Neuroendocrine Regulation of Reproduction by Glucocorticoids

糖皮质激素对生殖的神经内分泌调节

基本信息

批准号：
9895818
负责人：
KELLIE Breen Church
金额：
$ 32.16万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-10 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895818
关键词：
Affect Age Amenorrhea American Anterior Assisted Reproductive Technology Brain Cells Corticosterone Couples Cushing Syndrome Development Endocrine Estradiol Event Feedback Female Fertility Frequencies Functional disorder Funding GNRH1 gene Generations Glucocorticoids Goals Gonadotrope Cell Gonadotropin Hormone Releasing Hormone Gonadotropins Hormone secretion Hypothalamic structure Impairment Infertility KISS1 gene Laboratories Lead Location Luteinizing Hormone Mediating Mediator of activation protein Menstrual cycle Menstruation Disturbances Mus Neurons Neurosecretory Systems Ovarian Pathway interactions Periodicity Physiologic pulse Physiological Pituitary Gland Plasma Production Protocols documentation Psychosocial Stress Regulation Reporting Reproduction Research Research Personnel Rodent Sampling Serum Signal Transduction Societies Stress System Testing Treatment outcome Woman Women&apos s Health experience experimental study hypothalamic-pituitary-adrenal axis improved outcome in vivo male mouse model novel physical symptom programs reproductive reproductive function reproductive neuroendocrinology response stressor theories treatment optimization

项目摘要

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.

项目概要/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。压力对我们社会的影响是广泛的；超过 75% 的美国人表示经常经历压力对于女性来说，压力被认为是导致身体症状的一个主要因素。月经周期紊乱、闭经和不孕症影响 25% 的育龄妇女。应激性不孕症的神经内分泌原因尚不完全清楚。下丘脑-垂体-肾上腺 (HPA) 轴会被压力激活，这是一种常见且关键的反应。 HPA 轴控制循环糖皮质激素。被认为是压力引起的生殖抑制的关键介导因素，但人们对精确的影响知之甚少。糖皮质激素减少 GnRH 或促性腺激素分泌的位置或机制，无论是在正常女性或在糖皮质激素过量的情况下（例如库欣综合征）对压力的反应。我们实验室的初步研究表明，皮质酮（天然的皮质酮）会出现类似压力的增加。啮齿类动物中的糖皮质激素会扰乱雌性小鼠的排卵周期。糖皮质激素可降低平均血浆黄体生成素 (LH) 或阻止排卵前 LH 激增理论上，要么是平均 LH 减少，可能反映了 LH 脉冲的抑制，要么是干扰 LH 激增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，脉冲性 LH 分泌对于雌二醇的产生是必要的这导致排卵前 LH 激增，我们尚不清楚皮质酮如何扰乱 LH 脉冲。我们也不知道男性是否需要升高皮质酮。因压力而破坏男性和女性的排卵周期或生育能力这些是主要目标。该提议通过以下总体假设进行检验：应激期间皮质酮的分泌增强通过损害 LH 脉冲的调节来破坏男性和女性的生殖神经内分泌功能和/或通过抑制 Kisspeptin (Kiss1) 和促性腺激素释放激素而导致排卵前 LH 激增 (GnRH) 神经元激活和促性腺激素对 GnRH 的反应性降低将决定如何。皮质酮的应激水平抑制排卵前 LH 激增，目标 2 将决定其机制。因此，糖皮质激素升高会抑制 GnRH 和 LH 脉冲，目标 3 将评估 GR 的必要性。该提案的结果有可能带来新的发现。管理和治疗月经周期紊乱和不孕症，以及优化治疗或该提案的资金将改善那些需要辅助生殖技术的夫妇的结果。还允许 PI（早期和新研究者）在以下领域建立完全独立的研究计划：生殖神经内分泌学领域。