Since 1964, we have found positive estrogen feedback to be a relatively sex-specific reaction of the hypothalamo-hypophyseal system in rats as well as in human beings. It is dependent on the estrogen-convertible androgen level during sexual brain differentiation and also on estrogen priming in adulthood. The lower the estrogen-convertible androgen or primary estrogen level during brain differentiation, the higher the evocability of a positive estrogen action on LH secretion in later life. In clinical studies, we induced a positive estrogen feedback luteinizing hormone secretion in most intact homosexual men, in clear-cut contrast to intact heterosexual or bisexual men. In addition, the evocability of a positive estrogen feedback was also demonstrable in most homosexual male-to-female transsexuals in significant contrast to hetero-or bisexual male-to-female transsexuals. The following relations have been found between sex hormone levels during brain differentiation and sex-specific responses in adulthood: (i) Estrogens, which are mostly converted from androgens, are responsible for the sex-specific organization of gonadotropin secretion and hence the evocability of a positive estrogen feedback in later life; (ii) both estrogens and androgens, occurring during brain differentiation, predetermine sexual orientation, and (iii) androgens, without conversion to estrogens, are responsible for the sex-specific organization of gender role behavior. Furthermore, the organization periods for sex-specific gonadotropin secretion, sexual orientation, and gender role behavior are not identical but overlapping. Thus, combinations as well as dissociations between deviation of the neuroendocrine organization of sex-specific gonadotropin secretion, sexual orientation, and gender role behavior may occur.