Considerations in Understanding the Possible Role and Influence of Progestogens in Terms of Breast Development
By Aly | First published February 14, 2020 | Last modified May 15, 2023
Studies of Progestogen Therapy and Breast Development in Transfeminine People
As of writing, only a handful of studies have specifically assessed breast development with progestogens—either bioidentical progesterone or a progestin (synthetic progestogen) like medroxyprogesterone acetate (MPA) or cyproterone acetate (CPA)—in transfeminine people. The subject of progestogen therapy and breast development in transfeminine people has also been partly reviewed in papers like Wierckx, Gooren, & T’Sjoen (2014) and Reisman, Goldstein, & Safer (2019).
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” (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 here and elsewhere (Aly, 2019).
Dittrich et al. (2005) reported that the combination of oral estradiol valerate and a gonadotropin-releasing hormone (GnRH) agonist for 2 years 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% in transfeminine people. They noted however that 70% were unsatisfied with their breast development and wished to undergo breast augmentation. 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. It should be cautioned however that this study did not actually employ or study progestogens 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 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.
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, 2018). As such, progestogenic exposure in this study, and notably also in Igo & Visram (2021), 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 methodological limitations. In any case, this study is of noticeably higher quality than previous studies, and is notably likely to continue and report further follow-up at later points in the future.
Aside from the above studies, a variety of other studies have also reported breast development with estrogen and CPA in transfeminine people, often with objective physical measurements (e.g., breast volume, breast–chest difference, breast cup size, breast hemicircumference), but have lacked comparison groups and so have not been discussed in the present section. These studies are instead briefly discussed elsewhere (see the section below). In any case, to briefly summarize the findings, breast development in transfeminine people has unfortunately usually been poor in these studies.
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), short treatment durations, and small sample sizes, among others. This is likely to explain the conflicting results of the studies. More research is still needed to assess the influence of progestogens on breast development in transfeminine people. A 2014 review on hormone therapy in transfeminine people summarize the state of research on progestogens and breast development in transfeminine people (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.
Fortunately, several studies of progesterone and other progestogens in transfeminine people are currently underway. These studies include (1) a randomized controlled trial of oral progesterone added to hormone therapy by Dr. Sandeep Dhindsa and colleagues in St. Louis, Missouri in the United States (ClinicalTrials.gov; MediFind; ICH GCP); (2) prospective observational studies and a randomized controlled trial of addition of oral progesterone to hormone therapy by Ada Cheung and colleagues in Melbourne, Australia (University of Melbourne; University of Melbourne; University of Melbourne); (3) a randomized controlled trial of estradiol plus spironolactone versus estradiol plus CPA by Ada Cheung and colleagues in Melbourne, Australia (ANZCTR; WHO ICTRP; Trans Health Research [Flyer] [Poster]; University of Melbourne); and (4) a large randomized controlled trial 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 (General Info/Links; Info Sheet Dutch; Info Sheet English Translated). Unfortunately however, all of the studies of progesterone employ oral progesterone, which has major bioavailability and potency problems (Aly, 2018). In any case, it was said that the VUMC researchers may follow their trial up with studies of other progesterone routes (General Info/Links).
Progesterone and its Role in Breast Development During Normal Female 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 takes an average of 3 to 4 years, though with a possible range of about 2 to 6 years in most cases. Progesterone essentially doesn’t appear during puberty until ovulatory menstrual cycles begin. Menarche, the onset of menstruation and hence menstrual cycling, occurs on average at Tanner breast stage 4, although it occurs at Tanner breast stage 3 or Tanner breast stage 5 (complete breast development) in significant subsets of girls (Marshall & Tanner, 1969; Marshall, 1978; Hillard, 2007). Hence, a significant portion of girls reach Tanner breast stage 5 (complete breast development) before experiencing menarche or any progesterone production. This indicates that progesterone is not essential to reach Tanner breast stage 5, at least for a subset of girls. Tanner breast stage 4 is on average about 2.5 years into breast development, while breast development as a whole takes on average about 3.5 years. As such, the appearance of progesterone in normal female puberty is a relatively late event (Marshall, 1978; Begley, Firth, & Hoult, 1980; Drife, 1986).
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 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). A handful of studies provide progesterone levels during puberty across Tanner stages or by age, and show how limited progesterone exposure is during this time (e.g., Sizonenko, 1978 [Graph]; Lee, 2001 [Table]; Aly, 2020).
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.
Progesterone and Mammary Development in Animals
Pubertal Mammary Development
Knockout of the progesterone receptor in female rice results in complete infertility and severely compromised ovarian, uterine, and reproductive–behavioral functions (Lydon et al., 1995; Ismail et al., 2003). Conversely however, pubertal ductal mammary development in progesterone receptor knockout mice is normal and in fact morphologically indistinguishable from that of regular mice (Ismail et al., 2003). This is in contrast to the case of estrogen receptor alpha knockout mice, in which pubertal mammary development is abolished (Ismail et al., 2003; Wiki; Wiki). However, subsequent studies revealed that mammary ductal development during puberty is in fact delayed though eventually normal in female mice that have loss of progesterone production, loss of the progesterone receptor, or progesterone receptor antagonism (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). However, as mammary ductal development during puberty without progesterone is delayed but eventually completely normal, it has been stated that progesterone is dispensable for pubertal mammary gland development in mice (Ismail et al., 2003).
Breast Composition and Lobuloalveolar Content
Progestogens are involved primarily in lobuloalveolar development of the breasts. This type of breast development is necessary for lactation and breastfeeding and occurs mainly during pregnancy. The breasts are made up of two main types of tissue: (1) epithelial tissue (the actual 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. In women who are not pregnant or lactating, only about 5 to 20% of the volume of the breasts on average is composed of epithelial tissue, while the remaining 80 to 95% is composed of stromal tissue (Hutson, Cowen, & Bird, 1985; Drife, 1986; 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). More specifically, one study found that about 10 to 20% is epithelial tissue, about 10 to 35% is fat tissue, and about 60 to 80% is connective tissue in reproductive-age women (Hutson, Cowen, & Bird, 1985; Wilson et al., 2006). Similarly, in women with macromastia (breast hypertrophy), only a small proportion of the breasts is glandular tissue (e.g., 1–7%) (Bames, 1948; Cruz-Korchin et al., 2001). During pregnancy and lactation however, 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). In any case, under more normal physiological circumstances and progesterone exposure, the contribution of lobuloalveolar tissue to the size of the breasts is quite small. In relation to this, the significance of progestogen-mediated breast lobuloalveolar growth in terms of breast size is unclear but seemingly questionable (Wierkcx, Gooren, & T’Sjoen, 2014).
Complete Androgen Insensitivity Syndrome, Progesterone, and Breast Development
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 at this time (e.g., Prior, 2011; Prior, 2019a; Prior, 2020). It has also 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 development 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 it is needed to reach Tanner stage 5, or that it helps to round out the breasts. Moreover, such claims are contradicted by significant available literature and evidence, including notably 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 which makes them completely insensitive to the effects of androgens. CAIS women have a male-typical hormonal profile, generated by their testes, including high male-range levels of testosterone, low female-range but nonetheless significant estradiol levels, and no significant progesterone production with very low progesterone levels. 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 feminize them. The internal reproductive system in CAIS women is essentially that of an underdeveloped male, with testes instead of ovaries, and no uterus or fallopian tubes. The vagina is often short and is blind-ending with no cervix, which is related to the lack of a uterus.
Women with CAIS have breast development that is described throughout the literature as “good”, “excellent”, “normal”, “full”, “complete”, “well-developed”, “generous”, “typically above-average”, “large”, and even “voluptuous” (Morris, 1953; Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971; 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, 2017). The gynecologist, John McLean Morris, who reviewed and summarized all of the existing scientific literature on CAIS women in 1953 (including 82 cases) and gave their condition the since-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). In actuality however, some CAIS women have large breasts, while some have small breasts (Wisniewski et al., 2000), and we have no clear data that their breasts are actually larger on average. The variation in breast growth in CAIS women parallels the same large variation in breast size between individuals that is seen in natal 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 excellent, although subject to considerable variation between individuals in terms of breast size and shape as in women in general.
CAIS women have never been described as having “cone-shaped”, “pointy”, or otherwise abnormal breasts. The only exception is that they are often said to have “juvenile”—or relatively “small” and “pale”—areolas/nipples (e.g., Photo) (e.g., Morris, 1953; Morris & Mahesh, 1963; Khoo & Mackay, 1972; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; many others). This is probably because estradiol levels in CAIS women are only about 35 pg/mL on average (Table). This is relevant as estrogens dose-dependently induce nipple and areolar enlargement and pigmentation (Davis et al., 1945; Kennedy & Nathanson, 1953). Hence, higher estrogen levels may be necessary for full adult-like nipple and areolar maturation.
CAIS women also don’t have only Tanner stage 4 breast development. They reach full Tanner stage 5 breast development similarly to normal women (Quigley, 1988; Quigley et al., 1995; Fortner, 2007; Cheikhelard et al., 2008; Ramos et al., 2018). An excerpt on this matter (Quigley et al., 1995):
Individuals with complete [androgen insensitivity syndrome (AIS)] have excellent feminization at puberty, with normal or augmented breast development, and clear, smooth, acne-free complexions. Feminization of the breasts and body contours occurs in response to estrogen (produced mainly by testicular and, to a lesser extent, peripheral aromatization of androgens) that is unopposed by the effects of androgens. […] Breast development, ranging from mild gynecomastia to abundant Tanner stage V female breasts, can occur with all grades of AIS, tending to be more pronounced with the more severe grades.
By “more severe grades”, they mean CAIS, the complete form of the syndrome, as opposed to the incomplete forms of androgen insensitivity syndrome (AIS), including the partial and mild presentations (Quigley, 1988). The condition is a spectrum, and those with CAIS, the most “severe” grade, are the only ones who are completely insensitive to the androgen receptor-mediated actions of androgens and who have a fully feminized body. Even individuals with partial androgen insensitivity syndrome (PAIS) likewise have substantial breast development however (e.g., Saito et al., 2014; Lee et al., 2015).
As already touched on, CAIS women are notable because they have very low and negligible levels of progesterone (<2 ng/mL) due to their testes and lack of progesterone production (Table; Barbieri, 2017). CAIS women, perhaps more convincingly than any other evidence available at this time, suggest that progesterone is not needed for normal and complete breast development (Barbieri, 2017):
A genetic experiment of nature, androgen insensitivity syndrome, provides a clinical example of the important interplay between estrogens and androgens in the regulation of breast growth.38 In androgen insensitivity due to mutations in the androgen receptor (AR), genetic males (46,XY) do not have a fully functional AR. Testosterone is produced by the testis, but target tissues are not capable of responding to the high levels of circulating androgens. In this syndrome, circulating estradiol concentration is in the range of 50 pg/mL, comparable to early follicular-phase levels observed in women. Breast volume in individuals with androgen insensitivity is typically above average. This suggests that, in the complete absence of androgen inhibition, modest levels of estradiol are capable of stimulating significant breast growth. Progesterone levels are low in individuals with loss of the AR. This suggests that breast volume is not absolutely dependent on progesterone stimulation.
Despite their often large breasts, CAIS women are said to have relatively little breast glandular tissue (as opposed to fat and connective tissue) and minimal lobuloalveolar development (Morris, 1953; Morris & Mahesh, 1963; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982). This is potentially in accordance with their lack of progesterone, as progesterone is involved in lobuloalveolar maturation. It is notable that in women in general, the breasts are mostly composed of stromal fat and connective tissue (~80–90%), rather than glandular tissue (10–20%) (Wiki). Additionally, when lobuloalveolar development occurs, for instance during pregnancy, it replaces stromal tissue (Alex, Bhandary, & McGuire, 2020). Hence, greater glandular or lobuloalveolar formation in the breasts may not necessarily translate to greater breast size, as seems apparent in CAIS women. Also in spite of their well-developed breasts, breast cancer has never been reported in CAIS women (Aly, 2020a; Aly, 2020b). This may be related to factors like their lack of progesterone and lobuloalveolar maturation and/or their absence of a second X chromosome (Aly, 2020a; Aly, 2020b).
Early Progestogen Exposure and the Possibility of Suboptimal Breast Development
There have been suggestions in the literature that early or premature exposure to progestogens may result in suboptimal breast development. Animal studies using progestogens including progesterone and chlormadinone acetate (a progestin closely related to CPA) found that this was the case for mammary gland development in rabbits with high doses of these progestogens, though notably not with lower doses (Lyons & McGinty, 1941; Beyer, Cruz, & Martinez-Manautou, 1970). Besides animal studies, a number of clinical publications have warned that early or premature exposure to progestogens might result in suboptimal breast development in cisgender girls and 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, a progestogen is not added to estrogen therapy during puberty induction in girls with delayed puberty until after about 2 to 3 years of treatment, when breast development is generally considered complete.
However, species differences in mammary gland development and hormonal responses exist, and no hard data or evidence has been published to substantiate the claims of the clinical publications. As such, it is unknown whether suboptimal breast development could occur with early progestogen exposure in humans. Moreover, if it does occur in humans, it is unknown what level of progestogen exposure would be required to produce it. In any case, a few other areas of research interest are also relevant to the issue of progestogens possibly resulting in worse breast development, including the antiestrogenic effects of progestogens in the breasts, clinical studies of breast development with estrogen and CPA (a very strong progestogen) in transfeminine people, case reports of progestogens for treatment of macromastia in cisgender females, and theoretical suggestions of poor breast development in cisgender girls with 17α-hydroxylase/17,20-lyase deficiency being related to high progesterone exposure. These topics will 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, 1986; 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 (Malet et al., 1991; Kuttenn et al., 1994; Wren & Eden, 1996; 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). The antiestrogenic effects of progestogens in the breasts provide a plausible potential mechanism by which they might limit estrogen-mediated breast development.
Breast Development with Cyproterone Acetate in Transfeminine People
The possibility of suboptimal breast development with progestogens is of particular relevance to CPA. This is because CPA is a potent progestogen in addition to antiandrogen and is used in transfeminine people at doses that result in very strong progestogenic exposure (Aly, 2019). Studies using estrogen plus CPA in transfeminine people have generally reported poor breast development (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; de Blok et al., 2020; Meyer et al., 2020). However, transfeminine people could simply have poor breast development in general without this necessarily being related to CPA or progestogen exposure. Indeed, a study in transfeminine people who underwent pubertal suppression in adolescence presumably with GnRH agonists and then hormone therapy showed similarly poor breast development as in adults (Boogers et al., 2022). A randomized controlled trial of estradiol plus spironolactone versus estradiol plus CPA assessing breast development in transfeminine people is underway in Australia and may provide more insight on this issue (ANZCTR).
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; 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 and MPA were employed 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, it is difficult to draw reliable conclusions from these reports.
Poor Breast Development in 17α-Hydroxylase/17,20-Lyase Deficiency
Poor breast development with estrogen therapy has been reported in girls with 17α-hydroxylase/17,20-lyase deficiency, and prior exposure to high progesterone levels secondary 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 a theory, and at this time, there is no causal evidence that progesterone specifically is responsible.
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