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

 描述（由申请方提供）：多囊卵巢综合征（PCOS）是一种常见的生殖系统疾病，其特征为高雄激素血症（HA）和少排卵/无排卵伴生育力低下。它还与肥胖、胰岛素抵抗和代谢综合征有关。PCOS的特征是卵巢雄激素产生过多;卵巢HA部分与持续升高的促性腺激素释放激素（GnRH）脉冲频率有关，这促进了高促黄体激素（LH）水平和相对的促卵泡激素（FSH）缺乏。PCOS神经内分泌异常的机制尚不清楚。PCOS的出现通常可以追溯到青春期。青春期HA被认为是成年PCOS的前兆。青春期的开始以睡眠相关的LH脉冲幅度和频率增加（反映GnRH脉冲）为标志。在正常的青春期成熟过程中，LH（GnRH）脉冲频率存在昼夜变化。虽然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很重要。孕酮是成年女性每日GnRH脉冲频率的主要调节剂，最明显的是在月经周期的黄体期减缓GnRH脉冲频率（负反馈）。我们的小组报告的数据表明，在青春期的睡眠状态不同，GnRH脉冲发生器对孕酮负反馈的敏感性不同。这些数据与性类固醇（例如，孕酮）可能是青春期白天LH脉冲频率的重要调节因子，而夜间LH脉冲频率受较高睡眠中心的严重影响（对性类固醇反馈的反应较低）。在PCOS成人中，GnRH脉冲发生器对孕酮抑制的敏感性受损，这似乎与HA有关（雄激素受体阻断剂可逆转）。我们在青春期女孩中的初步数据表明，LH脉冲频率昼夜变化的调节改变是HA患者特有的。因此，我们认为青春期HA可能在GnRH分泌的异常模式中起重要作用，导致LH过量和相对FSH缺乏，这两者都有助于恶化HA和卵泡发育（和排卵）的障碍，如PCOS中所见。我们提出以下目标来检验我们的假设。在目标1中，我们将评估孕酮对青春期中晚期有和没有HA的女孩的觉醒与睡眠相关LH脉冲频率的急性影响。在目的2中，我们将评估雄激素受体阻断剂（螺内酯）对青春期中晚期HA女孩中孕酮相关LH脉冲频率抑制的影响。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，以降低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.