The interaction between sleep and reproductive hormone secretion during puberty

描述（由申请人提供）：在青春期时，下丘脑促性腺激素释放激素（GnRH）脉冲发生器重新唤醒，刺激垂体促黄体生成素（LH）和促卵泡激素（FSH）的分泌以及随后的性腺性类固醇分泌。虽然我们知道GnRH脉冲发生器最初只在睡眠时被重新激活，但还没有对青春期睡眠和生殖系统之间的潜在生理学联系进行调查。我的初步研究证明了黄体生成素脉冲启动与青春期儿童深波或慢波睡眠（SWS）之间的关联，这表明一定数量的不间断睡眠可能对正常的青春期成熟很重要。在青春期，睡眠结构发生了巨大的变化。δ功率（SWS的一个标志）下降了大约65%，这种下降首先发生在11-12岁，这也是男孩和女孩正常青春期开始的年龄。虽然已经假设性类固醇可能在塑造睡眠结构中发挥作用，但先前研究的观察设计已经排除了将青春期成熟与年龄本身对睡眠结构的影响分开。鉴于儿童性发育越来越早的趋势，重要的是

DESCRIPTION (provided by applicant): At the time of puberty, the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator reawakens, stimulating pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and consequent gonadal sex steroid secretion. While it is known that the GnRH pulse generator is initially reactivated only during sleep, there has been no investigation into the underlying physiology linking the sleep and reproductive systems during puberty. My preliminary studies demonstrated an association between LH pulse initiation and deep or slow-wave sleep (SWS) in pubertal children, suggesting that a critical amount of uninterrupted sleep may be important for normal pubertal maturation. Sleep architecture changes dramatically during adolescence. There is a > 65% decline in delta power (a marker of SWS) that first occurs at age 11-12 years which is also the age of normal pubertal onset in boys and girls. While it has been hypothesized that sex steroids may play a role in shaping sleep architecture, the observational design of previous studies has precluded separation of the effects of pubertal maturation from age per se on sleep structure. Given the increasing trend of earlier sexual development in children, it is important to gain a deeper understanding of the complex interaction between sex steroids and the brain during adolescence and the potential consequences of early sex steroid exposure. This proposal will examine the critical and reciprocal interactions between sleep and the reproductive system during puberty. In Specific Aim 1, I will use a SWS disruption protocol to determine whether pulsatile secretion of LH during puberty is specifically dependent on SWS. In Specific Aim 2, I will study children with central precocious puberty before and after treatment with a GnRH analogue to investigate the effects of sex steroids on sleep architecture, independent of chronologic age. My research career development plan involves close mentoring by an experienced team of interdisciplinary clinical investigators with expertise in reproductive endocrinology, sleep medicine, and integrative physiology. I will gain formal training in sleep medicine through participation in coursework, weekly conferences, and national meetings, and will gain hands-on experience by shadowing my mentors and collaborators in sleep clinic polysomnographic reading sessions. I will continue to participate in didactic conferences in the Reproductive Endocrine Unit and at Children's Hospital Boston to expand my knowledge of endocrinology and relevant research tools. Frequent meetings with a core team of my mentors and collaborators, including Drs. Hall, Malhotra, and Butler, will help me to integrate my knowledge in sleep and reproductive endocrinology. Under a K23, I will gain the additional training in clinical research and sleep medicine that I need to attain my ultimate career goal of becoming an independent clinical investigator at an academic medical center bridging the fields of sleep medicine and pediatric reproductive endocrinology. PUBLIC HEALTH RELEVANCE: The candidate for this Career Development Award is a pediatric endocrinologist studying 1) the effects of sleep disruption on reproductive hormone secretion during puberty and 2) the potential role of reproductive hormones in the changes in sleep structure that are seen across adolescence. This research will investigate whether sleep disruption, which is common in adolescence, interferes with hormone secretion and normal pubertal maturation.