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 pos sible organizing role of perinatal gonadal steroids in the manifestati on of known, albeit unexplained, male-female differences in basal and stress-related adrenocortical secretion. We document here the existenc e of gender-specific differences in the gene expression of hypothalami c corticotropin-releasing hormone (CRH), and hippocampal and hypothala mic glucocorticoid receptors (GR), diurnal corticosterone secretion, a s well as in the responsiveness of CRH and GR mRNA levels to exogenous estradiol, In addition, we report that neonatal estrogenization of fe male rats profoundly affects several regulatory substrates of the hypo thalamo-pituitary-adrenal (HPA) axis, namely, the gene expression of C RH, arginine-vasopressin (AVP) and GR in the brain, and the responsive ness 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 hormon al secretion, The results indicate a pivotal role for estrogens during early development for the determination of gender-specific difference s in HPA function in the mature animal and demonstrate for the first t ime that the brain-organizing actions of gonadal steroids may extend t o nonreproductive neuroendocrine axes.