MATURATIONAL ROLES OF GNRH PULSE FREQUENCY

GNRH 脉冲频率的成熟作用

• 批准号: 3313372
• 负责人: ROBERT P KELCH
• 金额: $ 15.95万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1982
• 资助国家: 美国
• 起止时间: 1982-03-01 至 1991-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3313372
• 关键词: adult human (21+); blood chemistry; child (0-11); circadian rhythms; estradiol; follicle stimulating hormone; gonadotropin releasing factor; gonadotropins; hormone regulation /control mechanism; human puberty; human subject; hyperprolactinemia; hypogonadism; injection /infusion; laboratory rat; luteinizing hormone; menstrual cycle; menstrual cycle disorder; middle childhood (6-11); naloxone; neuropeptide receptor; opioid receptor; precocious puberty; progesterone; prolactin; radioimmunoassay; reproductive development; testosterone; urinalysis

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.

这个项目的总体目标是测试假设 促性腺激素释放激素(GnRH)脉冲频率起调节作用 (S)在人性性成熟中的作用，特别是在维持 月经周期正常。我们认为分泌促性腺激素释放激素的能力 一个“快”的频率(大约是环形的或更快的)是在 青春期和保持“快”频率的能力是必要的 成人生殖系统的正常运作。这一假设 将通过几种方式与之接洽。具体地说，我们计划1)执行 促性腺激素释放激素分泌的神经内分泌调节的详细评估 在人的青春期；2)评估是否改变(减少)频率 GnRH分泌在特发性少精子症的发病机制中起一定作用； 以及3)评估GnRH脉冲频率改变在 维持正常月经周期与无排卵相关 伴有下丘脑闭经和高催乳素血症。校长 实现这些目标的办法将包括：a)间接评估 通过详细评估GnRH的分泌模式 免疫活性和生物活性的黄体生成素和阿尔法亚单位；b)评估 性激素输注对睡眠诱导性睡眠增加的急性影响 青春期儿童促性腺激素分泌；c)阿片受体阻断 通过纳洛酮或纳曲酮研究内源性阿片类药物的作用(S) 促性腺激素在青春期和闭经期的调节 女性和少精子症男性；d)性激素的纵向评估 人类青春期期间的反馈；e)评估可乐定的效果，a 可能是Alpha 2激动剂，对女性患者促性腺激素分泌的影响 下丘脑闭经；f)检查催乳素在 高催乳素血症妇女和女性促性腺激素释放激素脉冲频率的调节 正常妇女(通过甲氧氯普胺注射)；g)搏动性静脉注射。 合成促性腺激素释放激素以几种频率和剂量给药 其模拟脑下垂体门脉浓度；以及h)确定 雌二醇和孕酮的特异性反馈作用 月经周期。正常的成年男子和妇女以及成人和儿童 疑似或确诊的下丘脑/垂体功能障碍将参与 在临床研究中心执行的详细方案。 成熟的放射免疫检测和体外生物检测将用于 连续的荷尔蒙测定。这些研究应该提供更多的 对人类生殖的生理学有透彻的理解，应该 为早熟或延迟的儿童提供更合理的治疗方法 成熟和对患有低促性腺激素减退症的成人和 不孕不育。