Implications of estrogen-dependent brain organization for gender differences in hypothalamo-pituitary-adrenal regulation.

Estrogens, derived from the aromatization of testosterone in the brain, account for sex-specific organization of neural circuits controlling gonadotropin release and sexual behavior. This study examines the possible organizing role of perinatal gonadal steroids in the manifestation of known, albeit unexplained, male-female differences in basal and stress-related adrenocortical secretion. We document here the existence of gender-specific differences in the gene expression of hypothalamic corticotropin-releasing hormone (CRH), and hippocampal and hypothalamic glucocorticoid receptors (GR), diurnal corticosterone secretion, as well as in the responsiveness of CRH and GR mRNA levels to exogenous estradiol. In addition, we report that neonatal estrogenization of female rats profoundly affects several regulatory substrates of the hypothalamo-pituitary-adrenal (HPA) axis, namely, the gene expression of CRH, arginine-vasopressin (AVP) and GR in the brain, and the responsiveness of these parameters to estrogen. The neonatal treatment appeared to "defeminize" a number of neuroendocrine mechanisms related to HPA function; these changes were reminiscent of those observed in earlier studies on sexual differentiation of reproductive behavior and hormonal secretion. The results indicate a pivotal role for estrogens during early development for the determination of gender-specific differences in HPA function in the mature animal and demonstrate for the first time that the brain-organizing actions of gonadal steroids may extend to nonreproductive neuroendocrine axes.