F. Stahl

A neuroendocrine predisposition for homosexuality in men.

In male rats, androgen deficiency during a critical hypothalamic organizational period was shown to give rise to a predominantly female-differentiated brain, homosexual behavior, and demonstration of a positive estrogen feedback effect. A positive estrogen feedback effect was also induced in intact homosexual men in contrast to intact heterosexual and bisexual men. Thus in 21 homosexual men an intravenous injection of 20 mg Presomen (Premarin) produced a significant decrease of serum LH levels followed by an increase above initial LH values. In 20 heterosexual and in five bisexual men, by contrast, intravenous estrogen administration, while producing a significant decrease of the serum LH level, was not followed by an increase above the initial LH values. Using a radioimmunoassay, plasma testosterone levels and 24-hr urinary excretions of unconjugated testosterone of adult homosexual men were found to be in the normal range as observed in heterosexual men. This finding suggests that homosexual men possess a predominantly female-differentiated brain which may be activated to homosexual behavior by normal or approximately normal androgen levels in adulthood.

Short- and Long-Term Effects of Perinatal lnterleukin-1β-Application in Rats

Nervous, endocrine and immune systems are regarded as a complex functional unit, interacting by their specific chemical messengers – neurotransmitters, systemic hormones and hormone-like mediators of immune cells (cytokines). Cytokines are known to affect several endocrine axes. Interleukin-lβ (IL) was administered in rats intraperitoneally twice daily from day 17 to 21 of pregnancy. Some of the IL-treated mothers were rapidly decapitated 1.5 h after the last injection. The fetuses were delivered by cesarean section. Maternal plasma CRF, ACTH and corticosterone were found to be significantly elevated. Fetal adrenal and thymus weights were lower, and plasma corticosterone did not differ from controls. Fetal plasma testosterone was decreased in males, androstenedione was increased in females. Open-field testing revealed a higher total locomotor activity of IL offspring than of controls. IL offspring showed worse results in Skinner box learning than controls. Sexual behavior was only affected in males, showing a higher percentage of female-type lordosis behavior after castration and estrogen treatment compared to controls. At the age of 6 months responsiveness to ‘novel-environment stress’ of IL groups was significantly lower than that of controls in terms of plasma corticosterone. These results indicate that prenatal treatment with IL-lβ results in long-lasting alterations in psychomotor development, behavior as well as in the neuroendocrine system.

Sexual differentiation of gonadotrophin secretion, sexual orientation and gender role behavior

The positive estrogen feedback was found to be a relatively sex-specific reaction of the hypothalamo-hypophyseal system in rats as well as in human beings. It is dependent--most of all--on the estrogen convertible androgen level during sexual brain differentiation, but also on an estrogen priming effect in adulthood. The lower the estrogen convertible androgen or primary estrogen level during brain differentiation, the higher is the evocability of a positive estrogen action on LH secretion in later life. In clinical studies, we were able to induce a positive estrogen feedback on LH secretion in most intact homosexual men in clear-cut contrast to intact hetero- or bisexual men. These findings were strongly confirmed by Gladue and associates. 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. These findings suggest that homosexual males possess, at least in part, a predominantly female-differentiated brain, which may be caused by a low estrogen convertible androgen level during brain organization. Recently, the following relations were found between sex hormone levels during brain differentiation and sex-specific responses in adulthood: (1) estrogens--which are mostly converted, however, from androgens--are responsible for the sex-specific organization of gonadotrophin secretion and hence the evocability of a positive estrogen feedback in later life; (2) estrogens and androgens, occurring during brain differentiation, predetermine synergistically sexual orientation and (3) androgens--without conversion to estrogens--are responsible for the sex-specific organization of gender role behaviour in later life. Furthermore, the organization periods for sex-specific gonadotrophin secretion, sexual orientation and gender role behaviour are not identical but overlapping. Thus, combinations as well as dissociations between deviations of the neuroendocrine organization of sex-specific gonadotrophin secretion, sexual orientation and gender role behaviour are conceivable. Most recently, female-type sexual orientation could be converted to male-type sexual orientation in adult rats by administration of the dopamine agonist and serotonin antagonist lisuride.

Postovulatory sensitization to the negative oestrogen feedback in female rats is probably induced by the preceding decline of the oestrogen concentration in the medial preoptic area

To examine the question if an endogenous oestrogen-independent rhythm is involved in the cyclic variation of sensitivity to the negative feedback of oestrogen recorded in a former study, adult female rats were ovariectomized on subsequent days of a 4-day ovarian cycle, injected with 3 micrograms oestradiol benzoate (OB)/100 g b.w. or oil three days after castration, and autopsied on the following day. Estimation of the serum LH concentration revealed a similar LH-inhibiting effect of OB in all experimental groups. Female rats were then implanted with OB or cholesterol in the medial preoptic area (MPOA) in metoestrus. In part of the rats, the implants were removed on the presumptive day of pro-oestrus to imitate the periovulatory decline of the circulating oestrogen level acting on the MPOA. Evaluation of the sensitivity to the negative oestrogen feedback during oestrus and metoestrus demonstrated that s.c. injected OB was highly effective in suppressing the LH secretion after removal of the OB implants in pro-oestrus, but not in rats with the implants left in place till autopsy. In a final experiment, the pro-oestrous progesterone surge was inactivated by the injection of specific antibodies. An influence of this treatment on the LH-inhibiting effect of OB examined during oestrus and metoestrus could not be found. Taken together the results suggest that the high sensitivity to the negative oestrogen feedback recorded during the postovulatory period in cyclic female rats is mainly induced by the periovulatory fall of the circulating oestrogen level leading to reduction of the medial preoptic oestrogen concentration.

Insulin-Dependent Brain Organization and Diabetes Mellitus

When adult female rats (first generation) were injected with 30 mg of streptozotocin per kg body weight (b.w.) on the first day of pregnancy they developed a mild gestational diabetes. Their offspring (second as well as third generation) displayed increased plasma insulin levels in neonatal life and hypoplasia of the hypothalamic ventromedial nuclei throughout life as well as altered hypothalamic monoamine and β-endorphin concentrations. In adulthood, the offspring exhibited decreased tolerance and increased susceptibility to streptozotocin diabetes, associated with enhanced spleen cell cytotoxicity against β-cells. Such teratogenetic diabetes susceptibility is only transmitted on the maternal side via gestational diabetes, leading to pre- or early postnatal hyperinsulinism. Thus, hyperinsulinism during brain organization, produced by impaired glucose tolerance in pregnancy, is a predisposing teratogenetic factor for the development of diabetes in the offspring. Our experimental data are in agreement with clinical findings: (1) Diabetes transmission between generations was found to be 2–3 times higher on the maternal side than on the paternal side. (2) Subjects born in periods with high food supply showed a significantly higher diabetes prevalence than those born in periods with shortage of food supply. (3) A significantly decreased prevalence of childhood-onset diabetes could be achieved in Berlin/GDR since 1973 by improving systematically diagnostic and therapeutic measures for gestational diabetics.