Regulation of progestin receptors in medial amygdala: estradiol, phytoestrogens and sex.

Exposure to estrogens during critical developmental periods and in adulthood affects sex differences in the brain. We examined the roles of estradiol (E2) and phytoestrogens, and their interactions, on potential sex differences in brain. We used aromatase knockout (ArKO) mice, which cannot produce endogenous estrogens, along with wild type (WT) littermates. Mice were gestated, raised and maintained on a diet either rich in phytoestrogens or a diet virtually void of soy-derived phytoestrogens. Adult males and females were gonadectomized and received implants filled with 17-beta-estradiol to induce progestin receptors (PR), while controls received empty implants. Mice were sacrificed five days later and brain sections containing the posterodorsal medial amygdala (MePD) were processed for PR immunoreactivity. Activation of sex differences in PR required adult E2 treatment. A diet high in phytoestrogens was required for expression of sex differences in PR after E2 treatment. Our data underscore the important contribution of dietary phytoestrogens for the development of sex differences in PR-ir in the adult mouse medial amygdala. We hypothesize that both aromatization of androgens to estrogens and dietary sources of additional estrogens are part of the normal requirement for sex differences in the rodent brain.

Roles of oestrogen receptors alpha and beta in behavioural neuroendocrinology: beyond Yin/Yang.

Oestrogen receptor beta (ERbeta) was discovered more than 10 years ago. It is widely distributed in the brain. In some areas, such as the entorhinal cortex, it is present as the only ER, whereas in other regions, such as the bed nucleus of the stria terminalis and preoptic area, it can be found co-expressed with ERalpha, often within the same neurones. These ERs share ligands, and there are several complex relationships between the two receptors. Initially, the relationship between them was labelled as 'yin/yang', meaning that the actions of each complemented those of the other, but now, years later, other relationships have been described. Based on evidence from neuroendocrine and behavioural studies, three types of interactions between the two oestrogen receptors are described in this review. The first relationship is antagonistic; this is evident from studies on the role of oestrogen in spatial learning. When oestradiol is given in a high, chronic dose, spatial learning is impaired. This action of oestradiol requires ERalpha, and when ERbeta is not functional, lower doses of oestradiol have this negative effect on behaviour. The second relationship between the two receptors is one that is synergistic, and this is illustrated in the combined effects of the two receptors on the production of the neuropeptide oxytocin and its receptor. The third relationship is sequential; separate actions of the two receptors are postulated in activation and organisation of sexually dimorphic reproductive behaviours. Future studies on all of these topics will inform us about how ER selective ligands might affect oestrogen functions at the organismal level.

Glucocorticoids affect gonadotropin-releasing hormone immunoreactivity in musk shrew brain.

Multiple interactions between the hypothalamic-pituitary-adrenal and the hypothalamic-pituitary-gonadal systems exist. In this study, we asked if glucocorticoid administration affected gonadotropin-releasing hormone (GnRH) immunoreactivity. We found that musk shrews treated with dexamethasone (DEX), a synthetic glucocorticoid, had more GnRH-immunoreactive (ir) cells in the forebrain than did cortisol- or control-treated animals. The effects of DEX were noted rapidly, within 15 min, after administration. These effects were observed in the forebrain as a whole and also in specific subpopulations of GnRH-ir cells located in the medial septum/diagonal band and the hypothalamus.

Coumestrol antagonizes neuroendocrine actions of estrogen via the estrogen receptor alpha.

The phytoestrogen coumestrol has estrogenic actions on peripheral reproductive tissues. Yet in the brain this compound has both estrogenic and anti-estrogenic effects. We used estrogen receptor alpha knockout mice (ERalphaKO) to determine whether coumestrol has estrogenic actions in mice and also if these effects are mediated by the classic ERalpha. Female wild-type (WT) and ERalphaKO mice were ovariectomized and treated with estradiol (E2), dietary coumestrol, both, or neither compound. Ten days later the animals were sacrificed, blood was collected, and brain tissues were perfused. Fixed brains were sectioned and immunocytochemistry was employed to quantify progesterone receptors (PR) in the medial preoptic (POA) and ventromedial nucleus of the hypothalamus (VMN). Plasma was assayed for luteinizing hormone (LH). Estrogen treatment induced PR immunoreactivity in both regions in brains of WT females. In ERalphaKO mice, lower levels of PR were induced. The stimulatory effects of E2 on PR were attenuated in the POA by cotreatment with coumestrol, and the same trend was noted in the VMN. WT ovariectomized females treated with E2 had low levels of LH, while LH was high in untreated females and even higher in ovariectomized females treated with coumestrol. ERalphaKO females in all treatment groups had high levels of LH. Taken together, the results show that coumestrol has anti-estrogenic actions in the brain and pituitary and that ERalpha mediates these effects.

Steroid implants in the medial preoptic area or ventromedial nucleus of the hypothalamus activate female sexual behaviour in the musk shrew.

Female musk shrews are induced ovulators that do not exhibit a spontaneous behavioural oestrous cycle. Testosterone produced by the ovaries and adrenal glands, is the major steroid hormone in circulation at times of mating, and as such, regulates sexual behaviour. In the first experiment, we identified the neural site(s) of action for testosterone. Hormone implants were placed in one of three targeted brain regions. The neural sites selected were the medial anterior division of the bed nucleus of the stria terminalis (BNSTMA), medial preoptic area (mPOA) and the ventromedial nucleus of the hypothalamus (VMN). Ovariectomized females who received a unilateral testosterone propionate implant in either the mPOA or VMN, were significantly more likely to display sexual behaviour as compared to females who received an implant in the BNSTMA or any other hypothalamic nucleus. In experiments 2 and 3, we investigated whether the behavioural effects of testosterone propionate were mediated by an oestrogen receptor or the androgen receptor. Ovariectomized females that received oestradiol (E2) implants in either the mPOA or VMN were more likely to display receptivity, and had significantly shorter behavioural latencies, as compared to females implanted with either dihydrotestosterone or cholesterol. These data show that neural aromatization of testosterone to E2 in the mPOA or VMN is necessary for optimal activation of female musk shrew sexual behaviour. This finding implies a degree of neural redundancy in the networks that control the expression of sexual receptivity.