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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 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，这种异常可能导致PCOS的许多激素表现。虽然这种快速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。例如，一项研究评估了外源性P和E2给药前和给药后7天的LH（以及推断的GnRH）脉冲频率。对LH抑制作为平均P浓度的函数的评估显示，正常女性中P浓度<10 ng/ml比PCOS患者更有效地抑制LH脉冲频率。这种异常可通过雄激素受体拮抗剂氟替卡松治疗逆转，表明上述敏感性缺陷是由高雄激素血症引起的。然而，目前尚不清楚睾酮（T）本身或其更有效的代谢物双氢睾酮（DHT）是否介导了这些作用。我们将进一步研究这一点与使用的finaldide，一种特定的抑制剂的酶（5 α-还原酶），催化转化T的DHT。将对PCOS受试者和正常对照受试者进行研究。将确定基线LH脉冲频率。在重新评估LH脉冲频率之前，将给予Finlidade 4周。此后，除非那肽外，还将给予外源性P和E2一周，之后将再次测定LH脉冲频率。以这种方式，我们的目标是构建P剂量-LH脉冲频率响应曲线（即，平均P浓度与LH脉冲频率的变化）。我们假设，在PCOS中，芬那肽将恢复GnRH脉冲发生器对P和E2负反馈的敏感性，表明DHT介导异常反馈敏感性。

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 (5a-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.