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Troglitazone Therapy Improves Endothelial Function to Near Normal Levels in Women with Polycystic Ovary Syndrome

Departments of Medicine (G.P., H.O.S., G.H., A.D.B.) and Obstetrics and Gynecology (M.K.S.), Indiana University School of Medicine, Indianapolis, Indiana 46202; and Amylin Pharmaceuticals, Inc. (A.D.B.), San Diego, California 92121

Address all correspondence and requests for reprints to: Alain D. Baron, M.D., Amylin Pharmaceuticals, Inc., 9373 Towne Centre Drive, Suite 250, San Diego, California 92121. E-mail: abaron{at}amylin.com.

Obese women with polycystic ovary syndrome (PCOS) exhibit impaired endothelial function, which is strongly and directly correlated with both testosterone levels and insulin resistance. Endothelial dysfunction is considered a potent risk factor for macrovascular disease. Because troglitazone (Tgz) improves both hormonal profiles and insulin sensitivity, we tested whether Tgz treatment ameliorates endothelial function in these patients.

We studied leg blood flow (LBF) responses to graded intrafemoral artery infusion of the endothelium-dependent vasodilator methacholine chloride (MCh) and to a 4-h hyperinsulinemic euglycemic clamp (120 mU/m²·min) in 10 PCOS, before and after 3 months treatment with Tgz (600 mg/d). A group of 13 obese women (OBW) matched for age, weight, body fat (>40% in both groups), blood pressure, and total cholesterol served as controls.

PCOS patients exhibited elevated free testosterone (fT) and triglycerides (TG) and lower high density lipoprotein cholesterol levels compared with OBW [14.0 ± 1.0 vs. 3.7 ± 0.6 pmol/liter (P < 0.0001), 1.60 ± 0.28 vs. 0.94 ± 0.09 mmol/liter (P < 0.02), and 0.91 ± 0.04 vs. 1.1 ± 0.04 mmol/liter (P < 0.005), respectively]. Tgz treatment reduced fT levels, but did not improve the TG and high density lipoprotein profile [to 9.7 ± 2.8 pmol/liter (P < 0.007), 1.49 ± 0.34 mmol/liter (P = NS), and 0.93 ± 0.07 mmol/liter (P = NS), respectively]. Basal LBF was unchanged after Tgz. In PCOS compared with OBW, insulin stimulated glucose disposal (52.7 ± 6.6 vs. 85.5 ± 4.4 µmol/kg fat-free mass·min; P < 0.0005) and vasodilation (increase in LBF, 22 ± 14% vs. 59 ± 15%; P < 0.05) were significantly improved after Tgz treatment to 68.8 ± 7.2 µmol/kg fat-free mass·min (P < 0.0001) and 101 ± 48% (P < 0.03), respectively. The increase in LBF in response to MCh in PCOS was markedly more pronounced after treatment (P < 0.01, by ANOVA) and was similar to that observed in OBW. Before Tgz treatment, maximal LBF increments in response to MCh were 130 ± 25% and 233 ± 29% in PCOS and OBW, respectively (P < 0.01). After Tgz treatment, PCOS values improved, achieving increments similar to those in OBW (245 ± 45%; P < 0.04).

Tgz treatment in PCOS improves both hormonal and metabolic features. These modifications are associated with improvement of endothelial function, suggesting that Tgz could be a useful tool to reduce the risk of macrovascular disease in women with PCOS and perhaps in other insulin-resistant syndromes.

This work was supported by NIH Grants DK-42469, MO1-RR-750-19, and DK-20452 and a Veterans Affairs Merit Review Award.

G.P. is the recipient of a grant from the A. Griffini Foundation (Varese, Italy).

Abbreviations: FFA, Free fatty acid; fT, free testosterone; GDR, glucose disposal rate; HDL, high density lipoprotein; LBF, leg blood flow; MAP, mean arterial blood pressure; MCh, methacholine chloride; OBW, obese women; OGTT, oral glucose tolerance test; PAI-1, plasminogen activator inhibitor-1; PCOS, polycystic ovary syndrome; PPAR, peroxisome proliferator activating receptor-; TG, triglycerides; Tgz, troglitazone; TZD, thiazolidenedione.

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