Objective: To determine whether amelioration of insulin resistance in polycystic ovary syndrome (PCOS) with the insulin sensitizer troglitazone (TGZ) decreases circulating adrenal androgens (AAs), as reflected by DHEAS levels. Design: Prospective, randomized, double-blind clinical trial. Setting: Multicenter study. Subject(s): Three-hundred five women with PCOS. Intervention(s): Subjects were randomly assigned to receive either placebo (PBO; n = 73) or TGZ in doses of 150 mg/day (TGZ-150; n = 78), 300 mg/day (TGZ-300; n = 77), or 600 mg/day (TGZ-600; n =77) for 20 weeks. Blood was sampled before (week 0) and at week 20 of treatment. Main Outcome Measure(s): DHEAS, insulin, and glucose levels were determined in the blood samples. Result(s): There were no differences in age, body mass, or racial composition among the groups. Our results indicate that basal insulin declined in a dose-related fashion. Likewise, TGZ administration caused a dose-related decrease in DHEAS levels. To detect extreme effects, we subsequently subdivided patients receiving PBO or TGZ-600 into tertiles according to initial DHEAS levels. Patients receiving PBO in the lowest (n = 27) and highest (n = 22) DHEAS tertiles experienced a 16.8% ± 62.0% and a -11.1% ± 17.4% change in DHEAS levels during the study, respectively. Alternatively, patients with PCOS receiving TGZ-600 in both the lowest (n = 29) and the highest (n = 23) DHEAS tertiles experienced a drop in DHEAS levels (-18.7% ± 27.2% and -26.4% ± 17.2%, respectively), a significant difference from PBO. Conclusion(s): In conclusion, improving the insulin resistance-related hyperinsulinemia of PCOS with TGZ results in a decrease in DHEAS levels, regardless of initial DHEAS level. Whether the observed suppression is the direct result of decreased insulin levels or whether it reflects other direct and indirect effects of TGZ remains to be determined. © 2003 by American Society for Reproductive Medicine.