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

描述(申请人提供)：多囊卵巢综合征(PCOS)影响6-8%的女性，以睾酮(T)过多、月经不调、亚或不育为特征。PCOS的病因尚不清楚，但持续快速的促性腺激素释放激素(GnRH)脉冲导致黄体生成素(LH)升高和卵泡刺激素(FSH)分泌减少，进而导致雄激素过剩和排卵不规律。这种缺陷在一定程度上与过量的T有关，它干扰了孕酮(P)抑制GnRH脉冲的能力。在患有高雄激素血症(HA)的青春期女孩中也观察到类似的GnRH脉冲异常，这种情况可能导致成年后的多囊卵巢综合征。对低P水平反馈的抵抗可能会导致这些女孩的GnRH脉冲异常，但这如何影响正常的青春期GnRH分泌序列(或如何促进PCOS的发展)尚不清楚。我们的长期目标是描述控制高雄激素血症青春期女孩GnRH异常脉冲的机制，这些女孩继续发展为多囊卵巢综合征。从青春期早期到青春期晚期，夜间GnRH频率变化不大，而白天频率显著增加。早期数据表明，P显著抑制白天的GnRH频率，但不能抑制夜间的GnRH频率。这一建议涉及一种新的假设，即睡眠相关的GnRH频率和清醒的GnRH频率是不同的调节。因此，在正常青春期，不断上升的T水平降低了青春期P水平抑制觉醒的GnRH脉冲的能力，这是青春期白天GnRH频率正常增加的原因。然而，睡眠相关的GnRH频率保持不变，因为它不受青春期P水平的影响。早期数据表明，在青春期早期HA中，睡眠相关的GnRH频率的变化减少或消失。因此，在患有HA的女孩中，一旦GnRH活性增加，由于HA诱导的对P反馈的抵抗(即GnRH频率在24小时内很高)，唤醒GnRH的频率就会增加。这通过增加黄体生成素和降低卵泡刺激素水平来促进多囊卵巢综合征的进展。GnRH脉冲的夜间减慢通常持续到成年期，在卵泡早期(对支持FSH分泌和卵泡发育非常重要)最为明显；但PCOS中的HA干扰了这种减慢。AIM 1旨在确定觉醒和睡眠黄体生成素(GnRH)脉冲频率是否受P反馈的不同影响。研究将确定P是否比睡眠相关的黄体生成素频率更大程度(或更快)地抑制清醒的黄体生成素频率，以及这种影响是否在患有HA的女孩中减弱。AIM 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通过检验正常早期卵泡妇女维持快速过夜促黄体生成素(GnRH)频率会导致FSH减少的假说，探讨GnRH昼夜频率变化的重要性。这些实验将为控制正常的GnRH分泌日变化的机制以及PCOS中GnRH异常的发生提供关键的见解。这可能会导致早期多囊卵巢综合征的治疗靶点。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)的先兆，这种综合征影响6-8%的女性，以睾酮过多、月经不调和不孕不育为特征。多囊卵巢综合征的原因尚不清楚，但促性腺激素释放激素(GnRH)的异常脉动性分泌在成人多囊卵巢综合征和睾酮过剩的青春期女孩中起作用。通过拟议的研究收集的数据将加强对青春期GnRH脉冲分泌正常发育序列的控制机制的了解，以及该序列如何在睾酮过剩的情况下受到干扰，所有这些都旨在为PCOS的早期阶段设计合理的治疗策略。

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.