Role of hyperandrogenemia in abnormal pubertal gonadotropin-releasing hormone (GnRH) secretion and development of PCOS

 描述(申请人提供)：多囊卵巢综合征(PCOS)是一种流行的生殖障碍，以高雄激素血症(HA)和少/无排卵伴次生育为特征。它还与肥胖、胰岛素抵抗和代谢综合征有关。多囊卵巢综合征的特点是卵巢雄激素分泌过多；卵巢透明质酸部分与促性腺激素释放激素(GnRH)脉冲频率持续升高有关，GnRH脉冲频率导致黄体生成素(LH)水平升高和相对卵泡刺激素(FSH)缺乏。多囊卵巢综合征神经内分泌异常的机制尚不清楚。多囊卵巢综合征的出现通常可以追溯到青春期。青春期HA被认为是成人多囊卵巢综合征的先兆。青春期的开始标志着与睡眠相关的促黄体生成素脉冲幅度和频率的增加(反映促性腺激素释放激素脉冲)。在正常的青春期成熟过程中，促黄体生成素(GnRH)的脉冲频率有昼夜变化。尽管昼夜变化的潜在机制尚不清楚，但这些变化被认为对适当的促性腺激素分泌是重要的。孕酮是成年女性日常GnRH脉冲频率的主要调节器，最显著的是在月经周期的黄体期减慢GnRH脉冲频率(负反馈)。我们小组报告的数据表明，GnRH脉冲发生器对孕酮负反馈的不同敏感性取决于青春期的睡眠状态。这些数据与性激素(例如，黄体酮)可能是青春期白天黄体生成素脉冲频率的重要调节器的概念一致，而夜间黄体生成素脉冲频率受到睡眠中心较高(对性类固醇反馈反应较差)的严重影响。成年PCOS患者GnRH脉冲发生器对孕酮抑制的敏感性受损，这似乎与HA有关(雄激素受体拮抗剂逆转了这一敏感性)。我们在青春期女孩中的初步数据表明，黄体生成素脉冲频率的昼夜变化规律发生了变化，这是HA患者特有的。因此，我们认为青春期透明质酸可能在促性腺激素释放激素分泌异常模式中起重要作用，导致促黄体生成素过多和相对促卵泡激素缺乏，这两种情况都会导致多囊卵巢综合征的透明质酸恶化和卵泡发育(和排卵)障碍。为了验证我们的假设，我们提出了以下几点。在目标1中，我们将评估黄体酮对患有和不患有HA的青春期中晚期女孩觉醒和睡眠相关的黄体生成素脉冲频率的急性影响。在目标2中，我们将评估雄激素受体阻滞剂(螺内酯)对孕酮相关的黄体生成素抑制黄体生成素脉冲频率的影响。更好地了解青春期HA的潜在因果作用将有助于制定合理的预防和/或治疗策略，以减少与PCOS相关的发病率。

 DESCRIPTION (provided by applicant): Polycystic ovary syndrome (PCOS) is a prevalent reproductive disorder characterized by hyperandrogenism (HA) and oligo/anovulation with subfertility. It is also associated with obesity, insulin resistance and metabolic syndrome. PCOS is marked by excessive ovarian androgen production; ovarian HA is in part related to persistently elevated gonadotropin releasing hormone (GnRH) pulse frequency, which promotes high luteinizing hormone (LH) levels and relative follicle stimulating hormone (FSH) deficiency. The mechanisms underlying the neuroendocrine abnormalities of PCOS remain unclear. The emergence of PCOS is often traced back to puberty. Peripubertal HA is believed to represent a precursor to adult PCOS. The beginning of puberty is marked by sleep-related increases of LH pulse amplitude and frequency (mirroring GnRH pulses). Across normal pubertal maturation, there are day-night changes in LH (GnRH) pulse frequency. Although the underlying mechanisms for the diurnal changes are not known, these changes are thought to be important for appropriate gonadotropin secretion. Progesterone is the primary modulator of day-to-day GnRH pulse frequency in adult women, most notably by slowing GnRH pulse frequency (negative feedback) during the luteal phase of menstrual cycle. Our group has reported data suggesting a differential sensitivity of the GnRH pulse generator to progesterone negative feedback depending on sleep status during puberty. These data are consistent with the notion that sex steroids (e.g., progesterone) may be important regulators of daytime LH pulse frequency across puberty, while nighttime LH pulse frequency is heavily influenced by higher sleep centers (and less responsive to sex steroid feedback). The sensitivity of GnRH pulse generator to inhibition by progesterone is impaired in adults with PCOS, and this appears to be related to HA (it is reversed by androgen receptor blockade). Our preliminary data in pubertal girls suggested altered regulation of day-to-night change of LH pulse frequency that is specific to those with HA. Thus, we propose that pubertal HA may play an important role in aberrant pattern of GnRH secretion, causing LH excess and relative FSH deficiency, both of which contribute to worsening HA and disturbances of follicular development (and ovulation) as seen in PCOS. We propose the following aims to test our hypotheses. In Aim 1, we will assess the acute effect of progesterone on wake vs. sleep-related LH pulse frequency in mid- to late pubertal girls with and without HA. In Aim 2, we will assess effect of androgen receptor-blockade (spironolactone) on progesterone-associated suppression of LH pulse frequency in mid- to late pubertal girls with HA. A better understanding a potentially causal role of peripubertal HA will support the development of a rational preventive and/or treatment strategies to decrease morbidity associated with PCOS.