MATURATIONAL ROLES OF GNRH PULSE FREQUENCY

这个项目的总体目标是测试假设， 促性腺激素释放激素（GnRH）脉冲频率起着调节作用， 在人类性成熟中的作用，特别是在维持 正常的月经周期 我们认为，在正常情况下， 获得“快”（近似圆形或更快）频率， 青春期和保持“快速”频率的能力是必要的 成人生殖系统的正常功能。 这一假设 将以多种方式进行。 具体来说，我们计划1）执行一项 详细评估GnRH分泌的神经内分泌调节 在人类青春期; 2）评估是否改变（减少）的频率 GnRH分泌在特发性少精子症发病机制中的作用; 和3）评估GnRH脉冲频率改变在 维持正常的月经周期和相关的无排卵 下丘脑性闭经和高催乳素血症 校长 实现这些目标的方法将包括：a）间接评估 GnRH分泌通过详细评估的分泌模式 免疫反应性和生物活性LH和α-亚单位; B）评估 性类固醇输注对睡眠引起的 青春期儿童促性腺激素分泌; c）阿片受体阻滞 通过纳洛酮或纳洛酮研究内源性阿片类药物的作用 在整个人类青春期促性腺激素调节中以及在 女性和少精男性; d）性类固醇的纵向评估 反馈在人类青春期; e）评估可乐定的影响， 假定的α 2激动剂，对女性促性腺激素分泌的影响， 下丘脑性闭经; f）检查催乳素在下丘脑性闭经中的作用。 高催乳素血症妇女和正常妇女GnRH脉冲频率的调节 正常女性（通过甲氧氯普胺给药）; g）脉动i. v. 以几种频率但剂量给予合成GnRH 其模拟垂体门静脉浓度;以及h）确定 雌二醇和孕酮的特定反馈作用， 月经周期 正常的成年男女和成年人和儿童 疑似或证实的下丘脑/垂体功能障碍将参与 在临床研究中心执行的详细方案。 将使用成熟的放射免疫测定和体外生物测定， 连续的激素测定 这些研究应该提供更多的 深入了解人类生殖生理学，并应 从而为性早熟或迟发性早熟的儿童提供更合理的治疗， 成熟和低促性腺激素性性腺功能减退的成年人， 不孕

The overall goal of this project is to test the hypothesis that gonadotropin-releasing hormone (GnRH) pulse frequency plays a regulatory role(s) in human sexual maturation and in particular, in the maintenance of normal menstrual cyclicity. We propose that the ability to secrete GnRH at a "fast" (approximately circhoral or faster) frequency is acquired during puberty and that the ability to maintain a "fast" frequency is necessary for normal functioning of the adult reproductive system. This hypothesis will be approached in several ways. Specifically, we plan 1) to perform a detailed assessment of the neuroendocrine regulation of GnRH secretion during human puberty; 2) to assess whether altered (decreased) frequency of GnRH secretion plays a role in the pathogenesis of idiopathic oligospermia; and 3) to assess the role of altered GnRH pulse frequency in the maintenance of normal menstrual cycles and in the anovulation associated with hypothalamic amenorrhea and hyperprolactinemia. The principal approaches to these objectives will include: a) indirect assessment of GnRH secretion via detailed assessment of the secretory patterns of immunoreactive and bioactive LH and the Alpha-subunit; b) assessment of the acute effects of sex steroid infusion on the sleep-entrained increase in gonadotropin secretion in pubertal children; c) opiate receptor blockade via naloxone or naltrexone to investigate the role(s) of endogenous opiates in gonadotropin regulation throughout human puberty and in amenorrheic women and oligospermic men; d) longitudinal assessment of sex steroid feedback during human puberty; e) assessment of the effects of clonidine, a putative Alpha 2 agonist, on gonadotropin secretion in women with hypothalamic amenorrhea; f) examining the role of prolactin in the regulation of GnRH pulse frequency in hyperprolactinemic women and in normal women (via metoclopramide administration); g) pulsatile i.v. administration of synthetic GnRH at several frequencies but at dosages which mimic pituitary portal concentrations; and h) determining the specific feedback roles of estradiol and progesterone throughput the menstrual cycle. 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 and in vitro bioassays will be used for serial hormone determinations. These studies should provide a more thorough understanding of the physiology of human reproduction and should lead to more rational therapies for children with precocious or delayed maturation and for adults with hypogonadotropic hypogonadism and infertility.