1080/13697130500148875] [PDF]
  • Kuhl, H., & Wiegratz, I. (2017). Das Post-Finasterid-Syndrom. [Post Finasteride Syndrome.] Gynäkologische Endokrinologie, 15(2), 153–163. [DOI:10.1007/s10304-017-0126-2]
  • Kuijpers, S. M., Wiepjes, C. M., Conemans, E. B., Fisher, A. D., T’Sjoen, G., & den Heijer, M. (2021). Toward a Lowest Effective Dose of Cyproterone Acetate in Trans Women: Results From the ENIGI Study. The Journal of Clinical Endocrinology & Metabolism, 106(10), e3936–e3945. [DOI:10.1210/clinem/dgab427]
  • Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., & Rao, P. N. (2021). Cyproterone Acetate–Induced Acute Liver Failure: A Case Report and Review of the Literature. Journal of Clinical and Experimental Hepatology, 11(6), 739–741. [DOI:10.1016/j.jceh.2021.01.003]
  • Lauritzen, C. (1988). Natürliche und synthetische Sexualhormone – Biologische Grundlagen und Behandlungsprinzipien. [Natural and Synthetic Sexual Hormones – Biological Basis and Medical Treatment Principles.] In Lauritzen, C., Schneider, H. P. G., & Nieschlag, E. (Eds.). Grundlagen und Klinik der Menschlichen Fortpflanzung [Foundations and Clinic of Human Reproduction] (pp. 229–306). Berlin: de Gruyter. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat] [URL] [PDF] [Translation]
  • Lax, E. (1987). Mechanisms of physiological and pharmacological sex hormone action on the mammalian liver. Journal of Steroid Biochemistry, 27(4–6), 1119–1128. [DOI:10.1016/0022-4731(87)90198-1]
  • Layton, A. M., Eady, E. A., Whitehouse, H., Del Rosso, J. Q., Fedorowicz, Z., & van Zuuren, E. J. (2017). Oral Spironolactone for Acne Vulgaris in Adult Females: A Hybrid Systematic Review. American Journal of Clinical Dermatology, 18(2), 169–191. [DOI:10.1007/s40257-016-0245-x]
  • Legro, R. S., Schlaff, W. D., Diamond, M. P., Coutifaris, C., Casson, P. R., Brzyski, R. G., Christman, G. M., Trussell, J. C., Krawetz, S. A., Snyder, P. J., Ohl, D., Carson, S. A., Steinkampf, M. P., Carr, B. R., McGovern, P. G., Cataldo, N. A., Gosman, G. G., Nestler, J. E., Myers, E. R., Santoro, N., Eisenberg, E., Zhang, M., & Zhang, H. (2010). Total Testosterone Assays in Women with Polycystic Ovary Syndrome: Precision and Correlation with Hirsutism. The Journal of Clinical Endocrinology & Metabolism, 95(12), 5305–5313. [DOI:10.1210/jc.2010-1123]
  • Leinung, M. C. (2014). Variable Response to Oral Estradiol Therapy in Male to Female Transgender Patients. Endocrine Reviews, 35(Suppl 1) [Endocrine Society’s 96th Annual Meeting and Expo, June 21–24, 2014 – Chicago], ?–? (abstract no. OR42-1). [Google Scholar] [DOI:10.1093/edrv/35.supp.1] [DOI:10.1210/endo-meetings.2014.RE.2.OR42-1] [URL] [MedPage Today]
  • Leinung, M. C., Feustel, P. J., & Joseph, J. (2018). Hormonal Treatment of Transgender Women with Oral Estradiol. Transgender Health, 3(1), 74–81. [DOI:10.1089/trgh.2017.0035]
  • Liang, J. J., Jolly, D., Chan, K. J., & Safer, J. D. (2018). Testosterone Levels Achieved by Medically Treated Transgender Women in a United States Endocrinology Clinic Cohort. Endocrine Practice, 24(2), 135–142. [DOI:10.4158/ep-2017-0116]
  • Lobo, R. A., Shoupe, D., Serafini, P., Brinton, D., & Horton, R. (1985). The effects of two doses of spironolactone on serum androgens and anagen hair in hirsute women. Fertility and Sterility, 43(2), 200–205. [DOI:10.1016/s0015-0282(16)48373-1]
  • Loh, H. H., Yee, A., Loh, H. S., Kanagasundram, S., Francis, B., & Lim, L. (2020). Sexual dysfunction in polycystic ovary syndrome: a systematic review and meta-analysis. Hormones, 19(3), 413–423. [DOI:10.1007/s42000-020-00210-0]
  • Luong, J. H., Male, K. B., & Glennon, J. D. (2019). Biotin interference in immunoassays based on biotin-strept(avidin) chemistry: An emerging threat. Biotechnology Advances, 37(5), 634–641. [DOI:10.1016/j.biotechadv.2019.03.007]
  • MacLean, D. B., Shi, H., Faessel, H. M., & Saad, F. (2015). Medical Castration Using the Investigational Oral GnRH Antagonist TAK-385 (Relugolix): Phase 1 Study in Healthy Males. The Journal of Clinical Endocrinology & Metabolism, 100(12), 4579–4587. [DOI:10.1210/jc.2015-2770]
  • Mahler, C. (1996). A Review of the Clinical Studies with Nilutamide. In Denis, L. (Ed.). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment (ESO Monographs) (pp. 105–111). Berlin/Heidelberg: Springer Berlin Heidelberg. [DOI:10.1007/978-3-642-45745-6_10]
  • Maksym, R. B., Kajdy, A., & Rabijewski, M. (2019). Post-finasteride syndrome – does it really exist? The Aging Male, 22(4), 250–259. [DOI:10.1080/13685538.2018.1548589]
  • Marks, D. H., Prasad, S., De Souza, B., Burns, L. J., & Senna, M. M. (2019). Topical Antiandrogen Therapies for Androgenetic Alopecia and Acne Vulgaris. American Journal of Clinical Dermatology, 21(2), 245–254. [DOI:10.1007/s40257-019-00493-z]
  • Martinez-Martin, F. J., Kuzior, A., Hernandez-Lazaro, A., de Leon-Durango, R. J., Rios-Gomez, C., Santana-Ojeda, B., Perez-Rivero, J. M., Fernandez-Trujillo-Comenge, P. M., Gonzalez-Diaz, P., Arnas-Leon, C., Acosta-Calero, C., Perdomo-Herrera, E., Tocino-Hernandez, A. L., del Sol Sanchez-Bacaicoa, M., & del Pino Perez-Garcia, M. (2022). Incidence of hypertension in young transgender people after a 5-year follow-up: association with gender-affirming hormonal therapy. Hypertension Research, 46(1), 219–225. [DOI:10.1038/s41440-022-01067-z]
  • Masumori, N., Baba, T., Abe, T., & Niwa, K. (2021). What is the most anticipated change induced by treatment using gender‐affirming hormones in individuals with gender incongruence?. International Journal of Urology, 28(5), 526–529. [DOI:10.1111/iju.14499]
  • McFarlane, T., Zajac, J. D., & Cheung, A. S. (2018). Gender-affirming hormone therapy and the risk of sex hormone-dependent tumours in transgender individuals—A systematic review. Clinical Endocrinology, 89(6), 700–711. [DOI:10.1111/cen.13835]
  • Meriggiola, M. C., Bremner, W. J., Costantino, A., Bertaccini, A., Morselli-Labate, A. M., Huebler, D., Kaufmann, G., Oettel, M., & Flamigni, C. (2002). Twenty-One Day Administration of Dienogest Reversibly Suppresses Gonadotropins and Testosterone in Normal Men. The Journal of Clinical Endocrinology & Metabolism, 87(5), 2107–2113. [DOI:10.1210/jcem.87.5.8514]
  • Meyer, G., Mayer, M., Mondorf, A., Flügel, A. K., Herrmann, E., & Bojunga, J. (2020). Safety and rapid efficacy of guideline-based gender-affirming hormone therapy: an analysis of 388 individuals diagnosed with gender dysphoria. European Journal of Endocrinology, 182(2), 149–156. [DOI:10.1530/eje-19-0463]
  • Miles, R. A., Paulson, R. J., Lobo, R. A., Press, M. F., Dahmoush, L., & Sauer, M. V. (1994). Pharmacokinetics and endometrial tissue levels of progesterone after administration by intramuscular and vaginal routes: a comparative study. Fertility and Sterility, 62(3), 485–490. [DOI:10.1016/s0015-0282(16)56935-0]
  • Millington, K., Liu, E., & Chan, Y. (2019). The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone. Journal of the Endocrine Society, 3(5), 1031–1038. [DOI:10.1210/js.2019-00030]
  • Millward, C. P., Keshwara, S. M., Islim, A. I., Jenkinson, M. D., Alalade, A. F., & Gilkes, C. E. (2022). Development and Growth of Intracranial Meningiomas in Transgender Women Taking Cyproterone Acetate as Gender-Affirming Progestogen Therapy: A Systematic Review. Transgender Health, 7(6), 473–483. [DOI:10.1089/trgh.2021.0025]
  • Moretti, C., Guccione, L., Di Giacinto, P., Simonelli, I., Exacoustos, C., Toscano, V., Motta, C., De Leo, V., Petraglia, F., & Lenzi, A. (2017). Combined Oral Contraception and Bicalutamide in Polycystic Ovary Syndrome and Severe Hirsutism: A Double-Blind Randomized Controlled Trial. The Journal of Clinical Endocrinology & Metabolism, 103(3), 824–838. [DOI:10.1210/jc.2017-01186]
  • Nakamoto, J. (2016). Endocrine Testing. In Jameson, J. L., & De Groot, L. J. (Eds.). Endocrinology: Adult and Pediatric, 7th Edition (pp. 2655–2688.e1). Philadelphia: Saunders/Elsevier. [DOI:10.1016/B978-0-323-18907-1.00154-2]
  • Nakhjavani, M., Hamidi, S., Esteghamati, A., Abbasi, M., Nosratian-Jahromi, S., & Pasalar, P. (2009). Short term effects of spironolactone on blood lipid profile: a 3-month study on a cohort of young women with hirsutism. British Journal of Clinical Pharmacology, 68(4), 634–637. [DOI:10.1111/j.1365-2125.2009.03483.x]
  • Neyman, A., Fuqua, J. S., & Eugster, E. A. (2019). Bicalutamide as an Androgen Blocker With Secondary Effect of Promoting Feminization in Male-to-Female Transgender Adolescents. Journal of Adolescent Health, 64(4), 544–546. [DOI:10.1016/j.jadohealth.2018.10.296]
  • Nguyen, D., Marchese, M., Cone, E. B., Paciotti, M., Basaria, S., Bhojani, N., & Trinh, Q. (2021). Investigation of Suicidality and Psychological Adverse Events in Patients Treated With Finasteride. JAMA Dermatology, 157(1), 35–42. [DOI:10.1001/jamadermatol.2020.3385]
  • Nie, I., Wiepjes, C. M., Blok, C. J., Moorselaar, R. J., Pigot, G. L., Sluis, T. M., Barbé, E., Voorn, P., Mello, N. M., Huirne, J., & Heijer, M. (2021). Incidence of testicular cancer in trans women using gender‐affirming hormonal treatment: a nationwide cohort study. BJU International, 129(4), 491–497. [DOI:10.1111/bju.15575]
  • Nieschlag, E., Zitzmann, M., & Kamischke, A. (2003). Use of progestins in male contraception. Steroids, 68(10–13), 965–972. [DOI:10.1016/s0039-128x(03)00135-1]
  • Nieschlag, E. (2010). Clinical trials in male hormonal contraception. Contraception, 82(5), 457–470. [DOI:10.1016/j.contraception.2010.03.020]
  • Nieschlag, E., & Behre, H. M. (2012). The essential role of testosterone in hormonal male contraception. In Nieschlag, E., Behre, H. M., & Nieschlag, S. (Eds.). Testosterone: Action · Deficiency · Substitution, 4th Edition (pp. 470–493). Cambridge/New York: Cambridge University Press. [DOI:10.1017/cbo9781139003353.023]
  • Nishiyama, T. (2014). Serum testosterone levels after medical or surgical androgen deprivation: A comprehensive review of the literature. Urologic Oncology: Seminars and Original Investigations, 32(1), 38.e17–38.e28. [DOI:10.1016/j.urolonc.2013.03.007]
  • Nolan, B. J., & Cheung, A. S. (2021). Relationship Between Serum Estradiol Concentrations and Clinical Outcomes in Transgender Individuals Undergoing Feminizing Hormone Therapy: A Narrative Review. Transgender Health, 6(3), 125–131. [DOI:10.1089/trgh.2020.0077]
  • Nolan, B. J., Frydman, A. S., Leemaqz, S. Y., Carroll, M., Grossmann, M., Zajac, J. D., & Cheung, A. S. (2022). Effects of low-dose oral micronised progesterone on sleep, psychological distress, and breast development in transgender individuals undergoing feminising hormone therapy: a prospective controlled study. Endocrine Connections, 11(5), e220170. [DOI:10.1530/EC-22-0170]
  • Norman, A. W., & Henry, H. L. (2015). Androgens. In Norman, A. W., & Henry, H. L. Hormones, 3rd Edition (pp. 255–273). London: Academic Press/Elsevier. [DOI:10.1016/b978-0-08-091906-5.00012-4]
  • Norman, A. W., & Henry, H. L. (2015). Estrogens and Progestins. In Norman, A. W., & Henry, H. L. Hormones, 3rd Edition (pp. 275–296). London: Academic Press/Elsevier. [DOI:10.1016/b978-0-08-091906-5.00013-6]
  • Nota, N. M., Wiepjes, C. M., de Blok, C. J., Gooren, L. J., Peerdeman, S. M., Kreukels, B. P., & den Heijer, M. (2018). The occurrence of benign brain tumours in transgender individuals during cross-sex hormone treatment. Brain, 141(7), 2047–2054. [DOI:10.1093/brain/awy108]
  • North American Menopause Society. (2022). The 2022 hormone therapy position statement of The North American Menopause Society. Menopause, 29(7), 767–794. [DOI:10.1097/gme.0000000000002028]
  • O’Connell, M. B. (1995). Pharmacokinetic and Pharmacologic Variation Between Different Estrogen Products. The Journal of Clinical Pharmacology, 35(9S), 18S–24S. [DOI:10.1002/j.1552-4604.1995.tb04143.x]
  • Olsen, E. A., Hordinsky, M., Whiting, D., Stough, D., Hobbs, S., Ellis, M. L., Wilson, T., & Rittmaster, R. S. (2006). The importance of dual 5α-reductase inhibition in the treatment of male pattern hair loss: Results of a randomized placebo-controlled study of dutasteride versus finasteride. Journal of the American Academy of Dermatology, 55(6), 1014–1023. [DOI:10.1016/j.jaad.2006.05.007]
  • Plovanich, M., Weng, Q. Y., & Mostaghimi, A. (2015). Low Usefulness of Potassium Monitoring Among Healthy Young Women Taking Spironolactone for Acne. JAMA Dermatology, 151(9), 941–944. [DOI:10.1001/jamadermatol.2015.34]
  • Polyzos, S. A., Kountouras, J., Zavos, C., & Deretzi, G. (2011). Spironolactone Revisited. The Journal of Clinical Hypertension, 13(10), 783–784. [DOI:10.1111/j.1751-7176.2011.00484.x]
  • Powers, M. S., Schenkel, L., Darley, P. E., Good, W. R., Balestra, J. C., & Place, V. A. (1985). Pharmacokinetics and pharmacodynamics of transdermal dosage forms of 17β-estradiol: Comparison with conventional oral estrogens used for hormone replacement. American Journal of Obstetrics and Gynecology, 152(8), 1099–1106. [DOI:10.1016/0002-9378(85)90569-1]
  • Prince, J. C., & Safer, J. D. (2020). Endocrine treatment of transgender individuals: current guidelines and strategies. Expert Review of Endocrinology & Metabolism, 15(6), 395–403. [DOI:10.1080/17446651.2020.1825075]
  • Reiter, E. O., Mauras, N., McCormick, K., Kulshreshtha, B., Amrhein, J., De Luca, F., O’Brien, S., Armstrong, J., & Melezinkova, H. (2010). Bicalutamide plus Anastrozole for the Treatment of Gonadotropin-Independent Precocious Puberty in Boys with Testotoxicosis: A Phase II, Open-Label Pilot Study (BATT). Journal of Pediatric Endocrinology and Metabolism, 23(10), 999–1009. [DOI:10.1515/jpem.2010.161]
  • Rezende, H. D., Dias, M. F. R. G., & Trüeb, R. M. (2018). A Comment on the Post-Finasteride Syndrome. International Journal of Trichology, 10(6), 255–261. [PubMed] [PubMed Central] [DOI:10.4103/ijt.ijt_61_18]
  • Roberts, J. L., Fiedler, V., Imperato-McGinley, J., Whiting, D., Olsen, E., Shupack, J., Stough, D., DeVillez, R., Rietschel, R., Savin, R., Bergfeld, W., Swinehart, J., Funicella, T., Hordinsky, M., Lowe, N., Katz, I., Lucky, A., Drake, L., Price, V. H., Weiss, D., Whitmore, E., Millikan, L., Muller, S., Gencheff, C., Carrington, P., Binkowitz, B., Kotey, P., He, W., Bruno, K., Jacobsen, C., Terranella, L., Gormley, G. J., & Kaufman, K. D. (1999). Clinical dose ranging studies with finasteride, a type 2 5α-reductase inhibitor, in men with male pattern hair loss. Journal of the American Academy of Dermatology, 41(4), 555–563. [DOI:10.1016/s0190-9622(99)80052-8]
  • Roscioni, S. S., de Zeeuw, D., Bakker, S. J., & Lambers Heerspink, H. J. (2012). Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy. Nature Reviews Nephrology, 8(12), 691–699. [DOI:10.1038/nrneph.2012.217]
  • Rose, A. J., Hughto, J. M., Dunbar, M. S., Quinn, E. K., Deutsch, M., Feldman, J., Radix, A., Safer, J. D., Shipherd, J. C., Thompson, J., & Jasuja, G. K. (2023). Trends in Feminizing Hormone Therapy for Transgender Patients, 2006–2017. Transgender Health, 8(2), 188–194. [DOI:10.1089/trgh.2021.0041]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2008). Puberty and its disorders in the female. In Sperling, M. A. (Ed.). Pediatric Endocrinology, 3rd Edition (pp. 530–609). Philadelphia: Saunders. [Google Scholar] [Google Books] [OpenLibrary] [WorldCat]
  • Rosenfield, R. L., Cooke, D. W., & Radovick, S. (2021). Puberty in the Female and Its Disorders. In Sperling, M. A., Majzoub, J. A., Menon, R. K., & Stratakis, C. A. (Eds.). Sperling Pediatric Endocrinology, 5th Edition (pp. 528–626). Philadelphia: Elsevier. [DOI:10.1016/B978-0-323-62520-3.00016-6]
  • Samarasinghe, S., Meah, F., Singh, V., Basit, A., Emanuele, N., Emanuele, M. A., Mazhari, A., & Holmes, E. W. (2017). Biotin Interference with Routine Clinical Immunoassays: Understand the Causes and Mitigate the Risks. Endocrine Practice, 23(8), 989–998. [DOI:10.4158/ep171761.ra]
  • Schiller, C. E., Schmidt, P. J., & Rubinow, D. R. (2014). Allopregnanolone as a mediator of affective switching in reproductive mood disorders. Psychopharmacology, 231(17), 3557–3567. [DOI:10.1007/s00213-014-3599-x]
  • Schlatterer, K., Yassouridis, A., Werder, K. V., Poland, D., Kemper, J., & Stalla, G. K. (1998). Archives of Sexual Behavior, 27(5), 475–492. [DOI:10.1023/a:1018704630036]
  • Seaman, H. E., Langley, S. E., Farmer, R. D., & de Vries, C. S. (2007). Venous thromboembolism and cyproterone acetate in men with prostate cancer: a study using the General Practice Research Database. BJU International, 99(6), 1398–1403. [DOI:10.1111/j.1464-410x.2007.06859.x]
  • Shackleton, C. (2010). Clinical steroid mass spectrometry: A 45-year history culminating in HPLC–MS/MS becoming an essential tool for patient diagnosis. The Journal of Steroid Biochemistry and Molecular Biology, 121(3–5), 481–490. [DOI:10.1016/j.jsbmb.2010.02.017]
  • Shaw, J. C. (1996). Antiandrogen and hormonal treatment of acne. Dermatologic Clinics, 14(4), 803–811. [DOI:10.1016/s0733-8635(05)70405-8]
  • Slack, D., Krishnamurthy, N., Contreras-Castro, F., & Safer, J. D. (2023). Achieving Both Target Testosterone And Target Estradiol Levels May Not Be Practical In All Trans Feminine Users Of Estradiol - Which To Prioritize? Journal of the Endocrine Society, 7(Suppl 1), A1102–A1102 (abstract no. SAT404/bvad114.2075). [DOI:10.1210/jendso/bvad114.2075] [PubMed Central]
  • Sofer, Y., Yaish, I., Yaron, M., Bach, M. Y., Stern, N., & Greenman, Y. (2020). Differential Endocrine and Metabolic Effects of Testosterone Suppressive Agents in Transgender Women. Endocrine Practice, 26(8), 883–890. [DOI:10.4158/ep-2020-0032] [PDF]
  • SoRelle, J. A., Jiao, R., Gao, E., Veazey, J., Frame, I., Quinn, A. M., Day, P., Pagels, P., Gimpel, N., & Patel, K. (2019). Impact of Hormone Therapy on Laboratory Values in Transgender Patients. Clinical Chemistry, 65(1), 170–179. [DOI:10.1373/clinchem.2018.292730]
  • St-Jules, D. E., Goldfarb, D. S., & Sevick, M. A. (2016). Nutrient Non-equivalence: Does Restricting High-Potassium Plant Foods Help to Prevent Hyperkalemia in Hemodialysis Patients? Journal of Renal Nutrition, 26(5), 282–287. [DOI:10.1053/j.jrn.2016.02.005]
  • St-Jules, D. E., & Fouque, D. (2020). Is it time to abandon the nutrient-based renal diet model? Nephrology Dialysis Transplantation, 36(4), 574–577. [DOI:10.1093/ndt/gfaa257]
  • St-Jules, D. E., & Fouque, D. (2022). Etiology-based dietary approach for managing hyperkalemia in people with chronic kidney disease. Nutrition Reviews, 80(11), 2198–2205. [DOI:10.1093/nutrit/nuac026]
  • Stanczyk, F. Z., & Clarke, N. J. (2010). Advantages and challenges of mass spectrometry assays for steroid hormones. The Journal of Steroid Biochemistry and Molecular Biology, 121(3–5), 491–495. [DOI:10.1016/j.jsbmb.2010.05.001]
  • Stanczyk, F. Z., Hapgood, J. P., Winer, S., & Mishell, D. R. (2012). Progestogens Used in Postmenopausal Hormone Therapy: Differences in Their Pharmacological Properties, Intracellular Actions, and Clinical Effects. Endocrine Reviews, 34(2), 171–208. [DOI:10.1210/er.2012-1008]
  • Stanczyk, F. Z., Mathews, B. W., & Cortessis, V. K. (2017). Does the type of progestin influence the production of clotting factors? Contraception, 95(2), 113–116. [DOI:10.1016/j.contraception.2016.07.007]
  • Stege, R., Gunnarsson, P. O., Johansson, C., Olsson, P., Pousette, Å., & Carlström, K. (1996). Pharmacokinetics and testosterone suppression of a single dose of polyestradiol phosphate (Estradurin®) in prostatic cancer patients. The Prostate, 28(5), 307–310. [DOI:10.1002/(sici)1097-0045(199605)28:5<307::aid-pros6>3.0.co;2-8]
  • Steinberger, E., Ayala, C., Hsi, B., Smith, K. D., Rodriguez-Rigau, L. J., Weidman, E. R., & Reimondo, G. G. (1998). Utilization of Commercial Laboratory Results in Management of Hyperandrogenism in Women. Endocrine Practice, 4(1), 1–10. [DOI:10.4158/ep.4.1.1]
  • Sterling, J., & Garcia, M. M. (2020). Cancer screening in the transgender population: a review of current guidelines, best practices, and a proposed care model. Translational Andrology and Urology, 9(6), 2771–2785. [DOI:10.21037/tau-20-954]
  • Strauss, J. F., & FitzGerald, G. A. (2019). Steroid Hormones and Other Lipid Molecules Involved in Human Reproduction. In Strauss, J. F., & Barbieri, R. L. (Eds.). Yen and Jaffe’s Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management, 8th Edition (pp. 75–114.e7). Philadelphia: Elsevier. [Google Books] [DOI:10.1016/b978-0-323-47912-7.00004-4]
  • Stricker, R., Eberhart, R., Chevailler, M., Quinn, F. A., Bischof, P., & Stricker, R. (2006). Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT® analyzer. Clinical Chemistry and Laboratory Medicine (CCLM), 44(7), 883–887. [DOI:10.1515/cclm.2006.160]
  • Styne, D. M. (2016). Laboratory Values for Pediatric Endocrinology. In Styne, D. M. Pediatric Endocrinology: A Clinical Handbook (pp. 385–434). Cham: Springer International Publishing. [DOI:10.1007/978-3-319-18371-8_16]
  • Sudduth, S. L., & Koronkowski, M. J. (1993). Finasteride: The First 5α-Reductase Inhibitor. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 13(4), 309–329. [DOI:10.1002/j.1875-9114.1993.tb02739.x]
  • Sundström-Poromaa, I., Comasco, E., Sumner, R., & Luders, E. (2020). Progesterone – Friend or foe? Frontiers in Neuroendocrinology, 59, 100856. [DOI:10.1016/j.yfrne.2020.100856]
  • Swerdloff, R. S., Dudley, R. E., Page, S. T., Wang, C., & Salameh, W. A. (2017). Dihydrotestosterone: Biochemistry, Physiology, and Clinical Implications of Elevated Blood Levels. Endocrine Reviews, 38(3), 220–254. [DOI:10.1210/er.2016-1067]
  • T’Sjoen, G. G., Beguin, Y., Feyen, E., Rubens, R., Kaufman, J., & Gooren, L. (2005). Influence of exogenous oestrogen or (anti-) androgen administration on soluble transferrin receptor in human plasma. Journal of Endocrinology, 186(1), 61–67. [DOI:10.1677/joe.1.06112]
  • T’Sjoen, G., Arcelus, J., Gooren, L., Klink, D. T., & Tangpricha, V. (2018). Endocrinology of Transgender Medicine. Endocrine Reviews, 40(1), 97–117. [DOI:10.1210/er.2018-00011]
  • Tack, L. J., Heyse, R., Craen, M., Dhondt, K., Bossche, H. V., Laridaen, J., & Cools, M. (2017). Consecutive Cyproterone Acetate and Estradiol Treatment in Late-Pubertal Transgender Female Adolescents. The Journal of Sexual Medicine, 14(5), 747–757. [DOI:10.1016/j.jsxm.2017.03.251]
  • Thompson, J., Hopwood, R. A., deNormand, S., & Cavanaugh, T. (2021). Medical Care of Trans and Gender Diverse Adults. Boston: Fenway Health. [URL] [PDF]
  • Toorians, A. W., Thomassen, M. C., Zweegman, S., Magdeleyns, E. J., Tans, G., Gooren, L. J., & Rosing, J. (2003). Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual People. The Journal of Clinical Endocrinology & Metabolism, 88(12), 5723–5729. [DOI:10.1210/jc.2003-030520]
  • Traish, A. M., Krakowsky, Y., Doros, G., & Morgentaler, A. (2019). Do 5α-Reductase Inhibitors Raise Circulating Serum Testosterone Levels? A Comprehensive Review and Meta-Analysis to Explaining Paradoxical Results. Sexual Medicine Reviews, 7(1), 95–114. [DOI:10.1016/j.sxmr.2018.06.002]
  • Traish, A. M. (2020). Post-finasteride syndrome: a surmountable challenge for clinicians. Fertility and Sterility, 113(1), 21–50. [DOI:10.1016/j.fertnstert.2019.11.030]
  • Treleaven, M. M., Jackowich, R. A., Roberts, L., Wassersug, R. J., & Johnson, T. (2013). Castration and personality: Correlation of androgen deprivation and estrogen supplementation with the Big Five factor personality traits of adult males. Journal of Research in Personality, 47(4), 376–379. [DOI:10.1016/j.jrp.2013.03.005]
  • Usach, I., Martinez, R., Festini, T., & Peris, J. (2019). Subcutaneous Injection of Drugs: Literature Review of Factors Influencing Pain Sensation at the Injection Site. Advances in Therapy, 36(11), 2986–2996. [DOI:10.1007/s12325-019-01101-6]
  • van Zuuren, E. J., Fedorowicz, Z., Carter, B., & Pandis, N. (2015). Interventions for hirsutism (excluding laser and photoepilation therapy alone). Cochrane Database of Systematic Reviews, 2015, CD010334. [DOI:10.1002/14651858.cd010334.pub2]
  • Verdonk, S. J., Vesper, H. W., Martens, F., Sluss, P. M., Hillebrand, J. J., & Heijboer, A. C. (2019). Estradiol reference intervals in women during the menstrual cycle, postmenopausal women and men using an LC-MS/MS method. Clinica Chimica Acta, 495, 198–204. [DOI:10.1016/j.cca.2019.04.062]
  • Vermeulen, A., Giagulli, V., De Schepper, P., & Buntinx, A. (1991). Hormonal Effects of a 5α-Reductase Inhibitor (Finasteride) onHormonal Levels in Normal Men and in Patients withBenign Prostatic Hyperplasia. European Urology, 20(1), 82–86. [DOI:10.1159/000471752]
  • Vihtamäki, T., Luukkaala, T., & Tuimala, R. (2004). Skin contamination by oestradiol gel—a remarkable source of error in plasma oestradiol measurements during percutaneous hormone replacement therapy. Maturitas, 48(4), 347–353. [DOI:10.1016/s0378-5122(03)00043-4]
  • Wang, H., Liu, M., Fu, Q., & Deng, C. (2019). Pharmacokinetics of hard micronized progesterone capsules via vaginal or oral route compared with soft micronized capsules in healthy postmenopausal women: a randomized open-label clinical study. Drug Design, Development and Therapy, 13, 2475–2482. [DOI:10.2147/dddt.s204624]
  • Wang, Y., & Lipner, S. R. (2020). Retrospective analysis of adverse events with spironolactone in females reported to the United States Food and Drug Administration. International Journal of Women’s Dermatology, 6(4), 272–276. [DOI:10.1016/j.ijwd.2020.05.002]
  • Weill, A., Nguyen, P., Labidi, M., Cadier, B., Passeri, T., Duranteau, L., Bernat, A., Yoldjian, I., Fontanel, S., Froelich, S., & Coste, J. (2021). Use of High Dose Cyproterone Acetate and Risk of Intracranial Meningioma in Women: Cohort Study. BMJ, 372, n37. [DOI:10.1136/bmj.n37]
  • Welk, B., McArthur, E., Ordon, M., Anderson, K. K., Hayward, J., & Dixon, S. (2017). Association of Suicidality and Depression With 5α-Reductase Inhibitors. JAMA Internal Medicine, 177(5), 683–691. [DOI:10.1001/jamainternmed.2017.0089]
  • Wellington, K., & Keam, S. J. (2006). Bicalutamide 150mg: A Review of its Use in the Treatment of Locally Advanced Prostate Cancer. Drugs, 66(6), 837–850. [DOI:10.2165/00003495-200666060-00007]
  • Willemsen, W. N., Mastboom, J. L., Thomas, C. M., & Rolland, R. (1985). Absorption of 17β-estradiol in a neovagina constructed from the peritoneum. European Journal of Obstetrics & Gynecology and Reproductive Biology, 19(4), 247–253. [DOI:10.1016/0028-2243(85)90036-x]
  • Wilson, L. M., Baker, K. E., Sharma, R., Dukhanin, V., McArthur, K., & Robinson, K. A. (2020). Effects of antiandrogens on prolactin levels among transgender women on estrogen therapy: A systematic review. International Journal of Transgender Health, 21(4), 391–402. [DOI:10.1080/15532739.2020.1819505]
  • Wu, B., Shen, P., Yin, X., Yu, L., Wu, F., Chen, C., Li, J., & Xu, T. (2022). Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System. British Journal of Clinical Pharmacology, 89(2), 440–448. [DOI:10.1111/bcp.15336]
  • Wu, F. C., Balasubramanian, R., Mulders, T. M., & Coelingh-Bennink, H. J. (1999). Oral Progestogen Combined with Testosterone as a Potential Male Contraceptive: Additive Effects between Desogestrel and Testosterone Enanthate in Suppression of Spermatogenesis, Pituitary-Testicular Axis, and Lipid Metabolism. The Journal of Clinical Endocrinology & Metabolism, 84(1), 112–122. [DOI:10.1210/jcem.84.1.5412]
  • Yaish, I., Gindis, G., Greenman, Y., Moshe, Y., Arbiv, M., Buch, A., Sofer, Y., Shefer, G., & Tordjman, K. (2023). Sublingual Estradiol Offers No Apparent Advantage Over Combined Oral Estradiol and Cyproterone Acetate for Gender-Affirming Hormone Therapy of Treatment-Naive Trans Women: Results of a Prospective Pilot Study. Transgender Health, 8(6), 485–493. [DOI:10.1089/trgh.2023.0022]
  • Zaenglein, A. L., Pathy, A. L., Schlosser, B. J., Alikhan, A., Baldwin, H. E., Berson, D. S., Bowe, W. P., Graber, E. M., Harper, J. C., Kang, S., Keri, J. E., Leyden, J. J., Reynolds, R. V., Silverberg, N. B., Stein Gold, L. F., Tollefson, M. M., Weiss, J. S., Dolan, N. C., Sagan, A. A., Stern, M., Boyer, K. M., & Bhushan, R. (2016). Guidelines of care for the management of acne vulgaris. Journal of the American Academy of Dermatology, 74(5), 945–973.e33. [DOI:10.1016/j.jaad.2015.12.037]
  • Zhang, J., & Stanczyk, F. Z. (2013). LC-MS Bioanalysis of Steroids. In Li, W., Zhang, J., & Tse, F. L. S. (Eds.). Handbook of LC-MS Bioanalysis: Best Practices, Experimental Protocols, and Regulations (pp. 573–590). Hoboken, New Jersey: John Wiley & Sons. [DOI:10.1002/9781118671276.ch45]
  • Zhou, Z., Song, S., Gao, Z., Wu, J., Ma, J., & Cui, Y. (2019). The efficacy and safety of dutasteride compared with finasteride in treating men with androgenetic alopecia: a systematic review and meta-analysis. Clinical Interventions in Aging, 14, 399–406. [DOI:10.2147/cia.s192435]
  • Zitzmann, M., Rohayem, J., Raidt, J., Kliesch, S., Kumar, N., Sitruk-Ware, R., & Nieschlag, E. (2017). Impact of various progestins with or without transdermal testosterone on gonadotropin levels for non-invasive hormonal male contraception: a randomized clinical trial. Andrology, 5(3), 516–526. [DOI:10.1111/andr.12328]
  • Zuuren, E., & Fedorowicz, Z. (2016). Interventions for hirsutism excluding laser and photoepilation therapy alone: abridged Cochrane systematic review including GRADE assessments. British Journal of Dermatology, 175(1), 45–61. [DOI:10.1111/bjd.14486]
\ No newline at end of file diff --git a/transfemscience.org/feed-posts.xml b/transfemscience.org/feed-posts.xml index b4bf5342f..0862fdf45 100644 --- a/transfemscience.org/feed-posts.xml +++ b/transfemscience.org/feed-posts.xml @@ -1 +1 @@ -Jekyll2024-04-05T17:34:44-07:00https://transfemscience.org/feed-posts.xmlTransfeminine ScienceTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine Science \ No newline at end of file +Jekyll2024-04-11T21:03:56-07:00https://transfemscience.org/feed-posts.xmlTransfeminine ScienceTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine Science \ No newline at end of file diff --git a/transfemscience.org/feed.xml b/transfemscience.org/feed.xml index fa9f2436f..af4c7b8cb 100644 --- a/transfemscience.org/feed.xml +++ b/transfemscience.org/feed.xml @@ -1,4 +1,4 @@ -Jekyll2024-04-05T17:34:44-07:00https://transfemscience.org/feed.xmlTransfeminine Science | ArticlesTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine SciencePuberty Blockers: A Review of GnRH Analogues in Transgender Youth2022-01-30T15:04:00-08:002022-01-31T00:00:00-08:00https://transfemscience.org/articles/puberty-blockersPuberty Blockers: A Review of GnRH Analogues in Transgender Youth +Jekyll2024-04-11T21:03:56-07:00https://transfemscience.org/feed.xmlTransfeminine Science | ArticlesTransfeminine Science is a site for information on hormone therapy for transfeminine people.Transfeminine SciencePuberty Blockers: A Review of GnRH Analogues in Transgender Youth2022-01-30T15:04:00-08:002022-01-31T00:00:00-08:00https://transfemscience.org/articles/puberty-blockersPuberty Blockers: A Review of GnRH Analogues in Transgender Youth @@ -4521,13 +4521,13 @@ Using the term desistence in this way does not imply anything about the identity
  • Quaynor, S. D., Stradtman, E. W., Kim, H., Shen, Y., Chorich, L. P., Schreihofer, D. A., & Layman, L. C. (2013). Delayed Puberty and Estrogen Resistance in a Woman with Estrogen Receptor α Variant. New England Journal of Medicine, 369(2), 164–171. [DOI:10.1056/nejmoa1303611]
  • Rinaldi, S., Geay, A., Déchaud, H., Biessy, C., Zeleniuch-Jacquotte, A., Akhmedkhanov, A., Shore, R. E., Riboli, E., Toniolo, P., & Kaaks, R. (2002). Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. Cancer Epidemiology and Prevention Biomarkers, 11(10), 1065–1071. [Google Scholar] [PubMed] [URL]
  • Vermeulen, A., Verdonck, L., & Kaufman, J. M. (1999). A critical evaluation of simple methods for the estimation of free testosterone in serum. The Journal of Clinical Endocrinology & Metabolism, 84(10), 3666–3672. [DOI:10.1210/jcem.84.10.6079]
    • -]]>    {"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}    Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy2020-07-01T18:39:00-07:002024-04-02T00:00:00-07:00https://transfemscience.org/articles/bica-adoptionBicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy +]]>{"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}Bicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy2020-07-01T18:39:00-07:002024-04-06T00:00:00-07:00https://transfemscience.org/articles/bica-adoptionBicalutamide and its Adoption by the Medical Community for Use in Transfeminine Hormone Therapy

    By Aly | First published July 1, 2020 - | Last modified April 2, 2024

    + | Last modified April 6, 2024

    Abstract / TL;DR

    @@ -4667,8 +4667,8 @@ Using the term desistence in this way does not imply anything about the identity
  • Gómez-Aguilar, F., Martínez-Sánchez, L., Arias-Constantí, V., Muñoz-Santanach, D., & Sarquella-Brugada, G. (2023). QT prolongation and Torsade de Pointes in a 13-year-old transgender adolescent in treatment with bicalutamide and tacrolimus. Clinical Toxicology, 61(Suppl 1 [43rd International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT), 23–26 May 2023, Palma de Mallorca, Spain]), 81–82 (abstract no. 170). [DOI:10.1080/15563650.2023.2192024] [PDF] [Reactions Weekly]
  • Karakılıç Özturan, E., Öztürk, A. P., Baş, F., Erdoğdu, A. B., Kaptan, S., Kardelen Al, A. D., Poyrazoğlu, Ş., Yıldız, M., Direk, N., Yüksel, Ş., & Darendeliler, F. (2023). Endocrinological Approach to Adolescents with Gender Dysphoria: Experience of a Pediatric Endocrinology Department in a Tertiary Center in Turkey. Journal of Clinical Research in Pediatric Endocrinology, 15(3), 276–284. [DOI:10.4274/jcrpe.galenos.2023.2023-1-13]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (May 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
    • -
  • Vierregger, K. S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
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  • Warus, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
    • +
  • Vierregger, K., Tetzlaf, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (November 2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
    • +
  • Warus, J., Rincon, M. G., Salvetti, B., & Olson-Kennedy, J. (November 2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
  • Burgener, K., DeBosch, B., Wang, J., Lewis, C., & Herrick, C. J. (2024). Bicalutamide does not raise transaminases in comparison to alternative anti-androgen regimens among transfeminine adolescents and young adults: a retrospective cohort study. medRxiv, preprint. [DOI:10.1101/2024.02.21.24302999v1] [PDF]
  • Fuqua, J. S., Shi, E., & Eugster, E. A. (2024). A retrospective review of the use of bicalutamide in transfeminine youth; a single center experience. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2023.2294321]
    • @@ -4770,7 +4770,7 @@ Using the term desistence in this way does not imply anything about the identity
  • Tomson, A., McLachlan, C., Wattrus, C., Adams, K., Addinall, R., Bothma, R., Jankelowitz, L., Kotze, E., Luvuno, Z., Madlala, N., Matyila, S., Padavatan, A., Pillay, M., Rakumakoe, M. D., Tomson-Myburgh, M., Venter, W., & de Vries, E. (2021). Southern African HIV Clinicians’ Society gender-affirming healthcare guideline for South Africa. Southern African Journal of HIV Medicine, 22(1), a1299. [DOI:10.4102/sajhivmed.v22i1.1299] [PDF]
  • van Kemenade, J. F., Cohen-Kettenis, P. T., Cohen, L., & Gooren, L. J. (1989). Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals. Archives of Sexual Behavior, 18(3), 217–228. [DOI:10.1007/BF01543196]
  • Vierregger, K., Tetzlaff, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. National Transgender Health Summit (NTHS) 2023 Symposium. [Event Agenda PDF] [Symposium Session] [Symposium Abstracts/Program Book]
    • -
  • Vierregger, K. S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
    • -
  • Warus, J. (2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
    • +
  • Vierregger, K., Tetzlaf, M., Zimmerman, B., Dunn, N., Finney, N., Lewis, K., Slomoff, R., & Strutner, S. (2023). Bicalutamide Use as Antiandrogen in Trans Feminine Adults - A Safety Profile. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 96–96 (abstract no. SAT-B2-T4). [Symposium Schedule] [PDF] [Full Abstract Book]
    • +
  • Warus, J., Rincon, M. G., Salvetti, B., & Olson-Kennedy, J. (2023). Safety of Bicalutamide as Anti-Androgenic Therapy in Gender Affirming Care for Adolescents and Young Adults: A Retrospective Chart Review. USPATH Scientific Symposium, November 1-5, 2023, The Westin Westminster, Westminster, Colorado, Abstract Submissions, 124–124 (abstract no. SUN-B1-T5). [Symposium Schedule] [PDF] [Full Abstract Book]
  • Wilde, B., Diamond, J. B., Laborda, T. J., Frank, L., O’Gorman, M. A., & Kocolas, I. (2023). Bicalutamide-Induced Hepatotoxicity in a Transgender Male-to-Female Adolescent. Journal of Adolescent Health, 74(1), 202–204. [DOI:10.1016/j.jadohealth.2023.08.024]
    • -]]>    {"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}     \ No newline at end of file +]]>    {"first_name"=>"Aly", "last_name"=>"W.", "author-link"=>"/about/#aly", "articles-link"=>"/articles-by-author/aly/"}     \ No newline at end of file