ROLE OF DHT IN GNRH PULSE GENERATOR RESISTANCE TO STEROID FEEDBACK IN PCOS

DHT 在 GNRH 脉冲发生器对 PCOS 类固醇反馈抵抗中的作用

• 批准号: 7718536
• 负责人: Christopher Rolland McCartney
• 金额: $ 4.48万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7718536
• 关键词: Accounting; Androgen Receptor; Computer Retrieval of Information on Scientific Projects Database; Defect; Dose; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Estradiol; Etiology; Feedback; Finasteride; Flutamide; Frequencies; Funding; Gonadotropin Hormone Releasing Hormone; Grant; Hormonal; Institution; Mediating; Oxidoreductase; Physiologic pulse; Polycystic Ovary Syndrome; Progesterone; Pulse taking; Research; Research Personnel; Resistance; Resources; Role; Source; Stanolone; Steroids; Testosterone; United States National Institutes of Health; Week; Woman; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Polycystic ovary syndrome (PCOS) is associated with a persistently rapid gonadotropin hormone-releasing hormone (GnRH) pulse frequency, an abnormality that may account for many of the hormonal manifestations of PCOS. Although the etiology of this rapid GnRH pulse frequency is unclear, recent evidence suggests that the GnRH pulse generator in PCOS is relatively resistant to the feedback effects of progesterone (P) and estradiol (E2). For example, one study evaluated LH (and by inference GnRH) pulse frequency before and 7 d after exogenous P and E2 administration. Assessment of LH suppression as a function of mean P concentration revealed that P concentrations <10 ng/ml suppressed LH pulse frequency more effectively in normal women than in those with PCOS. This abnormality is reversed by treatment with the androgen receptor antagonist flutamide, suggesting that the aforementioned sensitivity defect results from hyperandrogenemia. However, it is unknown whether testosterone (T) itself, or its more potent metabolite dihydrotestosterone (DHT), mediates these effects. We will examine this further with the use of finasteride, a specific inhibitor of the enzyme (5?-reductase) that catalyzes conversion of T to DHT. Subjects with PCOS and normal controls will be studied. Baseline LH pulse frequency will be determined. Finasteride will then be given for 4 weeks prior to reassessment of LH pulse frequency. Thereafter, exogenous P and E2 will be given in addition to finasteride for one week, after which LH pulse frequency will again be determined. In this way we aim to construct a P dose-LH pulse frequency response curve (i.e., mean P concentration vs. change in LH pulse frequency) for women with PCOS and controls. We hypothesize that in PCOS, finasteride will restore GnRH pulse generator sensitivity to negative feedback by P and E2, suggesting that DHT mediates abnormal feedback sensitivity.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 多囊卵巢综合征(PCOS)与持续快速的促性腺激素释放激素(GnRH)脉冲频率有关，这种异常可能是PCOS的许多激素表现的原因。尽管这种快速的GnRH脉冲频率的病因尚不清楚，但最近的证据表明，PCOS中的GnRH脉冲发生器相对抵抗孕酮(P)和雌二醇(E2)的反馈效应。例如，一项研究评估了外源性P和E_2注射前和注射后7天的促黄体生成素(以及促性腺激素释放激素)脉冲频率。对黄体生成素抑制与平均P浓度的关系的评估表明，在正常女性中，10 ng/ml的P浓度比多囊卵巢综合征患者更有效地抑制了黄体生成素的脉冲频率。这种异常可以通过雄激素受体拮抗剂氟他胺的治疗而逆转，这表明上述敏感性缺陷是由高雄激素血症引起的。然而，目前尚不清楚是睾酮(T)本身还是其更有效的代谢物双氢睾酮(DHT)介导了这些效应。我们将使用非那雄胺进一步研究这一点，非那雄胺是一种催化T转化为DHT的酶(5？-还原酶)的特异性抑制剂。研究对象为多囊卵巢综合征患者和正常对照组。将确定基线的黄体生成素脉冲频率。在重新评估促黄体生成素脉冲频率之前，服用非那雄胺4周。此后，在非那雄胺的基础上加用外源性P和E_2一周，之后再次测定促黄体生成素的脉冲频率。通过这种方法，我们的目标是构建多囊卵巢综合征妇女和对照组的P剂量-黄体生成素脉冲频率响应曲线(即平均P浓度与黄体生成素脉冲频率变化的关系)。我们假设在PCOS中，非那雄胺将恢复GnRH脉冲发生器对P和E_2负反馈的敏感性，提示DHT介导了异常的反馈敏感性。