Selective ovary resistance to insulin signaling in women with polycystic ovary syndrome

Objective: Insulin resistance is a common feature of both polycystic ovary syndrome (PCOS) and non-insulin-dependent diabetes mellitus (NIDDM); however, the persistent reproductive disturbances appear to be limited to the former, suggesting that insulin resistance in the ovary itself may confer this susceptibility. Design: Prospective study. Setting: University-affiliated department. Patient(s): Forty-four women undergoing IVF treatment, of whom 11 had polycystic ovaries and 33 had normal ovulation (NO). Intervention(s): The various effects and signaling of insulin and insulin-like growth factor-1 (IGF-1) were examined in cultured ovarian granulosa cells treated with troglitazone (1 mug/mL) or with vehicle by reverse transcription-polymerase chain reaction, western blot, and in vitro functional analyses. Main Outcome Measure(s): Glycogen and DNA syntheses, mRNA and protein expression, and cellular localization of insulin/IGF-1 receptors and insulin receptor substrates (IRSs). Result(s): There were significant decreases in insulin-stimulated glucose incorporation into glycogen in PCOS cells, which is a metabolic action of insulin. However, IGF-1 stimulation was found to be greater in PCOS cells at all experimental concentrations with respect to thymidine incorporation compared with NO cells, which is a mitogenic action. Troglitazone increased the insulin-induced glycogen synthesis but reduced the IGF-1-augmented responses of DNA synthesis in PCOS cells to the range within those of NO granulosa cells. We then found that troglitazone treatment reversed the expression imbalance between IRS-1 and IRS-2 in PCOS cells. Conclusion(s): There is a selective defect in insulin actions in PCOS granulosa cells, which suggests ovarian insulin resistance, and this metabolic phenotype is associated with an enhanced IGF-1 mitogenic potential. Troglitazone could divergently alter expression of various IRS molecules and insulin actions and could be used as an ovarian insulin sensitizer and mitogen/steroidogenic inhibitor in PCOS. (C)2003 by American Society for Reproductive Medicine.