Gender specificity in the neural regulation of the response to stress: new leads from classical paradigms.

Pronounced gender-related differences are observable in the regulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) activity under basal and stress-related conditions, and by circulating glucocorticoid levels. This article reviews recent studies that have unequivocally demonstrated that these differences emerge from the organizational effects of gonadal steroids during early brain development. Although largely masked by the dominating role of glucocorticoids in maintaining feedback thresholds, gonadal steroids continue to exert gender-specific activational effects on the LHPA axis through adulthood. The importance of these modulatory effects of gonadal steroids may be reflected in gender differences in the incidence of psychopathologies that are accompanied by symptoms of LHPA dysregulation. One goal of this review is to highlight the need for further investigations into the (still elusive) cellular and molecular mechanisms underlying the activational effects of sex steroids, which may provide leads for neuroprotective hormone replacement strategies.