Patient B started cyproterone acetate and ethinyl estradiol therapy after being diagnosed transsexual at the age of 36 and underwent combined vaginoplasty and augmentation mammaplasty 18 months later. Histologic examination of the mammary biopsy specimens showed fatty breast tissue with well-developed acini and lobules. Several acini showed pseudolactational changes. The nuclei were relatively large and showed conspicuous nucleoli (Fig. 2).
After having been diagnosed as a male-to-female transsexual at age 21, patient F had 20 months of ethinyl estradiol and cyproterone acetate therapy. The patient often forgot to take this medication. After 20 months, she underwent combined vaginoplasty and augmentation mammaplasty, and mammary biopsy specimens were obtained. Histologic examination showed fibrous tissue and primitive lobules with a conspicuous myoepithelial layer. There was some nuclear activity and apoptosis indicative of insufficient hormonal stimulation of the breast tissue (Fig. 3).
Group 2: Surgically Castrated Male-to-Female Transsexuals
Patient J started cyproterone acetate and ethinyl estradiol therapy after being diagnosed transsexual at age 37. Twenty-seven months later, she underwent combined vaginoplasty and augmentative mammaplasty. The intake of cyproterone acetate and ethinyl estradiol was reduced to once daily after the orchidectomy and was stopped after 16 months. Her medication then was changed to 0.625 mg of Premarin (Wyeth, Hoofddorp, The Netherlands) daily. Seven years after the initial mammaplasty, biopsy specimens of the mammary glands were obtained during revision mammaplasty. Histologic examination showed primitive breast tissue with ducts showing hyperplasia. There were no lobules (Fig. 4). Enlarged nuclei with conspicuous nucleoli were indicative of hormonal stimulation.
Surgically Castrated Male-to-Female Transsexuals With Exceptional Histology
After having been diagnosed as a male-to-female transsexual by the Amsterdam gender team, patient N started cyproterone acetate and ethinyl estradiol therapy at age 41. Combined vaginoplasty and augmentative mammaplasty was performed 18 months later. Three years later, the patient requested to undo the sex conversion, and estrogen treatment was interrupted. After 2 years of testosterone undecanoate intake (Andriol, Organon, Oss, The Netherlands), the prostheses were removed and a subcutaneous mastectomy was performed. Histologic examination showed fibrous tissue with variably dilated ducts and only moderately developed inactive lobules, compatible with those of a postmenopausal breast. Focal apocrine metaplasia was observed (Fig. 5).
Group 3: Chemically Castrated Nontranssexual Men
Patient O started flutamide medication for prostatic carcinoma at age 68. No orchidectomy was performed, but a subcutaneous mastectomy was performed to correct a gynecomastia after 2 years of hormonal therapy. Histologic examination showed stroma with focal pseudoangiomatous changes. The fibrous tissue contained ample ducts showing variable degrees of the typical gynecomastia type of infraductal hyperplasia with many irregular micropapillae (Fig. 6). There were some moderately developed lobules with focal chronic lobulestis. Nuclei were relatively large and showed conspicuous nucleoli. The overall picture was between that seen in idiopathic gynecomastia and that of a normal female breast.
At age 73, patient P started bicalutamide intake for prostate carcinoma. He did not undergo an orchidectomy. Subcutaneous mastectomy was performed to correct the gynecomastia after 3 years of hormone therapy. Histologic examination showed typical gynecomastia with no lobular structures (Fig. 7).
Histology of Idiopathic Gynecomastia in Nontranssexual Men
Gynecomastia is the most common clinical and pathologic abnormality of the male breast. 12 It is generally considered to be caused by an increased plasma estrogen-to-androgen ratio. 8 Prepubertal gynecomastia has been attributed to the observation that plasma estradiol reaches an adult concentration earlier than does the plasma testosterone concentration, whereas senile gynecomastia is the combined result of an increase in estrogen concentration and a progressive diminution in plasma-free testosterone concentration with advancing age. 8,11 The mammary enlargement may result from a discrete nodular increase in subareolar tissue or a diffuse accumulation of tissue. Histopathologic studies show similar microscopic alterations regardless of etiologic factors. Three phases of proliferative change have been described. 12 Florid gynecomastia ordinarily occurs within 1 year of onset and is characterized by prominent epithelial proliferation in ducts that may have papillary and cribriformlike patterns. Fibrous or inactive gynecomastia typically occurs after the lesion has been present for 6 months or longer. The epithelial proliferation is much less conspicuous than in the florid phase; the stroma is more collagenous with less edema; and there is reduced vascularity. Intermediate gynecomastia that has florid and fibrous components tends to be present for 12 months or less. It constitutes a transitional phase in the maturation of the lesion. 12
Failure of true acinar and lobular formation in idiopathic enlargement of the male mammary gland has been confirmed and emphasized, 2,13 and Holleb et al. 6 even presumed the male breast not to possess lobules. This is not in accordance with our observation, nor with that of others. 12 Acinar and lobular formation, initially attributed to exogenous estrogen administration, has been associated with prepubertal gynecomastia but may be found in less than 1% of these idiopathic cases. 12
Influence of Castration and Estrogen Treatment
We observed moderate acinar and lobular formation to occur in men hormonally castrated for prostate cancer, and full acinar and lobular formation as a result of combined progestative and estrogenic treatment in chemically castrated male-to-female transsexuals. A further increase in the plasma estrogen-to-androgen ratio occurs in both groups because both are treated with antiandrogens. The difference between our treatment for men with prostatic cancer and that for male-to-female transsexuals lies in the administration of estrogens and progestative antiandrogens in the latter group. Cyproterone acetate is a progestative drug, whereas flutamide and bicalutamide are not, and progestative drugs are known to stimulate the formation of acini and lobules in females. 7 Because the nonprogestative chemical castration in our male patients treated for prostatic cancer did not result in full acinar and lobular formation, although progestative chemical castration combined with estrogen intake in the transsexual patients did, we conclude that exposure to exogenous estrogens and progestative drugs is needed to induce the occurrence of acini and lobules in chemically castrated men. Hence, Orentreich and Durr 9 appropriately concluded from their theoretical studies that estrogen alone or combined with orchidectomy may not always induce acinar formation in the male mammary gland. These authors thought that it could not be determined whether estrogen, orchidectomy, and progesterone together always produce lobules and acini, but they inferred that some castrated male-to-female transsexuals who had received estrogens and progestins for prolonged periods have breast tissue that histologically simulates that of the female, that is, with acinar and lobular formation. 9 Our study now shows their hypothesis in general to be correct, but it does not take an orchidectomy for the acinar and lobular formation to occur, and moreover, such formation seems to decrease when progestative antiandrogen treatment is stopped after surgical castration.
Our findings in patient F indicate that prolonged and regular intake of proper doses of progestins and estrogens is needed for the full development and maintenance of the female histology. In this case, only moderate acinar development and few hormonally stimulated nuclei could be observed and apoptosis was regularly found in the lobules.
Mammary Metaplasia in Male-to-Female Transsexuals
Pseudolactational changes occur rarely in lobules formed in idiopathic gynecomastia. Apocriene metaplasia may occur in all three phases of gynecomastia, but focal squamous metaplasia is most common in the florid stage. Extensive squamous metaplasia is present in rare cases only. 12 Focal apocrine metaplasia was observed in the breast of patient N and may be the result of a prolonged period of estrogen treatment. Apart from being exposed to estrogens, however, this patient's mammary tissue also had been exposed to exogenous androgens for 2 years after the development of the glands, and this might have had its influence on the development of metaplasia. Still, from an immunohistochemical study of the long-term effects of androgen on the female-to-male breast, Burgess and Shousha 3 concluded that the prevalence of apocrine metaplasia was not statistically different from that seen in normal female control subjects. They found the only statistically significant difference to be the presence of microcalcifications in the fully developed but androgen-exposed breasts in some female-to-male transsexual patients. The cause of this was not clear but probably did not indicate an increased risk of breast cancer in that population because microcalcification can be seen in association with benign and malignant breast diseases. 3 So far only four cases of breast cancer in male-to-female transsexuals allegedly induced by excessive exposure to exogenous estrogens have been documented. 4,10,14 The risk of breast cancer after hormonal feminization of male-to-female transsexuals remains unknown. The degree of risk may well be a function of the amount of hormone used, but comparative statistics have not been ascertained. It is most likely that the male-to-female transsexual patient has the same risk of breast malignancy as does a normal female, provided that she is treated conservatively with estrogens. 1,15,16 Still, the onset of exposure to progestative drugs and estrogens appears later in life than in the genetic female, and therefore the lifetime risk of breast cancer in male-to-female transsexuals is probably less.
A slight increase in the plasma estrogen-to-androgen ratio usually does not induce acinar and lobular formation in the male breast. In men treated with nonprogestative antiandrogens for prostate cancer, only moderate acinar and lobular formation occurs. Only in male-to-female transsexuals in whom progestative chemical castration is combined with feminizing estrogen therapy will full acini and lobular formation occur. Hence, combined progestative antiandrogens and estrogens is necessary for the genetically male breast to mimic the natural histology of the female breast. Orchidectomy does not contribute to the development of acini and lobules. Metaplasia may occur in breasts of male-to-female transsexuals, but so far, only four cases of breast cancer in male-to-female transsexuals have been documented. Provided that they are treated conservatively with estrogens, it is suggested that male-to-female transsexuals have the same annual risk of breast malignancy as do genetic females.
1. Asscheman H, Gooren LJG. Hormone treatment in transsexuals. J Psychol Hum Sexual 1992; 5:39–54.
2. Bartoli C, Zurrida SM, Clemente C. Phyllodes tumor in a male patient with bilateral gynaecomastia induced by oestrogen therapy for prostatic carcinoma. Eur J Surg Oncol 1991; 17:215–7.
3. Burgess HE, Shousha S. An immunohistochemical study of the long-term effects of androgen administration on female-to-male transsexual breast
: a comparison with normal female breast
and male breast
showing gynaecomastia. J Pathology 1993; 170:37–43.
4. Ganly I, Taylor EW. Breast
cancer in a trans-sexual man receiving hormone replacement therapy. Br J Surg 1995; 82:341.
5. Hage JJ. Medical requirements and consequences of sex reassignment surgery. Med Sci Law 1995; 35:17–24.
6. Holleb AI, Freeman HP, Farrow HJ. Cancer of male breast
, part II. N Y State J Medicine 1968; 68:656–63.
7. McCarty KS Jr Tucker JA. Breast
. In: Sternberg SS, ed. Histology
for pathologists. New York: Raven Press, 1992: 893–902.
8. Nuttall FQ. Gynecomastia as a physical finding in normal men. J Clin Endocrinol Metab 1979; 48:338–40.
9. Orentreich N, Durr NP. Mammogenesis in transsexuals. J Invest Dermatol 1974; 63:142–6.
10. Pritchard TJ, Pankowsky DA, Crowe JP, Abdul-Karim FW. Breast
cancer in a male-to-female transsexual—a case report. JAMA 1988; 259:2278–80.
11. Ribeiro GG, Phillips HV, Skinner LG. Serum oestradiol-17b, testosterone, luteinizing hormone, and follicle-stimulating hormone in males with breast
cancer. Br J Cancer 1980; 41:474–7.
12. Rosen PP. Benign proliferative lesions of the male breast
. In: Rosen PP, ed. Rosen's breast
pathology. Philadelphia: Lippincott-Raven, 1997: 609–17.
13. Schwartz IS, Wilens SL. The formation of acinar tissue in gynecomastia. Am J Pathol 1963; 43:797–803.
14. Symmers WC. Carcinoma of the breast
in trans-sexual individuals after surgical and hormonal interference with the primary and secondary sex characteristics. BMJ 1968; 2:83–5.
15. van Kesteren PJM, Asscheman H, Megens JAJ, Gooren LJG. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf) 1997; 47:337–42.
16. Wollman L. Office management of the postoperative male transsexual. In: Green R, Money J, eds. Transsexualism
and sex reassignment. Baltimore: Johns Hopkins Press, 1969: 331–3.
Keywords:© 2000 Lippincott Williams & Wilkins, Inc.
Transsexualism; Breast; Histology; Estrogens; Castration