TL;DR: AMAB people such as cisgender men and transgender women are exposed to high levels of testosterone in utero due to their testes. In rodents, prenatal testosterone exposure irreversibly masculinizes not only the genitals and brain but also the mammary glands, stunting their growth and limiting their developmental potential in response to estrogens later in life. It is unknown if this also occurs to any degree in humans. However, there is some clinical support for the notion that it may occur in us as well. Moreover, transgender women appear to generally show relatively poor breast development (link), and this phenomenon could, unfortunately, explain this. Alternatively, the phenomenon may not occur in humans, and other factors (e.g., hormonal regimens) might instead be responsible for the apparently relatively limited breast development in transgender women. More clinical research is needed to determine whether or not this phenomenon indeed occurs in humans or not.
Overview and animal findings
Male mice have testes due to their XY chromosomes, whereas female mice have ovaries due to their XX chromosomes. While in utero, the testes produce high levels of testosterone, whereas the ovaries do not. These high levels of testosterone masculinize the brain and genitals during a critical window in prenatal development, resulting in male-typical structures in male mouse fetuses, whereas the absence of testosterone results in the brain and genitals being feminized in female mouse fetuses. In addition to the brain and genitals, prenatal sexual differentiation occurs in the mammary glands of mice. Testosterone prevents the genesis of the nipples in male mouse fetuses during a critical period of prenatal development. It is unclear if testosterone itself is responsible for this or if testosterone is 5α-reduced into dihydrotestosterone (DHT) in the mammary gland, similarly to in the external genitalia, and DHT is responsible for the inhibition of the development of the mammary gland; findings appear to be mixed. Postnatally, the nipples are absent in male mice and the mammary glands of male mice have diminished responses to estrogens and progestogens; they are only capable of partial, stunted development following exogenous administration of estrogens and progestogens compared to female mice. This appears to be because exposure to testosterone in utero, in addition to prenatal inhibition of mammary gland growth, permanently reduces the expression of the estrogen receptor and aromatase in the mammary glands, limiting their capacity to respond to estrogens and by extension progestogens.
Treatment of pregnant mice with an antiandrogen such as cyproterone acetate (an androgen receptor antagonist), cyanoketone (a 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor and hence testicular testosterone biosynthesis inhibitor), or 390 MSD (a 5α-reductase inhibitor and hence DHT biosynthesis inhibitor) during the critical window of mammary gland sexual differentiation results in feminization of the mammary glands of male mouse fetuses such that they are indistinguishable postnatally from those of female mice. Likewise, destruction of the testes of male mouse fetuses via targeted external X-ray irradiation prior to the critical window of mammary gland sexual differentiation results in the same observations. Conversely, treatment of pregnant mice with an androgen (androgen receptor agonist) such as testosterone, methyltestosterone, or DHT during the critical window of mammary gland sexual differentiation results in masculinization of the mammary glands of female mouse fetuses such that they are indistinguishable postnatally from those of male mice. One study reported that testosterone was more potent than DHT in this context. Besides their determination of gonadal type (i.e., testes in males and ovaries in females) and the consequent prenatal hormonal milieu (i.e., high testosterone in males and absence of testosterone in females), karyotype (i.e., XY chromosomes in males and XX chromosomes in females) has no role in the sexual differentiation of the mammary glands in mice.
Although we know that prenatal androgen exposure masculinizes the genitals and brain in both mice and humans, and masculinizes the mammary glands in mice, it is unknown if prenatal androgen exposure similarly masculinizes the mammary glands in humans. There are important species differences between mice and humans concerning prenatal sexual differentiation. As an example, aromatization of androgens into estrogens masculinizes the brain in male mouse fetuses, whereas this does not appear to occur in male human fetuses, in whom testosterone is thought to be solely responsible for brain masculinization. Another notable species differences between mice and humans is of course that male mice do not have nipples whereas male humans do have nipples. It has also been stated that whereas the mammary glands of newborn male mice are smaller and structurally dimorphic relative to those of newborn female mice, the mammary glands of male and female human newborns are morphologically indistinguishable. These findings suggest that the phenomenon may not occur in humans, or that it may occur to a lesser and/or characteristically differential extent. However, unlike the case of mice, which can very easily be studied experimentally, it is not clear if it has been systematically confirmed in male and female human newborns that the mammary glands are truly identical (e.g., in size, etc.). In addition, although the mammary glands of male and female human newborns might be morphologically indistinguishable on a macroscopic level, there may nonetheless be microscopic differences such as differences in cellular gene expression (e.g., of the estrogen receptor) and hormonal sensitivity, as in mice. Moreover, there is some clinical evidence to support the notion that prenatal androgen exposure may indeed be involved in mammary gland sexual differentiation in humans, which I will address in the next section.
In contrast to rodents, the prenatal effects of androgens and antiandrogens on the mammary glands of monkeys via administration to pregnant monkey dams unfortunately do not seem to have been studied.
Supporting clinical findings
Congenital adrenal hyperplasia (CAH) due to 3β-HSD2 deficiency is a rare intersex condition in which undervirilization of males occurs due to deficiency of testicular 3β-HSD and hence deficiency of testosterone during prenatal development. Conversely, testicular 3β-HSD and hence testosterone levels are relatively normal postnatally (likely due to compensation by the 3β-HSD1 isoform of the enzyme), so these individuals undergo normal spontaneous puberty. A portion of males with 3β-HSD2 deficiency (approximately 35 to 55%, based on two reviews) develop gynecomastia during puberty, with some of these cases being described as "marked". Moreover, this can occur in spite of testosterone and estradiol levels that are in the normal male ranges. It has been theorized that this may be due to insufficient exposure of the mammary glands to androgens prenatally such that the breasts are more sensitive to estrogens in puberty and adulthood, as with animal models. However, there is high clinical heterogeneity in the reported cases of CAH due to 3β-HSD2 deficiency, and steroid hormone levels in general are also abnormal in the condition. It is possible that the gynecomastia that occurs in the condition might alternatively be due to aromatization of excessive adrenal androgens.
It has been theorized that gynecomastia in general, in addition to an imbalance in the ratio of androgens to estrogens, may have insufficient prenatal androgen exposure and hence prenatal mammary gland sexual differentiation as an important contributing factor in many cases. In accordance, small clinical studies have reported increased estrogen receptor and aromatase content in the breasts of men with gynecomastia. On the other hand however, it is notable that it is very rare for the breasts of males with gynecomastia to approximate those of females, even with high-dose antiandrogen and/or estrogen therapy, and this may reflect prenatal androgen exposure such that the developmental potential of the breasts is fundamentally limited compared to that of females.
Aromatase excess syndrome (AEXS) is a rare intersex condition in which peripheral aromatase, the enzyme that converts androgens into estrogens, is extremely overactive. As a result of this, both males and females with the condition are hyperestrogenic. In addition, both males and females with AEXS develop premature female-type pubertal maturation at a young age, including gynecomastia in the boys (photo). This begins shortly following adrenarche (average age about 6 years), when the adrenal glands begin secreting weak androgens. These adrenal androgens are excessively aromatized and induce breast development. However, whereas about 50% of women with AEXS are said to have "breast hypertrophy" (excessively large breasts, although I don't think it's meant in the form of the rare disease), males with the condition seem to on average have relatively small (and certainly not hypertrophic) breasts compared to females, even if their gynecomastia is definitely marked (photos). That said, these males also do have higher testosterone levels than females with the condition. However, their testosterone is excessively aromatized, is relatively low, and notably doesn't start to be secreted until the age of normal male puberty (~12 years old). If the prenatal androgen exposure hypothesis is true for breast development in humans, it may explain the divergent breast observations in males and females with AEXS.
Complete androgen insensitivity syndrome (CAIS) is a rare intersex condition in which 46,XY individuals ("biological/genetic males") have a defective and completely non-functional androgen receptor. As a result, these individuals, who have testes due to their Y sex chromosome and produce high testosterone levels in utero, experience no masculinization during prenatal development and are born perfectly phenotypically female. They are highly feminine both physically and behaviorally (as well as female in terms of gender identity and androphilic in terms of sexuoromantic orientation), and as a result, are, appropriately, assigned female at birth. The testes never descend in CAIS women, remaining internal in the abdominal cavity. At puberty, the testes produce high levels of testosterone and result in a male hormonal profile, although of course without any masculinization due to the insensitivity of CAIS women to androgens. The testosterone is aromatized into estradiol, which results in elevated but still relatively low estradiol levels (about 50 pg/mL). Nonetheless, estradiol levels are only about 10 to 55 pg/mL during Tanner stages 1 to 4 in normal pubertal girls (source), so this is sufficient for feminization and breast development in CAIS women (photos, photo). Conversely, CAIS women, lacking ovaries, produce no progesterone of importance (<1 ng/mL) (source).
In spite of their relatively low levels of estradiol and absence of progesterone, CAIS women show complete breast development at puberty, and actually have breasts that are said to be large on average for women (source). One review amusingly described the breasts in CAIS women as "jumbo-sized" in fact (source90359-7/pdf)). In accordance with their lack of progesterone, CAIS women show no lobuloalveolar tissue in the breasts on histological examination, suggesting that progesterone and lobuloalveolar maturation are not importantly involved in external morphological breast development (source90359-7/pdf)). The only fundamental biological difference between men and CAIS women is the presence versus absence of a functional androgen receptor, and this illustrates the powerful role of androgens in opposing feminization and breast development. Moreover, the excellent and even above-average breast development in CAIS women is in marked contrast to the relatively small breasts in most cases of gynecomastia in males, gynecomastia due to AEXS in males, and notably gynecomastia due to high-dose androgen receptor antagonist monotherapy (e.g., with bicalutamide or enzalutamide) in men. The last is described as only mild-to-moderate in 90% of cases (for an idea of what mild-to-moderate gynecomastia is like, the photos here are considered to be examples of severe gynecomastia). The comparatively large breasts in adult CAIS women may be due to their absence of prenatal androgen-receptor signaling. However, other factors might also or alternatively be involved in the divergent breast findings, such as postnatal androgen-receptor signaling, age, and others.
5α-Reductase type 2 deficiency is a rare intersex condition in which the type 2 isoform of 5α-reductase is absent, partial DHT deficiency is present, and undervirilization of male fetuses occurs. This manifests specifically as partially feminized genitalia at birth and as minimal androgen-dependent body hair growth and scalp hair loss in adulthood. However, masculinization at puberty is otherwise normal. Gynecomastia is said not to occur in males with the condition, which suggests that 5α-reductase type 2 may not be involved in prenatal androgen exposure-mediated mammary gland sexual differentiation, assuming of course that it occurs in humans. The type 1 and 3 isoforms of 5α-reductase remain functional in males with the condition however. Moreover, testosterone may be responsible for mammary gland sexual differentiation due to prenatal androgen exposure rather than DHT, as described previously. Gynecomastia occurs at only low rates of about 1.2 to 3.5% in men treated with 5α-reductase inhibitors like finasteride and dutasteride (source).
An implication of the notion that prenatal androgen exposure inhibits later breast development in humans is that transgender men, even if they started hormones before puberty, may be at a higher risk of gynecomastia with testosterone therapy due to the minimal exposure of their mammary glands to androgens in utero. I am unaware of whether this is the case or of whether we have any data on the issue or not.
Conclusion and relevance for transgender women
Transgender women appear to generally have relatively poor breast development (link). It is possible that exposure of the mammary glands to high levels of androgens prenatally, resulting in lower levels of estrogen receptors in the mammary glands, diminished responsiveness to estrogens, and an ultimately compromised capacity for breast development later in life, is either responsible for or is one of multiple contributing factors to this. This, unfortunately, would likely be irreversible and something that nothing could be done about. However, although sexual differentiation of the mammary glands due to prenatal androgen exposure is known to be the case in mice, and although it is supported by some clinical findings in humans, it is not yet certain whether it is actually the case in humans as well. In addition, there are some data that can be regarded as support against it (e.g., the presence of nipples in male humans and the reportedly indistinguishable mammary glands in male and female newborns), and other factors (e.g., hormonal regimens) might instead be responsible for the relatively poor breast development in transgender women. In any case, prenatal androgen exposure as a limiting factor in our breast development is nonetheless very plausible, and one that could still prove to be true. More clinical research is needed to confirm or reject the notion that this phenomenon indeed also occurs in humans.
Relevant excerpts from the literature
The following is an extensive collection of excerpts from literature publications (ordered by date) that are relevant to this topic. They are intended to source and provide elaboration on my discussion above.
The Role of Androgens in Differentiation of the Mammary Gland In Male Mouse Fetuses (Elger & Neumann, 1966)
Abstract. In male fetuses of the mouse, mammary gland tissue is stimulated and frequently also the development of teats is observed under the influence of the androgen antagonist cyproterone acetate (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate). The continuity of the glandular process, normally lost in male fetuses because of a destruction of the epidermal sector, is maintained by cyproterone acetate. Inhibition of the endogenous androgens thus results in a female organogenesis of the mammary glands.
Introduction. Teats do not occur in normal male rats whereas they do develop in male rat fetuses under the influence of antiandrogens. Male mammary bud also showed greater glandularity under the influence of antiandrogens than is seen in normal male animals (1,2). Since the embryonic development of the mammary gland in the mouse is better known than that of any other animal species (3,4) we have extended our observations to the mouse. This is also appropriate because the glandular bud in the male mouse fetus is inhibited more markedly by fetal androgens than is the case in any other murine animal. Concentration of periglandular mesenchyma causes by 15th day of the embryonal development either the complete destruction of the glandular rudiments or their separation from the epidermis by the strangulation of the proximal sector (3).
Results. On day 14 of embryonic development, the rudiments (anlagen) of the mammary glands begin to show slight differences in controls of both sexes. The cells of the glandular rudiments are smaller in male fetuses than in the female controls and in the male fetuses of treated mothers. The cells are arranged irregularly and the outline of the surrounding mesenchyma is not clearly defined (Fig. 1). The mesenchyma which surrounds the glandular rudiments shows a more advanced development in male controls and in male fetuses from mothers which had been treated with cyproterone acetate. On the following day differences between normal male and normal female fetuses are even more pronounced. In the male fetuses from cyproterone acetate-treated mothers organogenesis follows the female pattern of development. The chromophilic mammary bud is well developed and distinct from surrounding mesenchyma. The primary sprout is connected with the epidermis through a sturdy chain of epidermal cells that stain poorly. The concentration of mesenchyma which in normal male fetuses leads to strangulation of the mammary bud, does not occur in male fetuses under the influence of cyproterone acetate (Fig. 2). On day 18 the primary sprout of male fetuses from treated mothers is more extensively developed than that in male controls. In several of the 6 male fetuses from treated mothers a circular indentation of the epidermis has formed around the insertion site of the preserved mammary bud, representing a rudimentary teat (Fig. 3).
Discussion. As in the case in male rat fetuses, mammary bud and teats in male mouse fetuses as well as those in female fetuses will develop under the influence of an androgen antagonist. As far as can be ascertained, in those mice the primary sprout remains in contact with the epidermis and is always more extensively developed than in male controle, but not SQ fully developed as in female controls. The development of a mammilla is not always coupled with such anomalies.
The pronounced mesenchymal proliferation around the mammary bud that occurs in male fetuses after day 14 plays a leading role in destruction of the proximal mammary bud. The continuity of the primary sprout is preserved when the antiandrogen prevents the concentration of the mesenchyma.
Our findings emphasize the importance of androgens in differentiation of the mammary gland. Malformations in male fetuses, induced by antiandrogens, differ fundamentally from those that are induced by estrogens (3). In contrast to the estrogens, the antiandrogens induce a process which is already inherent in the biological “blueprint,” the realization of which apparently is prevented only by the androgens of the male fetus. Our data suggest that the female pattern of development will be expressed up to puberty, irrespective of sex, in the absence of androgens.
Summary. In male fetuses of the mouse, mammary gland tissue is stimulated and frequently also the development of teats is observed under the influence of the androgen antagonist cyproterone acetate (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate). The continuity of the glandular process, normally lost in male fetuses because of a destruction of the epidermal sector, is maintained by cyproterone acetate. Inhibition of the endogenous androgens thus results in a female organogenesis of the mammary glands.
Source: http://journals.sagepub.com/doi/abs/10.3181/00379727-123-31564
The Effect of the Anti-androgen 1,2α-Methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate (Cyproterone Acetate) on the Development of the Mammary Glands of Male Foetal Rats (Neumann & Elger, 1966)
Abstract. Treatment of pregnant rats with an anti-androgen (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate, 'cyproterone acetate') from the 13th day of pregnancy resulted in female organogenesis of the mammary glands, including the formation of nipples in the male foetuses and feminization of other male sexual characters. The continued development of the nipple primordium was also seen in all the subsequent foetal and postnatal stages even after termination of the treatment.
A more marked development of the foetal mammary tissue as compared with that of male controls was noted in the proximal areas of the mammary cord process between the 19th and the 21st day in male foetuses whose mothers had received the anti-androgen. In male foetuses of treated mothers, a further proliferation of the glandular tissue was also found after birth.
The role of androgens in the development of the mammary glands is discussed. It seems likely from our findings that the androgens of a male foetus inhibit the development of the mammary glands, emphasizing that for mammary development before puberty female gonadal hormones are not necessary.
Introduction. The mammary gland is under hormonal influence not only as a mature organ but its development during the embryonic stage is also influenced by sex hormones (Turner & Gomez, 1933; Greene, Burril & Ivy, 1941; Raynaud, 1942, 1961; Raynaud & Frilley, 1949; Raynaud & Raynaud, 1956, 1957). The first developmental stage of the undifferentiated organ is immediately followed by a hormone-sensitive phase in which its further fate is determined.
Administration to mice of oestrogen early in pregnancy or directly to the foetus can induce various deformities of the nipple of the foetus (see Raynaud & Raynaud, 1956).
In the female foetuses of rats treated with androgens, nipple formation was suppressed (Greene et al. 1941). In female mice, testosterone propionate prevented the circular invagination of the basal cell layers of the epidermis which normally develop in the mammillary area as a nipple precursor (Raynaud, 1942) producing a state of athelia. Androgens, moreover, tend to convert organogenesis of the female mammary primordium into that of the male. Raynaud & Frilley (1949) have concluded from their findings that the development of the male mammary primordium is normally directed by hormones of the foetal testes.
The purpose of this investigation was to study the morphological events during the foetal growth of the primordia of the male mammary gland under the influence of a powerful androgen-antagonist, cyproterone acetate. Since the blocking of androgen receptors of various androgen-dependent sex-linked organs in genetically male rat foetuses results in their differentiation in the female direction (Hamada, Neumann & Junkmann, 1963; Junkmann & Neumann, 1964; Neumann, Elger & Kramer, 1966) it seemed of interest to elucidate in rats the organogenesis of foetal male mammary glands in the 'absence' of androgen(s).
Results. [...]
Discussion. Treatment with cyproterone acetate of pregnant female rats induced in male foetuses the development ofnipples and of mammary gland tissue of the normal female type.
In all stages of development, the male primordia followed the female pattern of organogenesis. Even after birth, the development of the nipples was that of normal females. Since the anti-androgen used has no oestrogenic activity (which would have led to malformations, (Raynaud, 1961) rather than feminization), the feminizing effects of cyproterone acetate must be related to its antagonism to androgens. The blocking of the androgen receptors in the mammary gland primordium of the male foetus was sufficient to induce nipple development. This observation agrees with the findings of Raynaud & Frilley (1949) who showed that after destruction of the foetal testes by X-rays in mice at an early stage, the primordia of the male mammary gland developed in the female direction.
As shown previously (Hamada et al. 1963) the anti-androgenic action of steroids is not correlated with progestational or other biological activities. It seems, therefore, that the androgens of the foetal testes alone inhibit the development of the mammary gland in male animals. The basic 'femaleness' of mammals during ontogeny (Jost, 1955; Raynaud, 1961) is consistent with this concept.
Another conclusion may be drawn, namely that oestrogens probably do not play a key role in the organogenesis of mammary glands up to puberty (see also Raynaud, 1961).
Source: http://joe.endocrinology-journals.org/content/36/4/347.short
The Structure of the Mammary Glands and Lactogenesis in Feminized Male Rats (Neumann et al., 1966)
Abstract. Male rats which had been prenatally under the influence of the androgen antagonist cyproterone acetate (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate) developed nipples, teat ducts, a complete gland cistern, main milk ducts, and mammary glands. As shown by histological criteria, lactogenesis was induced in these feminized rats with adequate hormone therapy after orchidectomy when adult. The mammae contained secretion and were indistinguishable from those of nulliparous female controls under identical hormone treatment. Since male rats have no teats, it was concluded that normally the anlagen for the mammary adnexa are prevented by foetal androgens from undergoing complete female organogenesis.
It seems that in male rat foetuses cyproterone acetate prevents endogenous testosterone from producing the incomplete organogenesis with athelia and without adnexa that normally occurs in the male mamma.
Treatment of pregnant rats with adequate doses of the androgen antagonist cyproterone acetate induces feminization in genetically male foetuses. In addition to the effects on the central nervous system and other body structures (Hamada, Neumann & Junkmann, 1963; Neumann & Elger, 1965a, b) female organogénesis of the mammae occurs and the feminized male foetuses develop nipples, which are never found in normal male rats (Neumann & Elger, 1966).
After birth, the mammary glands of feminized male rats responded to treatment with progesterone plus oestradiol practically to the same extent as the mammary glands of females. Normal males treated with the same hormone combination developed much smaller mammary glands (Neumann & Elger, unpublished results).
The purpose of the present experiments was to investigate whether the feminized rats had mammary glands and adnexa, comparable with those in female rats. This seemed of interest, since in the normal male rat, there is no canalization from the mammary gland to the skin surface. It seemed also of interest to investigate whether lactogenesis could be induced in the feminized rats.
Results. [...]
Discussion. Histological evidence is presented in feminized, genetically male rats, of successfully induced lactogenesis extending into completely developed adnexa. The feminized and orchidectomized males had a complete duct system extending from the mammary alveoli to the body surface so that milk removal was possible. Normally, when working with mature males, one can only obtain a restricted stimulation of the mammary glands by hormone therapy (Neumann & Elger, unpublished results), since the teats and the adnexa necessary for milk removal are absent or rudimentary.
In mice, the male hormone acting during foetal life has been shown to cause in female foetuses a condition of athelia (Raynaud & Frilley, 1949). It seems likely therefore (see Raynaud, 1961) that in the rat the foetal androgens prevent normal development of the adnexa.
Our findings are consistent with the results of Raynaud & Frilley (1949). These authors observed that after early destruction of the testes in mouse foetuses by X-rays the mammary gland subsequently evolved in the female pattern as discussed extensively by Raynaud (1961).
Source: http://joe.endocrinology-journals.org/content/36/4/353.short
The Structure of the Mammary Glands and Lactogenesis in Feminized Male Rats (Neumann & Elger, 1967)
Abstract. When administered to gravid rats during pregnancy an anti-androgenic steroid (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate) induced development of nipples in male fetuses. These nipples and associated glandular tissues develop after birth as in normal female animals. Progestin-estrogen treatment of adult, castrated feminized males produced stimulation of the glandular tissue similar to that seen after treatment of castrated female animals. In castrated male rats this treatment produces little glandular proliferation. It is concluded that androgens normally prevent the development of nipples and extensive formation of mammary tissue in male fetuses. Female sex hormones seem to be without significance in differentiation of the mammary glands and their pre-pubertal development.
Introduction. Treatment of pregnant rats with an antiandrogenic steroid (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate, cyproterone acetate) produces a feminine organogenesis of the mammary gland in male fetuses (Neumann and Elger, 1966a), in addition to the feminization of other somatic- and CNS-sexual characteristics (Hamada, Neumann and Junkmann, 1963; Neumann, Elger and Kramer, 1966; Neumann and Elger, 1965). This effect is responsible for the development of the nipples, which normally do not develop in male rats. Even after discontinuation of treatment nipples continue to develop throughout post-natal stages.
However, in the feminized male rats, pronounced development of glandular tissue could be recognized with certainty in the proximal sections of the glandular bud only from day 19 to 21 of embryonic development. At the time of birth this observation was made difficult by the extensive area of glandular tissue (Neumann and Elger, 1966a).
The present paper will consider how the development of mammary tissue in male animals is influenced by treatment of their mothers with an antiandrogen during pregnancy and how their mammary tissues react to estrogen-progestin treatment when these feminized animals are adult.
Results. The existing nipples of feminized male animals and female controls developed under the influence of estrogen-progestin treatment (male controls have no nipples). On necropsy, all animals exhibited a more or less developed mammary gland. Fig. 2 shows the mammary gland weight of feminized male animals (group II), female controls (group I) and male controls (group III), following estrogen-progestin treatment. While in the male controls only a small amount of mammary tissue was found, there was a pronounced development in feminized male animals and in female animals. Pectoral and inguinal glandular tissues showed equivalent development.
The mammary glands of the feminized male animals reacted to estrogen-progestin treatment in a manner similar to those of female animals, while the male controls showed less reaction. Histological examination revealed no evident qualitative differences in the glandular structures of the various groups; in all cases considerable glandular proliferation was noticed. Qualitatively these glands correspond to those of pregnant female rats shortly before the onset of lactation. Some alveoli contained glandular secretion (see fig. 3).
Discussion. The findings indicate that under the influence of antiandrogens, not only can the development of nipples be induced in male rat fetuses (they are nonexistent in normal male rats), but the gland itself is subjected to the same development as is seen in female fetuses. The fact that estrogen-progestin treatment of adult feminized rats and female animals causes the same degree of proliferation of glandular tissue of the mammary gland, while the development of glandular tissue is quite limited in the male controls, serves to prove that in feminized male rats more glandular tissue existed at the beginning of the treatment than in normal male rats.
The differences in the development of glandular tissue in female controls and in feminized male animals and in male controls are merely quantitative. The histological pictures show no differences.
Cyproterone acetate inhibits the effect of androgens in a competitive manner at the receptors of the target organs. This was confirmed in earlier studies (Neumann, Richter and Günzel, 1965; Neumann and Von Berswordt-Wallrabe, 1966; Neumann and Elger, 1966b). Since this compound does not possess estrogenic properties (which would lead to entirely different mammary malformation (Raynaud and Raynaud, 1956, 1957)), the following conclusions may be drawn regarding the significance of the male and female sexual hormones for the differentiation of the mammary gland: The displacement of the fetal androgens (testosterone?) from the receptors of the mammary gland in the male fetuses at the time of the differentiation of this organ is sufficient to induce the development of both nipples and glandular tissue in the same manner as would normally take place only in female animals. On the basis of our studies, it appears to be extremely doubtful that any decided significance can be ascribed to the estrogens as taking part in any one phase of development of the mammary glands up to puberty.
It may thus be stated with certainty that only the androgens of the fetal testes prevent a more pronounced development of mammary tissue in male animals.
Source: https://www.sciencedirect.com/science/article/pii/0014299967900489
Abnormal Sexual Development: A Genetic and Endocrine Approach to Differential Diagnosis (Federman, 1967)
Another feature of all the hereditary forms of male pseudohermaphroditism is pubertal gynecomastia. That this is an integral part of the disorder is shown by its general occurrence plus the fact that it is not usually seen in dysgenetic male pseudohermaphroditism (Chapter VI) despite similar genital differentiation in the two groups of disorders. Since enlargement of the male breast is seldom understood, it is hardly surprising that the phenomenon is not readily accounted for in the syndromes under review. However, there is evidence in the male mouse that prenatal gonadectomy alters the anatomy and the postpubertal function of the breast, ostensibly by prevention of the conditioning of the breast anlage by a secretion from the testis.24 It is possible that the abnormal testis of the male pseudohermaphrodite fails to condition the breast primordia in such a way as to reverse or contain whatever causes gynecomastia in the normal male at puberty. Some support for this suggestion is derived from the existence of hereditary gynecomastia,25 which behaves genetically like the disorders we have reviewed here.
Source: https://books.google.com/books?id=AgxDuQEACAAJ (pp. 118–119)
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TL;DR: AMAB people such as cisgender men and transgender women are exposed to high levels of testosterone in utero due to their testes. In rodents, prenatal testosterone exposure irreversibly masculinizes not only the genitals and brain but also the mammary glands, stunting their growth and limiting their developmental potential in response to estrogens later in life. It is unknown if this also occurs to any degree in humans. However, there is some clinical support for the notion that it may occur in us as well. Moreover, transgender women appear to generally show relatively poor breast development (link), and this phenomenon could, unfortunately, explain this. Alternatively, the phenomenon may not occur in humans, and other factors (e.g., hormonal regimens) might instead be responsible for the apparently relatively limited breast development in transgender women. More clinical research is needed to determine whether or not this phenomenon indeed occurs in humans or not.Overview and animal findingsMale mice have testes due to their XY chromosomes, whereas female mice have ovaries due to their XX chromosomes. While in utero, the testes produce high levels of testosterone, whereas the ovaries do not. These high levels of testosterone masculinize the brain and genitals during a critical window in prenatal development, resulting in male-typical structures in male mouse fetuses, whereas the absence of testosterone results in the brain and genitals being feminized in female mouse fetuses. In addition to the brain and genitals, prenatal sexual differentiation occurs in the mammary glands of mice. Testosterone prevents the genesis of the nipples in male mouse fetuses during a critical period of prenatal development. It is unclear if testosterone itself is responsible for this or if testosterone is 5α-reduced into dihydrotestosterone (DHT) in the mammary gland, similarly to in the external genitalia, and DHT is responsible for the inhibition of the development of the mammary gland; findings appear to be mixed. Postnatally, the nipples are absent in male mice and the mammary glands of male mice have diminished responses to estrogens and progestogens; they are only capable of partial, stunted development following exogenous administration of estrogens and progestogens compared to female mice. This appears to be because exposure to testosterone in utero, in addition to prenatal inhibition of mammary gland growth, permanently reduces the expression of the estrogen receptor and aromatase in the mammary glands, limiting their capacity to respond to estrogens and by extension progestogens.Treatment of pregnant mice with an antiandrogen such as cyproterone acetate (an androgen receptor antagonist), cyanoketone (a 3β-hydroxysteroid dehydrogenase (3β-HSD) inhibitor and hence testicular testosterone biosynthesis inhibitor), or 390 MSD (a 5α-reductase inhibitor and hence DHT biosynthesis inhibitor) during the critical window of mammary gland sexual differentiation results in feminization of the mammary glands of male mouse fetuses such that they are indistinguishable postnatally from those of female mice. Likewise, destruction of the testes of male mouse fetuses via targeted external X-ray irradiation prior to the critical window of mammary gland sexual differentiation results in the same observations. Conversely, treatment of pregnant mice with an androgen (androgen receptor agonist) such as testosterone, methyltestosterone, or DHT during the critical window of mammary gland sexual differentiation results in masculinization of the mammary glands of female mouse fetuses such that they are indistinguishable postnatally from those of male mice. One study reported that testosterone was more potent than DHT in this context. Besides their determination of gonadal type (i.e., testes in males and ovaries in females) and the consequent prenatal hormonal milieu (i.e., high testosterone in males and absence of testosterone in females), karyotype (i.e., XY chromosomes in males and XX chromosomes in females) has no role in the sexual differentiation of the mammary glands in mice.Although we know that prenatal androgen exposure masculinizes the genitals and brain in both mice and humans, and masculinizes the mammary glands in mice, it is unknown if prenatal androgen exposure similarly masculinizes the mammary glands in humans. There are important species differences between mice and humans concerning prenatal sexual differentiation. As an example, aromatization of androgens into estrogens masculinizes the brain in male mouse fetuses, whereas this does not appear to occur in male human fetuses, in whom testosterone is thought to be solely responsible for brain masculinization. Another notable species differences between mice and humans is of course that male mice do not have nipples whereas male humans do have nipples. It has also been stated that whereas the mammary glands of newborn male mice are smaller and structurally dimorphic relative to those of newborn female mice, the mammary glands of male and female human newborns are morphologically indistinguishable. These findings suggest that the phenomenon may not occur in humans, or that it may occur to a lesser and/or characteristically differential extent. However, unlike the case of mice, which can very easily be studied experimentally, it is not clear if it has been systematically confirmed in male and female human newborns that the mammary glands are truly identical (e.g., in size, etc.). In addition, although the mammary glands of male and female human newborns might be morphologically indistinguishable on a macroscopic level, there may nonetheless be microscopic differences such as differences in cellular gene expression (e.g., of the estrogen receptor) and hormonal sensitivity, as in mice. Moreover, there is some clinical evidence to support the notion that prenatal androgen exposure may indeed be involved in mammary gland sexual differentiation in humans, which I will address in the next section.In contrast to rodents, the prenatal effects of androgens and antiandrogens on the mammary glands of monkeys via administration to pregnant monkey dams unfortunately do not seem to have been studied.Supporting clinical findingsCongenital adrenal hyperplasia (CAH) due to 3β-HSD2 deficiency is a rare intersex condition in which undervirilization of males occurs due to deficiency of testicular 3β-HSD and hence deficiency of testosterone during prenatal development. Conversely, testicular 3β-HSD and hence testosterone levels are relatively normal postnatally (likely due to compensation by the 3β-HSD1 isoform of the enzyme), so these individuals undergo normal spontaneous puberty. A portion of males with 3β-HSD2 deficiency (approximately 35 to 55%, based on two reviews) develop gynecomastia during puberty, with some of these cases being described as "marked". Moreover, this can occur in spite of testosterone and estradiol levels that are in the normal male ranges. It has been theorized that this may be due to insufficient exposure of the mammary glands to androgens prenatally such that the breasts are more sensitive to estrogens in puberty and adulthood, as with animal models. However, there is high clinical heterogeneity in the reported cases of CAH due to 3β-HSD2 deficiency, and steroid hormone levels in general are also abnormal in the condition. It is possible that the gynecomastia that occurs in the condition might alternatively be due to aromatization of excessive adrenal androgens.It has been theorized that gynecomastia in general, in addition to an imbalance in the ratio of androgens to estrogens, may have insufficient prenatal androgen exposure and hence prenatal mammary gland sexual differentiation as an important contributing factor in many cases. In accordance, small clinical studies have reported increased estrogen receptor and aromatase content in the breasts of men with gynecomastia. On the other hand however, it is notable that it is very rare for the breasts of males with gynecomastia to approximate those of females, even with high-dose antiandrogen and/or estrogen therapy, and this may reflect prenatal androgen exposure such that the developmental potential of the breasts is fundamentally limited compared to that of females.Aromatase excess syndrome (AEXS) is a rare intersex condition in which peripheral aromatase, the enzyme that converts androgens into estrogens, is extremely overactive. As a result of this, both males and females with the condition are hyperestrogenic. In addition, both males and females with AEXS develop premature female-type pubertal maturation at a young age, including gynecomastia in the boys (photo). This begins shortly following adrenarche (average age about 6 years), when the adrenal glands begin secreting weak androgens. These adrenal androgens are excessively aromatized and induce breast development. However, whereas about 50% of women with AEXS are said to have "breast hypertrophy" (excessively large breasts, although I don't think it's meant in the form of the rare disease), males with the condition seem to on average have relatively small (and certainly not hypertrophic) breasts compared to females, even if their gynecomastia is definitely marked (photos). That said, these males also do have higher testosterone levels than females with the condition. However, their testosterone is excessively aromatized, is relatively low, and notably doesn't start to be secreted until the age of normal male puberty (~12 years old). If the prenatal androgen exposure hypothesis is true for breast development in humans, it may explain the divergent breast observations in males and females with AEXS.Complete androgen insensitivity syndrome (CAIS) is a rare intersex condition in which 46,XY individuals ("biological/genetic males") have a defective and completely non-functional androgen receptor. As a result, these individuals, who have testes due to their Y sex chromosome and produce high testosterone levels in utero, experience no masculinization during prenatal development and are born perfectly phenotypically female. They are highly feminine both physically and behaviorally (as well as female in terms of gender identity and androphilic in terms of sexuoromantic orientation), and as a result, are, appropriately, assigned female at birth. The testes never descend in CAIS women, remaining internal in the abdominal cavity. At puberty, the testes produce high levels of testosterone and result in a male hormonal profile, although of course without any masculinization due to the insensitivity of CAIS women to androgens. The testosterone is aromatized into estradiol, which results in elevated but still relatively low estradiol levels (about 50 pg/mL). Nonetheless, estradiol levels are only about 10 to 55 pg/mL during Tanner stages 1 to 4 in normal pubertal girls (source), so this is sufficient for feminization and breast development in CAIS women (photos, photo). Conversely, CAIS women, lacking ovaries, produce no progesterone of importance (<1 ng/mL) (source).In spite of their relatively low levels of estradiol and absence of progesterone, CAIS women show complete breast development at puberty, and actually have breasts that are said to be large on average for women (source). One review amusingly described the breasts in CAIS women as "jumbo-sized" in fact (source90359-7/pdf)). In accordance with their lack of progesterone, CAIS women show no lobuloalveolar tissue in the breasts on histological examination, suggesting that progesterone and lobuloalveolar maturation are not importantly involved in external morphological breast development (source90359-7/pdf)). The only fundamental biological difference between men and CAIS women is the presence versus absence of a functional androgen receptor, and this illustrates the powerful role of androgens in opposing feminization and breast development. Moreover, the excellent and even above-average breast development in CAIS women is in marked contrast to the relatively small breasts in most cases of gynecomastia in males, gynecomastia due to AEXS in males, and notably gynecomastia due to high-dose androgen receptor antagonist monotherapy (e.g., with bicalutamide or enzalutamide) in men. The last is described as only mild-to-moderate in 90% of cases (for an idea of what mild-to-moderate gynecomastia is like, the photos here are considered to be examples of severe gynecomastia). The comparatively large breasts in adult CAIS women may be due to their absence of prenatal androgen-receptor signaling. However, other factors might also or alternatively be involved in the divergent breast findings, such as postnatal androgen-receptor signaling, age, and others.5α-Reductase type 2 deficiency is a rare intersex condition in which the type 2 isoform of 5α-reductase is absent, partial DHT deficiency is present, and undervirilization of male fetuses occurs. This manifests specifically as partially feminized genitalia at birth and as minimal androgen-dependent body hair growth and scalp hair loss in adulthood. However, masculinization at puberty is otherwise normal. Gynecomastia is said not to occur in males with the condition, which suggests that 5α-reductase type 2 may not be involved in prenatal androgen exposure-mediated mammary gland sexual differentiation, assuming of course that it occurs in humans. The type 1 and 3 isoforms of 5α-reductase remain functional in males with the condition however. Moreover, testosterone may be responsible for mammary gland sexual differentiation due to prenatal androgen exposure rather than DHT, as described previously. Gynecomastia occurs at only low rates of about 1.2 to 3.5% in men treated with 5α-reductase inhibitors like finasteride and dutasteride (source).An implication of the notion that prenatal androgen exposure inhibits later breast development in humans is that transgender men, even if they started hormones before puberty, may be at a higher risk of gynecomastia with testosterone therapy due to the minimal exposure of their mammary glands to androgens in utero. I am unaware of whether this is the case or of whether we have any data on the issue or not.Conclusion and relevance for transgender womenTransgender women appear to generally have relatively poor breast development (link). It is possible that exposure of the mammary glands to high levels of androgens prenatally, resulting in lower levels of estrogen receptors in the mammary glands, diminished responsiveness to estrogens, and an ultimately compromised capacity for breast development later in life, is either responsible for or is one of multiple contributing factors to this. This, unfortunately, would likely be irreversible and something that nothing could be done about. However, although sexual differentiation of the mammary glands due to prenatal androgen exposure is known to be the case in mice, and although it is supported by some clinical findings in humans, it is not yet certain whether it is actually the case in humans as well. In addition, there are some data that can be regarded as support against it (e.g., the presence of nipples in male humans and the reportedly indistinguishable mammary glands in male and female newborns), and other factors (e.g., hormonal regimens) might instead be responsible for the relatively poor breast development in transgender women. In any case, prenatal androgen exposure as a limiting factor in our breast development is nonetheless very plausible, and one that could still prove to be true. More clinical research is needed to confirm or reject the notion that this phenomenon indeed also occurs in humans.Relevant excerpts from the literatureThe following is an extensive collection of excerpts from literature publications (ordered by date) that are relevant to this topic. They are intended to source and provide elaboration on my discussion above.The Role of Androgens in Differentiation of the Mammary Gland In Male Mouse Fetuses (Elger & Neumann, 1966)Abstract. In male fetuses of the mouse, mammary gland tissue is stimulated and frequently also the development of teats is observed under the influence of the androgen antagonist cyproterone acetate (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate). The continuity of the glandular process, normally lost in male fetuses because of a destruction of the epidermal sector, is maintained by cyproterone acetate. Inhibition of the endogenous androgens thus results in a female organogenesis of the mammary glands.Introduction. Teats do not occur in normal male rats whereas they do develop in male rat fetuses under the influence of antiandrogens. Male mammary bud also showed greater glandularity under the influence of antiandrogens than is seen in normal male animals (1,2). Since the embryonic development of the mammary gland in the mouse is better known than that of any other animal species (3,4) we have extended our observations to the mouse. This is also appropriate because the glandular bud in the male mouse fetus is inhibited more markedly by fetal androgens than is the case in any other murine animal. Concentration of periglandular mesenchyma causes by 15th day of the embryonal development either the complete destruction of the glandular rudiments or their separation from the epidermis by the strangulation of the proximal sector (3).Results. On day 14 of embryonic development, the rudiments (anlagen) of the mammary glands begin to show slight differences in controls of both sexes. The cells of the glandular rudiments are smaller in male fetuses than in the female controls and in the male fetuses of treated mothers. The cells are arranged irregularly and the outline of the surrounding mesenchyma is not clearly defined (Fig. 1). The mesenchyma which surrounds the glandular rudiments shows a more advanced development in male controls and in male fetuses from mothers which had been treated with cyproterone acetate. On the following day differences between normal male and normal female fetuses are even more pronounced. In the male fetuses from cyproterone acetate-treated mothers organogenesis follows the female pattern of development. The chromophilic mammary bud is well developed and distinct from surrounding mesenchyma. The primary sprout is connected with the epidermis through a sturdy chain of epidermal cells that stain poorly. The concentration of mesenchyma which in normal male fetuses leads to strangulation of the mammary bud, does not occur in male fetuses under the influence of cyproterone acetate (Fig. 2). On day 18 the primary sprout of male fetuses from treated mothers is more extensively developed than that in male controls. In several of the 6 male fetuses from treated mothers a circular indentation of the epidermis has formed around the insertion site of the preserved mammary bud, representing a rudimentary teat (Fig. 3).Discussion. As in the case in male rat fetuses, mammary bud and teats in male mouse fetuses as well as those in female fetuses will develop under the influence of an androgen antagonist. As far as can be ascertained, in those mice the primary sprout remains in contact with the epidermis and is always more extensively developed than in male controle, but not SQ fully developed as in female controls. The development of a mammilla is not always coupled with such anomalies.The pronounced mesenchymal proliferation around the mammary bud that occurs in male fetuses after day 14 plays a leading role in destruction of the proximal mammary bud. The continuity of the primary sprout is preserved when the antiandrogen prevents the concentration of the mesenchyma.Our findings emphasize the importance of androgens in differentiation of the mammary gland. Malformations in male fetuses, induced by antiandrogens, differ fundamentally from those that are induced by estrogens (3). In contrast to the estrogens, the antiandrogens induce a process which is already inherent in the biological “blueprint,” the realization of which apparently is prevented only by the androgens of the male fetus. Our data suggest that the female pattern of development will be expressed up to puberty, irrespective of sex, in the absence of androgens.Summary. In male fetuses of the mouse, mammary gland tissue is stimulated and frequently also the development of teats is observed under the influence of the androgen antagonist cyproterone acetate (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate). The continuity of the glandular process, normally lost in male fetuses because of a destruction of the epidermal sector, is maintained by cyproterone acetate. Inhibition of the endogenous androgens thus results in a female organogenesis of the mammary glands.Source: http://journals.sagepub.com/doi/abs/10.3181/00379727-123-31564The Effect of the Anti-androgen 1,2α-Methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate (Cyproterone Acetate) on the Development of the Mammary Glands of Male Foetal Rats (Neumann & Elger, 1966)Abstract. Treatment of pregnant rats with an anti-androgen (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate, 'cyproterone acetate') from the 13th day of pregnancy resulted in female organogenesis of the mammary glands, including the formation of nipples in the male foetuses and feminization of other male sexual characters. The continued development of the nipple primordium was also seen in all the subsequent foetal and postnatal stages even after termination of the treatment.A more marked development of the foetal mammary tissue as compared with that of male controls was noted in the proximal areas of the mammary cord process between the 19th and the 21st day in male foetuses whose mothers had received the anti-androgen. In male foetuses of treated mothers, a further proliferation of the glandular tissue was also found after birth.The role of androgens in the development of the mammary glands is discussed. It seems likely from our findings that the androgens of a male foetus inhibit the development of the mammary glands, emphasizing that for mammary development before puberty female gonadal hormones are not necessary.Introduction. The mammary gland is under hormonal influence not only as a mature organ but its development during the embryonic stage is also influenced by sex hormones (Turner & Gomez, 1933; Greene, Burril & Ivy, 1941; Raynaud, 1942, 1961; Raynaud & Frilley, 1949; Raynaud & Raynaud, 1956, 1957). The first developmental stage of the undifferentiated organ is immediately followed by a hormone-sensitive phase in which its further fate is determined.Administration to mice of oestrogen early in pregnancy or directly to the foetus can induce various deformities of the nipple of the foetus (see Raynaud & Raynaud, 1956).In the female foetuses of rats treated with androgens, nipple formation was suppressed (Greene et al. 1941). In female mice, testosterone propionate prevented the circular invagination of the basal cell layers of the epidermis which normally develop in the mammillary area as a nipple precursor (Raynaud, 1942) producing a state of athelia. Androgens, moreover, tend to convert organogenesis of the female mammary primordium into that of the male. Raynaud & Frilley (1949) have concluded from their findings that the development of the male mammary primordium is normally directed by hormones of the foetal testes.The purpose of this investigation was to study the morphological events during the foetal growth of the primordia of the male mammary gland under the influence of a powerful androgen-antagonist, cyproterone acetate. Since the blocking of androgen receptors of various androgen-dependent sex-linked organs in genetically male rat foetuses results in their differentiation in the female direction (Hamada, Neumann & Junkmann, 1963; Junkmann & Neumann, 1964; Neumann, Elger & Kramer, 1966) it seemed of interest to elucidate in rats the organogenesis of foetal male mammary glands in the 'absence' of androgen(s).Results. [...]Discussion. Treatment with cyproterone acetate of pregnant female rats induced in male foetuses the development ofnipples and of mammary gland tissue of the normal female type.In all stages of development, the male primordia followed the female pattern of organogenesis. Even after birth, the development of the nipples was that of normal females. Since the anti-androgen used has no oestrogenic activity (which would have led to malformations, (Raynaud, 1961) rather than feminization), the feminizing effects of cyproterone acetate must be related to its antagonism to androgens. The blocking of the androgen receptors in the mammary gland primordium of the male foetus was sufficient to induce nipple development. This observation agrees with the findings of Raynaud & Frilley (1949) who showed that after destruction of the foetal testes by X-rays in mice at an early stage, the primordia of the male mammary gland developed in the female direction.As shown previously (Hamada et al. 1963) the anti-androgenic action of steroids is not correlated with progestational or other biological activities. It seems, therefore, that the androgens of the foetal testes alone inhibit the development of the mammary gland in male animals. The basic 'femaleness' of mammals during ontogeny (Jost, 1955; Raynaud, 1961) is consistent with this concept.Another conclusion may be drawn, namely that oestrogens probably do not play a key role in the organogenesis of mammary glands up to puberty (see also Raynaud, 1961).Source: http://joe.endocrinology-journals.org/content/36/4/347.shortThe Structure of the Mammary Glands and Lactogenesis in Feminized Male Rats (Neumann et al., 1966)Abstract. Male rats which had been prenatally under the influence of the androgen antagonist cyproterone acetate (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate) developed nipples, teat ducts, a complete gland cistern, main milk ducts, and mammary glands. As shown by histological criteria, lactogenesis was induced in these feminized rats with adequate hormone therapy after orchidectomy when adult. The mammae contained secretion and were indistinguishable from those of nulliparous female controls under identical hormone treatment. Since male rats have no teats, it was concluded that normally the anlagen for the mammary adnexa are prevented by foetal androgens from undergoing complete female organogenesis.It seems that in male rat foetuses cyproterone acetate prevents endogenous testosterone from producing the incomplete organogenesis with athelia and without adnexa that normally occurs in the male mamma.Treatment of pregnant rats with adequate doses of the androgen antagonist cyproterone acetate induces feminization in genetically male foetuses. In addition to the effects on the central nervous system and other body structures (Hamada, Neumann & Junkmann, 1963; Neumann & Elger, 1965a, b) female organogénesis of the mammae occurs and the feminized male foetuses develop nipples, which are never found in normal male rats (Neumann & Elger, 1966).After birth, the mammary glands of feminized male rats responded to treatment with progesterone plus oestradiol practically to the same extent as the mammary glands of females. Normal males treated with the same hormone combination developed much smaller mammary glands (Neumann & Elger, unpublished results).The purpose of the present experiments was to investigate whether the feminized rats had mammary glands and adnexa, comparable with those in female rats. This seemed of interest, since in the normal male rat, there is no canalization from the mammary gland to the skin surface. It seemed also of interest to investigate whether lactogenesis could be induced in the feminized rats.Results. [...]Discussion. Histological evidence is presented in feminized, genetically male rats, of successfully induced lactogenesis extending into completely developed adnexa. The feminized and orchidectomized males had a complete duct system extending from the mammary alveoli to the body surface so that milk removal was possible. Normally, when working with mature males, one can only obtain a restricted stimulation of the mammary glands by hormone therapy (Neumann & Elger, unpublished results), since the teats and the adnexa necessary for milk removal are absent or rudimentary.In mice, the male hormone acting during foetal life has been shown to cause in female foetuses a condition of athelia (Raynaud & Frilley, 1949). It seems likely therefore (see Raynaud, 1961) that in the rat the foetal androgens prevent normal development of the adnexa.Our findings are consistent with the results of Raynaud & Frilley (1949). These authors observed that after early destruction of the testes in mouse foetuses by X-rays the mammary gland subsequently evolved in the female pattern as discussed extensively by Raynaud (1961).Source: http://joe.endocrinology-journals.org/content/36/4/353.shortThe Structure of the Mammary Glands and Lactogenesis in Feminized Male Rats (Neumann & Elger, 1967)Abstract. When administered to gravid rats during pregnancy an anti-androgenic steroid (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate) induced development of nipples in male fetuses. These nipples and associated glandular tissues develop after birth as in normal female animals. Progestin-estrogen treatment of adult, castrated feminized males produced stimulation of the glandular tissue similar to that seen after treatment of castrated female animals. In castrated male rats this treatment produces little glandular proliferation. It is concluded that androgens normally prevent the development of nipples and extensive formation of mammary tissue in male fetuses. Female sex hormones seem to be without significance in differentiation of the mammary glands and their pre-pubertal development.Introduction. Treatment of pregnant rats with an antiandrogenic steroid (1,2α-methylene-6-chloro-Δ4,6-pregnadiene-17α-ol-3,20-dione-17α-acetate, cyproterone acetate) produces a feminine organogenesis of the mammary gland in male fetuses (Neumann and Elger, 1966a), in addition to the feminization of other somatic- and CNS-sexual characteristics (Hamada, Neumann and Junkmann, 1963; Neumann, Elger and Kramer, 1966; Neumann and Elger, 1965). This effect is responsible for the development of the nipples, which normally do not develop in male rats. Even after discontinuation of treatment nipples continue to develop throughout post-natal stages.However, in the feminized male rats, pronounced development of glandular tissue could be recognized with certainty in the proximal sections of the glandular bud only from day 19 to 21 of embryonic development. At the time of birth this observation was made difficult by the extensive area of glandular tissue (Neumann and Elger, 1966a).The present paper will consider how the development of mammary tissue in male animals is influenced by treatment of their mothers with an antiandrogen during pregnancy and how their mammary tissues react to estrogen-progestin treatment when these feminized animals are adult.Results. The existing nipples of feminized male animals and female controls developed under the influence of estrogen-progestin treatment (male controls have no nipples). On necropsy, all animals exhibited a more or less developed mammary gland. Fig. 2 shows the mammary gland weight of feminized male animals (group II), female controls (group I) and male controls (group III), following estrogen-progestin treatment. While in the male controls only a small amount of mammary tissue was found, there was a pronounced development in feminized male animals and in female animals. Pectoral and inguinal glandular tissues showed equivalent development.The mammary glands of the feminized male animals reacted to estrogen-progestin treatment in a manner similar to those of female animals, while the male controls showed less reaction. Histological examination revealed no evident qualitative differences in the glandular structures of the various groups; in all cases considerable glandular proliferation was noticed. Qualitatively these glands correspond to those of pregnant female rats shortly before the onset of lactation. Some alveoli contained glandular secretion (see fig. 3).Discussion. The findings indicate that under the influence of antiandrogens, not only can the development of nipples be induced in male rat fetuses (they are nonexistent in normal male rats), but the gland itself is subjected to the same development as is seen in female fetuses. The fact that estrogen-progestin treatment of adult feminized rats and female animals causes the same degree of proliferation of glandular tissue of the mammary gland, while the development of glandular tissue is quite limited in the male controls, serves to prove that in feminized male rats more glandular tissue existed at the beginning of the treatment than in normal male rats.The differences in the development of glandular tissue in female controls and in feminized male animals and in male controls are merely quantitative. The histological pictures show no differences.Cyproterone acetate inhibits the effect of androgens in a competitive manner at the receptors of the target organs. This was confirmed in earlier studies (Neumann, Richter and Günzel, 1965; Neumann and Von Berswordt-Wallrabe, 1966; Neumann and Elger, 1966b). Since this compound does not possess estrogenic properties (which would lead to entirely different mammary malformation (Raynaud and Raynaud, 1956, 1957)), the following conclusions may be drawn regarding the significance of the male and female sexual hormones for the differentiation of the mammary gland: The displacement of the fetal androgens (testosterone?) from the receptors of the mammary gland in the male fetuses at the time of the differentiation of this organ is sufficient to induce the development of both nipples and glandular tissue in the same manner as would normally take place only in female animals. On the basis of our studies, it appears to be extremely doubtful that any decided significance can be ascribed to the estrogens as taking part in any one phase of development of the mammary glands up to puberty.It may thus be stated with certainty that only the androgens of the fetal testes prevent a more pronounced development of mammary tissue in male animals.Source: https://www.sciencedirect.com/science/article/pii/0014299967900489Abnormal Sexual Development: A Genetic and Endocrine Approach to Differential Diagnosis (Federman, 1967)Another feature of all the hereditary forms of male pseudohermaphroditism is pubertal gynecomastia. That this is an integral part of the disorder is shown by its general occurrence plus the fact that it is not usually seen in dysgenetic male pseudohermaphroditism (Chapter VI) despite similar genital differentiation in the two groups of disorders. Since enlargement of the male breast is seldom understood, it is hardly surprising that the phenomenon is not readily accounted for in the syndromes under review. However, there is evidence in the male mouse that prenatal gonadectomy alters the anatomy and the postpubertal function of the breast, ostensibly by prevention of the conditioning of the breast anlage by a secretion from the testis.24 It is possible that the abnormal testis of the male pseudohermaphrodite fails to condition the breast primordia in such a way as to reverse or contain whatever causes gynecomastia in the normal male at puberty. Some support for this suggestion is derived from the existence of hereditary gynecomastia,25 which behaves genetically like the disorders we have reviewed here.Source: https://books.google.com/books?id=AgxDuQEACAAJ (pp. 118–119)[Continued in second post due to character limit.] http://ifttt.com/images/no_image_card.png https://www.reddit.com/r/MtFHRT/comments/9bdbbd/prenatal_androgen_exposure_might_compromise_later/?utm_source=ifttt
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