MATURATIONAL ROLES OF GNRH PULSE FREQUENCY

本项目的总体目标是研究 人类的脉冲式GnRH分泌：a）在整个性成熟过程中， 和B）维持正常的周期性排卵。 所有 提出的研究是针对统一的假设， 能够以近似圆形的"快速"或"更快"的速度分泌GnRH 一天中的频率在青春期发展，这种能力 改变GnRH脉冲分泌的频率和幅度， 对周期性卵巢卵泡成熟和排卵至关重要。 这 假设将以几种方式处理。 具体来说，我们计划（1） 详细评估GnRH和性类固醇的睡眠诱导模式 （T和E2）正常和性腺功能减退儿童的分泌; 2）检查 性类固醇的急性作用，无论是通过刺激脉冲 促性腺激素释放激素，静脉输注，或经皮吸收，对睡眠- 青春期男孩和男性GnRH分泌的夹带模式; 3） 通过阿片受体阻断检查内源性阿片类药物的作用 在青春期男孩和正常人的GnRH分泌的性类固醇调节中 男性; 4）检查E2在调节GnRH脉冲频率中的作用 在月经从黄体期到卵泡期的整个过渡期 多囊卵巢综合征的病因有哪些？ (PCO)结果从快速频率的GnRH分泌，和评价 E2和P在减缓GnRH分泌和诱导排卵中的作用; 6)检查过量下丘脑阿片样物质活性在 下丘脑性闭经促性腺激素释放激素慢频分泌及其评价 纳洛酮诱导排卵。 这些问题的主要解决办法 目的将包括：a）通过以下方法间接评估GnRH分泌： 详细评估免疫反应性LH的分泌模式; B） 性类固醇输注对睡眠的急性影响的评估- 青春期男孩中促性腺激素分泌的夹带增加; c）阿片样物质 通过纳洛酮或纳洛酮进行受体阻断，以研究 促性腺激素调节中的内源性阿片样物质; d）施用 正常女性和PCO女性的E2和P生理量， 测试PCO综合征是下丘脑过度分泌的结果这一假设。 GnRH的脉冲式分泌，和e）评估 地塞米松对下丘脑性闭经患者LH分泌的影响 但对阿片类药物阻断无反应 普通的成年男女， 以及成人和儿童疑似或证实患有下丘脑/垂体 功能障碍将参与在 临床研究中心。 将使用成熟的放射免疫测定法 进行一系列激素测定，并进行客观的计算机分析， 用于测定脉动分泌模式。 这些研究 应该提供一个更深入的了解人体的生理 生殖，并应导致更合理的治疗患者 早熟或延迟成熟。 此外， 无排卵也可能是由于GnRH分泌频率快（或 无法减缓GnRH分泌）将进行检查，结果可能导致 新的生理方法来诱导排卵， 患者

The overall goal of this project is to examine the regulation and roles of pulsatile GnRH secretion in human beings: a) throughout sexual maturation, and b) in the maintenance of normal cyclical ovulation. All of the proposed studies are directed toward the unifying hypothesis that the ability to secrete GnRH at a "fast" approximately circhoral, or "faster" frequency throughout the day develops during puberty, and that the ability to change the frequency and amplitude of pulsatile GnRH secretion is critical for cyclical ovarian follicular maturation and ovulation. This hypothesis will be approached in several ways. Specifically we plan 1) detailed evaluation of the sleep-entrained patterns of GnRH and sex steroid (T and E2) secretion in normal and hypogonadal children; 2) examination of the acute effects of sex steroids, either via stimulation by pulsatile GnRH, intravenous infusion, or transcutaneous absorption, on the sleep- entrained patterns of GnRH secretion in pubertal boys and men; 3) examination of the role of endogenous opioids, via opioid receptor blockade in the sex steroid regulation of GnRH secretion in pubertal boys and normal men; 4) examination of the role of E2 in regulating GnRH pulse frequency throughout the transition from luteal to follicular stages of the menstrual cycle; 5) examination of the hypothesis that polycystic ovarian disease (PCO) results from fast frequency GnRH secretion, and evaluation of the effects of E2 and P in slowing GnRH secretion and inducing ovulation; and 6) examination of the role of excess hypothalamic opioid activity in the slow frequency GnRH secretion in hypothalamic amenorrhea, and evaluation of naltrexone in inducing ovulation. The principal approaches to these objectives will include: a) indirect assessment of GnRH secretion via detailed assessment of the secretory patterns of immunoreactive LH; b) assessment of the acute effects of sex steroid infusion on the sleep- entrained increase in gonadotropin secretion in pubertal boys; c) opioid receptor blockade via nalaxone or naltrexone to investigate the role(s) of endogenous opioids in gonadotropin regulation; d) administration of physiological amounts of E2 and P to normal women and women with PCO to test the hypothesis that PCO syndrome is the result of excess hypothalamic pulsatile secretion of GnRH, and e) evaluation of the effects of dexamethasone on LH secretion in patients who have hypothalamic amenorrhea but who are unresponsive to opioid blockade. Normal adult men and women, and adults and children with suspected or proven hypothalamic/pituitary dysfunction will participate in detailed protocols performed in the Clinical Research Center. Well established radioimmunoassays will be used for serial hormone determinations, and objective computer analyses will be used for determination of pulsatile secretory patterns. These studies should provide a more thorough understanding of the physiology of human reproduction and should lead to more rational therapies for patients with precocious or delayed maturation. Moreover, the possibilities that anovulation can also result from fast frequency GnRH secretion (or an inability to slow GnRH secretion) will be examined and the results may lead to novel, physiological approaches to ovulation induction in these patients.