Neuroendocrine mediation of socially induced anovulation

社会诱发的无排卵的神经内分泌调节

• 批准号: 7096581
• 负责人: Mark E Wilson
• 金额: $ 44.59万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-20 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7096581
• 关键词: Macaca mulatta; arginine vasopressin; behavior test; behavioral /social science research tag; blood tests; enzyme linked immunosorbent assay; female; gene expression; genetic polymorphism; gonadotropin releasing factor; hormone biosynthesis; hormone inhibitor; hormone regulation /control mechanism; hypothalamic pituitary adrenal axis; in situ hybridization; ovary disorder; ovulation; psychological stressor; receptor expression; serotonin inhibitor; social dominance; social status; statistics /biometry

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.

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过少在女性中很常见，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），是卵巢功能衰竭的一种可逆形式，其中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）分泌。 由于FHCA女性是皮质激素过多的，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如何产生这种失调，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分泌。 此外，遗传因素可能是重要的，因为在编码5-羟色胺再摄取转运蛋白（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。 与女性FHCA一样，生活在稳定群体中的社会从属雌性恒河猴表现出HPA失调和持续的促性腺激素缺乏症。 使用这种动物模型，该项目将确定社会压力抑制GnRH的神经内分泌和分子机制。 具体目标1将检验雌二醇通过减少糖皮质激素负反馈增强应激诱导的CRH和AVP增加的假设，并且这在SERT基因中具有短变体的女性中增强。 这一目标也将测试的假设，低肽血症，从属女性的特点，行为，以维持这种HPA失调。 使用特异性CRH和AVP受体拮抗剂以及CRH和/或AVP的输注，目的2将检验以下假设：CRH-AVP协同抑制减少了下级雌性的促性腺激素分泌。 目的3：验证雌激素诱导的CRH-AVP协同抑制雌性动物促性腺激素分泌是通过阿片途径和抑制下丘脑GnRH表达介导的假说。 该项目将阐明介导社会诱导的促性腺激素缺乏症的神经内分泌机制，从而提高卫生服务提供者诊断和治疗女性FHCA的能力。