Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People
By Aly | First published July 1, 2019 | Last modified March 30, 2024
Abstract / TL;DR
Cyproterone acetate (CPA) is a progestogen and antiandrogen which is widely used in transfeminine hormone therapy. It is far more potent as a progestogen than as an androgen receptor antagonist. CPA has typically been used at doses of 1 to 2 mg/day as a progestogen in cisgender women and at doses of 50 to 300 mg/day as an antiandrogen. At typical antiandrogen doses of CPA, there is profound progestogenic overdosage as well as associated side effects and risks. CPA has antigonadotropic effects due to its progestogenic activity and thereby suppresses testosterone levels. By itself, CPA can maximally suppress testosterone levels by 50 to 70%, and in combination with even small amounts of estrogen, it can fully suppress gonadal testosterone production and thereby reduce testosterone levels by about 95%—or well into the female range. Although doses of CPA of 50 to 100 mg/day have been used in transfeminine people historically, it is now clear that 5 to 10 mg/day CPA has maximal or near-maximal effectiveness in terms of suppression of testosterone levels. CPA alone is most commonly available as 50-mg tablets. These tablets can be split with a pill cutter and taken once every day to once every other day to achieve an overall CPA dosage of 6.25 to 12.5 mg/day. These lower doses of CPA are not only much more cost-effective than traditional doses but are also likely to have better tolerability and safety. Due to the retained effectiveness of lower CPA doses and the known dose-dependent risks of CPA, doses of CPA used clinically in transfeminine people have been in a rapid decline.
Introduction
This article is about the dosage of cyproterone acetate (CPA), a progestin and antiandrogen, for use in hormone therapy for transfeminine people. It argues for the use of lower doses of CPA and goes fairly in-depth to justify these doses. If you are only interested in recommended doses of CPA for transfeminine people, they can be found in the Recommended Dosages section below.
Potency, Conventional Dosages, and Health Risks
CPA is a potent progestogen, with an ovulation-inhibiting dosage of about 1 mg/day and endometrial transformation dosage of about 1 to 3 mg/day in cisgender women (Wiki; Table; Endrikat et al., 2011). These dosages of CPA are similar in strength of progestogenic effect to those of normal progesterone production and levels during the luteal phase of the menstrual cycle in premenopausal women (which are about 25 mg/day and 15 ng/mL, respectively). In relation to the preceding, when CPA is used as a progestogen in cisgender women, for instance in birth control pills and menopausal hormone therapy preparations, it is formulated at a dose of 1 or 2 mg per tablet (Wiki).
In contrast to its progestogenic activity, CPA is far less potent as an androgen receptor antagonist (Wiki). When used as an antiandrogen, it is generally given at a dosage of 50 to 300 mg/day, both in cisgender women and men. A dosage of 50 to 100 mg/day is typical for androgen-dependent skin and hair conditions like acne and hirsutism in women and a dosage of 100 to 300 mg/day is typically used for prostate cancer in men (specifically 100–200 mg/day for CPA combined with castration and 200–300 mg/day for CPA monotherapy) (Wiki). As such, CPA is generally formulated at a dose of 50 or 100 mg per tablet for use in androgen-dependent conditions (Wiki). As an antiandrogen, CPA has a dual mechanism of action of both suppressing testosterone levels via its progestogenic activity at low doses and additionally blocking the actions of testosterone directly at the androgen receptor at higher doses.
Because CPA is so much more potent as a progestogen than as an androgen receptor antagonist, there is profound overdosage of progestogenic effect when CPA is used as an antiandrogen at typical clinical dosages. This is described in the following three literature excerpts by Jürgen Hammerstein, one of the scientists who developed CPA (Hammerstein et al., 1975; Hammerstein, 1990; Hammerstein, 1979):
Like chlormadinone acetate, its parent compound, CPA is also a strong progestogen with the endometrial transformation dose of both drugs being between 20 and 30 mg. […] To take full therapeutic advantage of its antiandrogenicity, CPA must be administered in doses per month that are 30 times the physiological equivalent of progesterone production in the cycle. CPA, although the most useful compound available in this field at the moment, cannot be considered therefore an ideal antiandrogen, all the more as some of the side effects may be related to the progestational overdosage rather than to the administered antiandrogenic activity. […] Adverse reactions like tiredness, lassitude, and increase in body weight are possibly due to the enormous overdose of progestational activity in the formula which is necessary to take full advantage of the antiandrogenicity of CPA.
Fixson (1963) tested CPA in ovariectomized women after pre-treatment with oestrogens; with a transformation dose of 20–30 mg this proved a powerful progestogen. The potency of CPA in the menses delay test is not exactly known, but has been estimated to be below 1 mg/day (Miller and Jacobs 1986). In relation to this progestational potency, its antiandrogenicity must be considered rather weak. Thus, in order to take full advantage of the latter, 100 mg CPA must be given daily, i.e. three times the cyclic transformation dose per day (Hammerstein and Cupceancu 1969); notably, this parameter is equivalent to the total progesterone production of a corpus luteum throughout its entire cyclic life span.
CPA may be characterized endocrinologically as possessing strong progestational [and] moderate anti-androgenic […] potencies. […] Its progestational activity, in terms of the transformation dose in the oestrogen-primed human endometrium, is 20–30 mg [per month/cycle] which is comparable to that of chlormadinone acetate and other strong progestogens. To take full clinical advantage of its anti-androgenicity not less than 50–100 mg CPA must be taken orally per day, which totals 2 to 3 times the progestational activity the female organism is exposed to throughout a complete ovulatory menstrual cycle. Thus unless much lower and less efficacious doses of CPA are used, a tremendous progestational overdosage must be accepted. […] As already pointed out CPA is endocrinologically not a well-balanced compound because of the strong preponderance of the progestational over the anti-androgenic potency. A way to avoid the heavy progestogen overdosage inherent with the high-dose reverse sequential therapy would be to combine the low-dose contraceptive formulation just mentioned with a pure anti-androgen such as free cyproterone. […] It must be emphasized that CPA is far from being an ideal drug for the anti-androgenic treatment of hirsutism because its progestational potency is much too strong and it is not effective when administered topically. Therefore it is worthwhile looking for better-balanced anti-androgenic compounds for the future.
The massive overdosage of progestogenic effect that occurs at such doses of CPA is likely responsible for the known adverse effects and risks of higher doses of CPA (Wiki). Examples of these side effects include fatigue, depression, weight gain, high prolactin levels (Wiki), benign brain tumors (Aly, 2020; Wiki; Table; Table), blood clots (Wiki), and cardiovascular problems (Wiki). Such risks are dose-dependent and have not been associated with 1 or 2 mg/day CPA (with the exception of an expected increase in the risk of blood clots in combination with oral estrogens for birth control or menopausal hormone therapy). The risk of liver toxicity with CPA is also dose-dependent, with elevated liver enzymes occurring mostly only at a dosage of 20 mg/day and above and rare cases of liver failure occurring almost exclusively at dosages of 100 mg/day and above (Wiki; Table). As such, there is good rationale for using the lowest possible effective dosage of CPA, an approach that is likely to minimize risks.
In transfeminine people, CPA has historically been used at a dosage of 50 to 100 mg/day (e.g., Moore, Wisniewski, & Dobs, 2003). Some earlier papers have recommended even higher doses of CPA, for instance 100 to 150 mg/day (Asscheman & Gooren, 1993). In 2017, the Endocrine Society published the latest edition of their clinical practice guidelines on hormone therapy for transgender people and reduced their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day (Hembree et al., 2017; Hembree et al., 2009). This was motivated in part by increasing knowledge and awareness of the risks of higher doses of CPA and by findings that these lower doses of CPA were still effective. However, it is likely that even these new lower dosages are still far in excess of what is really needed.
Testosterone Suppression with Low and High Doses
Progestogens by themselves, including CPA, are able to considerably suppress testosterone levels in gonadally intact people assigned male at birth. Around a dozen small and low-quality but nonetheless notable studies of low-dose CPA from the 1970s and early 1980s found that 5 to 10 mg/day CPA suppressed testosterone levels by about 40 to 70% in healthy young men (Table 1). A couple of individual studies notably reported virtually identical suppression of testosterone levels with 5 mg/day versus 10 mg/day CPA (both ~50% suppression) (Wang & Yeung, 1980; Graph) and with 10 mg/day versus 20 mg/day CPA (both ~60–70% suppression) (Koch et al., 1976; Koch et al., 1975; Graph). This lack of additional testosterone suppression with a doubling of dosage within studies suggests that testosterone suppression with CPA might have actually been maximal at a dosage of only 5 or 10 mg/day. A more modern study, which used a newer and more reliable analytic method for quantification of blood testosterone, found that 10 mg/day CPA suppressed testosterone levels by 66%, from about 600 ± 150 ng/dL to about 185 ng/dL (Meriggiola et al., 2002a; Graph). Similarly, another more modern study found that 10 to 20 mg/day CPA suppressed testosterone levels by 65%, from about 431 ng/dL to about 149 ng/dL, with no reported differences between doses (Zitzmann et al., 2017; Graph).
Table 1: Levels of testosterone and other sex hormones with CPA at low doses (5–30 mg/day):
Treatment and subjects
Findings
Source(s)
30 mg/day CPA in 5 normal males
T decreased “remarkably”. Exact values not given, but has graphs of T levels in a few individuals. After 30 mg/day, 5 mg/day was tried in one case and was not as effective in suppressing sperm production or T. Also reported decreases in gonadotropin excretion.
10 or 20 mg/day CPA in 15 normal healthy fertile males (age 25–35 years) (7 in 10 mg/day group and 8 in 20 mg/day group)
“Androgens (mainly T)” decreased by 60% for both 10 and 20 mg/day. Inconsistent changes in LH and slight decrease in FSH. Exact values not given, except in graphs.
10 mg/day CPA in 10 young healthy fertile men (age mean 27.2 ± 3.2 (range 21–35) years)
T decreased by 70%, DHT by 50%, LH by 30%, and FSH by 40%, while PRL increased by 75%. T was 495 ± 66 ng/dL before, 154 ± 23 ng/dL after 4 weeks, and 187 ± 38 ng/dL after 12 weeks. Also has values and graphs for other hormones.
20 mg/day CPA in 10 healthy males (age 26–55 years)
T decreased by 73% (range 71–75%), from 482 ng/dL (range 410–560 ng/dL) to 130 ng/dL (110–162 ng/dL). DHT decreased by 51% (range 47–55%), LH by 39% (range 34–45%), FSH by 66% (range 47–78%), 17-OH-P4 by 59%, A4 by 30%, TS by 34%, and DHTS by 35%. Also has exact values and graphs for other hormones.
5 or 10 mg/day CPA in 7 males (4 in each group; 1 received both 5 and 10 mg/day CPA at different times)
T change was “−40%” or “–50%”. At 5 mg/day, T was 745 ng/dL before, 460 ng/dL with treatment (–38%), and 668 ng/dL after discontinuation. At 10 mg/day, T was 708 ng/dL before, 398 ng/dL with t (reatment–44%), and 670 ng/dL after discontinuation. Also reported LH and FSH levels.
0, 5, or 10 mg/day CPA in 25 normal healthy males (age 20–51 years); 7 in 5 mg group (mean 37 ± 10 years), 8 in 10 mg group (mean 32 ± 8 years), 10 in 0 mg group (mean 32 ± 10 years)
At 5 mg/day, T decreased from 663 ± 120 ng/dL to 320 ± 160 ng/dL (−52%), and at 10 mg/day, T decreased from 692 ± 180 ng/dL to 340 ± 160 ng/dL (−51%). E2 decreased in parallel to T. At 5 mg/day, LH decreased from 2.1 ± 0.7 IU/L to 1.4 ± 0.5 IU/L (−33%), and at 10 mg/day, LH decreased from 2.3 ± 1.0 IU/L to 1.2 ± 0.5 IU/L (−48%). At 5 mg/day, FSH decreased from 3.1 ± 1.9 IU/L to 1.8 ± 0.9 IU/L (−42%), and at 10 mg/day, FSH decreased from 2.7 ± 1.0 IU/L to 1.5 ± 0.7 IU/L (−44%).
10 or 25 mg/day CPA in 4 healthy men (age 29–37 years); 3 in 10 mg group, 1 in 25 mg group
T “slightly reduced”. E “more significantly lowered”. LH not significantly changed. FSH “reduced” in “more or less all cases”. Exact hormone levels not given, but graphs provided with the values.
10 mg/day CPA (also placebo and 2, 5, and 10 mg/day dienogest) in 5 healthy men in each group
With CPA, T decreased from ~600 ± 150 ng/dL to ~185 ng/dL (–66 ± 4%). Also reported LH, FSH, and SHBG, as well as hormonal changes with placebo and dienogest (2, 5, and 10 mg/day).
10 or 20 mg/day CPA in 14 healthy young men (7 in each group)
T decreased from ~431 ng/dL at baseline to ~149 ng/dL with CPA (–65%) for the 10 and 20 mg/day doses combined. Values for dose subgroups not given. No significant differences between LH/FSH suppression between groups (which is indirectly suggestive of no differences in T suppression as well). Also reported hormone levels with other progestins.
Studies with other progestogens, such as desogestrel, dienogest, and medroxyprogesterone acetate, have consistently found that maximal suppression of testosterone levels in men occurs at a dosage that is between 5 and 10 times that of the ovulation-inhibiting dosage in cisgender women (Wiki; Wiki; Wiki). Another study is likewise suggestive of this for norethisterone acetate and levonorgestrel (Zitzmann et al., 2017; Graph). Along similar lines, doses of progestogens investigated for use in male hormonal contraception, in which the goal is antigonadotropic effects and the lowest fully effective dose is targeted, have been noted as being between 5 and 12 times the doses used in cisgender women (Foegh, 1983). Based on an ovulation-inhibiting dosage of CPA of 1 mg/day, these findings would imply that suppression of testosterone levels with CPA would likely be maximal at a dose of between 5 and 10 mg/day. In accordance, this dose range matches up with the findings of the studies above.
Although progestogens can considerably suppress testosterone levels at maximally effective dosages, it has been found that a “recovery” or “escape phenomenon”, in which testosterone levels eventually increase back to higher levels, occurs when progestogen monotherapy is used on a long-term basis. This has most notably been observed with the related progestogen megestrol acetate (Wiki), but has also been seen with CPA (Goldenberg & Bruchovsky, 1991; Saborowski, 1987; Jacobi, Tunn, & Senge, 1982). In one of these studies, testosterone levels were initially suppressed by CPA by about 70%, but increased back to about 50% of baseline between 6 and 12 months of therapy, remaining stable thereafter up to 24 months. The testosterone escape phenomenon should be kept in mind in the context of progestogen monotherapy for testosterone suppression. In contrast to progestogen monotherapy, this phenomenon has not been associated with combined estrogen and progestogen therapy.
Testosterone Suppression in Combination with Estrogen
CPA is generally used in combination with an estrogen in transfeminine people. Estrogens suppress testosterone levels similarly to progestogens. The combination of an estrogen and a progestogen is synergistic in terms of testosterone suppression and results in suppression of testosterone levels with lower doses than with either an estrogen or progestogen alone (Fink, 1979; Geller & Albert, 1983; Bastianelli et al., 2018). Although estrogens can suppress testosterone levels to an equivalent extent as surgical or medical castration (i.e., orchiectomy or GnRH agonists/antagonists), this usually requires relatively high estrogen levels, for instance in the range of 200 to 500 pg/mL (Wiki; Graphs). Because of the high and supraphysiological estradiol levels required for maximal or near-maximal suppression of testosterone levels, lower doses of estradiol are frequently combined with antiandrogens and/or progestogens to block or suppress remaining testosterone levels instead.
CPA, as mentioned earlier, leads to an incomplete suppression of plasma testosterone levels, which decrease by about 70% and remain at about three times castration values. In a very systematic approach to the problem, Rennie et al. (59) investigated and compared 12 different procedures of androgen deprivation. These authors found that the combination of CPA with an extremely low dose (0.1 mg/d) of [diethylstilbestrol (DES)] led to a very effective withdrawal of androgens in terms of plasma testosterone and tissue dihydrotestosterone. The same group later showed that 200 mg of CPA, and even 100 mg/day, was sufficient to achieve a similar endocrine response, which was correlated to very favorable clinical responses in a Phase II situation (60,61). The approach has many potential advantages, and, from an endocrinological point of view, is very logical: this regimen combines the testosterone-reducing effects of two compounds, therefore, only small amounts of estrogen are required to bring down plasma testosterone to approximately castrate levels. Once castrate levels have been achieved, only low doses of CPA are necessary to counteract remaining androgens, mainly of adrenal origin. The regimen was shown to be associated with few side effects and a very low cost. The combination of low-dose CPA with low-dose DES was never studied in a Phase III situation in comparison to standard management. Considering the endocrine results and the observations in patients treated with this regimen (60), this combination treatment is very likely to be competitive with other standard forms of therapy.
A 2016 study of 50 mg/day CPA and 1 to 2 mg/day transdermal estradiol gel in transfeminine people showed that estradiol levels of about 45 pg/mL with CPA were insufficient to achieve female/castrate levels of testosterone, instead resulting in testosterone levels of about 120 to 190 ng/dL (Gava et al., 2016; Graph). Conversely, estradiol levels of about 85 pg/mL with CPA achieved complete suppression of gonadal testosterone production, with resulting testosterone levels of about 20 ng/dL. As such, a certain minimum level of estradiol with CPA appears to be required for complete testosterone suppression. A 2019 study of CPA and oral estradiol valerate in transfeminine people indicated that testosterone levels were still fully suppressed with median estradiol levels of 76 pg/mL and 25th percentile estradiol levels of 63 pg/mL (Angus et al., 2019; Graph).
Figures 5–7: Testosterone levels with CPA plus low doses/levels of estrogens in men and transfeminine people. Sources: Top-left: Goldenberg et al. (1988). Top-right: Gava et al. (2016). Bottom: Angus et al. (2019). See also on Wikipedia: Gallery. Note for the graph on the top right that the mean transdermal estradiol dosage increased between 6 and 12 months and this was likely responsible for the improvement in testosterone suppression.
Fung and colleagues showed that the combination of either 25 or 50 mg/day CPA with a moderate dosage of oral estradiol (~3.5 mg/day) or transdermal estradiol (~3.5 mg/day gel or ~100 μg/day patch) resulted in equivalent and complete suppression of gonadal testosterone production (~95% suppression of testosterone levels) in transfeminine people (Fung, Hellstern-Layefsky, & Lega, 2017). These dosages of estradiol would be expected to achieve estradiol levels of around 100 pg/mL on average (Aly, 2020; Wiki). This study was notably published 6 months before the 2017 second edition of the Endocrine Society guidelines were released (Hembree et al., 2017), and was probably responsible for the decrease in their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day.
Few studies to date have assessed testosterone suppression with low-dose CPA in combination with a low or moderate dosage of an estrogen. However, based on the fact that 5 to 10 mg/day CPA alone is probably maximal in terms of suppression of testosterone levels, it is likely that such dosages of CPA will be similarly effective as higher dosages. In accordance, studies of 5 to 12.5 mg/day CPA plus upper physiological replacement dosages of testosterone have demonstrated undetectable gonadotropin levels (<0.5 IU/L) and hence complete suppression of testicular function in healthy young men (Meriggiola et al., 1998; Meriggiola et al., 2002b). Estradiol is a more powerful antigonadotropin than testosterone (Wiki), so these findings probably apply to CPA in combination with physiological replacement levels of estradiol as well (e.g., mean estradiol levels of 100–200 pg/mL).
Accordingly, Meyer et al. (2020) assessed a dosage of CPA in combination with estradiol in 155 transfeminine people and found no difference in testosterone levels with 10, 25, or 50 mg/day CPA; testosterone levels were strongly suppressed with all three doses (to about 15–20 ng/dL on average, or into the lower end of the normal female range). The estradiol forms and doses used in this study were oral estradiol valerate (median 6 mg/day, range 3–10 mg/day), transdermal estradiol gel (median 2.25 mg/day, range 1.5–6 mg/day), and transdermal estradiol patches (100 μg/day in all cases). Estradiol levels were about 100 pg/mL on average, with an interquartile range (i.e., difference between 75th and 25th percentiles) of about 100 pg/mL. This study demonstrates that, provided estradiol levels are adequate, no more than 10 mg/day CPA is needed to fully suppress testosterone levels in transfeminine people. Another study likewise found no difference between <20 mg/day and >50 mg/day CPA in terms of testosterone suppression in transfeminine people (Even-Zohar et al., 2020).
Even doses of CPA lower than 5 mg/day (e.g., 2 mg/day) may be usefully effective for testosterone suppression if combined with sufficient levels of estradiol, although this has not been studied and remains to be validated. But there is certainly precedent for the notion when looking at studies with other progestogens. As an example, one study using 10 mg/day oral medroxyprogesterone acetate (which is roughly equivalent to 1 mg/day CPA in terms of ovulation inhibition in premenopausal women; Table) observed 63% lower testosterone levels (215 ng/dL vs. 79 ng/dL) when added to estradiol and spironolactone therapy in transfeminine people (Jain, Kwan, & Forcier, 2019). Analogous effects on testosterone levels would be anticipated for very-low-dose CPA. Moreover, such dosages of CPA would have the advantage of actually being physiological in terms of progestogenic exposure.
The androgen receptor antagonism of CPA is relatively weak in terms of potency; dosages of CPA of 50 to 300 mg/day seem to be necessary for meaningful or considerable androgen receptor antagonism. Unfortunately, such doses also result in extreme progestogenic overdosage and are associated with considerably greater risks and adverse effects. As a result, the use of such doses of CPA should no longer be considered advisable. Instead, CPA should be used at lower doses simply as a progestogen to suppress testosterone levels. As such, the highest effective dosage of CPA for testosterone suppression, which is probably about 10 mg/day or less (12.5 mg/day also being acceptable), should be around the maximal dosage of CPA that is used in transfeminine people.
It should be emphasized that since the combination of an estrogen and CPA can easily suppress testosterone levels well into the female/castrate range (typically to below average female levels), there isn’t necessarily a requirement for concomitant androgen receptor blockade. In any case, if androgen receptor antagonism to neutralize the remaining female/castrate levels of testosterone is still necessary or desired (e.g., to treat persisting acne or for some other purpose), a low dosage of a non-progestogenic androgen-receptor antagonist like spironolactone (e.g., 100–200 mg/day) or bicalutamide (e.g., 12.5–25 mg/day) can be added to CPA to more safely achieve this than use of higher CPA doses.
Recommended Dosages
Dosage for Testosterone Suppression
Estrogen Plus Cyproterone Acetate
The following recommended dosages of CPA in transfeminine people are for the combination of CPA with an estrogen and are specifically for achieving maximal suppression of testosterone levels:
Table 2: Recommended doses of CPA in combination with estrogen for maximal testosterone suppression in transfeminine people:
Form
Min. dosage
Max. dosage
Amount
10 mg tablets
5 mg/day
10 mg/day
1/2 of a tablet to 1 whole tablet per day
50 mg tablets
6.25 mg/day
12.5 mg/day
1/8th of a tablet to 1/4th of a tablet per day
Start with the minimum dosage of CPA for one month. After one month, have testosterone levels tested and confirm that they are in the normal female/castrate range (<50 ng/dL). Regardless of dosage, a concomitant minimum estradiol level of around 65 pg/mL needs to be attained in order to allow for complete suppression of testosterone levels with CPA. If testosterone levels aren’t sufficiently suppressed after a month and estradiol levels are adequate, increase to the maximum CPA dosage and re-check testosterone levels after another month. Alternatively, the dosage of estradiol can be increased instead; higher estradiol levels result in greater testosterone suppression as well.
Cyproterone Acetate Alone
The use of CPA alone (i.e., as a monotherapy for testosterone suppression) is not recommended due to the risk of decreased bone mineral density and other symptoms of sex-hormone deficiency (Wiki; Aly, 2019). In any case, the recommended dosages for CPA without an estrogen are essentially the same as those listed above of the combination of an estrogen with CPA for testosterone suppression. However, the higher CPA dose (10–12.5 mg/day) may be preferable for good measure in this scenario.
Dosage for Progestogenic Effects
The following recommended dosages of CPA in transfeminine people are for progestogenic effects similar to normal physiological exposure (equivalent of luteal-phase progesterone levels):
Table 3: Recommended doses of CPA for physiological progestogenic effects in transfeminine people:
Form
Dosage
Amount
10 mg tablets
2.5 mg/day
1/4th of a tablet per day
50 mg tablets
3.125 mg/day
1/16th of a tablet per day
Achieving Desired Dosages
CPA is available pharmaceutically most widely as 50-mg tablets. This can make achieving desired low doses of CPA more difficult. For splitting CPA tablets into small fractions, a pill cutter can be used. Additionally, CPA can be taken once every 2 or 3 days instead of once every day to help further divide doses. It is notable that CPA has a relatively long half-life in the body of about 1.5 to 2 days (but possibly up to 4 days) (Wiki; Graph). Hence, taking it once every other day instead of once per day, or even less frequently like once every 3 days, has sound basis and is likely to be entirely viable.
Updates
Update 1: GoLoCypro Study (In-Progress)
The GoLoCypro study (2019–2022) (more info) is being conducted by Dr. Judith Dean at the University of Queensland in Australia. It’s assessing the influence of estradiol plus CPA on testosterone levels at five different CPA dose levels (12.5 mg 2x/week, 12.5 mg/2 days, 12.5 mg/day, 25 mg/day, and 50 mg/day) in a total of 120 to 350 transfeminine people. CPA doses are being titrated to the minimum that maintain testosterone levels within the therapeutic goal range of 0.5 to 1.5 nmol/L (14–43 ng/dL). The study is among the first dose-ranging studies of CPA in transfeminine people to be conducted and is eagerly anticipated due to the valuable information that it should provide in terms of the minimum effective dosage of CPA for adequate testosterone suppression in transfeminine hormone therapy.
Update 2: Kuijpers et al. (2021) and Even Zohar et al. (2021)
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]
The study employed estradiol (2–6 mg/day oral (as estradiol valerate), 50–150 μg/day patch, or gel) plus five different dose levels of CPA—0 mg/day (no CPA), 10 mg/day, 25 mg/day, 50 mg/day, and 100 mg/day. It found incompletely suppressed testosterone in the no CPA group but full and equivalent testosterone suppression with all doses of CPA. The results were as follows:
CPA dosage
0 mg/day
10 mg/day
25 mg/day
50 mg/day
100 mg/day
Initial subjects (n)
34
4
234
599
11
Dose increased (n)
16
1
11
2
0
Dose decreased (n)
0
0
4
40
7
T levels (nmol/L)
5.5
0.9
0.9
1.1
0.9
T levels (ng/dL)
~160
~26
~26
~32
~26
T <2 nmol/L [<~58 ng/dL] (%)
46.3
92.3
96.2
93.4
100.0
Abbreviations: T = testosterone.
The total numbers of subjects and blood tests after CPA dose increases/decreases were not provided. Hence, the exact total number of people and tests for the 10 mg/day group can’t be stated with certainty. The total number of tests for this group was at least 13 based on the testosterone suppression percentage provided however (92.3% or 12/13 but could potentially be 24/26, etc.). Regarding the small number of subjects/tests for the 10 mg/day group, the authors stated the following:
This study is part of the ENIGI initiative, a multicenter prospective cohort study. The main treatment protocol for trans women in this study was 50 mg of CPA daily combined with estrogens. In the first year of study inclusion, a few participants received a dose of 100 mg of CPA. Shortly thereafter, inhospital protocol changed to 50 mg of CPA. As more health concerns related to CPA use were raised over the years, the dose was further lowered from 50 mg to 25 mg and, finally, to 10 mg. However, due to the coronavirus (COVID-19) pandemic, limited results of participants with 10 mg of CPA were available for analysis.
Besides testosterone suppression, the study found that 10 mg/day CPA had less influence on prolactin and high-density lipoprotein (HDL) cholesterol levels than the higher doses of CPA. The study also assessed liver enzyme levels but found no differences between CPA doses.
The authors concluded with the following:
In conclusion, in this cohort of trans women, 10 mg of CPA was found to be effective in lowering testosterone concentrations to the range observed in cis women. A dose of 10 mg was equally effective as higher doses, was found to have less influence on prolactin concentrations and allows higher HDL-C concentrations to be maintained. While GnRH agonists are preferred over CPA due to the fewer associated long-term side effects, this study shows that CPA at a low dose is a viable option when GnRH agonists are contra-indicated, not available, or not reimbursed. Future research should focus on assessing the effectiveness of an even lower dose of CPA (e.g., 5 mg) and the potential long-term side effects.
Around the same that this study was published, Guy T’Sjoen (one of the authors of the study) and other colleagues in a review of optimal hormone therapy for transfeminine people recommended a dosage of no more than 10 or 12.5 mg/day CPA for no longer than 2 years (Glintborg et al., 2021). T’Sjoen is notable in being regarded as one of the foremost experts in transgender medicine and is a coauthor of the Endocrine Society transgender care guidelines (Hembree et al., 2017).
Shortly after the study of Kuijpers and colleagues and also in June 2021, Even Zohar and colleagues in Israel published the following study on low doses of CPA in transfeminine people:
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. [10.1016/j.jsxm.2021.04.008]
This study was initially reported as a conference abstract in May 2020 (Even-Zohar et al., 2020).
In the introduction section of the paper, the authors stated the following:
Treatment guidelines published by several organizations are available and assist clinicians in treating transgender women.4,7−9 A wide range of regimens for CPA administration have been proposed. By and large, the recommended doses have decreased over the years: doses of 50–100 mg/day were suggested in the 2009 Endocrine Society Guidelines,10 and amended to 25–50 mg/day in 2017.7 The proposed CPA doses were 12.5–25 mg/day in the 2019 guidelines of the Australian Professional Association for Transgender Health,4 and they were amended to 10–50 mg/day in the 2020 guidelines of the European Society for Sexual Medicine.8 There are no publications on data that compare different doses of CPA for efficacy or safety.
The researchers found that estradiol plus low-dose CPA (10–20 mg/day) suppressed testosterone levels to an equivalent extent as estradiol plus high-dose CPA (50–100 mg/day). Testosterone levels were suppressed into the female/castrate range or near so in both groups (generally ≤2 nmol/L or ≤58 pg/mL). Of the 38 transfeminine people on low-dose CPA, 32 (84%) were on 10 mg/day CPA and 6 (16%) were on 20 mg/day CPA (mean dose 11.6 ± 3.7 mg/day). Estradiol was given as transdermal estradiol patch (mean dose 83.7 ± 36.5 μg/day), transdermal estradiol gel (mean dose 3.8 ± 1.2 g/day), or oral estradiol (mean dose 4.1 ± 1.7 mg/day). Mean estradiol levels ranged from ~110 to 350 pmol/L (~30–95 pg/mL) in the low- and high-dose CPA groups over the follow-up period. Besides showing equivalent testosterone suppression, prolactin levels were significantly lower with low-dose CPA than with high-dose CPA (398 ± 69 mIU/mL vs. 804 ± 121 mIU/mL at 12 months of hormone therapy, respectively).
Based on their findings, the authors stated the following:
We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women.
Both Kuijpers et al. (2021) and Even Zohar et al. (2021) claimed to be the first to demonstrate the efficacy of low-dose CPA in transfeminine people. However, that achievement actually appears to belong to Meyer et al. (2020), who in February 2020 found that estradiol plus 10, 25, or 50 mg/day CPA gave equivalent testosterone suppression across CPA doses in transfeminine people.
Although their study was not about CPA and testosterone suppression, Lim et al. (2020) reported in May/July 2020 that testosterone levels in transfeminine people were median (IQR) 0.6 (0.4–1.0) nmol/L for oral estradiol and 0.9 (0.7–1.6) nmol/L for transdermal estradiol in a mixed group of transfeminine people (n=26 total) on estradiol plus low-dose CPA (12.5 (12.5–18.8) mg/day) (n=14), estradiol alone post-gonadectomy (n=9), and estradiol plus spironolactone (n=3).
In December 2021, the following case report of fatal liver failure with low-dose CPA was published:
Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., & Rao, P. N. (2021). Cyproterone acetate induced Acute liver failure: 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]
The case report describes a 30-year-old cisgender woman who was on 25 mg/day CPA for treatment of hirsutism (excessive facial/body hair growth) for 6 months and developed acute liver failure. Four days following hospitalization, she died. This is the second published case report of liver toxicity with CPA at a dosage below 100 mg/day (the first and only other case was at 50 mg/day) (Wiki; Table). It is also the first report of liver failure in a cisgender woman taking CPA. The case indicates that CPA even at a relatively low dose of 25 mg/day is not fully safe in terms of liver toxicity. It further emphasizes the importance of using the lowest effective doses of CPA in transfeminine people (no more than 10–12.5 mg/day).
Update 4: 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 and made recommendations for transgender hormone therapy for the first time (Coleman et al., 2022). These guidelines recommended a dose of CPA of 10 mg/day in transfeminine people (Coleman et al., 2022). This dose is substantially lower than previous doses recommended by transgender care guidelines and is the first time that major guidelines have recommended a CPA dosage this low. The WPATH SOC8 cited Kuijpers et al. (2021) in support of this recommendation (though notably not Even Zohar et al. (2021) or Meyer et al. (2020)) and also discussed the dose-dependent risks of CPA such as meningiomas and high prolactin levels (Coleman et al., 2022). Considering the key position and importance of the WPATH SOC in transgender health, it is likely that lower CPA doses in transfeminine hormone therapy will now be widely adopted throughout the world. Continued use of higher CPA doses should be considered out of step with current accepted evidence-based practice.
Update 5: Collet et al. (2023)
In October 2022, a study more carefully assessing androgen suppression with estradiol plus CPA in transfeminine people was published:
Collet, S., Gieles, N., Wiepjes, C. M., Heijboer, A. C., Reyns, T., Fiers, T., Lapauw, B., den Heijer, M., & T’Sjoen, G. (2023). 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]
In the study, 275 transfeminine people were treated with estradiol plus CPA, and levels of total testosterone, free testosterone, and the adrenal androgensdehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4) were measured using liquid chromatography–mass spectrometry (LC–MS) at baseline and during follow-ups at 3 months, 12 months, 2 to 4 years, and after surgical gonadal removal (at which time CPA was discontinued). Estradiol was measured both with LC–MS (Amsterdam clinic) and with immunoassays (Ghent clinic). The forms and doses of estradiol used were most commonly oral estradiol valerate 4 mg/day or a transdermal estradiol patch 100 μg/day, while the dosage of CPA was usually 25 or 50 mg/day. About half of the transfeminine people eventually underwent surgical gonadal removal, usually after 2 years of hormone therapy.
Median estradiol levels ranged from 49 to 75 pg/mL (180–275 pmol/L) with LC–MS and from 63 to 69 pg/mL (232–255 pmol/L) with immunoassays at different follow-ups. After 3 months of hormone therapy, total testosterone decreased by 97.1%, from 536 ng/dL (18.6 nmol/L) to 12 ng/dL (0.40 nmol/L), and free testosterone decreased by 98.3%, from 109 pg/mL (378 pmol/L) to 2.0 pg/mL (7.1 pmol/L). Thereafter, total and free testosterone levels remained stable. Levels of DHEA, DHEA-S, and A4 decreased by 24.9 to 28.0%, 20.1 to 23.5%, and 36.5%, respectively, and likewise did not further change after the first 3 to 12 months of hormone therapy. No changes in androgen levels occurred upon surgical gonadal removal with discontinuation of CPA. The authors noted that testosterone levels in the transfeminine people on hormone therapy in the study were similar to or lower than those in cisgender women.
Update 6: Warzywoda et al. (2024) [GoLoCypro Study]
The GoLoCypro study, by Judith Dean and colleagues, was published online in February 2024:
Warzywoda, S., Fowler, J. A., Wood, P., Bisshop, F., Russell, D., Luu, H., Kelly, M., Featherstone, V., & Dean, J. A. (2024). How low can you go? Titrating the lowest effective dose of cyproterone acetate for transgender and gender diverse people who request feminizing hormones. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2317395]
The following are some noteworthy excerpts from the paper:
Of participants who completed the protocol, 74.0% (34/46) were able to achieve the target T-range (0.5–1.5 nmol/L) and 41.3% (19/46) were titrated to the lowest CPA level (12.5 mg cyproterone twice weekly).
Almost all participants who completed the protocol (91.3.0%, 42/46) recorded their CPA levels as level 3 (12.5 mg daily/25 [mg] alternate days) or lower, with 69.0% (29/42) of these being able to achieve the target T-range. Of those that completed, 41.3% (19/46) were able to achieve the lowest CPA level (12.5 mg cyproterone twice week) with 57.9% (11/19) being able to achieve the target T-range.
The study findings showed that for some patients, CPA doses as low as 12.5 mg on alternate days or less can successfully reduce testosterone to pre-menopausal ranges whilst ensuring testosterone was not over-suppressed.
Our study found that doses of CPA lower than the standard dose (12.5 mg CPA daily and/or 25 mg alternate days) were achievable for suppression of testosterone. Several studies have supported this finding that a lower dosage (10 mg CPA daily) is effective in testosterone reduction in individuals undergoing hormone feminization (Even Zohar et al., 2021; Kuijpers et al., 2021). While not all individuals within our study were able to titrate down CPA dosages, almost a quarter of participants who completed the protocol were achieving target T-ranges on 12.5 mg CPA twice weekly (equivalent to 3.5 mg/daily). To our knowledge ours is the first study to demonstrate that doses lower than 10 mg/daily as well as alternate days or twice weekly CPA are clinically effective in maintaining testosterone reduction within target ranges.
Update 7: More New Low-Dose CPA Studies (2023–2024)
Other new studies of low-dose CPA in transfeminine people have also been published in 2023 and 2024:
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]
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]
Korpaisarn, S., Arunakul, J., Chaisuksombat, K., & Rattananukrom, T. (2023). A Low Dose Cyproterone Acetate In Feminizing Hormone Treatment. Journal of the Endocrine Society, 7(Suppl 1), A1098–A1099 (abstract no. SAT397/bvad114.2068). [DOI:10.1210/jendso/bvad114.2068]
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]
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+Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People - Transfeminine Science
Low Doses of Cyproterone Acetate Are Maximally Effective for Testosterone Suppression in Transfeminine People
By Aly | First published July 1, 2019 | Last modified August 14, 2025
Abstract / TL;DR
Cyproterone acetate (CPA) is a progestogen and antiandrogen which is widely used in transfeminine hormone therapy. It is far more potent as a progestogen than as an androgen receptor antagonist. CPA has typically been used at doses of 1 to 2 mg/day as a progestogen in cisgender women and at doses of 50 to 300 mg/day as an antiandrogen. At typical antiandrogen doses of CPA, there is profound progestogenic overdosage as well as associated side effects and risks. CPA has antigonadotropic effects due to its progestogenic activity and thereby suppresses testosterone levels. By itself, CPA can maximally suppress testosterone levels by 50 to 70%, and in combination with even small amounts of estrogen, it can fully suppress gonadal testosterone production and thereby reduce testosterone levels by about 95%—or well into the female range. Although doses of CPA of 50 to 100 mg/day have been used in transfeminine people historically, it is now clear that 5 to 10 mg/day CPA has maximal or near-maximal effectiveness in terms of suppression of testosterone levels. CPA alone is most commonly available as 50-mg tablets. These tablets can be split with a pill cutter and taken once every day to once every other day to achieve an overall CPA dosage of 6.25 to 12.5 mg/day. These lower doses of CPA are not only much more cost-effective than traditional doses but are also likely to have better tolerability and safety. Due to the retained effectiveness of lower CPA doses and the known dose-dependent risks of CPA, doses of CPA used clinically in transfeminine people have been in a rapid decline.
Introduction
This article is about the dosage of cyproterone acetate (CPA), a progestin and antiandrogen, for use in hormone therapy for transfeminine people. It argues for the use of lower doses of CPA and goes fairly in-depth to justify these doses. If you are only interested in recommended doses of CPA for transfeminine people, they can be found in the Recommended Dosages section below.
Potency, Conventional Dosages, and Health Risks
CPA is a potent progestogen, with an ovulation-inhibiting dosage of about 1 mg/day and endometrial transformation dosage of about 1 to 3 mg/day in cisgender women (Wiki; Table; Endrikat et al., 2011). These dosages of CPA are similar in strength of progestogenic effect to those of normal progesterone production and levels during the luteal phase of the menstrual cycle in premenopausal women (which are about 25 mg/day and 15 ng/mL, respectively). In relation to the preceding, when CPA is used as a progestogen in cisgender women, for instance in birth control pills and menopausal hormone therapy preparations, it is formulated at a dose of 1 or 2 mg per tablet (Wiki).
In contrast to its progestogenic activity, CPA is far less potent as an androgen receptor antagonist (Wiki). When used as an antiandrogen, it is generally given at a dosage of 50 to 300 mg/day, both in cisgender women and men. A dosage of 50 to 100 mg/day is typical for androgen-dependent skin and hair conditions like acne and hirsutism in women and a dosage of 100 to 300 mg/day is typically used for prostate cancer in men (specifically 100–200 mg/day for CPA combined with castration and 200–300 mg/day for CPA monotherapy) (Wiki). As such, CPA is generally formulated at a dose of 50 or 100 mg per tablet for use in androgen-dependent conditions (Wiki). As an antiandrogen, CPA has a dual mechanism of action of both suppressing testosterone levels via its progestogenic activity at low doses and additionally blocking the actions of testosterone directly at the androgen receptor at higher doses.
Because CPA is so much more potent as a progestogen than as an androgen receptor antagonist, there is profound overdosage of progestogenic effect when CPA is used as an antiandrogen at typical clinical dosages. This is described in the following three literature excerpts by Jürgen Hammerstein, one of the scientists who developed CPA (Hammerstein et al., 1975; Hammerstein, 1990; Hammerstein, 1979):
Like chlormadinone acetate, its parent compound, CPA is also a strong progestogen with the endometrial transformation dose of both drugs being between 20 and 30 mg. […] To take full therapeutic advantage of its antiandrogenicity, CPA must be administered in doses per month that are 30 times the physiological equivalent of progesterone production in the cycle. CPA, although the most useful compound available in this field at the moment, cannot be considered therefore an ideal antiandrogen, all the more as some of the side effects may be related to the progestational overdosage rather than to the administered antiandrogenic activity. […] Adverse reactions like tiredness, lassitude, and increase in body weight are possibly due to the enormous overdose of progestational activity in the formula which is necessary to take full advantage of the antiandrogenicity of CPA.
Fixson (1963) tested CPA in ovariectomized women after pre-treatment with oestrogens; with a transformation dose of 20–30 mg this proved a powerful progestogen. The potency of CPA in the menses delay test is not exactly known, but has been estimated to be below 1 mg/day (Miller and Jacobs 1986). In relation to this progestational potency, its antiandrogenicity must be considered rather weak. Thus, in order to take full advantage of the latter, 100 mg CPA must be given daily, i.e. three times the cyclic transformation dose per day (Hammerstein and Cupceancu 1969); notably, this parameter is equivalent to the total progesterone production of a corpus luteum throughout its entire cyclic life span.
CPA may be characterized endocrinologically as possessing strong progestational [and] moderate anti-androgenic […] potencies. […] Its progestational activity, in terms of the transformation dose in the oestrogen-primed human endometrium, is 20–30 mg [per month/cycle] which is comparable to that of chlormadinone acetate and other strong progestogens. To take full clinical advantage of its anti-androgenicity not less than 50–100 mg CPA must be taken orally per day, which totals 2 to 3 times the progestational activity the female organism is exposed to throughout a complete ovulatory menstrual cycle. Thus unless much lower and less efficacious doses of CPA are used, a tremendous progestational overdosage must be accepted. […] As already pointed out CPA is endocrinologically not a well-balanced compound because of the strong preponderance of the progestational over the anti-androgenic potency. A way to avoid the heavy progestogen overdosage inherent with the high-dose reverse sequential therapy would be to combine the low-dose contraceptive formulation just mentioned with a pure anti-androgen such as free cyproterone. […] It must be emphasized that CPA is far from being an ideal drug for the anti-androgenic treatment of hirsutism because its progestational potency is much too strong and it is not effective when administered topically. Therefore it is worthwhile looking for better-balanced anti-androgenic compounds for the future.
The massive overdosage of progestogenic effect that occurs at such doses of CPA is likely responsible for the known adverse effects and risks of higher doses of CPA (Wiki). Examples of these side effects include fatigue, depression, weight gain, high prolactin levels (Wiki), benign brain tumors (Aly, 2020; Wiki; Table; Table), blood clots (Wiki), and cardiovascular problems (Wiki). Such risks are dose-dependent and have not been associated with 1 or 2 mg/day CPA (with the exception of an expected increase in the risk of blood clots in combination with oral estrogens for birth control or menopausal hormone therapy). The risk of liver toxicity with CPA is also dose-dependent, with elevated liver enzymes occurring mostly only at a dosage of 20 mg/day and above and rare cases of liver failure occurring almost exclusively at dosages of 100 mg/day and above (Wiki; Table). As such, there is good rationale for using the lowest possible effective dosage of CPA, an approach that is likely to minimize risks.
In transfeminine people, CPA has historically been used at a dosage of 50 to 100 mg/day (e.g., Moore, Wisniewski, & Dobs, 2003). Some earlier papers have recommended even higher doses of CPA, for instance 100 to 150 mg/day (Asscheman & Gooren, 1993). In 2017, the Endocrine Society published the latest edition of their clinical practice guidelines on hormone therapy for transgender people and reduced their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day (Hembree et al., 2017; Hembree et al., 2009). This was motivated in part by increasing knowledge and awareness of the risks of higher doses of CPA and by findings that these lower doses of CPA were still effective. However, it is likely that even these new lower dosages are still far in excess of what is really needed.
Testosterone Suppression with Low and High Doses
Progestogens by themselves, including CPA, are able to considerably suppress testosterone levels in gonadally intact people assigned male at birth. Around a dozen small and low-quality but nonetheless notable studies of low-dose CPA from the 1970s and early 1980s found that 5 to 10 mg/day CPA suppressed testosterone levels by about 40 to 70% in healthy young men (Table 1). A couple of individual studies notably reported virtually identical suppression of testosterone levels with 5 mg/day versus 10 mg/day CPA (both ~50% suppression) (Wang & Yeung, 1980; Graph) and with 10 mg/day versus 20 mg/day CPA (both ~60–70% suppression) (Koch et al., 1976; Koch et al., 1975; Graph). This lack of additional testosterone suppression with a doubling of dosage within studies suggests that testosterone suppression with CPA might have actually been maximal at a dosage of only 5 or 10 mg/day. A more modern study, which used a newer and more reliable analytic method for quantification of blood testosterone, found that 10 mg/day CPA suppressed testosterone levels by 66%, from about 600 ± 150 ng/dL to about 185 ng/dL (Meriggiola et al., 2002a; Graph). Similarly, another more modern study found that 10 to 20 mg/day CPA suppressed testosterone levels by 65%, from about 431 ng/dL to about 149 ng/dL, with no reported differences between doses (Zitzmann et al., 2017; Graph).
Table 1: Levels of testosterone and other sex hormones with CPA at low doses (5–30 mg/day):
Treatment and subjects
Findings
Source(s)
30 mg/day CPA in 5 normal males
T decreased “remarkably”. Exact values not given, but has graphs of T levels in a few individuals. After 30 mg/day, 5 mg/day was tried in one case and was not as effective in suppressing sperm production or T. Also reported decreases in gonadotropin excretion.
10 or 20 mg/day CPA in 15 normal healthy fertile males (age 25–35 years) (7 in 10 mg/day group and 8 in 20 mg/day group)
“Androgens (mainly T)” decreased by 60% for both 10 and 20 mg/day. Inconsistent changes in LH and slight decrease in FSH. Exact values not given, except in graphs.
10 mg/day CPA in 10 young healthy fertile men (age mean 27.2 ± 3.2 (range 21–35) years)
T decreased by 70%, DHT by 50%, LH by 30%, and FSH by 40%, while PRL increased by 75%. T was 495 ± 66 ng/dL before, 154 ± 23 ng/dL after 4 weeks, and 187 ± 38 ng/dL after 12 weeks. Also has values and graphs for other hormones.
20 mg/day CPA in 10 healthy males (age 26–55 years)
T decreased by 73% (range 71–75%), from 482 ng/dL (range 410–560 ng/dL) to 130 ng/dL (110–162 ng/dL). DHT decreased by 51% (range 47–55%), LH by 39% (range 34–45%), FSH by 66% (range 47–78%), 17-OH-P4 by 59%, A4 by 30%, TS by 34%, and DHTS by 35%. Also has exact values and graphs for other hormones.
5 or 10 mg/day CPA in 7 males (4 in each group; 1 received both 5 and 10 mg/day CPA at different times)
T change was “−40%” or “–50%”. At 5 mg/day, T was 745 ng/dL before, 460 ng/dL with treatment (–38%), and 668 ng/dL after discontinuation. At 10 mg/day, T was 708 ng/dL before, 398 ng/dL with t (reatment–44%), and 670 ng/dL after discontinuation. Also reported LH and FSH levels.
0, 5, or 10 mg/day CPA in 25 normal healthy males (age 20–51 years); 7 in 5 mg group (mean 37 ± 10 years), 8 in 10 mg group (mean 32 ± 8 years), 10 in 0 mg group (mean 32 ± 10 years)
At 5 mg/day, T decreased from 663 ± 120 ng/dL to 320 ± 160 ng/dL (−52%), and at 10 mg/day, T decreased from 692 ± 180 ng/dL to 340 ± 160 ng/dL (−51%). E2 decreased in parallel to T. At 5 mg/day, LH decreased from 2.1 ± 0.7 IU/L to 1.4 ± 0.5 IU/L (−33%), and at 10 mg/day, LH decreased from 2.3 ± 1.0 IU/L to 1.2 ± 0.5 IU/L (−48%). At 5 mg/day, FSH decreased from 3.1 ± 1.9 IU/L to 1.8 ± 0.9 IU/L (−42%), and at 10 mg/day, FSH decreased from 2.7 ± 1.0 IU/L to 1.5 ± 0.7 IU/L (−44%).
10 or 25 mg/day CPA in 4 healthy men (age 29–37 years); 3 in 10 mg group, 1 in 25 mg group
T “slightly reduced”. E “more significantly lowered”. LH not significantly changed. FSH “reduced” in “more or less all cases”. Exact hormone levels not given, but graphs provided with the values.
10 mg/day CPA (also placebo and 2, 5, and 10 mg/day dienogest) in 5 healthy men in each group
With CPA, T decreased from ~600 ± 150 ng/dL to ~185 ng/dL (–66 ± 4%). Also reported LH, FSH, and SHBG, as well as hormonal changes with placebo and dienogest (2, 5, and 10 mg/day).
10 or 20 mg/day CPA in 14 healthy young men (7 in each group)
T decreased from ~431 ng/dL at baseline to ~149 ng/dL with CPA (–65%) for the 10 and 20 mg/day doses combined. Values for dose subgroups not given. No significant differences between LH/FSH suppression between groups (which is indirectly suggestive of no differences in T suppression as well). Also reported hormone levels with other progestins.
Studies with other progestogens, such as desogestrel, dienogest, and medroxyprogesterone acetate, have consistently found that maximal suppression of testosterone levels in men occurs at a dosage that is between 5 and 10 times that of the ovulation-inhibiting dosage in cisgender women (Wiki; Wiki; Wiki). Another study is likewise suggestive of this for norethisterone acetate and levonorgestrel (Zitzmann et al., 2017; Graph). Along similar lines, doses of progestogens investigated for use in male hormonal contraception, in which the goal is antigonadotropic effects and the lowest fully effective dose is targeted, have been noted as being between 5 and 12 times the doses used in cisgender women (Foegh, 1983). Based on an ovulation-inhibiting dosage of CPA of 1 mg/day, these findings would imply that suppression of testosterone levels with CPA would likely be maximal at a dose of between 5 and 10 mg/day. In accordance, this dose range matches up with the findings of the studies above.
Although progestogens can considerably suppress testosterone levels at maximally effective dosages, it has been found that a “recovery” or “escape phenomenon”, in which testosterone levels eventually increase back to higher levels, occurs when progestogen monotherapy is used on a long-term basis. This has most notably been observed with the related progestogen megestrol acetate (Wiki), but has also been seen with CPA (Goldenberg & Bruchovsky, 1991; Saborowski, 1987; Jacobi, Tunn, & Senge, 1982). In one of these studies, testosterone levels were initially suppressed by CPA by about 70%, but increased back to about 50% of baseline between 6 and 12 months of therapy, remaining stable thereafter up to 24 months. The testosterone escape phenomenon should be kept in mind in the context of progestogen monotherapy for testosterone suppression. In contrast to progestogen monotherapy, this phenomenon has not been associated with combined estrogen and progestogen therapy.
Testosterone Suppression in Combination with Estrogen
CPA is generally used in combination with an estrogen in transfeminine people. Estrogens suppress testosterone levels similarly to progestogens. The combination of an estrogen and a progestogen is synergistic in terms of testosterone suppression and results in suppression of testosterone levels with lower doses than with either an estrogen or progestogen alone (Fink, 1979; Geller & Albert, 1983; Bastianelli et al., 2018). Although estrogens can suppress testosterone levels to an equivalent extent as surgical or medical castration (i.e., orchiectomy or GnRH agonists/antagonists), this usually requires relatively high estrogen levels, for instance in the range of 200 to 500 pg/mL (Wiki; Graphs). Because of the high and supraphysiological estradiol levels required for maximal or near-maximal suppression of testosterone levels, lower doses of estradiol are frequently combined with antiandrogens and/or progestogens to block or suppress remaining testosterone levels instead.
CPA, as mentioned earlier, leads to an incomplete suppression of plasma testosterone levels, which decrease by about 70% and remain at about three times castration values. In a very systematic approach to the problem, Rennie et al. (59) investigated and compared 12 different procedures of androgen deprivation. These authors found that the combination of CPA with an extremely low dose (0.1 mg/d) of [diethylstilbestrol (DES)] led to a very effective withdrawal of androgens in terms of plasma testosterone and tissue dihydrotestosterone. The same group later showed that 200 mg of CPA, and even 100 mg/day, was sufficient to achieve a similar endocrine response, which was correlated to very favorable clinical responses in a Phase II situation (60,61). The approach has many potential advantages, and, from an endocrinological point of view, is very logical: this regimen combines the testosterone-reducing effects of two compounds, therefore, only small amounts of estrogen are required to bring down plasma testosterone to approximately castrate levels. Once castrate levels have been achieved, only low doses of CPA are necessary to counteract remaining androgens, mainly of adrenal origin. The regimen was shown to be associated with few side effects and a very low cost. The combination of low-dose CPA with low-dose DES was never studied in a Phase III situation in comparison to standard management. Considering the endocrine results and the observations in patients treated with this regimen (60), this combination treatment is very likely to be competitive with other standard forms of therapy.
A 2016 study of 50 mg/day CPA and 1 to 2 mg/day transdermal estradiol gel in transfeminine people showed that estradiol levels of about 45 pg/mL with CPA were insufficient to achieve female/castrate levels of testosterone, instead resulting in testosterone levels of about 120 to 190 ng/dL (Gava et al., 2016; Graph). Conversely, estradiol levels of about 85 pg/mL with CPA achieved complete suppression of gonadal testosterone production, with resulting testosterone levels of about 20 ng/dL. As such, a certain minimum level of estradiol with CPA appears to be required for complete testosterone suppression. A 2019 study of CPA and oral estradiol valerate in transfeminine people indicated that testosterone levels were still fully suppressed with median estradiol levels of 76 pg/mL and 25th percentile estradiol levels of 63 pg/mL (Angus et al., 2019; Graph).
Figures 5–7: Testosterone levels with CPA plus low doses/levels of estrogens in men and transfeminine people. Sources: Top-left: Goldenberg et al. (1988). Top-right: Gava et al. (2016). Bottom: Angus et al. (2019). See also on Wikipedia: Gallery. Note for the graph on the top right that the mean transdermal estradiol dosage increased between 6 and 12 months and this was likely responsible for the improvement in testosterone suppression.
Fung and colleagues showed that the combination of either 25 or 50 mg/day CPA with a moderate dosage of oral estradiol (~3.5 mg/day) or transdermal estradiol (~3.5 mg/day gel or ~100 μg/day patch) resulted in equivalent and complete suppression of gonadal testosterone production (~95% suppression of testosterone levels) in transfeminine people (Fung, Hellstern-Layefsky, & Lega, 2017). These dosages of estradiol would be expected to achieve estradiol levels of around 100 pg/mL on average (Aly, 2020; Wiki). This study was notably published 6 months before the 2017 second edition of the Endocrine Society guidelines were released (Hembree et al., 2017), and was probably responsible for the decrease in their recommended dosage of CPA from 50–100 mg/day to 25–50 mg/day.
Few studies to date have assessed testosterone suppression with low-dose CPA in combination with a low or moderate dosage of an estrogen. However, based on the fact that 5 to 10 mg/day CPA alone is probably maximal in terms of suppression of testosterone levels, it is likely that such dosages of CPA will be similarly effective as higher dosages. In accordance, studies of 5 to 12.5 mg/day CPA plus upper physiological replacement dosages of testosterone have demonstrated undetectable gonadotropin levels (<0.5 IU/L) and hence complete suppression of testicular function in healthy young men (Meriggiola et al., 1998; Meriggiola et al., 2002b). Estradiol is a more powerful antigonadotropin than testosterone (Wiki), so these findings probably apply to CPA in combination with physiological replacement levels of estradiol as well (e.g., mean estradiol levels of 100–200 pg/mL).
Accordingly, Meyer et al. (2020) assessed a dosage of CPA in combination with estradiol in 155 transfeminine people and found no difference in testosterone levels with 10, 25, or 50 mg/day CPA; testosterone levels were strongly suppressed with all three doses (to about 15–20 ng/dL on average, or into the lower end of the normal female range). The estradiol forms and doses used in this study were oral estradiol valerate (median 6 mg/day, range 3–10 mg/day), transdermal estradiol gel (median 2.25 mg/day, range 1.5–6 mg/day), and transdermal estradiol patches (100 μg/day in all cases). Estradiol levels were about 100 pg/mL on average, with an interquartile range (i.e., difference between 75th and 25th percentiles) of about 100 pg/mL. This study demonstrates that, provided estradiol levels are adequate, no more than 10 mg/day CPA is needed to fully suppress testosterone levels in transfeminine people. Another study likewise found no difference between <20 mg/day and >50 mg/day CPA in terms of testosterone suppression in transfeminine people (Even-Zohar et al., 2020).
Even doses of CPA lower than 5 mg/day (e.g., 2 mg/day) may be usefully effective for testosterone suppression if combined with sufficient levels of estradiol, although this has not been studied and remains to be validated. But there is certainly precedent for the notion when looking at studies with other progestogens. As an example, one study using 10 mg/day oral medroxyprogesterone acetate (which is roughly equivalent to 1 mg/day CPA in terms of ovulation inhibition in premenopausal women; Table) observed 63% lower testosterone levels (215 ng/dL vs. 79 ng/dL) when added to estradiol and spironolactone therapy in transfeminine people (Jain, Kwan, & Forcier, 2019). Analogous effects on testosterone levels would be anticipated for very-low-dose CPA. Moreover, such dosages of CPA would have the advantage of actually being physiological in terms of progestogenic exposure.
The androgen receptor antagonism of CPA is relatively weak in terms of potency; dosages of CPA of 50 to 300 mg/day seem to be necessary for meaningful or considerable androgen receptor antagonism. Unfortunately, such doses also result in extreme progestogenic overdosage and are associated with considerably greater risks and adverse effects. As a result, the use of such doses of CPA should no longer be considered advisable. Instead, CPA should be used at lower doses simply as a progestogen to suppress testosterone levels. As such, the highest effective dosage of CPA for testosterone suppression, which is probably about 10 mg/day or less (12.5 mg/day also being acceptable), should be around the maximal dosage of CPA that is used in transfeminine people.
It should be emphasized that since the combination of an estrogen and CPA can easily suppress testosterone levels well into the female/castrate range (typically to below average female levels), there isn’t necessarily a requirement for concomitant androgen receptor blockade. In any case, if androgen receptor antagonism to neutralize the remaining female/castrate levels of testosterone is still necessary or desired (e.g., to treat persisting acne or for some other purpose), a low dosage of a non-progestogenic androgen-receptor antagonist like spironolactone (e.g., 100–200 mg/day) or bicalutamide (e.g., 12.5–25 mg/day) can be added to CPA to more safely achieve this than use of higher CPA doses.
Recommended Dosages
Dosage for Testosterone Suppression
Estrogen Plus Cyproterone Acetate
The following recommended dosages of CPA in transfeminine people are for the combination of CPA with an estrogen and are specifically for achieving maximal suppression of testosterone levels:
Table 2: Recommended doses of CPA in combination with estrogen for maximal testosterone suppression in transfeminine people:
Form
Min. dosage
Max. dosage
Amount
10 mg tablets
5 mg/day
10 mg/day
1/2 of a tablet to 1 whole tablet per day
50 mg tablets
6.25 mg/day
12.5 mg/day
1/8th of a tablet to 1/4th of a tablet per day
Start with the minimum dosage of CPA for one month. After one month, have testosterone levels tested and confirm that they are in the normal female/castrate range (<50 ng/dL). Regardless of dosage, a concomitant minimum estradiol level of around 65 pg/mL needs to be attained in order to allow for complete suppression of testosterone levels with CPA. If testosterone levels aren’t sufficiently suppressed after a month and estradiol levels are adequate, increase to the maximum CPA dosage and re-check testosterone levels after another month. Alternatively, the dosage of estradiol can be increased instead; higher estradiol levels result in greater testosterone suppression as well.
Cyproterone Acetate Alone
The use of CPA alone (i.e., as a monotherapy for testosterone suppression) is not recommended due to the risk of decreased bone mineral density and other symptoms of sex-hormone deficiency (Wiki; Aly, 2019). In any case, the recommended dosages for CPA without an estrogen are essentially the same as those listed above of the combination of an estrogen with CPA for testosterone suppression. However, the higher CPA dose (10–12.5 mg/day) may be preferable for good measure in this scenario.
Dosage for Progestogenic Effects
The following recommended dosages of CPA in transfeminine people are for progestogenic effects similar to normal physiological exposure (equivalent of luteal-phase progesterone levels):
Table 3: Recommended doses of CPA for physiological progestogenic effects in transfeminine people:
Form
Dosage
Amount
10 mg tablets
2.5 mg/day
1/4th of a tablet per day
50 mg tablets
3.125 mg/day
1/16th of a tablet per day
Achieving Desired Dosages
CPA is available pharmaceutically most widely as 50-mg tablets. This can make achieving desired low doses of CPA more difficult. For splitting CPA tablets into small fractions, a pill cutter can be used. Additionally, CPA can be taken once every 2 or 3 days instead of once every day to help further divide doses. It is notable that CPA has a relatively long half-life in the body of about 1.5 to 2 days (but possibly up to 4 days) (Wiki; Graph). Hence, taking it once every other day instead of once per day, or even less frequently like once every 3 days, has sound basis and is likely to be entirely viable.
Updates
Update 1: GoLoCypro Study (In-Progress)
The GoLoCypro study (2019–2022) (more info) is being conducted by Dr. Judith Dean at the University of Queensland in Australia. It’s assessing the influence of estradiol plus CPA on testosterone levels at five different CPA dose levels (12.5 mg 2x/week, 12.5 mg/2 days, 12.5 mg/day, 25 mg/day, and 50 mg/day) in a total of 120 to 350 transfeminine people. CPA doses are being titrated to the minimum that maintain testosterone levels within the therapeutic goal range of 0.5 to 1.5 nmol/L (14–43 ng/dL). The study is among the first dose-ranging studies of CPA in transfeminine people to be conducted and is eagerly anticipated due to the valuable information that it should provide in terms of the minimum effective dosage of CPA for adequate testosterone suppression in transfeminine hormone therapy.
Update 2: Kuijpers et al. (2021) and Even Zohar et al. (2021)
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]
The study employed estradiol (2–6 mg/day oral (as estradiol valerate), 50–150 μg/day patch, or gel) plus five different dose levels of CPA—0 mg/day (no CPA), 10 mg/day, 25 mg/day, 50 mg/day, and 100 mg/day. It found incompletely suppressed testosterone in the no CPA group but full and equivalent testosterone suppression with all doses of CPA. The results were as follows:
CPA dosage
0 mg/day
10 mg/day
25 mg/day
50 mg/day
100 mg/day
Initial subjects (n)
34
4
234
599
11
Dose increased (n)
16
1
11
2
0
Dose decreased (n)
0
0
4
40
7
T levels (nmol/L)
5.5
0.9
0.9
1.1
0.9
T levels (ng/dL)
~160
~26
~26
~32
~26
T <2 nmol/L [<~58 ng/dL] (%)
46.3
92.3
96.2
93.4
100.0
Abbreviations: T = testosterone.
The total numbers of subjects and blood tests after CPA dose increases/decreases were not provided. Hence, the exact total number of people and tests for the 10 mg/day group can’t be stated with certainty. The total number of tests for this group was at least 13 based on the testosterone suppression percentage provided however (92.3% or 12/13 but could potentially be 24/26, etc.). Regarding the small number of subjects/tests for the 10 mg/day group, the authors stated the following:
This study is part of the ENIGI initiative, a multicenter prospective cohort study. The main treatment protocol for trans women in this study was 50 mg of CPA daily combined with estrogens. In the first year of study inclusion, a few participants received a dose of 100 mg of CPA. Shortly thereafter, inhospital protocol changed to 50 mg of CPA. As more health concerns related to CPA use were raised over the years, the dose was further lowered from 50 mg to 25 mg and, finally, to 10 mg. However, due to the coronavirus (COVID-19) pandemic, limited results of participants with 10 mg of CPA were available for analysis.
Besides testosterone suppression, the study found that 10 mg/day CPA had less influence on prolactin and high-density lipoprotein (HDL) cholesterol levels than the higher doses of CPA. The study also assessed liver enzyme levels but found no differences between CPA doses.
The authors concluded with the following:
In conclusion, in this cohort of trans women, 10 mg of CPA was found to be effective in lowering testosterone concentrations to the range observed in cis women. A dose of 10 mg was equally effective as higher doses, was found to have less influence on prolactin concentrations and allows higher HDL-C concentrations to be maintained. While GnRH agonists are preferred over CPA due to the fewer associated long-term side effects, this study shows that CPA at a low dose is a viable option when GnRH agonists are contra-indicated, not available, or not reimbursed. Future research should focus on assessing the effectiveness of an even lower dose of CPA (e.g., 5 mg) and the potential long-term side effects.
Around the same that this study was published, Guy T’Sjoen (one of the authors of the study) and other colleagues in a review of optimal hormone therapy for transfeminine people recommended a dosage of no more than 10 or 12.5 mg/day CPA for no longer than 2 years (Glintborg et al., 2021). T’Sjoen is notable in being regarded as one of the foremost experts in transgender medicine and is a coauthor of the Endocrine Society transgender care guidelines (Hembree et al., 2017).
Shortly after the study of Kuijpers and colleagues and also in June 2021, Even Zohar and colleagues in Israel published the following study on low doses of CPA in transfeminine people:
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. [10.1016/j.jsxm.2021.04.008]
This study was initially reported as a conference abstract in May 2020 (Even-Zohar et al., 2020).
In the introduction section of the paper, the authors stated the following:
Treatment guidelines published by several organizations are available and assist clinicians in treating transgender women.4,7−9 A wide range of regimens for CPA administration have been proposed. By and large, the recommended doses have decreased over the years: doses of 50–100 mg/day were suggested in the 2009 Endocrine Society Guidelines,10 and amended to 25–50 mg/day in 2017.7 The proposed CPA doses were 12.5–25 mg/day in the 2019 guidelines of the Australian Professional Association for Transgender Health,4 and they were amended to 10–50 mg/day in the 2020 guidelines of the European Society for Sexual Medicine.8 There are no publications on data that compare different doses of CPA for efficacy or safety.
The researchers found that estradiol plus low-dose CPA (10–20 mg/day) suppressed testosterone levels to an equivalent extent as estradiol plus high-dose CPA (50–100 mg/day). Testosterone levels were suppressed into the female/castrate range or near so in both groups (generally ≤2 nmol/L or ≤58 pg/mL). Of the 38 transfeminine people on low-dose CPA, 32 (84%) were on 10 mg/day CPA and 6 (16%) were on 20 mg/day CPA (mean dose 11.6 ± 3.7 mg/day). Estradiol was given as transdermal estradiol patch (mean dose 83.7 ± 36.5 μg/day), transdermal estradiol gel (mean dose 3.8 ± 1.2 g/day), or oral estradiol (mean dose 4.1 ± 1.7 mg/day). Mean estradiol levels ranged from ~110 to 350 pmol/L (~30–95 pg/mL) in the low- and high-dose CPA groups over the follow-up period. Besides showing equivalent testosterone suppression, prolactin levels were significantly lower with low-dose CPA than with high-dose CPA (398 ± 69 mIU/mL vs. 804 ± 121 mIU/mL at 12 months of hormone therapy, respectively).
Based on their findings, the authors stated the following:
We suggest an adjustment of current clinical practice guidelines to recommend lower doses of CPA for the treatment of transgender women.
Both Kuijpers et al. (2021) and Even Zohar et al. (2021) claimed to be the first to demonstrate the efficacy of low-dose CPA in transfeminine people. However, that achievement actually appears to belong to Meyer et al. (2020), who in February 2020 found that estradiol plus 10, 25, or 50 mg/day CPA gave equivalent testosterone suppression across CPA doses in transfeminine people.
Although their study was not about CPA and testosterone suppression, Lim et al. (2020) reported in May/July 2020 that testosterone levels in transfeminine people were median (IQR) 0.6 (0.4–1.0) nmol/L for oral estradiol and 0.9 (0.7–1.6) nmol/L for transdermal estradiol in a mixed group of transfeminine people (n=26 total) on estradiol plus low-dose CPA (12.5 (12.5–18.8) mg/day) (n=14), estradiol alone post-gonadectomy (n=9), and estradiol plus spironolactone (n=3).
In December 2021, the following case report of fatal liver failure with low-dose CPA was published:
Kumar, P., Reddy, S., Kulkarni, A., Sharma, M., & Rao, P. N. (2021). Cyproterone acetate induced Acute liver failure: 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]
The case report describes a 30-year-old cisgender woman who was on 25 mg/day CPA for treatment of hirsutism (excessive facial/body hair growth) for 6 months and developed acute liver failure. Four days following hospitalization, she died. This is the second published case report of liver toxicity with CPA at a dosage below 100 mg/day (the first and only other case was at 50 mg/day) (Wiki; Table). It is also the first report of liver failure in a cisgender woman taking CPA. The case indicates that CPA even at a relatively low dose of 25 mg/day is not fully safe in terms of liver toxicity. It further emphasizes the importance of using the lowest effective doses of CPA in transfeminine people (no more than 10–12.5 mg/day).
Update 4: 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 and made recommendations for transgender hormone therapy for the first time (Coleman et al., 2022). These guidelines recommended a dose of CPA of 10 mg/day in transfeminine people (Coleman et al., 2022). This dose is substantially lower than previous doses recommended by transgender care guidelines and is the first time that major guidelines have recommended a CPA dosage this low. The WPATH SOC8 cited Kuijpers et al. (2021) in support of this recommendation (though notably not Even Zohar et al. (2021) or Meyer et al. (2020)) and also discussed the dose-dependent risks of CPA such as meningiomas and high prolactin levels (Coleman et al., 2022). Considering the key position and importance of the WPATH SOC in transgender health, it is likely that lower CPA doses in transfeminine hormone therapy will now be widely adopted throughout the world. Continued use of higher CPA doses should be considered out of step with current accepted evidence-based practice.
Update 5: Collet et al. (2023)
In October 2022, a study more carefully assessing androgen suppression with estradiol plus CPA in transfeminine people was published:
Collet, S., Gieles, N., Wiepjes, C. M., Heijboer, A. C., Reyns, T., Fiers, T., Lapauw, B., den Heijer, M., & T’Sjoen, G. (2023). 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]
In the study, 275 transfeminine people were treated with estradiol plus CPA, and levels of total testosterone, free testosterone, and the adrenal androgensdehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione (A4) were measured using liquid chromatography–mass spectrometry (LC–MS) at baseline and during follow-ups at 3 months, 12 months, 2 to 4 years, and after surgical gonadal removal (at which time CPA was discontinued). Estradiol was measured both with LC–MS (Amsterdam clinic) and with immunoassays (Ghent clinic). The forms and doses of estradiol used were most commonly oral estradiol valerate 4 mg/day or a transdermal estradiol patch 100 μg/day, while the dosage of CPA was usually 25 or 50 mg/day. About half of the transfeminine people eventually underwent surgical gonadal removal, usually after 2 years of hormone therapy.
Median estradiol levels ranged from 49 to 75 pg/mL (180–275 pmol/L) with LC–MS and from 63 to 69 pg/mL (232–255 pmol/L) with immunoassays at different follow-ups. After 3 months of hormone therapy, total testosterone decreased by 97.1%, from 536 ng/dL (18.6 nmol/L) to 12 ng/dL (0.40 nmol/L), and free testosterone decreased by 98.3%, from 109 pg/mL (378 pmol/L) to 2.0 pg/mL (7.1 pmol/L). Thereafter, total and free testosterone levels remained stable. Levels of DHEA, DHEA-S, and A4 decreased by 24.9 to 28.0%, 20.1 to 23.5%, and 36.5%, respectively, and likewise did not further change after the first 3 to 12 months of hormone therapy. No changes in androgen levels occurred upon surgical gonadal removal with discontinuation of CPA. The authors noted that testosterone levels in the transfeminine people on hormone therapy in the study were similar to or lower than those in cisgender women.
Update 6: Warzywoda et al. (2024) [GoLoCypro Study]
The GoLoCypro study, by Judith Dean and colleagues, was published online in February 2024:
Warzywoda, S., Fowler, J. A., Wood, P., Bisshop, F., Russell, D., Luu, H., Kelly, M., Featherstone, V., & Dean, J. A. (2024). How low can you go? Titrating the lowest effective dose of cyproterone acetate for transgender and gender diverse people who request feminizing hormones. International Journal of Transgender Health, advance online publication. [DOI:10.1080/26895269.2024.2317395]
The following are some noteworthy excerpts from the paper:
Of participants who completed the protocol, 74.0% (34/46) were able to achieve the target T-range (0.5–1.5 nmol/L) and 41.3% (19/46) were titrated to the lowest CPA level (12.5 mg cyproterone twice weekly).
Almost all participants who completed the protocol (91.3.0%, 42/46) recorded their CPA levels as level 3 (12.5 mg daily/25 [mg] alternate days) or lower, with 69.0% (29/42) of these being able to achieve the target T-range. Of those that completed, 41.3% (19/46) were able to achieve the lowest CPA level (12.5 mg cyproterone twice week) with 57.9% (11/19) being able to achieve the target T-range.
The study findings showed that for some patients, CPA doses as low as 12.5 mg on alternate days or less can successfully reduce testosterone to pre-menopausal ranges whilst ensuring testosterone was not over-suppressed.
Our study found that doses of CPA lower than the standard dose (12.5 mg CPA daily and/or 25 mg alternate days) were achievable for suppression of testosterone. Several studies have supported this finding that a lower dosage (10 mg CPA daily) is effective in testosterone reduction in individuals undergoing hormone feminization (Even Zohar et al., 2021; Kuijpers et al., 2021). While not all individuals within our study were able to titrate down CPA dosages, almost a quarter of participants who completed the protocol were achieving target T-ranges on 12.5 mg CPA twice weekly (equivalent to 3.5 mg/daily). To our knowledge ours is the first study to demonstrate that doses lower than 10 mg/daily as well as alternate days or twice weekly CPA are clinically effective in maintaining testosterone reduction within target ranges.
Update 7: More New Low-Dose CPA Studies (2023–2025)
Other new studies of low-dose CPA in transfeminine people have also been published in 2023 and 2024:
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]
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]
Korpaisarn, S., Arunakul, J., Chaisuksombat, K., & Rattananukrom, T. (2023). A Low Dose Cyproterone Acetate In Feminizing Hormone Treatment. Journal of the Endocrine Society, 7(Suppl 1), A1098–A1099 (abstract no. SAT397/bvad114.2068). [DOI:10.1210/jendso/bvad114.2068]
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]
Bonadonna, S., Amer, M., Foletti, F., Federici, S., Persani, L., Bonomi, M. (2025). Evaluation of Antiandrogen Therapy Effectiveness in Transgender individuals Assigned Male At Birth (AMAB). EPATH 6th Conference, September 4–6, 2025 in Hamburg Germany. [PDF]
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-Oral Progesterone Achieves Very Low Levels of Progesterone and Has Only Weak Progestogenic Effects - Transfeminine Science
Oral Progesterone Achieves Very Low Levels of Progesterone and Has Only Weak Progestogenic Effects
By Aly | First published August 4, 2018 | Last modified May 8, 2025
Abstract / TL;DR
Oral progesterone is the most widely used form of progesterone in transfeminine hormone therapy. Because of previous studies using inaccurate blood tests (immunoassays without adequate chromatographic purification), it was thought that typical therapeutic dosages of oral progesterone produced progesterone levels that reached typical luteal-phase levels in cisgender women (which range from about 7 to 22 ng/mL). However, newer studies using more accurate blood tests (immunoassays with adequate purification and mass spectrometry-based assays) have shown that 100 mg/day progesterone—with or without food—achieves very low peak progesterone levels of only about 2 to 3 ng/mL and average progesterone levels over 24 hours of only about 0.1 to 0.6 ng/mL. In accordance, oral progesterone has often shown only weak progestogenic effects in clinical studies. Higher doses of oral progesterone that might achieve better levels are limited by persistingly low progesterone levels, pronounced neurosteroid side effects caused by the first pass of progesterone through the liver, and substantial variability between individuals. While the progesterone levels with oral progesterone are apparently sufficient for endometrial protection in cisgender women, they are unlikely to be adequate for desired effects in transfeminine people. For these reasons, transfeminine people and their clinicians may wish to avoid oral progesterone if the aim is therapeutic progestogenic effects. Instead, non-oral forms of progesterone with greater bioavailability like rectal or injectable progesterone can be used. Alternatively, progestins, which are likewise fully effective progestogens, can be employed.
Introduction
The major female sex hormones are estrogens and progestogens, and both may be used in transfeminine hormone therapy. Progestogens are useful in transfeminine people for helping to suppress testosterone levels and possibly though not certainly influencing breast development. Progestogens include progesterone as well as synthetic progestogens known as progestins. Progesterone has relatively unfavorable pharmacokinetics, which has been overcome with progestins. However, progestins have differing pharmacodynamic properties compared to progesterone, which can potentially be unfavorable. As such, there is interest in using progesterone instead of progestins in transfeminine people and other populations like cisgender women despite its poor pharmacokinetic properties.
Progesterone is available in formulations for use via a variety of different routes, including oral, sublingual, topical, vaginal, rectal, and injectable administration (Wiki; Table). Among these routes, oral administration is the easiest and most convenient, and in relation to this, oral progesterone is the most widely used form of progesterone in transfeminine people. However, the pharmacokinetic problems of progesterone limit the favorability of oral progesterone. Moreover, these limitations of oral progesterone actually appear to be much more substantial than is generally realized, a fact that has been obscured by methodological limitations of many—but not all—of the pharmacokinetic studies that have characterized oral progesterone. The purpose of this article is to explain and review these findings, as well as to explore solutions and alternatives to oral progesterone for progestogen therapy in transfeminine people.
Progesterone Levels with Oral Progesterone
Oral micronized progesterone, or simply oral progesterone, is the form of progesterone that is used by the oral route as a pharmaceutical medication. It is an oil suspension of micronized progesterone crystals contained in gelatin capsules. The formulation is marketed under brand names including Prometrium, Utrogestan, and Microgest, among many others. Oral progesterone has very low bioavailability (≤10%) due to the first pass through the intestines and liver with oral administration. As a result of the first pass, most of the delivered progesterone with oral progesterone is metabolized into neurosteroid metabolites such as allopregnanolone and pregnanolone before reaching the bloodstream (de Lignieres, Dennerstein, & Backstrom, 1995). This is why oral progesterone has alcohol-like side effects like sedation that are not shared by typical doses of non-oral progesterone such as vaginal progesterone or progesterone by injection. In spite of the low bioavailability of oral progesterone, typical clinical doses of oral progesterone, such as 100 to 300 mg/day, have been reported to produce progesterone levels measured with immunoassays that are similar to those in the normal luteal phase of the menstrual cycle in cisgender women (Simon et al., 1993). For this reason, it has been believed that oral progesterone can achieve high and physiologically adequate levels of progesterone.
Figure 1: Progesterone levels during the menstrual cycle in normal premenopausal women (Stricker et al., 2006). The dashed horizontal lines are the mean levels for each curve and the dashed vertical line demarcates mid-cycle (when ovulation occurs). Progesterone levels are normally elevated only during the luteal phase.
Figure 2: Progesterone levels measured by immunoassay after single 100 to 300 mg doses of oral micronized progesterone in postmenopausal women (Simon et al., 1993). The horizontal dashed lines are mean levels over 24 hours. Progesterone levels appeared to reach concentrations comparable to normal luteal-phase levels. However, these levels were in fact not accurate due to the use of immunoassays (Nahoul & de Ziegler, 1994).
A notable study using LC–MS found maximal progesterone levels of only about 2 ng/mL and average progesterone levels over a period of 24 hours of only about 0.14 ng/mL after a single 100 mg dose of oral progesterone (Levine & Watson, 2000; Kuhl & Schneider, 2013). Another more recent study with LC–MS found progesterone levels of around 2.5 to 3 ng/mL at peak and average progesterone levels over 24 hours of around 0.6 ng/mL after a single 100 mg dose of oral progesterone with food (Lobo et al., 2019). (It should be noted that intake with food is known to increase the bioavailability of oral progesterone by a few-fold (Wiki; Bijuva FDA Label; Simon et al., 1993; Prometrium FDA Review, 1996; Pickar et al., 2015).) These progesterone levels are well below normal luteal-phase levels of progesterone, which range from 7 to 22 ng/mL with LC–MS (Nakamoto, 2016). Studies that have directly compared quantification of progesterone with immunoassays against more reliable methods have found that immunoassays overestimate progesterone levels by 5- to 8-fold (Nahoul, Dehennin, & Scholler, 1987; Nahoul & de Ziegler, 1994; Levine & Watson, 2000; Kuhl, 2011; Kuhl & Schneider, 2013; Davey, 2018). In one small study of a few individuals, the degree of overestimation varied from 2-fold to 40-fold with several different commercial immunoassays (Sapin et al., 2000). These findings are obscure and still relatively little-known in the scientific and medical communities. In any case, it is clear that oral progesterone achieves progesterone levels that are far lower than once thought and are well below the luteal-phase levels that would be therapeutically desirable for transfeminine people.
Figure 3: Progesterone levels measured by immunoassay or LC–MS after a single dose of oral or vaginal micronized progesterone in postmenopausal women (Levine & Watson, 2000; Kuhl & Schneider, 2013). Levels of progesterone with oral progesterone measured by immunoassay were falsely high due to cross-reactivity. Conversely, progesterone levels measured by LC–MS or with vaginal progesterone can be considered accurate.
Figure 4: Progesterone levels measured by LC–MS with 100 mg/day oral micronized progesterone taken with food in postmenopausal women (Lobo et al., 2019). The horizontal dashed line is the mean level over 24 hours. Food increases progesterone levels with oral progesterone by about 2- to 3-fold (Bijuva FDA Label; Simon et al., 1993). The progesterone levels measured in this study can be considered accurate to due to the use of LC–MS.
Therapeutic Implications
Progestogenic Potency and Effects
A variety of perplexing findings on the clinical progestogenic effects of oral progesterone have been made over the decades and can now be readily explained by the newer data on oral progesterone with better analytic methods. Oral progesterone is used in clinical medicine mainly to protect the endometrium from unopposed stimulation by estrogens in menopausal cisgender women and is able to reliably prevent endometrial hyperplasia induced by estrogens even with the low progesterone levels that typical clinical doses achieve (Wiki). However, oral progesterone failed to provide adequate protection against estrogen-mediated endometrial cancer risk in a large observational study (Davey, 2018). Oral progesterone even at very high doses also is unable to produce full endometrial transformation—a normal effect of luteal-phase levels of progesterone—whereas vaginal and injectable progesterone are effective (de Ziegler et al., 2013). For this reason, oral progesterone, in contrast to parenteral progesterone, is considered to be inappropriate for use in assisted reproduction (de Ziegler et al., 2013). Oral progesterone additionally failed to suppress testosterone levels even at high doses (400 mg/day) in cisgender males (Trollan et al., 1993; Wiki). Conversely, progestins, rectal progesterone, and injectable progesterone can all produce robust testosterone suppression in cisgender males (Wiki; Aly, 2019). Similarly, oral progesterone has little or no apparent antigonadotropic effect in menopausal cisgender women, which is again in notable contrast to progestins (Holst, 1983; Holst et al., 1983; Ottosson, 1984; Maxson & Hargrove, 1985; Saarikoski, Yliskosk, & Penttilä, 1990).
Unlike other clinically used progestogens, the addition of oral progesterone to estrogen therapy in menopausal women has not been associated with increased risk of venous thromboembolism (VTE; blood clots) (Wiki). Nor has it been associated with increased breast cancer risk in the short-term (<5 years of therapy) (Wiki). However, with long-term use (≥5 years), the combination of estrogen plus oral progesterone is associated with significantly greater risk of breast cancer relative to estrogen alone similarly to other progestogens (Aly, 2020; Sam, 2020; Wiki; Table). This has been said to be consistent with a weak proliferative effect of oral progesterone on the breasts such that a longer duration of exposure is necessary for a quantifiable increase in breast cancer risk to manifest (Kuhl & Schneider, 2013; Davey, 2018). It is also consistent with preclinical research, which clearly suggests a carcinogenic role for progesterone and progesterone receptor activation in the breast (Kuhl & Schneider, 2013; Trabert et al., 2020). The preceding clinical findings on endometrial efficacy, testosterone and gonadotropin suppression, VTE risk, and breast cancer risk with oral progesterone are in contrast to those with almost all clinically used progestins (with the exception of the oral progesterone-like dydrogesterone). These previously perplexing discrepancies can be readily explained by the very low levels of progesterone that are now known to be achieved with oral progesterone.
Bioavailability, Half-Life, and Duration
Considering the much lower levels of progesterone observed with oral progesterone in studies using reliable analytic methods, the bioavailability of oral progesterone needs to be reassessed. In studies with immunoassays, the bioavailability of oral progesterone has been reported to be around 10% (Wiki). The true oral bioavailability of progesterone is unknown at this time as studies with reliable analytic methods have not been conducted. In any case, it can be assumed that it may be closer to around 1 or 2% based on the findings that immunoassays overestimate progesterone levels by 5- to 8-fold.
The elimination half-life of progesterone with oral progesterone has been determined in studies employing immunoassays to be 16 to 18 hours (Wiki). Based on the fact that the blood half-life of progesterone administered by intravenous injection is very short at a range of only 3 minutes to 1.5 hours (Wiki), the reported half-life of progesterone with oral progesterone is much longer than one would expect. Oral estradiol has a relatively long half-life of 13 to 20 hours due to formation with the first pass of a circulating reservoir of estrogen conjugates that are slowly converted back into estradiol (Kuhl, 2005; Wiki). In contrast to estradiol however, progesterone itself has no available hydroxyl groups for conjugation and an analogous circulating reservoir of progesterone conjugates that can be converted back into progesterone is not known to be the case (Kuhl, 2005).
Studies with more reliable analytic methods like LC–MS have found a half-life of progesterone with oral progesterone of 5 to 10 hours and a duration of highly elevated progesterone levels of only about 4 to 8 hours (Wiki; Graphs). These findings indicate that oral progesterone has a much shorter duration than previously thought as well. As such, if oral progesterone is used, it may be advisable to take it in divided doses multiple times per day to allow for more sustained progestogenic exposure.
Higher Oral Progesterone Doses and Neurosteroid Side Effects
Use of higher doses of oral progesterone than typical doses is likely to achieve dose-dependently higher progesterone levels (Table). However, based on how low progesterone levels are with oral progesterone using reliable analytic techniques, even very high doses would still be expected to achieve only low progesterone levels in most cases. Moreover, high doses of oral progesterone result in very high levels of its neurosteroid metabolites and have been found to produce substantial alcohol-like side effects (i.e., central depression and effects within that umbrella) (Wiki; Wiki). These limitations are likely to preclude higher doses of oral progesterone from being practical.
Figure 5: Levels of progesterone, allopregnanolone, and pregnanolone in premenopausal women following a single dose of oral progesterone or vaginal progesterone (as a suppository) (de Lignieres, Dennerstein, & Backstrom, 1995). Allopregnanolone and pregnanolone levels were determined by MS-based assays while progesterone levels were measured by immunoassay with chromatographic separation. Hence, the levels should be reliable.
A Note on Oral Progesterone’s Metabolites
Although progesterone levels with oral progesterone are very low, the metabolites of progesterone are formed in disproportionate amounts with the first pass (Sitruk-Ware et al., 1987; de Lignieres, Dennerstein, & Backstrom, 1995; de Lignieres, 1999; de Ziegler & Fanchin, 2000; Lobo, 2000; Kuhl, 2005). Moreover, while much less potent than progesterone, some of these metabolites have been found to have progestogenic activity similarly to progesterone (e.g., Besch et al., 1965; Junkermann, Runnebaum, & Lisboa, 1977; Lobo, 2000). This activity derives either from them having intrinsic progestogenic activity of their own or from being converted back into progesterone or other progestogenic metabolites (including in an intracrine fashion within tissues, for instance in the uterus). Examples of such metabolites include 20α-dihydroprogesterone, 20β-dihydroprogesterone, 5α-dihydroprogesterone, 3β-dihydroprogesterone, allopregnanolone, and 11-deoxycorticosterone. If the metabolites of oral progesterone contribute significantly to its progestogenic activity, then the progestogenic strength of oral progesterone would be greater than that implied by the progesterone levels that occur with it alone. However, this possibility is only theoretical and there is little literature discussing it. More research would be needed to determine if the metabolites of oral progesterone do indeed play a meaningful role in its progestogenic potency. In any case, oral progesterone is still a relatively weak progestogen based on clinical studies of its progestogenic effects.
Alternative Options to Oral Progesterone
Non-Oral Forms of Progesterone
Non-oral forms of progesterone, such as vaginal progesterone, rectal progesterone, sublingual progesterone, and progesterone by injection, have been found to achieve much higher progesterone levels than oral progesterone (Wiki). They can be used instead of oral progesterone to achieve higher and more adequate progesterone levels. Unfortunately however, while more effective than oral progesterone, non-oral progesterone routes have various limitations of their own.
Vaginal progesterone is of course not possible in transfeminine people who have not undergone vaginoplasty. And in those who have undergone vaginoplasty, the lining of the neovagina is either skin (penile inversion vaginoplasty) or intestine (sigmoid colon vaginoplasty) rather than the normal vaginal mucosa. As such, the absorptive characteristics of neovaginal administration are likely not the same as vaginal administration (Aly, 2018). It is notable that transdermal progesterone achieves very low progesterone levels similarly to oral progesterone and is not a good option for progesterone therapy (Wiki; Hermann et al., 2005; Graph). Progesterone levels with neovaginal administration of progesterone in those who have undergone penile inversion vaginoplasty are likely to be low similarly.
Rectal progesterone is an excellent route that achieves high progesterone levels comparable to the levels of progesterone that occur during the normal luteal phase (Wiki; Graphs). It has a somewhat short duration and twice daily use may be warranted for more sustained levels however. A more important problem is that the availability of pharmaceutical rectal progesterone suppositories throughout the world is limited and they are not marketed in most countries (Wiki). In any case, rectal progesterone suppositories may be available from compounding pharmacies in some countries. In addition, oral micronized progesterone capsules are available ubiquitously and have been administered vaginally instead of orally with success (Miles et al., 1994; Wang et al., 2019). Administration of oral micronized progesterone capsules rectally instead of orally likewise may be effective and may achieve much higher progesterone levels than oral administration (Aly, 2018). However, rectal administration of oral progesterone capsules has not been formally studied. Although rectal progesterone is effective, it is fairly inconvenient. This may be especially true with long-term therapy. In any case, of the available non-oral forms of progesterone, rectal progesterone is probably the best overall. A significant subset of transfeminine people on progestogens take progesterone rectally (Chang et al., 2024).
Figure 6: Progesterone levels with a single suppository containing 100 mg progesterone administered rectally or vaginally in premenopausal women (Chakmakjian & Zachariah, 1987).
Sublingual progesterone appears to achieve high and more physiological progesterone levels than oral progesterone but has a short duration of highly elevated progesterone levels similarly and necessitates administration several times per day (Wiki; Graph). Moreover, although sublingual progesterone may have been more widely available in the past (Wiki), it is available today only in a couple of Eastern European countries (Wiki). It might be available from compounding pharmacies in some countries however. While never formally studied, it may be possible to use oral micronized progesterone capsules sublingually instead of orally. However, this route is complicated by the fact that this form of progesterone is suspended in oil within gelatin capsules. Hence, sublingual administration of oral micronized progesterone is likely to be difficult and potentially unpleasant.
Progesterone by intramuscular or subcutaneous injection can easily achieve very high progesterone levels (Wiki; Graphs; Wiki; Graph). However, progesterone administered by this route has a relatively short duration when compared to other injectable sex-hormone formulations and requires injection once every 1 to 3 days. This is simply too frequent for most people, especially with long-term therapy. In addition, progesterone by subcutaneous injection, which is more convenient than progesterone by intramuscular injection, has limited availability and is marketed mostly only in Europe (Wiki). In contrast to other sex hormones like estradiol and testosterone, progesterone esters that are more fat-soluble than progesterone and extend its duration when used in injectable form are not possible since progesterone has no free hydroxyl groups available for esterification. Injectable aqueous suspensions of progesterone that had much longer durations than the oil solutions and aqueous solutions that are used by injection today were previously available (Wiki; Wiki; Aly, 2019). However, they were associated with painful injection site reactions and this led to their discontinuation. In any case, injectable aqueous suspensions of progesterone do actually seem to remain available for people in a couple of Eastern European countries today (Aly, 2019).
In conclusion, oral progesterone achieves very low progesterone levels at typical clinical doses and produces only weak progestogenic effects that seem to be far from physiologically adequate. Although use of higher doses of oral progesterone is likely to achieve higher progesterone levels, such doses are likely to be impractical because progesterone levels will still be low even at higher doses and the neurosteroid side effects of oral progesterone will be much more substantial and difficult to tolerate.
Due to its limitations, transfeminine people and clinicians treating them may wish to avoid oral progesterone if the intended goal is to produce therapeutic progestogenic effects. Instead, non-oral progesterone routes, such as rectal and injected progesterone, although with various limitations such as limited availability and inconvenience, can be used. Alternatively, progestins, particularly those with more favorable profiles, can be used instead of progesterone altogether.
Oral progesterone may perhaps be most appropriately conceptualized as a potent neurosteroid prodrug with weak progestogenic effects. Conversely, non-oral progesterone, as well as progestins, can be regarded as potent progestogens with either physiological or no neurosteroid effects, respectively.
Additional Content
Literature
The sources and excerpts collected here go in-depth on much of what has been described in this article on the topic of the measurement problems and low progesterone levels with oral progesterone.
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+Oral Progesterone Achieves Very Low Levels of Progesterone and Has Only Weak Progestogenic Effects - Transfeminine Science
Oral Progesterone Achieves Very Low Levels of Progesterone and Has Only Weak Progestogenic Effects
By Aly | First published August 4, 2018 | Last modified August 14, 2025
Abstract / TL;DR
Oral progesterone is the most widely used form of progesterone in transfeminine hormone therapy. Because of previous studies using inaccurate blood tests (immunoassays without adequate chromatographic purification), it was thought that typical therapeutic dosages of oral progesterone produced progesterone levels that reached typical luteal-phase levels in cisgender women (which range from about 7 to 22 ng/mL). However, newer studies using more accurate blood tests (immunoassays with adequate purification and mass spectrometry-based assays) have shown that 100 mg/day progesterone—with or without food—achieves very low peak progesterone levels of only about 2 to 3 ng/mL and average progesterone levels over 24 hours of only about 0.1 to 0.6 ng/mL. In accordance, oral progesterone has often shown only weak progestogenic effects in clinical studies. Higher doses of oral progesterone that might achieve better levels are limited by persistingly low progesterone levels, pronounced neurosteroid side effects caused by the first pass of progesterone through the liver, and substantial variability between individuals. While the progesterone levels with oral progesterone are apparently sufficient for endometrial protection in cisgender women, they are unlikely to be adequate for desired effects in transfeminine people. For these reasons, transfeminine people and their clinicians may wish to avoid oral progesterone if the aim is therapeutic progestogenic effects. Instead, non-oral forms of progesterone with greater bioavailability like rectal or injectable progesterone can be used. Alternatively, progestins, which are likewise fully effective progestogens, can be employed.
Introduction
The major female sex hormones are estrogens and progestogens, and both may be used in transfeminine hormone therapy. Progestogens are useful in transfeminine people for helping to suppress testosterone levels and possibly though not certainly influencing breast development. Progestogens include progesterone as well as synthetic progestogens known as progestins. Progesterone has relatively unfavorable pharmacokinetics, which has been overcome with progestins. However, progestins have differing pharmacodynamic properties compared to progesterone, which can potentially be unfavorable. As such, there is interest in using progesterone instead of progestins in transfeminine people and other populations like cisgender women despite its poor pharmacokinetic properties.
Progesterone is available in formulations for use via a variety of different routes, including oral, sublingual, topical, vaginal, rectal, and injectable administration (Wiki; Table). Among these routes, oral administration is the easiest and most convenient, and in relation to this, oral progesterone is the most widely used form of progesterone in transfeminine people. However, the pharmacokinetic problems of progesterone limit the favorability of oral progesterone. Moreover, these limitations of oral progesterone actually appear to be much more substantial than is generally realized, a fact that has been obscured by methodological limitations of many—but not all—of the pharmacokinetic studies that have characterized oral progesterone. The purpose of this article is to explain and review these findings, as well as to explore solutions and alternatives to oral progesterone for progestogen therapy in transfeminine people.
Progesterone Levels with Oral Progesterone
Oral micronized progesterone, or simply oral progesterone, is the form of progesterone that is used by the oral route as a pharmaceutical medication. It is an oil suspension of micronized progesterone crystals contained in gelatin capsules. The formulation is marketed under brand names including Prometrium, Utrogestan, and Microgest, among many others. Oral progesterone has very low bioavailability (≤10%) due to the first pass through the intestines and liver with oral administration. As a result of the first pass, most of the delivered progesterone with oral progesterone is metabolized into neurosteroid metabolites such as allopregnanolone and pregnanolone before reaching the bloodstream (de Lignieres, Dennerstein, & Backstrom, 1995). This is why oral progesterone has alcohol-like side effects like sedation that are not shared by typical doses of non-oral progesterone such as vaginal progesterone or progesterone by injection. In spite of the low bioavailability of oral progesterone, typical clinical doses of oral progesterone, such as 100 to 300 mg/day, have been reported to produce progesterone levels measured with immunoassays that are similar to those in the normal luteal phase of the menstrual cycle in cisgender women (Simon et al., 1993). For this reason, it has been believed that oral progesterone can achieve high and physiologically adequate levels of progesterone.
Figure 1: Progesterone levels during the menstrual cycle in normal premenopausal women (Stricker et al., 2006). The dashed horizontal lines are the mean levels for each curve and the dashed vertical line demarcates mid-cycle (when ovulation occurs). Progesterone levels are normally elevated only during the luteal phase.
Figure 2: Progesterone levels measured by immunoassay after single 100 to 300 mg doses of oral micronized progesterone in postmenopausal women (Simon et al., 1993). The horizontal dashed lines are mean levels over 24 hours. Progesterone levels appeared to reach concentrations comparable to normal luteal-phase levels. However, these levels were in fact not accurate due to the use of immunoassays (Nahoul & de Ziegler, 1994).
A notable study using LC–MS found maximal progesterone levels of only about 2 ng/mL and average progesterone levels over a period of 24 hours of only about 0.14 ng/mL after a single 100 mg dose of oral progesterone (Levine & Watson, 2000; Kuhl & Schneider, 2013). Another more recent study with LC–MS found progesterone levels of around 2.5 to 3 ng/mL at peak and average progesterone levels over 24 hours of around 0.6 ng/mL after a single 100 mg dose of oral progesterone with food (Lobo et al., 2019). (It should be noted that intake with food is known to increase the bioavailability of oral progesterone by a few-fold (Wiki; Bijuva FDA Label; Simon et al., 1993; Prometrium FDA Review, 1996; Pickar et al., 2015).) These progesterone levels are well below normal luteal-phase levels of progesterone, which range from 7 to 22 ng/mL with LC–MS (Nakamoto, 2016). Studies that have directly compared quantification of progesterone with immunoassays against more reliable methods have found that immunoassays overestimate progesterone levels by 5- to 8-fold (Nahoul, Dehennin, & Scholler, 1987; Nahoul & de Ziegler, 1994; Levine & Watson, 2000; Kuhl, 2011; Kuhl & Schneider, 2013; Davey, 2018). In one small study of a few individuals, the degree of overestimation varied from 2-fold to 40-fold with several different commercial immunoassays (Sapin et al., 2000). These findings are obscure and still relatively little-known in the scientific and medical communities. In any case, it is clear that oral progesterone achieves progesterone levels that are far lower than once thought and are well below the luteal-phase levels that would be therapeutically desirable for transfeminine people.
Figure 3: Progesterone levels measured by immunoassay or LC–MS after a single dose of oral or vaginal micronized progesterone in postmenopausal women (Levine & Watson, 2000; Kuhl & Schneider, 2013). Levels of progesterone with oral progesterone measured by immunoassay were falsely high due to cross-reactivity. Conversely, progesterone levels measured by LC–MS or with vaginal progesterone can be considered accurate.
Figure 4: Progesterone levels measured by LC–MS with 100 mg/day oral micronized progesterone taken with food in postmenopausal women (Lobo et al., 2019). The horizontal dashed line is the mean level over 24 hours. Food increases progesterone levels with oral progesterone by about 2- to 3-fold (Bijuva FDA Label; Simon et al., 1993). The progesterone levels measured in this study can be considered accurate to due to the use of LC–MS.
Therapeutic Implications
Progestogenic Potency and Effects
A variety of perplexing findings on the clinical progestogenic effects of oral progesterone have been made over the decades and can now be readily explained by the newer data on oral progesterone with better analytic methods. Oral progesterone is used in clinical medicine mainly to protect the endometrium from unopposed stimulation by estrogens in menopausal cisgender women and is able to reliably prevent endometrial hyperplasia induced by estrogens even with the low progesterone levels that typical clinical doses achieve (Wiki). However, oral progesterone failed to provide adequate protection against estrogen-mediated endometrial cancer risk in a large observational study (Davey, 2018). Oral progesterone even at very high doses also is unable to produce full endometrial transformation—a normal effect of luteal-phase levels of progesterone—whereas vaginal and injectable progesterone are effective (de Ziegler et al., 2013). For this reason, oral progesterone, in contrast to parenteral progesterone, is considered to be inappropriate for use in assisted reproduction (de Ziegler et al., 2013). Oral progesterone additionally failed to suppress testosterone levels even at high doses (400 mg/day) in cisgender males (Trollan et al., 1993; Wiki). Conversely, progestins, rectal progesterone, and injectable progesterone can all produce robust testosterone suppression in cisgender males (Wiki; Aly, 2019). Similarly, oral progesterone has little or no apparent antigonadotropic effect in menopausal cisgender women, which is again in notable contrast to progestins (Holst, 1983; Holst et al., 1983; Ottosson, 1984; Maxson & Hargrove, 1985; Saarikoski, Yliskosk, & Penttilä, 1990).
Unlike other clinically used progestogens, the addition of oral progesterone to estrogen therapy in menopausal women has not been associated with increased risk of venous thromboembolism (VTE; blood clots) (Wiki). Nor has it been associated with increased breast cancer risk in the short-term (<5 years of therapy) (Wiki). However, with long-term use (≥5 years), the combination of estrogen plus oral progesterone is associated with significantly greater risk of breast cancer relative to estrogen alone similarly to other progestogens (Aly, 2020; Sam, 2020; Wiki; Table). This has been said to be consistent with a weak proliferative effect of oral progesterone on the breasts such that a longer duration of exposure is necessary for a quantifiable increase in breast cancer risk to manifest (Kuhl & Schneider, 2013; Davey, 2018). It is also consistent with preclinical research, which clearly suggests a carcinogenic role for progesterone and progesterone receptor activation in the breast (Kuhl & Schneider, 2013; Trabert et al., 2020). The preceding clinical findings on endometrial efficacy, testosterone and gonadotropin suppression, VTE risk, and breast cancer risk with oral progesterone are in contrast to those with almost all clinically used progestins (with the exception of the oral progesterone-like dydrogesterone). These previously perplexing discrepancies can be readily explained by the very low levels of progesterone that are now known to be achieved with oral progesterone.
Bioavailability, Half-Life, and Duration
Considering the much lower levels of progesterone observed with oral progesterone in studies using reliable analytic methods, the bioavailability of oral progesterone needs to be reassessed. In studies with immunoassays, the bioavailability of oral progesterone has been reported to be around 10% (Wiki). The true oral bioavailability of progesterone is unknown at this time as studies with reliable analytic methods have not been conducted. In any case, it can be assumed that it may be closer to around 1 or 2% based on the findings that immunoassays overestimate progesterone levels by 5- to 8-fold.
The elimination half-life of progesterone with oral progesterone has been determined in studies employing immunoassays to be 16 to 18 hours (Wiki). Based on the fact that the blood half-life of progesterone administered by intravenous injection is very short at a range of only 3 minutes to 1.5 hours (Wiki), the reported half-life of progesterone with oral progesterone is much longer than one would expect. Oral estradiol has a relatively long half-life of 13 to 20 hours due to formation with the first pass of a circulating reservoir of estrogen conjugates that are slowly converted back into estradiol (Kuhl, 2005; Wiki). In contrast to estradiol however, progesterone itself has no available hydroxyl groups for conjugation and an analogous circulating reservoir of progesterone conjugates that can be converted back into progesterone is not known to be the case (Kuhl, 2005).
Studies with more reliable analytic methods like LC–MS have found a half-life of progesterone with oral progesterone of 5 to 10 hours and a duration of highly elevated progesterone levels of only about 4 to 8 hours (Wiki; Graphs). These findings indicate that oral progesterone has a much shorter duration than previously thought as well. As such, if oral progesterone is used, it may be advisable to take it in divided doses multiple times per day to allow for more sustained progestogenic exposure.
Higher Oral Progesterone Doses and Neurosteroid Side Effects
Use of higher doses of oral progesterone than typical doses is likely to achieve dose-dependently higher progesterone levels (Table). However, based on how low progesterone levels are with oral progesterone using reliable analytic techniques, even very high doses would still be expected to achieve only low progesterone levels in most cases. Moreover, high doses of oral progesterone result in very high levels of its neurosteroid metabolites and have been found to produce substantial alcohol-like side effects (i.e., central depression and effects within that umbrella) (Wiki; Wiki). These limitations are likely to preclude higher doses of oral progesterone from being practical.
Figure 5: Levels of progesterone, allopregnanolone, and pregnanolone in premenopausal women following a single dose of oral progesterone or vaginal progesterone (as a suppository) (de Lignieres, Dennerstein, & Backstrom, 1995). Allopregnanolone and pregnanolone levels were determined by MS-based assays while progesterone levels were measured by immunoassay with chromatographic separation. Hence, the levels should be reliable.
A Note on Oral Progesterone’s Metabolites
Although progesterone levels with oral progesterone are very low, the metabolites of progesterone are formed in disproportionate amounts with the first pass (Sitruk-Ware et al., 1987; de Lignieres, Dennerstein, & Backstrom, 1995; de Lignieres, 1999; de Ziegler & Fanchin, 2000; Lobo, 2000; Kuhl, 2005). Moreover, while much less potent than progesterone, some of these metabolites have been found to have progestogenic activity similarly to progesterone (e.g., Besch et al., 1965; Junkermann, Runnebaum, & Lisboa, 1977; Lobo, 2000). This activity derives either from them having intrinsic progestogenic activity of their own or from being converted back into progesterone or other progestogenic metabolites (including in an intracrine fashion within tissues, for instance in the uterus). Examples of such metabolites include 20α-dihydroprogesterone, 20β-dihydroprogesterone, 5α-dihydroprogesterone, 3β-dihydroprogesterone, allopregnanolone, and 11-deoxycorticosterone. If the metabolites of oral progesterone contribute significantly to its progestogenic activity, then the progestogenic strength of oral progesterone would be greater than that implied by the progesterone levels that occur with it alone. However, this possibility is only theoretical and there is little literature discussing it. More research would be needed to determine if the metabolites of oral progesterone do indeed play a meaningful role in its progestogenic potency. In any case, oral progesterone is still a relatively weak progestogen based on clinical studies of its progestogenic effects.
Alternative Options to Oral Progesterone
Non-Oral Forms of Progesterone
Non-oral forms of progesterone, such as vaginal progesterone, rectal progesterone, sublingual progesterone, and progesterone by injection, have been found to achieve much higher progesterone levels than oral progesterone (Wiki). They can be used instead of oral progesterone to achieve higher and more adequate progesterone levels. Unfortunately however, while more effective than oral progesterone, non-oral progesterone routes have various limitations of their own.
Vaginal progesterone is of course not possible in transfeminine people who have not undergone vaginoplasty. And in those who have undergone vaginoplasty, the lining of the neovagina is either skin (penile inversion vaginoplasty) or intestine (sigmoid colon vaginoplasty) rather than the normal vaginal mucosa. As such, the absorptive characteristics of neovaginal administration are likely not the same as vaginal administration (Aly, 2018). It is notable that transdermal progesterone achieves very low progesterone levels similarly to oral progesterone and is not a good option for progesterone therapy (Wiki; Hermann et al., 2005; Graph). Progesterone levels with neovaginal administration of progesterone in those who have undergone penile inversion vaginoplasty are likely to be low similarly.
Rectal progesterone is an excellent route that achieves high progesterone levels comparable to the levels of progesterone that occur during the normal luteal phase (Wiki; Graphs). It has a somewhat short duration and twice daily use may be warranted for more sustained levels however. A more important problem is that the availability of pharmaceutical rectal progesterone suppositories throughout the world is limited and they are not marketed in most countries (Wiki). In any case, rectal progesterone suppositories may be available from compounding pharmacies in some countries. In addition, oral micronized progesterone capsules are available ubiquitously and have been administered vaginally instead of orally with success (Miles et al., 1994; Wang et al., 2019). Administration of oral micronized progesterone capsules rectally instead of orally likewise may be effective and may achieve much higher progesterone levels than oral administration (Aly, 2018). However, rectal administration of oral progesterone capsules has not been formally studied. Although rectal progesterone is effective, it is fairly inconvenient. This may be especially true with long-term therapy. In any case, of the available non-oral forms of progesterone, rectal progesterone is probably the best overall. A significant subset of transfeminine people on progestogens take progesterone rectally (Chang et al., 2024).
Figure 6: Progesterone levels with a single suppository containing 100 mg progesterone administered rectally or vaginally in premenopausal women (Chakmakjian & Zachariah, 1987).
Sublingual progesterone appears to achieve high and more physiological progesterone levels than oral progesterone but has a short duration of highly elevated progesterone levels similarly and necessitates administration several times per day (Wiki; Graph). Moreover, although sublingual progesterone may have been more widely available in the past (Wiki), it is available today only in a couple of Eastern European countries (Wiki). It might be available from compounding pharmacies in some countries however. While never formally studied, it may be possible to use oral micronized progesterone capsules sublingually instead of orally. However, this route is complicated by the fact that this form of progesterone is suspended in oil within gelatin capsules. Hence, sublingual administration of oral micronized progesterone is likely to be difficult and potentially unpleasant.
Progesterone by intramuscular or subcutaneous injection can easily achieve very high progesterone levels (Wiki; Graphs; Wiki; Graph). However, progesterone administered by this route has a relatively short duration when compared to other injectable sex-hormone formulations and requires injection once every 1 to 3 days. This is simply too frequent for most people, especially with long-term therapy. In addition, progesterone by subcutaneous injection, which is more convenient than progesterone by intramuscular injection, has limited availability and is marketed mostly only in Europe (Wiki). In contrast to other sex hormones like estradiol and testosterone, progesterone esters that are more fat-soluble than progesterone and extend its duration when used in injectable form are not possible since progesterone has no free hydroxyl groups available for esterification. Injectable aqueous suspensions of progesterone that had much longer durations than the oil solutions and aqueous solutions that are used by injection today were previously available (Wiki; Wiki; Aly, 2019). However, they were associated with painful injection site reactions and this led to their discontinuation. In any case, injectable aqueous suspensions of progesterone do actually seem to remain available for people in a couple of Eastern European countries today (Aly, 2019).
In conclusion, oral progesterone achieves very low progesterone levels at typical clinical doses and produces only weak progestogenic effects that seem to be far from physiologically adequate. Although use of higher doses of oral progesterone is likely to achieve higher progesterone levels, such doses are likely to be impractical because progesterone levels will still be low even at higher doses and the neurosteroid side effects of oral progesterone will be much more substantial and difficult to tolerate.
Due to its limitations, transfeminine people and clinicians treating them may wish to avoid oral progesterone if the intended goal is to produce therapeutic progestogenic effects. Instead, non-oral progesterone routes, such as rectal and injected progesterone, although with various limitations such as limited availability and inconvenience, can be used. Alternatively, progestins, particularly those with more favorable profiles, can be used instead of progesterone altogether.
Oral progesterone may perhaps be most appropriately conceptualized as a potent neurosteroid prodrug with weak progestogenic effects. Conversely, non-oral progesterone, as well as progestins, can be regarded as potent progestogens with either physiological or no neurosteroid effects, respectively.
Additional Content
Literature
The sources and excerpts collected here go in-depth on much of what has been described in this article on the topic of the measurement problems and low progesterone levels with oral progesterone.
In August 2025, a conference abstract of a randomized controlled trial of oral progesterone and breast development in transfeminine people was published (Dreijerink et al., 2025). This study had been preregistered and its protocol had been previously published in 2023 (Dijkman et al., 2023). The trial found that oral micronized progesterone (Utrogestan) at doses of 200 to 400 mg/day, in conjunction with estradiol therapy and especially with higher estradiol levels in the range of 400 to 800 pmol/L (109–218 pg/mL), could significantly increase breast volume in transfeminine people. The study is discussed in greater detail elsewhere on this site (Aly, 2020). Based on the trial’s findings, although oral progesterone can only achieve low progesterone levels measured with mass spectrometry, it appears that these low levels are nonetheless able to produce significant effects on the breasts. Hence, while oral progesterone may still prove to be less efficacious than non-oral progesterone or progestins, it would appear that it is not absent of value in terms of potential therapeutic effects in transfeminine people.
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-A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People - Transfeminine Science
A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People
By Aly | First published February 14, 2020 | Last modified June 28, 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 bioidenticalprogesterone, 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
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.
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 prospectiveobservational 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 (ANZCTR; WHO ICTRP; Trans Health Research [Flyer] [Poster]; University of Melbourne) (update: see below); 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 ovulatorymenstrual 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.
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 postpartumlactation and breastfeeding.
Table 1: Changes in hormone levels (estradiol, progesterone, and prolactin) during normal pregnancy:
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).
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.
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 a highly underdeveloped male, with testes instead of ovaries, no uterus, fallopian tubes, or cervix, and no prostate gland or seminal vesicles. The testes are internally located, either intra-abdominally, inguinally, or labially. They are usually surgically removed by early adulthood, as they otherwise have a high risk of developing testicular cancer because of their location. The vagina in CAIS women is often short and is blind-ending, which is related to their lack of a uterus. In terms of behavior, gender, and sexuality, CAIS women are described as feminine.
Despite claims that CAIS women have generous breast sizes however, in actuality, some CAIS women have large breasts, while some have small breasts. One study found a wide range of breast size measurements of 16×14 cm to 41×31 cm, which equates to an almost 6-fold variation in breast size as quantified by area (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). Interestingly, it has been claimed anecdotally by some researchers that breast development is much better in CAIS women who are allowed to naturally undergo puberty with their own endogenous hormones compared to CAIS women who undergo gonadectomy before puberty and have pubertal maturation induced with exogenous estrogen therapy (Dewhurst, 1972; Glenn, 1976; Dewhurst, 1981; Reindollar & McDonough, 1985; Shearman, 1985; Laufer, Goldstein, & Hendren, 2005). This is to the extent that some CAIS women who have had induced puberty have needed to undergo surgical breast augmentation due to poorly developed breasts (Dewhurst, 1981; Shearman, 1985). In relation to the preceding, it is usually standard clinical practice to delay gonadectomy in CAIS women until puberty has fully completed (Laufer, Goldstein, & Hendren, 2005). However, one clinical study reported good breast development rated as Tanner stage 5 in all cases in CAIS women who experienced either spontaneous or therapeutic puberty (Cheikhelard et al., 2008). It may be important to mimic normal pubertal estrogen exposure with puberty induction in CAIS females by employing low physiological estradiol levels that are slowly and gradually increased over a few years (Dewhurst, 1981; Cheikhelard et al., 2008; Bertelloni et al., 2011).
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 point 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 adult-like nipple and areolar maturation.
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 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 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 about 6-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
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).
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
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
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
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 was 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, was 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 estrogen-induced breast growth gradually slows and ceases in people who do not have menstrual cycles and luteal phases or progestogenic exposure just as it does in normal cisgender girls. Prominent examples of such individuals include CAIS women, transfeminine people, and cisgender men with prostate cancer treated with estrogen therapy.
Poor Breast Development in 17α-Hydroxylase/17,20-Lyase Deficiency
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 produces 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, benignbrain 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, are why there are concerns about and hesitations 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.
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.
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+A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People - Transfeminine Science
A Comprehensive Review of the Potential of Progestogens for Enhancing Breast Development in Transfeminine People
By Aly | First published February 14, 2020 | Last modified August 14, 2025
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 bioidenticalprogesterone, 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
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.
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 prospectiveobservational 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 (ANZCTR; WHO ICTRP; Trans Health Research [Flyer] [Poster]; University of Melbourne) (update: see below); 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) (update: see below). 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 ovulatorymenstrual 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.
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 postpartumlactation and breastfeeding.
Table 1: Changes in hormone levels (estradiol, progesterone, and prolactin) during normal pregnancy:
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).
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.
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 a highly underdeveloped male, with testes instead of ovaries, no uterus, fallopian tubes, or cervix, and no prostate gland or seminal vesicles. The testes are internally located, either intra-abdominally, inguinally, or labially. They are usually surgically removed by early adulthood, as they otherwise have a high risk of developing testicular cancer because of their location. The vagina in CAIS women is often short and is blind-ending, which is related to their lack of a uterus. In terms of behavior, gender, and sexuality, CAIS women are described as feminine.
Despite claims that CAIS women have generous breast sizes however, in actuality, some CAIS women have large breasts, while some have small breasts. One study found a wide range of breast size measurements of 16×14 cm to 41×31 cm, which equates to an almost 6-fold variation in breast size as quantified by area (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). Interestingly, it has been claimed anecdotally by some researchers that breast development is much better in CAIS women who are allowed to naturally undergo puberty with their own endogenous hormones compared to CAIS women who undergo gonadectomy before puberty and have pubertal maturation induced with exogenous estrogen therapy (Dewhurst, 1972; Glenn, 1976; Dewhurst, 1981; Reindollar & McDonough, 1985; Shearman, 1985; Laufer, Goldstein, & Hendren, 2005). This is to the extent that some CAIS women who have had induced puberty have needed to undergo surgical breast augmentation due to poorly developed breasts (Dewhurst, 1981; Shearman, 1985). In relation to the preceding, it is usually standard clinical practice to delay gonadectomy in CAIS women until puberty has fully completed (Laufer, Goldstein, & Hendren, 2005). However, one clinical study reported good breast development rated as Tanner stage 5 in all cases in CAIS women who experienced either spontaneous or therapeutic puberty (Cheikhelard et al., 2008). It may be important to mimic normal pubertal estrogen exposure with puberty induction in CAIS females by employing low physiological estradiol levels that are slowly and gradually increased over a few years (Dewhurst, 1981; Cheikhelard et al., 2008; Bertelloni et al., 2011).
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 point 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 adult-like nipple and areolar maturation.
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 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 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 about 6-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
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).
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
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
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
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 was 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, was 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 estrogen-induced breast growth gradually slows and ceases in people who do not have menstrual cycles and luteal phases or progestogenic exposure just as it does in normal cisgender girls. Prominent examples of such individuals include CAIS women, transfeminine people, and cisgender men with prostate cancer treated with estrogen therapy.
Poor Breast Development in 17α-Hydroxylase/17,20-Lyase Deficiency
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 produces 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, benignbrain 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, are why there are concerns about and hesitations 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.
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.
In 2023, a study protocol for a randomized controlled trial of oral progesterone and breast development in transfeminine people was published (Dijkman et al., 2023). The protocol was published by Benthe Dijkman and colleagues at the Vrije Universiteit University Medical Center (VUMC) in Amsterdam, the Netherlands. The trial would be the first prospective randomized controlled trial of progesterone and breast development in transfeminine people.
In this non-blinded non-placebo-controlled randomized trial, 90 transfeminine people would be randomized into 6 study arms with 15 people each. The transfeminine people would be individuals who had been on hormone therapy for at least one year and had undergone vaginoplasty or orchiectomy. Those who were currently or previously taking a progestogen, including CPA, would be excluded. The study’s treatment arms or groups would include the following:
Standard-dose estradiol alone (control group)
Double-dose estradiol alone
Standard-dose estradiol plus progesterone 200 mg/day
Double-dose estradiol plus progesterone 200 mg/day
Standard-dose estradiol plus progesterone 400 mg/day
Double-dose estradiol plus progesterone 400 mg/day
The estradiol therapy was specifically oral estradol valerate, oral estradiol hemihydrate, transdermal estradiol patches, transdermal estradiol gel, or transdermal estradiol spray, at doses resulting in estradiol levels of 200 to 400 pmol/L (54–109 pg/mL) in the standard-dose group and 400 to 800 pmol/L (109–218 pg/mL) in the double-dose group. The progesterone therapy was specifically oral micronized progesterone (Utrogestan). It was noted that in order to maximize adherence, progesterone would be prescribed for limited 1 to 3 month intervals, but no further details on this were provided.
The duration of the study would be 3 years and initial phase would be 12 months, with breast development and/or hormone levels measured at baseline, 3 months, 6 months, and 12 months of treatment. Estradiol levels would be measured with mass spectrometry, whereas progesterone levels would be measured with immunoassays. Breast development would be measured with 3D scanning (Artec Leo 3D) and breast–chest difference. Bra cup size would additionally be calculated from these measures. In the protocol, it was stated that an average breast volume increase of 30%, which was said to correspond to one bra cup size increase, would be considered a clinically relevant outcome. There would also be a number of secondary outcomes, including side effects/safety, satisfaction, mood, sleep, and sexual pleasure. It was noted that the study may serve as a pilot project for a larger future study of progesterone and breast development initiated at the start of hormone therapy prior to surgery.
In August 2025, an EPATH conference abstract with briefly described results of the study was published online in advance of the 6th EPATH conference to be held in September 2025 (Dreijerink et al., 2025):
Dreijerink, K., den Heijer, M., Geels, R. (2025). Increased breast volume due to addition of progesterone and increasing the estradiol dose in feminizing gender-affirming hormone therapy. EPATH 6th Conference, September 4–6, 2025 in Hamburg Germany. [PDF]
It was reported that mean breast volume, relative to standard-dose estradiol alone, changed as follows:
Treatment group
n
Breast volume change
E2 double-dose alone
15
+6% (95% CI, –13 to 24)
E2 standard-dose plus P4 200 mg/day
15
+13% (95% CI, –7 to 33)
E2 double-dose plus P4 200 mg/day
15
+37% (95% CI, 18 to 57)
E2 standard-dose plus P4 400 mg/day
15
+20% (95% CI, 0 to 40)
E2 double-dose plus P4 400 mg/day
15
+27% (95% CI, 8 to 47)
The authors concluded that progesterone and higher estradiol dose increased breast volume in transfeminine people. The results of significance tests for breast volume between individual treatment groups or relative to controls were not provided in the abstract. Subjective satisfaction with breast growth and size was said to be improved in all treatment groups relative to the control group (p < 0.05). Aside from breast size changes, side effects with oral progesterone included tiredness (44%), breast/nipple tenderness (27%), and mood changes (22%). There were no treatment-related serious adverse events. No other results or data were provided in the abstract. The full results of the this trial by Dreijerink and colleagues will be published in a journal article at some point in the future. It was concluded that oral progesterone was safe but did cause some side effects. Moreover, the study concluded that their results supported a future role of progesterone in transfeminine hormone therapy. However, it was noted that the long-term effects of progesterone in transfeminine people still need to be studied.
The findings of Dreijerink and colleagues are the highest-quality data on progesterone and breast changes in transfeminine people that are currently available. Their findings suggest that addition of oral progesterone to estradiol increases breast volume and that higher-dose estradiol levels synergize with progesterone to increase breast volume. There was a 13 to 37% increase in volume with oral progesterone depending on the estradiol and progesterone doses. It is important to note however that, as extensively reviewed in the present article, higher estradiol levels and progesterone are associated with increased breast volume due to effects like increased local fluid retention, increased blood flow, and/or temporary growth, but these effects are reversible and regress following withdrawal of the hormonal exposure. Unfortunately, Dreijerink and colleagues do not appear to have included a discontinuation phase to assess whether the breast volume increases observed in the trial were reversible or not. As such, while higher-dose estradiol and oral progesterone can significantly increase breast volume during treatment in transfeminine people, it is still not possible to draw conclusions about whether these interventions actually improve breast development—that is, lasting/permanent breast growth. Only future research that includes discontinuation phases will be able to answer this question.
Other limitations of Dreijerink and colleagues’ study include the use of oral progesterone, the employment of immunoassays to measure progesterone levels, the relatively small sample sizes of the individual treatment subgroups in the study and consequent risk of statistical error, and the patient population being transfeminine people who were post-vaginoplasty or -orchiectomy and hence had already been on hormone therapy for a long period of time (at least 1 year but likely longer on average, such as 2 or 3 years). Oral progesterone is known to achieve relatively low progesterone levels and may be inferior in general effectiveness to non-oral progesterone and progestins (Aly, 2019). Immunoassays are known to substantially overestimate and hence provide a misleading idea of progesterone levels, whereas mass spectrometry-based assays provide accurate progesterone levels (Aly, 2019). Individuals who have been on hormone therapy for many years may have near- or fully-complete breast development and hence less potential for enhancement of true breast development. In any case, caveats aside, Dreijerink and colleagues are relatively high-quality data, and demonstrate with decent confidence that oral progesterone can, at least exposure-dependently and in conjunction with sufficiently high estradiol levels, provide an increase in breast volume in transfeminine people.
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-A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People - Transfeminine Science
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.
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 subjects
Findings
Source(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.
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).
100 or 400 mg/day spironolactone for 8 weeks in 7 orchiectomized men (46–78 years) with metastatic prostate cancer
T, 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.
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.
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 hypertension
P4 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.
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.
200–400 mg/day (mean 330 mg/day) for 20–27 days in 5 gonadally intact men (50–76 years) with prostate cancer
P4 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.
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.
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.
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.
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.
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.
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.
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).
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 function
Significantly 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.
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 subjects
Findings
Source(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.
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 subjects
Findings
Source(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.
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.
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).
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.
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.
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.
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.
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%).
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.
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.
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).
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 200 mg/day relative to a dosage of 100 mg/day (30% ± 3% and 19% ± 8% (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.
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+A Review of Studies on Spironolactone and Testosterone Suppression in Cisgender Men, Cisgender Women, and Transfeminine People - Transfeminine Science
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 August 14, 2025
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.
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 subjects
Findings
Source(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.
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).
100 or 400 mg/day spironolactone for 8 weeks in 7 orchiectomized men (46–78 years) with metastatic prostate cancer
T, 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.
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.
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 hypertension
P4 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.
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.
200–400 mg/day (mean 330 mg/day) for 20–27 days in 5 gonadally intact men (50–76 years) with prostate cancer
P4 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.
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.
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.
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.
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.
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.
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.
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).
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 function
Significantly 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.
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 subjects
Findings
Source(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.
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 subjects
Findings
Source(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.
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.
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).
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.
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.
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.
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.
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%).
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.
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.
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).
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 200 mg/day relative to a dosage of 100 mg/day (30% ± 3% and 19% ± 8% (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.
Update 3: Bonadonna et al. (2025)
In August 2025, the following conference abstract was published online:
Bonadonna, S., Amer, M., Foletti, F., Federici, S., Persani, L., Bonomi, M. (2025). Evaluation of Antiandrogen Therapy Effectiveness in Transgender individuals Assigned Male At Birth (AMAB). EPATH 6th Conference, September 4–6, 2025 in Hamburg Germany. [PDF]
It was an abstract for a retrospective observational study of spironolactone versus CPA, presumably in combination with estrogen, in 149 transfeminine people. The study found that testosterone and gonadotropin levels were significantly higher with spironolactone than with CPA. In addition, it found that spironolactone was associated with less suppression of libido and spontaneous erections than CPA. Conversely, there was no difference in waist–hip ratio between the groups. The authors concluded that spironolactone appears to be less effective than CPA as an antiandrogen in transfeminine people. The full study may be published in a journal article at some point in the future.
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-WPATH Symposia Materials - Transfeminine Science
Note: WPATH was renamed from the Harry Benjamin International Gender Dysphoria Association (HBIGDA) to the World Professional Association for Transgender Health (WPATH) in 2007.
Note: WPATH was renamed from the Harry Benjamin International Gender Dysphoria Association (HBIGDA) to the World Professional Association for Transgender Health (WPATH) in 2007.
a ANZPATH (Australian and New Zealand Professional Association for Transgender Health) was formed in 2009 at the 21st WPATH conference in Oslo, Norway. ANZPATH split into AusPATH and PATHA or ANZPATH was renamed to AusPATH in 2019. b Conference was postponed from August 2021 to May 2022 due to COVID-19 pandemic. c AusPATH and PATHA joint conference.
