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Short-Term and Long-Term Histologic Effects of Castration and Estrogen Treatment on Breast Tissue of 14 Male-to-Female Transsexuals in Comparison With Two Chemically Castrated Men

Kanhai, Robert C.J. M.D.; Hage, J. Joris M.D., Ph.D.; van Diest, Paul J. M.D., Ph.D.; Bloemena, Elisabeth M.D., Ph.D.; Mulder, J. Wiebe M.D., Ph.D.

The American Journal of Surgical Pathology: January 2000 - Volume 24 - Issue 1 - p 74
Original Articles

The histologic changes induced in the mammary gland of male-to-female transsexuals have not yet been reported in the literature. We studied the histologic changes induced by chemical and surgical castration and estrogen therapy in the breasts of 14 such patients, with particular reference to acinar and lobular formation. To objectify the influence of cross-sex treatment, the histologic findings were compared with those in two men treated hormonally for prostate cancer. The slight increase in the plasma estrogen-to-androgen ratio seen in idiopathic gynecomastia 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 acinar and lobular formation occur with hormonally stimulated nuclei and pseudolactational changes. Hence, combined progestative antiandrogens and estrogens are necessary for genetically male breast tissue to mimic the natural histology of the female breast. Orchidectomy does not contribute to this. Apocrine 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.

From the Departments of Plastic and Reconstructive Surgery (R.C.J.K., J.J.H., J.W.M.) and Pathology (P.J.v.D., E.B.), Academisch Ziekenhuis Vrije Universiteit, Amsterdam, The Netherlands.

Address correspondence and reprint requests to Dr. J. Joris Hage, Department of Plastic and Reconstructive Surgery, Academisch Ziekenhuis Vrije Universiteit, PO Box 7057, NL-1007 MB Amsterdam, The Netherlands.

Driven by a persistent and unchangeable need to undo the discrepancy between physical reality of the body and gender of the mind, most male-to-female transsexuals seek demasculinization and feminization through hormonal and surgical treatment. 5 For this, they are chemically and subsequently surgically castrated and exposed to lifelong estrogen administration. 1,15 The histologic changes induced by such treatment in the mammary gland have not yet been reported in the literature. Orentreich and Durr 9 described the clinical effects of prolonged estrogen administration on the breast of male-to-female transsexuals but did not examine the breast tissue histologically. Pritchard et al. 10 described the pathohistology of breast tissue observed in a male-to-female transsexual with breast cancer, but not the normal mammary histology.

In this article, we present the short-term and long-term histologic changes induced in the male-to-female transsexual breast by chemical and surgical castration and estrogen therapy, with particular reference to acinar and lobular formation. To objectify the influence of estrogen treatment, the findings were compared with the histologic findings in men treated hormonally for prostate cancer.

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MATERIALS AND METHODS

The first series of biopsy specimens of breast tissue was obtained from six chemically castrated male-to-female transsexuals (group 1, Table 1) when they underwent initial augmentation mammaplasty after having been subjected to approximately 18 months of chemical castration by 50 mg of cyproterone acetate (Androcur, Schering AG, Berlin, Germany) twice daily and 50 μg of ethinyl estradiol (Lynoral, Organon, Oss, The Netherlands) twice daily. 1 Cyproteron acetate is a progestative drug with antigonadotropic properties and a strong androgen receptor–blocking effect at tissue level. Ethinyl estradiol is a potent estrogenic chemical modification of 17β-estradiol, with the latter being the main estrogen of the body. The combination of ethinyl estradiol and cyproterone acetate results in maximal suppression of serum testosterone levels and blocking of the androgen receptor. 1

TABLE 1

TABLE 1

The second series of biopsy specimens of breast tissue was obtained from seven male-to-female transsexuals during revision mammaplasty, 1 to 7 years after surgical castration. Before orchidectomy, all had been subjected to chemical castration by 50 mg of cyproterone acetate twice daily, and treatment with 50 μg of ethinyl estradiol twice daily was continued after orchidectomy in all patients. Some patients continued taking cyproterone acetate medication even after orchidectomy had been performed. 1 One additional case is presented in group 2 because the medical history and histologic findings were exceptional. Subcutaneous mastectomy was performed to undo initial male-to-female sex reassignment in this patient, 5 years after starting hormonal treatment.

A third series of biopsy specimens was obtained from two chemically, but not surgically, castrated nontranssexual men treated for prostate cancer (group 3). At the time of surgical correction of clinical gynecomastia by subcutaneous mastectomy, one had been treated for 24 months with 250 mg of flutamide (Eulexin, Schering-Plough, Brussels, Belgium) three times a day, whereas the other one had been treated for 36 months with 50 mg of bicalutamide (Casodex, Zeneca, Ridderkerk, The Netherlands) daily. Flutamide and bicalutamide are nonprogestative antiandrogens. Flutamide stimulates gonadotropin production and subsequently androgen production, but interferes with receptor binding of androgens. Bicalutamide is a nonsteroid antiandrogen that binds competitively to androgen receptors without any other hormonal effect.

Informed consent was obtained from all patients. Biopsy specimens were taken at random and bilateral locations. The surgical specimens were fixed in neutral buffered formaldehyde and embedded in paraffin. All 4-μm thick hematoxylin and eosin–stained slides were reviewed by one pathologist (P.J.v.D.). The results of our study are illustrated by case reports. The observations presented in these reports are representative of the studied groups (Table 1).

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CASE REPORTS

Group 1: Chemically Castrated Male-to-Female Transsexuals

Patient A started cyproterone acetate and ethinyl estradiol therapy after being diagnosed transsexual at the age of 19. Eighteen months later, she underwent combined vaginoplasty and augmentation mammaplasty, and a biopsy specimen of the mammary glands was obtained. Histologic examination showed well-developed acini and lobules (Fig. 1A). Some ducts contained fatty milklike secretions, and several acini showed pseudolactational changes. The nuclei were relatively large and showed conspicuous nucleoli (Fig. 1B).

FIG. 1

FIG. 1

Figure 1

Figure 1

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).

FIG. 2.

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).

FIG. 3.

FIG. 3.

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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.

FIG. 4.

FIG. 4.

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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).

FIG. 5.

FIG. 5.

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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.

FIG. 6.

FIG. 6.

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).

FIG. 7.

FIG. 7.

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DISCUSSION

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

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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.

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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.

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CONCLUSIONS

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.

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REFERENCES

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.
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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:

Transsexualism; Breast; Histology; Estrogens; Castration

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