F. Döcke

Paradoxical Effects of Estrogen on Brain Differentiation

In female rats treated with 100 µg estradiol benzoate on the first day of life, the following data were obtained in adult or juvenile life: (1) predominance of vaginal estrus; (2) significantly enhanc

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.

Studies on the Puberty-Controlling Function of the Mediocortical Amygdala in the Immature Female Rat

The puberty-controlling function of the mediocortical amygdala in immature female rats was investigated by lesioning this region at different ages and by studying the effects on the onset of spontaneous and experimentally-induced precocious puberty. At 21 days of age, bilateral lesions in the anterior mediocortical amygdala (AMCA) caused precocious puberty and enhanced the puberty-accelerating effect of bilateral lesions produced simultaneously in the medial preoptic area (MPA). Similar lesions, ineffective on day 26, delayed the onset of puberty when produced on day 32 in otherwise untreated rats. Lesions in the posterior mediocortical amygdala (PMCA) at 26 or 32 days of age postponed puberty in untreated rats and inhibited the advancement of their 1st pubertal ovulation that resulted from damage to the ventromedial-arcuate region (VAH) or daily administration of 0.05 mug estradiol benzoate (EB) per 100 g b.w. The results confirm earlier findings of different gonadotropin-controlling activities of the AMCA and PMCA in immature female rats and suggest maturational changes in the function of both areas. The gonadotropin-inhibiting action exerted by the AMCA at 3 weeks of age is lost when puberty approaches; a gonadotropin-stimulating activity seems to develop in both the AMCA and PMCA.

Influence of the medial preoptic dopaminergic activity on the efficiency of the negative estrogen feedback in prepubertal and cyclic female rats.

Immature and adult female rats were bilaterally implanted in the medial preoptic area (MPOA) or hypothalamic ventromedial-arcuate region (VMAR) with the dopamine (DA) antagonist, pimozide, or the DA agonist, apomorphine, and the sensitivity to the LH-inhibiting effect of a subcutaneous injection of estradiol benzoate (EB), the onset of puberty and ovarian cyclicity were investigated. Diminution of the inhibitory effect of EB on LH secretion was recorded in ovariectomized immature and adult females implanted in the MPOA with pimozide. This response was not obtained in rats implanted in the VMAR. In contrast, medial preoptic, but not intrahypothalamic, implantation of agar pellets containing apomorphine resulted in enhanced sensitivity to estrogen both prepubertally and during the ovarian cycle. The sensitizing effect of apomorphine was completely prevented in prepubertal rats by pretreatment with EB for 6 days. Bilateral implantation of pimozide-agar pellets in the MPOA of 28-day-old intact females induced significant advancement of the onset of puberty, whereas sexual maturation was not affected by daily subcutaneous injections of the DA antagonist from day 28 till the day of vaginal opening. In adult 4-day-cyclic rats fitted with guide cannulae, the forthcoming ovulation was delayed for about 7 days as compared to the controls implanted with agar if apomorphine was placed in the MPOA from the morning of metestrus to the morning of diestrus. Similar implants located in the VMAR were ineffective in this regard. The results suggest that: (1) low DA activity in the MPOA reduces and high activity enhances the sensitivity of the negative estrogen feedback in immature and adult female rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Medial Preoptic Area, Estrogen, and the Peripubertal Desensitization to the Negative Estrogen Feedback in Female Rats

Bilateral lesions placed in the medial preoptic area (MPOA) markedly diminished the luteinizing hormone-(LH-) and follicle-stimulating hormone- (FSH-) inhibiting effects of s.c. injected or intrahypothalamically implanted estradiol benzoate (EB) in ovariectomized immature rats. Desensitization to the negative estrogen feedback was also recorded in immature rats implanted into the MPOA with a mixture of 1 part EB and 240 or 360 parts cholesterol. Estrogen implants located in the hypothalamic ventromedial-arcuate region were ineffective in this regard. Whereas precocious puberty resulted from the implantation of EB into the MPOA, a delay of puberty onset was induced by medial preoptic implants of the antiestrogen clomiphene citrate which also enhanced the LH-suppressing effect of s.c. administered EB in prepubertal females. It is proposed that an increase of the estrogen concentration in the MPOA inactivates medial preoptic neurons that exert a restraining influence on tonic LH (and FSH) secretion by sensitizing the mediobasal hypothalamus to the negative feedback action of estrogen. This mechanism may be involved in the control of the onset of puberty in female rats.

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.