Neuroendocrine mediation of socially induced anovulation

描述（由申请人提供）：压力引起的卵巢功能障碍和相关的雌激素分泌不足在女性中很常见，对健康有负面影响。这种综合征被称为功能性下丘脑慢性无排卵（FHCA），是一种可逆性卵巢功能衰竭，对生活事件的认知反应激活中枢神经回路，破坏促性腺激素释放激素（GnRH）的分泌。由于患有FHCA的女性是高肾上腺皮质激素，这种无排卵可能是由于下丘脑-垂体-肾上腺（HPA）轴失调产生的促肾上腺皮质激素释放激素（CRH）和精氨酸加压素（AVP）释放增加所致。然而，目前尚不清楚行为事件是如何产生这种失调的，失调是如何持续的，以及过量的CRH和/或AVP是如何抑制促性腺激素分泌的。此外，遗传因素可能很重要，因为在编码血清素再摄取转运蛋白（SERT）的基因中具有短变异多态性的个体更容易受到压力的影响。与患有FHCA的女性一样，生活在稳定群体中的社会从属雌性恒河猴也表现出HPA失调和持续的促性腺激素缺乏。利用这种动物模型，该项目将确定社会压力抑制GnRH的神经内分泌和分子机制。特异性目标1将验证雌二醇通过减少糖皮质激素负反馈来增强应激诱导的CRH和AVP增加的假设，这在SERT基因短变体的女性中得到增强。这一目的也将检验低肽血症（从属女性的特征）维持这种HPA失调的假设。使用特异性的CRH和AVP受体拮抗剂以及输注CRH和/或AVP， Aim 2将测试促性腺激素分泌在从属雌性中通过CRH - AVP协同抑制而减少的假设。Aim 3将检验雌二醇诱导的CRH - AVP协同抑制下属雌性促性腺激素分泌的假设是通过阿片通路和下丘脑GnRH表达的抑制来介导的。该项目将阐明介导社会诱导的促性腺激素缺乏的神经内分泌机制，从而提高保健提供者诊断和治疗妇女FHCA的能力。

DESCRIPTION (provided by applicant): Stress-induced ovarian dysfunction and associated hypoestrogenism is common in women and can have a negative impact on health. Termed functional hypothalamic chronic anovulation (FHCA), this syndrome is a reversible form of ovarian failure in which cognitive responses to life events activate central neural circuits that disrupt gonadotropin releasing hormone (GnRH) secretion. Since women with FHCA are hypercortisolemic, this anovulation may result from increased release of corticotropin releasing hormone (CRH) and arginine vasopressin (AVP) produced by a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. However, it is not clear how behavioral events produce this dysregulation, how the dysregulation is sustained, and how excess CRH and/or AVP inhibit gonadotropin secretion. Also, genetic factors may be important as individuals with a short variant polymorphism in the gene encoding the serotonin reuptake transporter, SERT, are more susceptible to stress. Like women with FHCA, socially subordinate female rhesus monkeys living in stable groups show HPA dysregulation and sustained periods of gonadotropin deficiency. Using this animal model, the project will determine the neuroendocrine and molecular mechanisms by which social stress inhibits GnRH. Specific Aim 1 will test the hypothesis that estradiol potentiates stress-induced increases in CRH and AVP by decreasing glucocorticoid negative feedback and this is enhanced in females with the short variant in the SERT gene. This aim will also test the hypothesis that hypoleptinemia, characteristic of subordinate females, acts to sustain this HPA dysregulation. Using specific CRH and AVP receptor antagonists as well as infusions of CRH and/or AVP, Aim 2 will test the hypothesis that gonadotropin secretion is diminished in subordinate females by a CRH - AVP synergistic inhibition. Aim 3 will test the hypothesis that the estradiol-induced CRH - AVP synergistic inhibition of gonadotropin secretion in subordinate females is mediated through an opioid pathway and the inhibition of hypothalamic GnRH expression. This project will clarify the neuroendocrine mechanisms mediating socially-induced gonadotropin deficiency and will thus enhance the ability of health providers to diagnose and treat FHCA in women.