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

描述（由申请人提供）：多囊卵巢综合征（PCOS）影响6-8%的女性，其特征是睾酮(T)过量，月经不规则，亚或不孕症。多囊卵巢综合征的病因尚不清楚，但持续快速的促性腺激素释放激素（GnRH）脉冲会导致黄体生成素（LH）升高和促卵泡激素（FSH）分泌减少，这反过来又会导致雄激素过量和不规则排卵。这种缺陷部分与过量的T有关，它干扰了黄体酮(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，这种情况可导致成人多囊卵巢综合征。对低P水平反馈的抵抗可能导致这些女孩的GnRH脉冲异常，但这如何影响GnRH分泌的正常青春期序列（或它如何导致多囊卵巢综合征的发展）尚不清楚。我们的长期目标是描述控制GnRH脉冲异常的机制在高雄激素性青春期女孩谁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频率没有明显变化，而白天的频率则明显增加。早期数据表明，P能明显抑制白天GnRH频率，而非夜间。这一提议涉及到一个新的假设，即睡眠相关的GnRH频率和清醒GnRH频率受到不同的调节。因此，在正常的青春期，升高的T水平降低了青春期P水平抑制清醒GnRH脉冲的能力，这解释了青春期白天GnRH频率的正常增加。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，睡眠相关的GnRH频率变化在青春期早期HA中减少或不存在。因此，HA女孩的GnRH活性一旦增加，醒时GnRH频率就会升高，这是由于HA诱导的对P反馈的抵抗（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，在卵泡早期最为突出（此时支持FSH分泌和卵泡发育很重要）；但多囊卵巢综合征中的HA会干扰这种减缓。目的1旨在确定清醒和睡眠LH （GnRH）脉冲频率是否受P反馈的差异影响。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）地抑制醒时黄体生成素频率，以及这种影响是否在HA女孩中减弱。目的2旨在正式评估血凝素中睡眠-觉醒差异改变的存在及其原因。目的3将通过检验在正常的早期卵泡女性中维持快速的夜间LH （GnRH）频率导致FSH降低的假设来研究GnRH昼夜频率变化的重要性。这些实验将为GnRH分泌正常昼夜变化的机制以及PCOS中GnRH异常的成因提供关键见解。这可能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，影响6-8%的女性，其特征是睾丸激素过量、月经不规律和不孕。PCOS的病因尚不清楚，但促性腺激素释放激素（GnRH）的异常搏动分泌在PCOS成人和睾酮过量的青春期女孩中起作用。通过本研究收集的数据将有助于了解青春期GnRH脉冲分泌正常发育序列的控制机制，以及该序列在睾酮过量的情况下如何受到干扰，从而为早期PCOS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.