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Discussion on Women with Complete Androgen Insensitivity Syndrome, Breast Development, and Progesterone

By Aly W. | First published March 30, 2020 | Last modified October 23, 2020

The contents of this page are reproduced from Reddit discussion located here.

Progesterone doesn’t really give any breast development it more just takes you from tanner stage 4 to 5 (rounds them out). Almost all brands and generic bio progesterone are suppositories even if they don’t say it on the box, just make sure they are a gel type capsule (looks like an egg), a good dose is about 100-200mg once a night (just before bed as it makes you tired).

Responding to this and to other comments (Reddit)…

Progesterone doesn’t really give any breast development it more just takes you from tanner stage 4 to 5 (rounds them out).

Yes but [breast development in CAIS women is] only around 50% same as trans women it’s possible [for CAIS women to have round breasts] but doesn’t always happen, most have cone shaped [breasts].

So you understand that this says [CAIS women] are stuck at tanner stage 3 that’s why they don’t go cone shaped unlike trans women who take a higher dose of estradiol (cais have very little estrogen in general and even less estradiol causing them to be larger and stuck at tanner3).

There is no evidence that progesterone is required for normal pubertal breast development or for reaching Tanner stage 5. Nor that it helps to round out breasts.

Progesterone has been shown to be dispensable for pubertal mammary gland development in rodents (Ismail et al., 2003):

As a way of directly delineating progesterone’s involvement in general reproductive endocrinology and in mammary gland development in particular, a progesterone receptor knockout (PRKO) mouse was generated in which both isoforms of the PR were functionally ablated through gene targeting approaches [37]. As expected, abrogation of the progesterone signal resulted in an overt female infertility phenotype in which normal ovarian-, uterine-, and behavioral-functions were severely compromised.

Despite the above reproductive phenotypes, the PRKO mammary epithelium responded to the pubertal rise in serum levels of estrogen to generate a ductal architecture that was morphologically indistinguishable from that of the wild type (WT) virgin [37]. The normal development of the PRKO pubertal gland contrasted with the ER-α knockout (ERKO) gland in which the absence of the ER-α resulted in a defect in mammary ductal outgrowth at puberty [38]. In sum, the comparative analysis of the PRKO and ERKO mammary glands underscored the unique importance of ovarian estrogen, rather than progesterone, in the early postnatal stages of mammary gland development.

In other words, researchers knocked out progesterone’s biological targets, the progesterone receptors, in mice, and pubertal mammary gland development outcome in these mice was indistinguishable from that of regular mice. Progesterone is very important for maturation of the milk lobules of the breasts during pregnancy (when progesterone levels are as much as 20-fold higher than luteal-phase levels in adult women). But not for pubertal breast growth, at least per animals.

In humans, the appearance of progesterone in puberty is a relatively late event (Marshall, 1978; Begley, Firth, & Hoult, 1980). And progesterone exposure even during puberty is modest compared to adulthood. The onset of menstruation, which is when progesterone production first starts, occurs on average in Tanner stage 4 (Marshall & Tanner, 1969). But it takes a while for the menstrual cycle to mature, and because of this, progesterone production is sporadic and low initially. This is the case not only by the time of Tanner stage 5 but for many years after it as well. Moreover, about 10% of girls reach Tanner stage 5 before experiencing menarche and hence before any progesterone exposure (Marshall, 1978; Hillard, 2007). This demonstrates that progesterone is not a requisite to reach Tanner stage 5.

Women with complete androgen insensitivity syndrome (CAIS) have breast development that’s described as “excellent”, “normal”, “full”, “complete”, “well-developed”, “generous”, “typically above-average”, and “voluptuous” (Morris, 1953; Roy Hertz et al., 1966; Valentine, 1969; Adams et al., 1970; Polani, 1970; Weisberg, Malkasian, & Pratt, 1970; Dewhurst, 1971; Glenn, 1976; Patterson, McPhaul, & Hughes, 1994; Quigley et al., 1995; McPhaul, 2002; Galani et al., 2008; Oakes et al., 2008; Tiefenbacher & Daxenbichler, 2008; Barbieri, 2017). 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-obsolete) 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’s seen in women in general. Here is a collection of photos of CAIS women and their breast development from published case reports throughout the literature.

Breast development in transfeminine people tends to be suboptimal (Wierckx, Gooren, & T’Sjoen, 2014; de Blok et al., 2018; Reisman, Goldstein, & Safer, 2019), while as can be seen from the photos just linked, breast development is excellent in CAIS women. Only the most lucky transfeminine individuals with the best circumstances and outcomes have breast development that’s on par with that of the average CAIS woman.

CAIS women have never been described as having “cone-shaped”, “pointy”, or otherwise abnormal breasts. The only exception is that they’re sometimes said to have “juvenile”—or relatively “small” and “pale”—areolas/nipples (Photo). This is probably because their estradiol levels are only about 35 pg/mL on average (Table), which is relevant as estrogens dose-dependently induce areolar/nipple enlargement/pigmentation (Davis et al., 1945; Kennedy & Nathanson, 1953). Hence, higher estrogen levels may be necessary for full adult-like areolar/nipple maturation.

CAIS women also do not have only Tanner stage 3 breast development. They reach full Tanner stage 5 breast development similarly to regular women (Quigley, 1988; Quigley et al., 1995; Fortner, 2007; Cheikhelard et al., 2008; Ramos et al., 2018). An excerpt (Quigley et al., 1995):

Individuals with complete 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 as opposed to the incomplete forms of androgen insensitivity syndrome 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 physical constitution. Even individuals with partial androgen insensitivity syndrome have substantial breast development though (e.g., Lee et al., 2015; Saito et al., 2014).

CAIS women are notable because they have very low and negligible levels of progesterone, just like males (Wiki-Table; Barbieri, 2017). CAIS women demonstrate, once again, and perhaps more convincingly than anything else, that progesterone is not needed for normal and complete pubertal 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 have relatively little breast glandular tissue (as opposed to fat and connective tissue) and minimal lobuloalveolar development, which is in accordance with their lack of progesterone (Morris, 1953; Simmer, Pion, & Dignam, 1965; McMillan, 1966; Perez-Palacios & Jaffe, 1972; Dewhurst & Spence, 1977; Shapiro, 1982).

Studies, although quite limited, have so far found no better breast development with progestins—progesterone receptor agonists just like progesterone—than without them (Wierckx, Gooren, & T’Sjoen, 2014; Reisman, Goldstein, & Safer, 2019). In fact, studies that have used cyproterone acetate have tended to have poor breast growth outcomes relative to studies using other antiandrogens. It’s possible that premature introduction of progestogens may actually interfere with normal breast development (Kay C. & Aly W., 2019), which is notable in that cyproterone acetate is a very strong progestogen at typical doses.

Of course, progesterone itself has never been studied for breast development in either transfeminine people or cisgender girls, only a couple of progestins have. And people argue that since progesterone is bioidentical and progestins aren’t, maybe it’s different. However, both progesterone and progestins are progesterone receptor agonists, and there is no real valid justification that they would be different for breast development.

We have no direct clinical data for or against progesterone for breast development at this time due to a lack of studies. So it’s true, we don’t know whether it’s helpful or neutral—or harmful—when it comes to breast development. But what we do know currently via theory and extrapolation from other situations (e.g., animal research, normal female puberty, CAIS women, progestins) indicates that progesterone is not a promising therapeutic modality for breast development in transfeminine people. Other discussion on the role of progesterone in breast development can also be found elsewhere (Aly W., 2020; Wiki; Aly W., 2018; Aly W., 2019).

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