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: 7606677
• 负责人: Christopher Rolland McCartney
• 金额: $ 8.2万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7606677
• 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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 多囊卵巢综合征（PCOS）与持续快速的促性腺激素激素释放激素（GNRH）脉冲频率有关，这种异常可能会解释PCOS的许多激素表现。尽管这种快速GNRH脉冲频率的病因尚不清楚，但最近的证据表明，PCOS中的GnRH脉冲发生器对孕酮（P）和雌二醇（E2）的反馈作用相对抵抗力。例如，一项研究在外源P和E2给药后评估了LH（和推理GNRH）脉冲频率和7 d。对LH抑制作的评估是平均P浓度的函数，表明PCOS的P浓度<10 ng/ml抑制LH脉冲频率比正常女性更有效。用雄激素受体拮抗剂氟丁酰胺治疗逆转了这种异常，这表明上述敏感性缺陷来自高雄激素血症。但是，尚不清楚睾丸激素（T）本身或其更有效的代谢产物二氢睾丸激素（DHT）是否介导了这些作用。我们将通过使用非那雄胺的使用，这是一种催化t转化为DHT的酶（5？还原酶）的特异性抑制剂。将研究具有PCOS和正常对照的受试者。将确定基线LH脉冲频率。然后，在重新评估LH脉冲频率之前，将给予非那雄胺4周。此后，除非那雄胺外，还将给出外源P和E2，此后将再次确定LH脉冲频率。通过这种方式，我们旨在为患有PCOS和对照的女性构建P剂量LH脉冲频率响应曲线（即平均P浓度与LH脉冲频率变化）。我们假设在PCOS中，非那雄胺将恢复P和E2对负反馈的GNRH脉冲发生器的敏感性，这表明DHT介导异常的反馈灵敏度。