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

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

Abstract / TL;DR

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

Introduction

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

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

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

Progestogen Therapy and Breast Development in Humans

Progestogens and Breast Development in Transfeminine People

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Future Studies Currently Underway

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

Progestogens and Breast Development in Cisgender Females

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

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

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

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

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

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

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

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

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

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

Progesterone and its Physiological Role in Breast Development in Humans

Progesterone and Breast Development in Puberty

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

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

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

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

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

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

Progesterone and Breast Development in Pregnancy

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

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

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

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

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

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

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

Breast Composition and Lobuloalveolar Tissue Proportion

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Menstrual Cycles and Temporary Cyclic Breast Enlargement

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

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

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

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

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

Progesterone and Mammary Development in Animals

Progesterone and Pubertal Mammary Development in Animals

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

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

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

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

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

Progesterone and Gestational Mammary Development in Animals

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

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

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

Breast Changes with Therapeutic Pseudopregnancy

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

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

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

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

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

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

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

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

Early Progestogen Exposure and the Possibility of Suboptimal Breast Development

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

Antiestrogenic Effects of Progestogens in the Breasts

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

Stunted Mammary Growth with Progestogens in Animal Studies

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

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

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

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

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

Progestogens in the Treatment of Breast Hypertrophy

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

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

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

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

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

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

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

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

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

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

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

Additional Considerations for Progestogen Therapy and Breast Development in Transfeminine People

Anecdotes About Progestogens and Breast Development

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

Therapeutic Limitations of Oral Progesterone

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

Tolerability and Safety Considerations for Progestogens

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

Updates

Update 1: Angus et al. (2023–2024)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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