Pubertal hyperandrogenemia, modification of day-night GnRH secretion, and PCOS

青春期高雄激素血症、昼夜 GnRH 分泌改变和 PCOS

• 批准号: 8089176
• 负责人: Christopher Rolland McCartney
• 金额: $ 6.48万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-14 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089176
• 关键词: Accounting; Adolescence; Adult; Affect; Androgens; Automobile Driving; Data; Defect; Development; Disease; Dyslipidemias; Etiology; Feedback; Female Adolescents; Follicle Stimulating Hormone; Frequencies; Goals; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Grant; Hormones; Hour; Hypothalamic structure; Infertility; Insulin Resistance; Lead; Luteinizing Hormone; Menstrual cycle; Menstruation; Metabolic; Modeling; Modification; Neurons; Neurosecretory Systems; Obesity; Ovulation; Pathogenesis; Physiologic pulse; Pituitary Gland; Play; Polycystic Ovary Syndrome; Progesterone; Puberty; Research; Resistance; Role; Sleep; Staging; Steroids; Testing; Testosterone; Time; Variant; Woman; Women' s Health; Work; awake; design; girls; insight; novel; proliferative phase Menstrual cycle; public health relevance; research study; response; sleep abnormalities; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) affects 6-8% of women and is marked by excess testosterone (T), irregular menses, and sub- or infertility. The cause of PCOS is unclear, but persistently rapid gonadotropin- releasing hormone (GnRH) pulses contribute to high luteinizing hormone (LH) and diminished follicle- stimulating hormone (FSH) secretion, which in turn contribute to androgen excess and irregular ovulation. This defect is in part related to excess T, which interferes with the ability of progesterone (P) to suppress GnRH pulses. Similar abnormalities of GnRH pulses are observed in adolescent girls with hyperandrogenemia (HA), a condition that can lead to adult PCOS. Resistance to feedback by low P levels likely contributes to abnormal GnRH pulses in these girls, but how this could affect the normal pubertal sequence of GnRH secretion (or how it could contribute to development of PCOS) is unknown. Our long-term goal is to delineate mechanisms governing abnormal GnRH pulses in hyperandrogenemic pubertal girls who go on to develop PCOS. Nocturnal GnRH frequency does not change significantly from early to late puberty, whereas daytime frequency demonstrates a marked increase. Early data suggests that P acutely suppresses daytime, but not nighttime, GnRH frequency. This proposal involves the novel hypothesis that sleep-associated GnRH frequency and waking GnRH frequency are differentially regulated. Thus, during normal puberty, rising T levels reduce the ability of pubertal P levels to suppress waking GnRH pulses, accounting for the normal pubertal increase of daytime GnRH frequency. However, sleep-associated GnRH frequency remains constant since it is not influenced by pubertal levels of P. Early data imply that sleep-associated changes of GnRH frequency are diminished or absent in early pubertal HA. Thus, as soon as GnRH activity increases in girls with HA, waking GnRH frequency is elevated due to HA-induced resistance to P feedback (i.e., GnRH frequency is high over 24 hours). This promotes progression toward PCOS by increasing LH and reducing FSH levels. Overnight slowing of GnRH pulses normally persists into adulthood, being most prominent in the early follicular phase (when it is important to support FSH secretion and follicular development); but HA in PCOS interferes with such slowing. Aim 1 is designed to determine if wake and sleep LH (GnRH) pulse frequencies are differentially affected by P feedback. Studies will determine if P suppresses waking LH frequency to a greater extent (or more rapidly) than sleep-associated LH frequency, and if such an effect is diminished in girls with HA. Aim 2 is designed to formally evaluate the presence and cause of altered sleep-wake differences in HA. Aim 3 will investigate the importance of diurnal GnRH frequency changes by testing the hypothesis that maintaining a rapid overnight LH (GnRH) frequency in normal early follicular women results in reduced FSH. These experiments will provide key insights into mechanisms governing normal diurnal changes of GnRH secretion as well as the genesis of GnRH abnormalities in PCOS. This may lead to therapeutic targets for early PCOS. PUBLIC HEALTH RELEVANCE: Hyperandrogenemia during adolescence can represent a forerunner of adult polycystic ovary syndrome (PCOS), which affects 6-8% of women and is marked by excess testosterone, irregular menses, and infertility. The causes of PCOS are unclear, but abnormal pulsatile secretion of gonadotropin-releasing hormone (GnRH) plays a role in adults with PCOS and adolescent girls with excess testosterone. The data gathered through the proposed research will enhance understanding of the mechanisms controlling the normal developmental sequence of GnRH pulse secretion across puberty, and how this sequence is perturbed in the setting of excess testosterone all with a view to designing rational treatment strategies for the early stages of PCOS.

描述（申请人提供）：多囊卵巢综合征（PCOS）影响6-8%的妇女，其特征是睾酮（T）过多，月经不规则，不孕或不育。PCOS的病因尚不清楚，但持续快速的促性腺激素释放激素（GnRH）脉冲导致高促黄体生成激素（LH）和促卵泡激素（FSH）分泌减少，这反过来又导致雄激素过多和不规则排卵。这种缺陷部分与过量的T有关，过量的T干扰孕酮（P）抑制GnRH脉冲的能力。在患有高雄激素血症（HA）的青春期女孩中观察到类似的GnRH脉冲异常，这种情况可能导致成年PCOS。低P水平对反馈的抵抗可能导致这些女孩的异常GnRH脉冲，但这如何影响GnRH分泌的正常青春期序列（或如何促进PCOS的发展）尚不清楚。我们的长期目标是阐明青春期高雄激素血症女孩发生PCOS时异常GnRH脉冲的机制。从青春期早期到后期，夜间GnRH频率没有显著变化，而白天的频率则显著增加。早期数据表明，P急性抑制白天，但不是夜间，GnRH频率。该提议涉及新的假设，即睡眠相关的GnRH频率和清醒时的GnRH频率受到不同的调节。因此，在正常青春期，T水平的上升降低了青春期P水平抑制清醒GnRH脉冲的能力，解释了白天GnRH频率的正常青春期增加。然而，睡眠相关的GnRH频率保持不变，因为它是不受青春期水平的P.早期的数据意味着，睡眠相关的GnRH频率的变化减少或不存在在青春期早期HA。因此，一旦患有HA的女孩的GnRH活性增加，由于HA诱导的对P反馈的抵抗，觉醒的GnRH频率就会升高（即，GnRH频率在24小时内很高）。这通过增加LH和降低FSH水平促进PCOS的进展。GnRH脉冲的夜间减慢通常持续到成年期，在卵泡早期最突出（此时支持FSH分泌和卵泡发育很重要）;但PCOS中的HA会干扰这种减慢。目的1旨在确定唤醒和睡眠LH（GnRH）脉冲频率是否受到P反馈的不同影响。研究将确定P是否比睡眠相关LH频率更大程度（或更快）地抑制清醒LH频率，以及这种作用是否在HA女孩中减弱。目的2旨在正式评估HA中睡眠-觉醒差异改变的存在和原因。目的3将调查昼夜GnRH频率变化的重要性，通过测试的假设，保持快速的夜间LH（GnRH）的频率在正常的早期卵泡妇女的结果减少FSH。这些实验将提供关键的洞察机制，管理正常的昼夜变化的GnRH分泌，以及在PCOS的GnRH异常的成因。这可能会导致早期PCOS的治疗目标。公共卫生相关性：青春期高雄激素血症可能是成人多囊卵巢综合征（PCOS）的前兆，PCOS影响6-8%的女性，并以过量睾酮，月经不规则和不孕为标志。PCOS的病因尚不清楚，但促性腺激素释放激素（GnRH）的异常脉冲式分泌在PCOS成人和睾酮过量的青春期女孩中起作用。通过拟议的研究收集的数据将增强对控制青春期GnRH脉冲分泌正常发育序列的机制的理解，以及该序列如何在过量睾酮的情况下受到干扰，所有这些都旨在为PCOS的早期阶段设计合理的治疗策略。