Sex differences in the hypothalamic-pituitary-adrenal axis: Roles of estrogen receptor-beta in the adult female rat brain

In animals and humans, the hypothalamic-pituitary-adrenal (HPA) axis represents the major neuroendocrine axis responding to stress. Interestingly, a sex difference exists in HPA function in response to stress, where females exhibit a more robust response than males. Previous studies have shown that this sex difference is at least partly due to the differences in circulating levels of estrogen. The purpose of this project was to reveal the mechanisms of estrogen action in enhancing the activity of HPA axis. In the present studies, we have demonstrated the presence of estrogen receptor-beta (ER-β) in neurons that express corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP), the two important regulators of the HPA axis, in the paraventricular (PVN) and supraoptic (SON) nuclei of the female rat hypothalamus. These findings may represent one mechanism by which estrogen directly increases tone of the two key HPA regulators. This may further underlie the reported gender differences in the HPA response to stress. In addition, it is shown that ER-β is differentially regulated by estrogen vs. glucocorticoids. Estrogen down-regulates, while glucocorticoids up-regulate, ER-β immunoreactivity and mRNA levels in the hypothalamus. Since changes in ER-β concentrations in a given cell could influence its sensitivity to estrogen signals, ER-β autologous down-regulation by estrogen in neurons of the PVN and SON will likely to suppress estrogen sensitivity of these neurons. In contrast, increases in cellular ER-β levels in response to exposure to glucocorticoids will likely enhance cellular sensitivity to estrogen. In light of reports showing that estrogen increases the expression of CRH and AVP in the rodent hypothalamus, an increase in the ER-β protein by glucocorticoids could therefore potentiate activational properties of estrogen on HPA function following chronic glucocorticoid receptor activation. Thus, an additional mechanism underlying the known sex difference in HPA regulation might be through up-regulation of ER-β by stress-elevated levels of glucocorticoids. Taken together, these findings help to define a picture of how estrogen participates in the enhancement of HPA function following stress. This may provide a foundation for further research into the roles of estrogen in a reported sex difference in stress response.