Neuroendocrine mediation of socially induced anovulation

描述(申请人提供)：应激引起的卵巢功能障碍和相关的雌激素减少症在女性中很常见，并可能对健康产生负面影响。这种综合征被称为功能性下丘脑慢性无排卵(FHCA)，是一种可逆的卵巢衰竭形式，其中对生活事件的认知反应激活了中枢神经回路，扰乱了促性腺激素释放激素(GnRH)的分泌。由于患有FHCA的女性患有高皮质醇血症，这种无排卵可能是由于下丘脑-垂体-肾上腺(HPA)轴调节失调导致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导致这种失调的，这种失调是如何持续的，以及过量的CRH和/或AVP如何抑制促性腺激素的分泌。此外，遗传因素可能也很重要，因为编码5-羟色胺再摄取转运体(SERT)基因的短变异多态性的个体更容易受到压力的影响。与患有FHCA的雌性恒河猴一样，生活在稳定群体中的社会地位较低的雌性恒河猴表现出HPA失调和持续的促性腺激素缺乏期。利用这个动物模型，该项目将确定社会压力抑制促性腺激素释放激素的神经内分泌和分子机制。具体目标1将测试这一假设，即雌激素通过减少糖皮质激素的负反馈来增强应激诱导的CRH和AVP的增加，这在SERT基因短变异的女性中得到加强。这一目标也将检验这一假说，即作为从属女性的特征的低蛋白血症，是维持这种HPA失调的因素。使用特定的CRH和AVP受体拮抗剂以及输注CRH和/或AVP，AIM 2将验证以下假设：通过CRH-AVP协同抑制，下属女性的促性腺激素分泌减少。目的3验证雌激素对下丘脑促性腺激素释放激素分泌的协同抑制作用是通过阿片途径和抑制下丘脑促性腺激素释放激素的表达来实现的。该项目将阐明调节社会引起的促性腺激素缺乏症的神经内分泌机制，从而提高保健提供者诊断和治疗女性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.