MATURATIONAL ROLES OF GNRH PULSE FREQUENCY

这个项目的总体目标是检查规则和角色 人类促性腺激素释放激素的脉动分泌：a)在性成熟过程中， 以及b)维持正常的周期排卵。所有的 拟议的研究针对的是统一的假设，即 分泌促性腺激素释放激素的能力接近于绕圈，或更快 一天中的频率在青春期发展，而这种能力 改变GnRH搏动性分泌的频率和幅度 对周期卵泡成熟和排卵至关重要。这 假说将以几种方式进行探讨。具体来说，我们计划1) 详细评估促性腺激素释放激素和性激素的睡眠模式 性腺功能正常和性腺功能低下儿童的(T和E_2)分泌； 性激素的急性作用，无论是通过脉搏刺激 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分泌的携带模式；3) 通过阿片受体阻断研究内源性阿片类药物的作用 性激素对青春期男孩和正常人促性腺激素释放激素分泌的调节 男性；4)研究雌激素在调节促性腺激素释放激素脉冲频率中的作用 在月经从黄体到卵泡的整个过渡阶段 周期；5)多囊卵巢疾病假说的检验 (PCO)由GnRH快速分泌所致，并对 雌二醇和孕酮延缓促性腺激素释放激素分泌和促排卵作用； 6)检查过量的下丘脑阿片活动在 低频率促性腺激素释放激素分泌在下丘脑闭经中的作用 纳曲酮诱导排卵。解决这些问题的主要方法是 目标将包括：a)通过以下途径间接评估GnRH分泌 详细评估免疫反应性黄体生成素的分泌模式；b) 评估性类固醇注射对睡眠的急性影响-- 青春期男孩促性腺激素分泌增加；c)阿片类药物 用纳洛酮或纳曲酮阻断受体探讨其作用(S) 促性腺激素调节中的内源性阿片类药物；d)给予 正常妇女和多囊卵巢综合征患者生理水平的E_2和P水平 检验多囊卵巢综合征是下丘脑过度活动的假说 促性腺激素释放激素的脉动性分泌，以及e)对 地塞米松对下丘脑闭经患者促黄体生成素分泌的影响 但他们对阿片类药物的阻断没有反应。正常的成年男女， 以及怀疑或证实患有下丘脑/脑垂体症的成人和儿童 功能障碍将参与在 临床研究中心。将使用成熟的放射免疫分析方法 对于连续的激素测定，客观的计算机分析将是 用于测定搏动性分泌模式。这些研究 应该让我们对人类的生理学有更透彻的了解 生殖，并应导致更合理的治疗患者 早熟的或延迟成熟的。此外，有可能 无排卵也可由快速分泌促性腺激素释放激素(或 无法减缓GnRH的分泌)将进行检查，结果可能会导致 新的生理学方法来诱导这些人排卵 病人。

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.