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

多囊卵巢综合症中促性腺激素激增：高雄激素血症在正反馈中的作用

• 批准号: 9328928
• 负责人: Jessica Lundgren
• 金额: $ 6.85万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-13 至 2019-06-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328928
• 关键词: Acute; Address; Affect; Androgen Receptor; Androgenization; Animal Model; Aromatase Inhibitors; Blood specimen; Clomiphene; Data; Defect; Disease; Dose; Endocrine System Diseases; Estradiol; Exhibits; Feedback; Flutamide; Follicle Stimulating Hormone; Frequencies; Functional disorder; Future; GNRH1 gene; Generations; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Gonadotropins; Hyperandrogenism; Hyperinsulinism; Impairment; Infertility; Insulin Resistance; Luteinizing Hormone; Mediating; Morphology; Neurosecretory Systems; Obesity; Oral; Ovarian; Ovarian Follicle; Overweight; Ovulation; Ovulation Induction; Pathway interactions; Physiologic pulse; Pituitary Gland; Polycystic Ovary Syndrome; Progesterone; Protocols documentation; Research; Resistance; Role; Sampling; Serum; Steroid biosynthesis; Testing; Therapeutic; Thinness; Woman; Work; base; fertility improvement; hormone deficiency; improved; infertility treatment; novel; novel strategies; prenatal; proliferative phase Menstrual cycle; reproductive; response; success; urinary

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.

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。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，PCOS是无排卵性不孕症的最常见原因。尽管进行了广泛的研究， PCOS的病理生理机制仍不完全清楚。PCOS的一个标志是神经内分泌 功能障碍：PCOS女性表现出持续增加的促性腺激素释放激素（GnRH） 脉冲频率，促进黄体生成素（LH）过量和相对卵泡刺激素 (FSH)缺乏-这两者都有助于HA和排卵功能障碍。快速GnRH频率部分是 与孕酮（P4）负反馈的相对抗性有关。我们之前的研究表明， 这种对P4负反馈的抗性可以用雄激素受体阻断剂逆转。排卵依赖于 在周期中期促性腺激素激增时，这是对高雌二醇（E2）的正反馈的反应 水平和排卵前P4水平的增加。迄今为止，人们对HA的潜在存在知之甚少- 介导的缺陷性类固醇正反馈和促性腺激素激增的产生与PCOS妇女。 然而，我们在8名PCOS妇女和11名正常周期妇女中的初步数据表明， 正反馈可能在PCOS中功能失调。这些数据表明，促性腺激素的显着不足 与E2预处理对照相比，E2预处理PCOS妇女对P4给药的反应 妇女本文提出的研究将解决以下假设：（a）HA拮抗正 P4对促性腺激素分泌的反馈作用和（B）PCOS与E2阳性细胞缺陷有关。 对促性腺激素分泌的反馈作用。在本研究中，我们将（1）检验P4正反馈 在基线和雄激素受体阻断4周后， （2）通过比较P4正反馈，评估过度肥胖对P4正反馈的影响 在超重/肥胖PCOS妇女、超重/肥胖对照组和瘦对照组中;和（3）评估 通过比较E2诱导的促性腺激素峰的产生， PCOS与BMI匹配的对照组。通过识别PCOS排卵功能障碍的新途径， 发生，这项工作的结果可能建立新的方法，提高排卵诱导率，从而 提高PCOS生育治疗的成功率。