Department of Basic Medical Sciences, University of Arizona College of Medicine - Phoenix Phoenix, AZ, USA.
Front Endocrinol (Lausanne). 2011 Nov 10;2:65. doi: 10.3389/fendo.2011.00065. eCollection 2011.
Activation of the hypothalamo-pituitary-adrenal (HPA) axis is a basic reaction of animals to environmental perturbations that threaten homeostasis. These responses are ultimately regulated by neurons residing within the paraventricular nucleus (PVN) of the hypothalamus. Within the PVN, corticotrophin-releasing hormone (CRH), vasopressin (AVP), and oxytocin (OT) expressing neurons are critical as they can regulate both neuroendocrine and autonomic responses. Estradiol (E2) and testosterone (T) are well known reproductive hormones; however, they have also been shown to modulate stress reactivity. In rodent models, evidence shows that under some conditions E2 enhances stress activated adrenocorticotropic hormone (ACTH) and corticosterone secretion. In contrast, T decreases the gain of the HPA axis. The modulatory role of testosterone was originally thought to be via 5 alpha reduction to the potent androgen dihydrotestosterone (DHT) and its subsequent binding to the androgen receptor, whereas E2 effects were thought to be mediated by estrogen receptors alpha (ERalpha) and beta (ERbeta). However, DHT has been shown to be metabolized to the ERbeta agonist, 5α- androstane 3β, 17β Diol (3β-Diol). The actions of 3β-Diol on the HPA axis are mediated by ERbeta which inhibits the PVN response to stressors. In gonadectomized rats, ERbeta agonists reduce CORT and ACTH responses to restraint stress, an effect that is also present in wild-type but not ERbeta-knockout mice. The neurobiological mechanisms underlying the ability of ERbeta to alter HPA reactivity are not currently known. CRH, AVP, and OT have all been shown to be regulated by estradiol and recent studies indicate an important role of ERbeta in these regulatory processes. Moreover, activation of the CRH and AVP promoters has been shown to occur by 3β-Diol binding to ERbeta and this is thought to occur through alternate pathways of gene regulation. Based on available data, a novel and important role of 3β-Diol in the regulation of the HPA axis is suggested.
下丘脑-垂体-肾上腺 (HPA) 轴的激活是动物对威胁内稳态的环境干扰的基本反应。这些反应最终由下丘脑室旁核 (PVN) 内的神经元调节。在 PVN 中，促肾上腺皮质激素释放激素 (CRH)、血管加压素 (AVP) 和催产素 (OT) 表达神经元至关重要，因为它们可以调节神经内分泌和自主反应。雌二醇 (E2) 和睾酮 (T) 是众所周知的生殖激素；然而，它们也被证明可以调节应激反应。在啮齿动物模型中，有证据表明，在某些情况下，E2 增强应激激活的促肾上腺皮质激素 (ACTH) 和皮质酮分泌。相比之下，T 降低了 HPA 轴的增益。睾酮的调节作用最初被认为是通过 5α 还原为强效雄激素二氢睾酮 (DHT) 及其随后与雄激素受体结合，而 E2 作用被认为是通过雌激素受体 alpha (ERalpha) 和 beta (ERbeta) 介导的。然而，已经表明 DHT 被代谢为 ERbeta 激动剂，5α-雄烷 3β，17β 二醇 (3β-Diol)。3β-Diol 对 HPA 轴的作用是通过抑制 PVN 对应激源的反应的 ERbeta 介导的。在去势大鼠中，ERbeta 激动剂减少了束缚应激引起的 CORT 和 ACTH 反应，这种作用在野生型但不在 ERbeta 敲除小鼠中也存在。目前尚不清楚 ERbeta 改变 HPA 反应性的神经生物学机制。CRH、AVP 和 OT 均受雌二醇调节，最近的研究表明 ERbeta 在这些调节过程中起重要作用。此外，已经表明 3β-Diol 通过与 ERbeta 结合来激活 CRH 和 AVP 启动子，并且这被认为是通过基因调控的替代途径发生的。基于现有数据，提出了 3β-Diol 在调节 HPA 轴中的一个新的和重要作用。
