Women with polycystic ovary syndrome (PCOS) are known to exhibit insulin resistance with compensatory hyperinsulinemia. To determine the role of hyperinsulinemia on follicle function in PCOS, we examined 24-h estradiol (E(2)) responses to recombinant human FSH (r-hFSH), 75 IU, before and during insulin infusion both before and after administration of pioglitazone (30 mg/d) in seven PCOS women. Each subject underwent two 10-h hyperinsulinemic-euglycemic clamps at rates of 30 (low dose) and 200 (high dose) mU/m(2).min, respectively. During both low- and high-dose insulin infusions, E(2) responses to r-hFSH were unaltered compared with that observed in the absence of insulin. Pioglitazone administration for 5 months improved insulin sensitivity as indicated by significantly (P < 0.05) increased glucose infusion rates during the clamp studies. At 3 months of treatment, r-hFSH-stimulated E(2) responses were not different from those observed before treatment. With pioglitazone treatment, E(2) responses to r-hFSH remained unchanged during low-dose insulin infusion, whereas a highly significant (P < 0.02) increased response was noted with the high-dose hyperinsulinemic-euglycemic clamp. In addition to a greater magnitude of response, peak levels of E(2) were sustained longer compared with that seen before treatment. The data indicate that granulosa cell responsiveness to FSH was enhanced by insulin after improved insulin sensitivity induced by pioglitazone. These findings are consistent with the possibility that PCOS granulosa cells are insulin resistant.