alexa Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome.
Pharmaceutical Sciences

Pharmaceutical Sciences

Journal of Pharmacological Reports

Author(s): Strauss JF rd

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Abstract Polycystic ovary syndrome (PCOS) is a common disorder of unknown etiology, but several lines of evidence suggest that there is an underlying genetic cause for PCOS. Studies of first-degree relatives of women diagnosed with PCOS reveal familial clustering of the disease, particularly hyperandrogenemia. A prospective study of first-degree female relatives of PCOS women found that 46\% of ascertainable sisters of PCOS women were hyperandrogenemic. The serum bioavailable testosterone in the cohort of sisters showed a bimodal distribution. These observations suggest a dominantly inherited trait controlling androgen levels. Studies on cultures of human theca cells derived from follicles isolated from the ovaries of PCOS and normal women demonstrated that PCOS theca cells produce greater amounts of testosterone, 17alpha-hydroxyprogesterone, and progesterone than normal theca cells, despite the fact that cells were cultured under identical conditions for multiple population doublings. Examination of the metabolism of radiolabeled steroid hormone precursors and steady-state levels of mRNAs encoding steroidogenic enzymes revealed that there are multiple alterations in the steroidogenic machinery of PCOS theca cells, including elevated expression of the CYP11A, 3BHSD2, and CYP17 genes. The increased mRNA levels are the result, in least in part, of increased gene transcription. Interestingly, the STAR gene is not expressed at a higher level in PCOS theca cells. The stable up-regulation of steroidogenesis in PCOS thecal cells indicates either a genetic abnormality in these cells or a persistent metabolic imprint established in vivo. Linkage and association studies conducted by the National Cooperative Program in Infertility Research using affected sib-pair analysis and the transmission/disequilibrium test to explore candidate genes point a finger at a region on chromosome 19p13.3. The putative PCOS gene lying in this region has yet to be identified. However, existing data suggest that it is probably involved in signal transduction mechanisms leading to altered expression of a suite of genes that affect theca cell steroidogenic activity as well as the metabolic phenotype of other cell types, including muscle and fat.
This article was published in Ann N Y Acad Sci and referenced in Journal of Pharmacological Reports

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