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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.