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
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
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DOI：
10.1523/jneurosci.3777-05.2006
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发表时间：
2006-02-01
影响因子：
5.3
通讯作者：
Handa, RJ
中科院分区：
文献类型：
--
作者：
Lund, TD;Hinds, LR;Handa, RJ
雌激素受体β (ER β)和雄激素受体（AR）在下丘脑神经元群中含量很高。为了确定AR或ER β是否通过直接作用于这些神经元来调节下丘脑-垂体-肾上腺（HPA）轴功能，我们研究了17 β -雌二醇（E2）、5 α -二氢睾酮（DHT）、DHT代谢物5 α -雄激素-3 β、17 β -二醇（3 β -二醇）和几种ER亚型选择性激动剂对固定应激下皮质酮和促肾上腺皮质激素（ACTH）反应的影响。此外，通过检测c-fos mRNA表达，监测室旁核（PVN）神经元的激活情况。将含有这些化合物的微球立体定向植入去性腺的雄性大鼠的PVN附近。7天后，直接将动物从它们的家庭笼子中杀死（非应激）或在杀死之前被限制30分钟（应激）。与对照组相比，E2和ER α选择性激动剂莫司孕酮和丙基吡唑三醇显著增加应激诱导的皮质酮和ACTH释放。相比之下，中央给药DHT、3 β -二醇和ER β -选择性化合物二乙基丙腈显著降低皮质酮和ACTH对固定的反应。与内质网拮抗剂他莫昔芬共同治疗完全阻断了3 - β -二醇的作用，部分阻断了DHT的作用，而AR拮抗剂氟他胺没有作用。此外，DHT、3 - β -二醇和二乙基丙腈处理显著降低了抑制诱导的PVN中c-fos mRNA的表达。总之，这些研究表明DHT对HPA轴活性的抑制作用可能部分是通过其转化为3 - β -二醇并随后与ER β结合介导的。
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.