Polycystic ovary syndrome affects approximately 5-10% of reproductive-aged women. A cardinal feature of this disorder is chronic anovulation, which manifests clinically by irregular menstrual bleeding and is a primary cause for infertility. Notably, chronic anovulation in PCOS also predisposes women to increased risk for endometrial cancer. The mechanism(s) responsible for ovulatory disruption are not well understood. While recognizing the well-documented decrease in pituitary FSH secretion, a growing body of evidence indicates that ovarian follicular function in PCOS is abnormal. We hypothesize that women with PCOS exhibit a bimodal follicle response to gonadotropin stimulation in which the FSH threshold dose range is narrowed. At the lower end of the spectrum, increased FSH stimulation is required to initiate follicle growth compared to that observed in normal women, which warrants greater drug use. At the high end of the FSH threshold dose range, granulosa cell (GC) responses are significantly greater in PCOS women than those observed in normal women at equivalent amounts of FSH. As a result, once follicle growth has commenced in PCOS women, the dose of FSH that exceeds the upper threshold range tends to be lower than that for normal women. The latter consideration has important clinical relevance as excessive GC stimulation may lead to ovarian hyperstimulation syndrome and potential serious life-threatening complications. We have shown previously in vitro, and more recently in vivo, that GCs from PCOS ovaries exhibit greater E2 responsiveness to FSH stimulation compared to responses observed in GCs of normal women. Furthermore, our assessment of FSH-stimulated E2 release in PCOS women undergoing insulin infusion suggests that GCs may exhibit insulin resistant, which may result from or contribute to functional abnormalities of the follicle. The mechanisms responsible for these alterations of GC function are unknown. Of those factors which have been shown, in vitro, to impact GC responses to FSH, estrogen, androgen, and insulin are uniquely linked to PCOS by virtue of their abnormal secretion, production, and metabolism, respectively. However, translational studies to specifically test whether these factors may be responsible for abnormal GC function in women with PCOS have not been performed. In this project, we propose to address the hypotheses that each of these factors, either alone or in combination, may be responsible for abnormal GC function in PCOS.
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