Impaired Gonadotropin Surges in Polycystic Ovary Syndrome: The Role of Hyperandrogenemia in Positive Feedback

项目摘要 多囊卵巢综合征(PCOS)是影响女性的最常见的内分泌疾病。它是 定义为高雄激素血症(HA)、排卵功能障碍和多囊卵巢形态。 重要的是，多囊卵巢综合征是无排卵性不孕最常见的原因。尽管进行了广泛的研究，但 PCOS的病理生理学基础仍不完全清楚。多囊卵巢综合征的一个特征是神经内分泌 功能障碍：多囊卵巢综合征患者的促性腺激素释放激素(GnRH)持续升高 促进黄体生成素过多和相对的卵泡刺激素的脉冲频率 卵泡刺激素(FSH)缺乏--两者都会导致HA和排卵功能障碍。快速的GnRH频率在一定程度上 与黄体酮相对抵抗(P4)负反馈有关。我们之前的研究表明 这种对P4负反馈的抵抗可以通过雄激素受体阻断而逆转。排卵依赖于 在周期中期促性腺激素激增，这是对高雌二醇(E_2)的正反馈的反应 排卵前P4水平升高。到目前为止，人们对HA的潜在存在知之甚少- 多囊卵巢综合征女性性激素正反馈和促性腺激素激增的介导性缺陷。 然而，我们在8名患有多囊卵巢综合征的女性和11名正常骑行的女性中的初步数据表明，性激素 正反馈在多囊卵巢综合征患者中可能存在功能障碍。这些数据表明促性腺激素明显缺乏。 多囊卵巢综合征患者接受雌二醇预处理后对P4的反应与雌二醇组对照 女人。这里提出的研究将解决以下假设：(A)HA对抗积极的 P4对促性腺激素分泌的反馈作用和(B)多囊卵巢综合征与E2阳性缺陷相关 促性腺激素分泌的反馈作用。在拟议的研究中，我们将(1)检查P4正反馈 雄激素受体阻断4周后对PCOS促性腺激素分泌的影响 (2)通过比较P4正反馈评估过度肥胖对P4正反馈的影响 在患有多囊卵巢综合征的超重/肥胖女性中，超重/肥胖对照和瘦身对照；以及(3)评估 比较多囊卵巢综合征患者雌激素诱导的促性腺激素释放峰的产生 多囊卵巢综合征与体重指数匹配的对照组。通过确定多囊卵巢综合征排卵障碍的新途径 这项工作的结果可能会建立提高排卵诱导率的新方法，从而 提高多囊卵巢综合征生育治疗的成功率。

Project Summary Polycystic ovary syndrome (PCOS) is the most highly prevalent endocrine disorder affecting women. It is defined by the presence of hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovarian morphology. Importantly, PCOS is the most common cause of anovulatory infertility. Despite extensive study, the pathophysiology underlying PCOS remains incompletely understood. A hallmark of PCOS is neuroendocrine dysfunction: women with PCOS demonstrate consistently increased gonadotropin-releasing hormone (GnRH) pulse frequency, which promotes luteinizing hormone (LH) excess and relative follicle-stimulating hormone (FSH) deficiency—both of which contribute to HA and ovulatory dysfunction. Rapid GnRH frequency is in part related to relative resistance to progesterone (P4) negative feedback. Our prior research demonstrated that such resistance to P4 negative feedback can be reversed with androgen-receptor blockade. Ovulation relies upon the midcycle gonadotropin surge, which occurs in response to positive feedback from high estradiol (E2) levels and a preovulatory increase in P4 levels. To date, little is known regarding the potential existence of HA- mediated defects in sex steroid positive feedback and gonadotropin surge generation in women with PCOS. However, our preliminary data in 8 women with PCOS and 11 normally-cycling women indicate that sex steroid positive feedback may be dysfunctional in PCOS. These data demonstrate a significant deficit in gonadotropin response to administration of P4 in E2-pretreated women with PCOS as compared to E2-pretreated control women. The research proposed herein will address the hypotheses that (a) HA antagonizes the positive feedback actions of P4 on gonadotropin secretion and (b) PCOS is associated with defects in E2 positive feedback actions on gonadotropin secretion. In the proposed studies, we will (1) examine P4 positive feedback on gonadotropin secretion in PCOS, both at baseline and after 4 weeks of androgen-receptor blockade with flutamide; (2) assess how excess adiposity influences P4 positive feedback by comparing P4 positive feedback among overweight/obese women with PCOS, overweight/obese controls, and lean controls; and (3) evaluate potential defects in E2 positive feedback in PCOS by comparing E2-induced gonadotropin surge generation in PCOS vs. BMI-matched controls. By identifying novel pathways through which PCOS ovulatory dysfunction occurs, the results of this work may establish new approaches for enhancing ovulation induction rates, thereby improving the success of fertility treatments in PCOS.