Sexual Dimorphism of the Human Stress Response May Be Due to Estradiol-Mediated Stimulation of Hypothalamic Corticotropin-Releasing Hormone Synthesis1

Kirschbaum et al.(1) reported that short-term estradiol treatment enhanced hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system responses to psychosocial stress in men.Subtle gender differences in human HPA axis responses, such as increased ACTH and cortisol secretion after ovine corticotropin-releasing hormone (CRH) are well established (2).Also, human female hypothalami have increased CRH content relative to male hypothalami (3).The authors proposed several potential mechanisms for their observation that estradiol enhanced human HPA axis activity, including reduced brain glucocorticoid receptor function, as previously shown in rats (4).Such an effect would reduce the inhibitory effects of glucocorticoid feedback on CRH and ACTH secretion.A further plausible mechanism for their findings may be direct estradiol receptor-mediated stimulation of CRH synthesis and subsequent secretion.The human CRH gene contains five perfect half-palindromic estrogen responsive elements (EREs) within its 5Ј flanking region.Specific and reproducible estrogen receptor-and ERE-mediated enhancement of the human CRH gene promoter was observed in chloramphenicol acetyltransferase reporter constructs (5).Indeed, estradiol-induced stimulation of CRH gene transcription could account for the enhanced HPA axis responses to stress observed in men given estrogen.It would also explain the exaggerated sympathetic nervous system responses to stress, as CRH neurons from the paraventricular nuclei and the amygdala innervate and stimulate arousal and autonomic nonadrenergic centers (6 -8).Estradiol stimulation of CRH gene transcription may also provide, at least in part, the biological basis for the observation that melancholic depression and anorexia nervosa, both disorders associated with central CRH hypersecretion (9), are more prevalent in women than men.