THE INSULIN-SENSITIZING AGENT TROGLITAZONE IMPROVES METABOLIC AND REPRODUCTIVE ABNORMALITIES IN THE POLYCYSTIC-OVARY-SYNDROME

We performed this study to investigate the hypothesis that insulin res istance plays a role in the pathogenesis of reproductive abnormalities in women with the polycystic ovary syndrome (PCOS). Twenty-five women with PCOS were enrolled in a double-blind randomized 3-month trial of two doses of the insulin-sensitizing agent, troglitazone, 21 of whom completed the study: 200 mg, n = 10; 400 mg, n = 11. Baseline hormonal parameters and glucose tolerance were compared with 12 age- and weigh t-matched ovulatory control women. There were no significant changes i n body mass index during the study. Fasting (P < 0.01) and 2-h post-75 -g glucose load insulin levels (P < 0.05), as well as integrated insul in responses to the glucose load, decreased (P < 0.05), and insulin se nsitivity assessed by a frequently sampled iv glucose tolerance test i ncreased significantly (P < 0.001) during troglitazone treatment. This was accompanied by significant decreases in the levels of nonsex horm one-binding globulin-bound testosterone (P < 0.01), dehydroepiandroste rone sulfate (P < 0.001), estradiol (P < 0.01), and estrone (P < 0.001 ). Stepwise regression analysis indicated that decreases in nonsex hor mone-binding globulin testosterone levels were significantly correlate d with decreases in integrated insulin responses to the glucose load ( r(2) 0.44, P < 0.01). The only significant changes at the 200-mg trogl itazone dose were an increase in insulin sensitivity (P < 0.05) and de creases in dehydroepiandrosterone sulfate (P < 0.01) and estrone (P < 0.05) levels. At the 400-mg dose, in addition to the changes noted in the entire troglitazone treatment group, increases in the disposition index (the product of insulin sensitivity and secretion) achieved sign ificance, as did decreases in androstenedione (P < 0.01) and LH (P < 0 .05) levels and increases in sex hormone-binding globulin levels (P < 0.01). Two PCOS women had ovulatory menses. We conclude that 1) trogli tazone improves total body insulin action in PCOS, resulting in lower circulating insulin levels; 2) insulin resistance, probably via hyperi nsulinemia, results in a general augmentation of steroidogenesis and L H release in PCOS; and 3) insulin-sensitizing agents, such as troglita zone, may provide a novel therapy for PCOS.