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: 9177432
• 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 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9177432
• 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; Generations; Glucocorticoids; Goals; Gonadotrope Cell; Gonadotropin Hormone Releasing Hormone; Gonadotropins; 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; Staging; Stress; System; Testing; Treatment outcome; Woman; Women' s Health; abstracting; base; experience; hypothalamic-pituitary-adrenal axis; improved outcome; in vivo; male; mouse model; novel; physical symptom; programs; reproductive; reproductive function; reproductive neuroendocrinology; research study; response; stressor; theories

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.

项目总结/文摘