Neuroendocrine Regulation of Reproduction by Glucocorticoids

糖皮质激素对生殖的神经内分泌调节

• 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
• 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' 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

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。这 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 归因于压力的身体症状。对于女性来说，压力被认为是发展的主要因素。 月经周期紊乱、闭经和不孕症影响 25% 的育龄妇女。迄今为止， 应激性不孕症的神经内分泌原因尚不完全清楚。内的几条途径 大脑会因压力而激活。下丘脑-垂体-肾上腺 (HPA) 轴是一种常见且关键的反应 所有压力源。 HPA 轴控制循环糖皮质激素。尽管糖皮质激素已 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。 啮齿动物中的糖皮质激素会扰乱雌性小鼠的排卵周期。此外，压力水平 糖皮质激素可以降低平均血浆黄体生成素 (LH) 或阻止排卵前 LH 激增 女性。理论上，要么平均 LH 减少，大概反映了 LH 脉冲的抑制，要么 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 这会导致排卵前 LH 激增。我们还不知道皮质酮如何扰乱 LH 脉冲 女性以及这种机制在男性中是否不同。我们也不知道升高皮质酮是否是必要的 男性和女性因压力而破坏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) 神经元激活并降低促性腺激素对 GnRH 的反应。目标 1 将决定如何 皮质酮的应激水平抑制排卵前 LH 激增。目标 2 将确定机制 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 应激对生殖影响的信号。该提案的结果有可能带来新发现 管理和治疗月经周期紊乱和不孕症，以及优化治疗或 改善那些需要辅助生殖技术的夫妇的结果。该提案的资金将 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。