Polycystic ovary syndrome (PCOS) is the most common reproductive endocrine disease in women of reproductive age. Many serious health problems are associated with PCOS, including infertility, hirsutism, increased pregnancy loss, markedly increased risk for cardiovascular disease and endometrial cancer at a young age. Despite the seriousness of PCOS and the high prevalence of this disorder, the etiology of PCOS remains a mystery. The metabolic profile of the PCOS patient is heterogenous and has led to controversy regarding even the definition of PCOS but the common physiological link in all subtypes of PCOS is a lack of follicle development beyond the early antral stage. Therefore, in order to understand the causes of PCOS and to develop an effective treatment it is critical to understand the mechanisms regulating selection of the dominant follicle in normal women and how these mechanisms are altered in women with PCOS. The studies performed to date lead to the conclusion that there is an endogenous inhibitor of aromatase (P450AROM) in PCOS that is not present in normal follicles. In preliminary studies, we showed that the concentration of 5-alpha-androstane-3,17-dione, a competitive inhibitor of P450AROM activity in human GC, is significantly higher in PCOS than normal follicles. Interestingly, it appears that 5-alpha-A production decreases markedly in dominant follicles, raising the possibility that regulation of 5-alpha reductase activity may play a role in selection of the dominant follicles and the genesis of polycystic ovaries. The overall goals of this proposal are to assess the role of 5-alpha A in the genesis of PCOS and to understand the regulation of 5-alpha reductase mRNA expression and enzyme activity in the ovary. Specific goals are to determine the magnitude of the effects of 5-alpha A on P450AROM activity in PCOS follicles, to determine if P450AROM expression is blocked in PCOS or if P450AROM is expressed but its activity is inhibited, and to determine if there are abnormalities in P45017alpha and P450scc expression in PCOS. The expression of the two 5-alpha-reductase mRNAs and the localization and activities of the two 5-alpha-reductase isoenzymes in normal and PCOS ovaries will be examined. Finally, the regulation of 5 alpha-reductase gene expression in the ovary will be studied. The results of these studies will provide a wealth of important information regarding the molecular biology of normal follicle development and the abnormalities that occur in PCOS. There is a strong probability that this new knowledge could lead directly to novel therapies that may restore reproductive cyclicity and eliminate many of the increased risks for cardiovascular and malignant disease in women with PCOS.
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