The androgen 5α-dihydrotestosterone and its metabolite 5α-androstan-3β,17β-diol inhibit the hypothalamo pituitary-adrenal response to stress by acting through estrogen receptor β-expressing neurons in the hypothalamus

Estrogen receptor beta(ER beta) and androgen receptor (AR) are found in high levels within populations of neurons in the hypothalamus. To determine whether AR or ER beta plays a role in regulating hypothalamo-pituitary-adrenal (HPA) axis function by direct action on these neurons, we examined the effects of central implants of 17 beta-estradiol (E2), 5 alpha-dihydrotestosterone (DHT), the DHT metabolite 5 alpha-androstan-3 beta,17 beta-diol (3 beta-diol), and several ER subtype-selective agonists on the corticosterone and adrenocorticotropin (ACTH) response to immobilization stress. In addition, activation of neurons in the paraventricular nucleus (PVN) was monitored by examining c-fos mRNA expression. Pellets containing these compounds were stereotaxically implanted near the PVN of gonadectomized male rats. Seven days later, animals were killed directly from their home cage (nonstressed) or were restrained for 30 min (stressed) before they were killed. Compared with controls, E2 and the ER alpha-selective agonists moxestrol and propyl-pyrazole-triol significantly increased the stress induced release of corticosterone and ACTH. In contrast, central administration of DHT, 3 beta-diol, and the ER beta-selective compound diarylpropionitrile significantly decreased the corticosterone and ACTH response to immobilization. Cotreatment with the ER antagonist tamoxifen completely blocked the effects of 3 beta-diol and partially blocked the effect of DHT, whereas the AR antagonist flutamide had no effect. Moreover, DHT, 3 beta-diol, and diarylpropionitrile treatment significantly decreased restraint-induced c-fos mRNA expression in the PVN. Together, these studies indicate that the inhibitory effects of DHT on HPA axis activity may be in part mediated via its conversion to 3 beta-diol and subsequent binding to ER beta.