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（由申请人提供）：多囊卵巢综合征（PCOS）影响6-8％的女性，并以过剩睾丸激素（T），不规则的月经和亚属性或不育为特征。 PCOS的原因尚不清楚，但持续快速的促性腺激素释放激素（GNRH）脉冲有助于高黄曲霉激素（LH）和减少的卵泡激素（FSH）分泌，这反过来促进了雄激素过量和非正规排除。该缺陷部分与多余的T有关，这会干扰孕酮（P）抑制GNRH脉冲的能力。在患有超雄激素血症（HA）的青少年女孩中，观察到GNRH脉冲的异常异常，这种疾病可能导致成人PCOS。低P水平对反馈的抵抗力可能导致这些女孩的GNRH脉冲异常，但是这可能影响GNRH分泌的正常青春期序列（或它如何有助于PCOS的发展）是未知的。我们的长期目标是描述有关继续开发PCOS的高狂力青春期女孩中GNRH异常脉冲的机制。夜间GNRH频率从早期到晚期的频率不会显着变化，而白天的频率显示出明显的增加。早期数据表明，P急性抑制白天，但夜间不抑制GNRH频率。该建议涉及一个新的假设，即睡眠相关的GnRH频率和醒来的GNRH频率受到差异调节。因此，在正常的青春期，T升高的水平降低了青春期P水平抑制醒来的GnRH脉冲的能力，这构成了白天GnRH频率正常的青春期增加。然而，由于睡眠相关的GNRH频率不受青春期的影响。因此，一旦HA患者的GnRH活性增加，醒来的GnRH频率由于HA诱导的对P反馈的耐药性而升高（即GNRH频率在24小时内高度高）。这通过增加LH并降低FSH水平来促进向PCOS的发展。 GNRH脉冲的过夜通常会持续到成年，在早期卵泡阶段最突出（当支持FSH分泌和卵泡发育很重要时）；但是，PCOS中的HA会干扰如此缓慢。 AIM 1旨在确定唤醒和睡眠LH（GNRH）脉冲频率是否受P反馈差异影响。研究将确定P是否比与睡眠相关的LH频率更大程度地抑制LH频率（或更快），并且HA的女孩中这种影响是否会降低。 AIM 2旨在正式评估HA中睡眠效果差异改变的存在和原因。 AIM 3将通过检验以下假设来研究昼夜GNRH频率变化的重要性，即在正常的早期卵泡女性中保持迅速的LH（GNRH）频率的假设导致FSH降低。这些实验将提供有关管理GNRH分泌正常昼夜变化以及PCOS中GNRH异常的起源机制的关键见解。这可能会导致早期PCOS的治疗靶标。公共卫生相关性：青春期的高雄激素血症可以代表成人多囊卵巢综合征（PCOS）的先驱，该综合症（PCOS）影响了6-8％的女性，并以多余的睾丸激素，不规则的月经和不育的标记。 PCOS的原因尚不清楚，但是促性腺激素释放激素（GNRH）的异常搏动性分泌在患有过量睾丸激素过多的PCOS和青少年女孩的成年人中起作用。通过拟议的研究收集的数据将增强对控制整个青春期GnRH脉冲分泌的正常发育序列的机制的理解，以及如何在过量睾丸激素的情况下扰动该序列，以期设计PCOS早期阶段的合理治疗策略。