Neuroendocrine Regulation of Reproduction by Glucocorticoids

项目总结/摘要 这项研究的总体目标是了解压力如何破坏生殖功能和生育能力。的 压力的影响在我们的社会中是广泛的;超过75%的美国人报告经常经历 压力引起的身体症状在女性中，压力被认为是发展的主要因素， 月经周期紊乱、闭经和不孕，影响25%的育龄妇女。迄今为止 神经内分泌引起的应激性不孕症的原因还不完全清楚。其中的几条路径 大脑被压力激活。下丘脑-垂体-肾上腺（HPA）轴是一种常见的和关键的反应 所有的压力源。HPA轴控制循环糖皮质激素。虽然糖皮质激素一直是 被认为是应激诱导的生殖抑制的关键介质，关于其精确的表达方式知之甚少。 糖皮质激素减少GnRH或促性腺激素分泌的部位或机制， 正常女性或糖皮质激素过量的情况下，如库欣综合征对应激的反应。 我们实验室的初步研究表明，皮质酮的应激样增加， 糖皮质激素在啮齿类动物中，可以破坏雌性小鼠的排卵周期。此外， 糖皮质激素可降低平均血浆促黄体生成激素（LH）或阻断排卵前LH峰， 女性理论上，平均LH减少，可能反映LH脉冲抑制，或 干扰LH峰的产生可能会导致女性排卵周期中断，因为 作为内分泌事件链的早期步骤，脉冲式LH分泌对于雌二醇的产生是必需的 导致排卵前LH激增我们还不知道皮质酮如何干扰LH脉冲， 女性，如果这种机制在男性中不同。我们也不知道皮质酮升高是否是必要的， 由于压力而引起的男性和女性排卵周期或生育能力的中断。这些是主要目标 这一建议，测试了以下总体假设：增强分泌皮质酮在压力 通过损害LH脉冲的调节来破坏雄性和雌性的生殖神经内分泌功能 和/或通过抑制kisspeptin（Kiss 1）和促性腺激素释放激素（gonadotropin releasing hormone） （GnRH）神经元激活和促性腺激素对GnRH的反应性降低。目标1将决定 应激水平的皮质酮抑制排卵前LH峰。目标2将确定机制 由此升高的糖皮质激素抑制GnRH和LH脉冲。目标3将评估GR的必要性 压力对繁殖的影响。这项提议的结果有可能导致新的发现 管理和治疗月经周期紊乱和不孕症，以及优化治疗或 改善需要辅助生殖技术的夫妇的结局。该提案的资金将 还允许PI，一个早期阶段和新的研究者，建立一个完全独立的研究计划， 生殖神经内分泌学领域

Project Summary/Abstract The overall goal of this research is to understand how stress disrupts reproductive function and fertility. The impact of stress within our society is widespread; over 75% of Americans report frequently experiencing physical symptoms attributed to stress. In women, stress is considered a major factor in the development of menstrual cycle disorders, amenorrhea, and infertility, affecting 25% of reproductive age women. To date, the neuroendocrine causes of stress-induced infertility are not completely understood. Several pathways within the brain are activated by stress. The hypothalamic-pituitary-adrenal (HPA) axis is a common and critical response to all stressors. The HPA axis controls circulating glucocorticoids. Though glucocorticoids have been considered a key mediator of stress-induced reproductive suppression, little is known about the precise location(s) or mechanism(s) by which glucocorticoids diminish GnRH or gonadotropin secretion, either in response to stress in normal women or in conditions of glucocorticoid excess, such as Cushing’s syndrome. Preliminary studies in our laboratory demonstrate that a stress-like increment in corticosterone, the natural glucocorticoid in rodents, can disrupt the ovulatory cycle of the female mouse. Furthermore, stress levels of glucocorticoids can reduce mean plasma luteinizing hormone (LH) or can block the preovulatory LH surge in females. In theory, either a reduction in mean LH, presumably reflecting a suppression in LH pulses, or interference with LH surge generation could contribute to ovulatory cycle disruption in the female, because pulsatile LH secretion is necessary for estradiol production as an early step in the chain of endocrine events which leads to the preovulatory LH surge. We do not yet know how corticosterone disrupts LH pulses in females and if this mechanism differs in males. Nor do we know if elevated corticosterone is necessary for disruption of the ovulatory cycle or fertility in males and females in response to stress. These are major goals of this proposal, tested by the following overall hypothesis: Enhanced secretion of corticosterone during stress disrupts reproductive neuroendocrine function in males and females by impairing the regulation of LH pulses and/or the preovulatory LH surge via inhibition of kisspeptin (Kiss1) and gonadotropin-releasing hormone (GnRH) neuronal activation and decreased gonadotrope responsiveness to GnRH. Aim 1 will determine how a stress level of corticosterone inhibits the preovulatory LH surge. Aim 2 will determine the mechanism(s) whereby elevated glucocorticoids suppress GnRH and LH pulses. Aim 3 will assess the necessity of GR signaling for stress effects on reproduction. Results from this proposal have the potential to lead to discoveries in management and treatment of menstrual cycle disturbances and infertility, as well as, optimized treatment or improved outcome for those couples requiring assisted reproductive technologies. Funding of this proposal will also allow the PI, an Early-Stage and New Investigator, to establish a fully-independent research program in the field of reproductive neuroendocrinology.