An estrogenic effect of 5α-androstane-3β, 17β-diol on the behavioral response to stress and on CRH regulation

The gender difference in behavioral and hormonal response to stress is well known, but the underlying mechanism remains elusive. Arginine-vasopressin (AVP) and corticotrophin-releasing hormone (CRH) are two major regulatory peptides in the brain involved in stress regulation. Their response to stress has been shown to be modulated by sex hormones. The androgen metabolite, 5α-androstane-3β, 17β-diol (3β-diol), has been identified as an estrogenic hormone. It binds to estrogen receptors (ERs) and modulates estrogen response element mediated promoter activities via the ER pathway. The present study involved in vitro transfection assays to examine whether 3β-diol can directly modulate CRH and AVP promoter activity. Our results demonstrate that in CHO-K1 cell lines, when ERs were over-expressed, 3β-diol could significantly stimulate CRH and AVP promoter activity through an ER pathway. The effect of 3β-diol on the behavioral, the CRH and the AVP response to stress in the rat was also investigated. We found that chronic, but not acute administration of 3β-diol significantly decreased the immobile duration in the forced swim test. In rats exposed to the forced swim test, CRH mRNA expression in the hypothalamus was enhanced by chronic 3β-diol administration, while the AVP mRNA expression was not affected. These results suggest that 3β-diol may play an anti-depressive role in affective behavior and may have a direct effect on CRH expression.