AGING AND THE HYPOTHALAMIC-PITUITARY REPRODUCTIVE AXIS

衰老与下丘脑-垂体生殖轴

• 批准号: 2457578
• 负责人: JANET E HALL
• 金额: $ 28.93万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2457578
• 关键词: aging; circadian rhythms; electroencephalography; estrogens; female; follicle stimulating hormone; gonadotropin releasing factor; gonadotropins; hormone receptor; hormone regulation /control mechanism; hormone therapy; human middle age (35-64); human old age (65+); human subject; hypothalamic pituitary axis; luteinizing hormone; menopause; progesterone; protein isoforms; secretion; sleep; women's health

The combination of an increase in the average life expectancy of women with no recent change in the age of menopause has resulted in a dramatic increase in the number of years of postmenopausal life. Epidemiologic studies have associated increases in cardiovascular disease and osteoporosis with menopause and the loss of gonadal steroids, and undoubtedly there are other important physiologic changes which stem from the loss ovarian function making it critical that efforts be made to understand the process of aging of the reproductive system and to separate those factors which result from changes in the sex steroid environment from those due to aging per se. The broad goals of this project are to determine the hypothalamic and pituitary contributions to aging of the reproductive endocrine system and to differentiate the specific effects of aging from those due to sex steroid deprivation. By using a combination of clinical models, pharmacologic probes and new measurement techniques, we aim to address the hypothesis that ovarian senescence is not the sole mediator of the end of reproductive competence, but that important age-related changes occur in hypothalamic GnRH and pituitary gonadotropin secretion. We hypothesize that neuroendocrine aging and sex steroid changes contribute independently and synergistically to the clinical features of the menopause. The loss of gonadal hormone secretion during the menopause makes it possible to isolate the independent effects of aging and changes in gonadal hormone secretion on the hypothalamic and pituitary components of the reproductive system. We propose to determine: 1) changes in hypothalamic GnRH secretion which occur with aging in the absence of ovarian feedback on the hypothalamus by assessment of the frequency of the hypothalamic GnRH pulse generator, the impact of sleep and circadian rhythms on hypothalamic and pituitary function, and the overall quantity of hypothalamic GnRH secretion using a GnRH antagonist as a probe of endogenous GnRH secretion in the intact human; 2) alterations in the quantitative and differential control of FSH, LH and follistatin secretion by GnRH versus other determinants of secretion as a function of age and ovarian hormonal status by complete blockade of the GnRH receptor; and 3) changes in the qualitative characteristics of pituitary FSH and LH with age and hormonal status by examination of changes in gonadotropin bioactivity and isoform heterogeneity in relation to serum follistatin levels and overall amount of GnRH secreted. The information derived from these studies will provide important insights into the neuroendocrine changes which occur with aging per se and the degree to which these changes can be overcome by gonadal steroid replacement.

女性平均预期寿命的增加的结合 由于最近没有变化，因此导致了戏剧性 绝经后生活的数量增加。 流行病学 研究与心血管疾病和 骨质疏松症与更年期和性腺类固醇的丧失，以及 毫无疑问，还有其他重要的生理变化 卵巢功能的损失使得努力做出至关重要 了解生殖系统衰老的过程并分开 那些因性类固醇环境变化而导致的因素 来自衰老本身的人。 该项目的广泛目标是确定下丘脑和 对生殖内分泌系统衰老的垂体贡献 将衰老的特定影响与性别区分开 类固醇剥夺。 通过结合临床模型， 药理学探针和新测量技术，我们旨在解决 假设卵巢衰老不是末尾的唯一中介者 生殖能力，但与年龄相关的重要变化发生在 下丘脑GNRH和垂体性促性腺激素分泌。 我们假设 神经内分泌衰老和性类固醇的变化独立贡献 并与更年期的临床特征协同作用。 损失 更年期期间的性腺激素分泌使得 隔离衰老的独立影响和性腺激素的变化 生殖的下丘脑和垂体成分的分泌 系统。 我们建议确定：1）下丘脑GNRH分泌的变化 在没有对下丘脑的卵巢反馈的情况下，发生衰老 评估下丘脑GNRH脉冲发生器的频率， 睡眠和昼夜节律对下丘脑和垂体的影响 功能，以及下丘脑GNRH分泌的总数 GnRH拮抗剂作为完整中内源性GnRH分泌的探针 人类; 2）更改FSH的定量和差异控制， LH和Follistatin分泌GnRH与其他决定因素 分泌与年龄和卵巢激素状态的函数 GNRH受体的封锁； 3）定性的变化 垂体FSH和LH的特征随着年龄的增长和荷尔蒙状态 检查促性腺激素生物活性和同工型的变化 与血清follistatin水平和整体量有关的异质性 Gnrh分泌。 这些研究得出的信息将提供重要的见解 进入衰老本身和衰老的神经内分泌变化 性腺类固醇可以克服这些变化的程度 替代品。