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

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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.