Paradisi Giancarlo, Steinberg Helmut O, Shepard Marguerite K, Hook Ginger, Baron Alain D
Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
J Clin Endocrinol Metab. 2003 Feb;88(2):576-80. doi: 10.1210/jc.2002-020386.
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/m(2) x 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 micromol/kg fat-free mass x 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 micromol/kg fat-free mass x 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.
患有多囊卵巢综合征（PCOS）的肥胖女性存在内皮功能受损的情况，这与睾酮水平和胰岛素抵抗均密切且直接相关。内皮功能障碍被认为是大血管疾病的一个重要危险因素。由于曲格列酮（Tgz）可改善激素水平和胰岛素敏感性，我们测试了Tgz治疗是否能改善这些患者的内皮功能。我们研究了10名PCOS患者在接受Tgz（600mg/d）治疗3个月前后，股动脉内分级输注内皮依赖性血管舒张剂氯化乙酰甲胆碱（MCh）时的腿部血流（LBF）反应，以及4小时高胰岛素正常血糖钳夹试验（120mU/m²×min）时的LBF反应。选取13名年龄、体重、体脂（两组均>40%）、血压和总胆固醇相匹配的肥胖女性（OBW）作为对照组。与OBW相比，PCOS患者的游离睾酮（fT）和甘油三酯（TG）升高，高密度脂蛋白胆固醇水平降低[分别为14.0±1.0 vs. 3.7±0.6pmol/L（P<0.0001），1.60±0.28 vs. 0.94±0.09mmol/L（P<0.02），以及0.91±0.04 vs. 1.1±0.04mmol/L（P<0.005）]。Tgz治疗降低了fT水平，但未改善TG和高密度脂蛋白水平[分别降至9.7±2.8pmol/L（P<0.007），1.49±0.34mmol/L（P=无显著性差异），以及0.93±0.07mmol/L（P=无显著性差异）]。Tgz治疗后基础LBF未改变。与OBW相比，PCOS患者在Tgz治疗后，胰岛素刺激的葡萄糖处置（52.7±6.6 vs. 85.5±4.4μmol/kg去脂体重×min；P<0.0005）和血管舒张（LBF增加，22±14% vs. 59±15%；P<0.05）显著改善，分别达到68.8±7.2μmol/kg去脂体重×min（P<0.0001）和101±48%（P<0.03）。PCOS患者治疗后对MCh的LBF增加更为明显（方差分析，P<0.01），且与OBW中观察到的相似。在Tgz治疗前，PCOS和OBW对MCh的最大LBF增加分别为130±25%和233±29%（P<0.01）。Tgz治疗后，PCOS的值有所改善，增加幅度与OBW相似（245±45%；P<0.04）。PCOS患者的Tgz治疗改善了激素和代谢特征。这些改变与内皮功能的改善相关，表明Tgz可能是降低PCOS女性以及其他胰岛素抵抗综合征女性发生大血管疾病风险的一种有用手段。
