Increased endothelin-1 levels in women with polycystic ovary syndrome and the beneficial effect of metformin therapy

Women with polycystic ovary syndrome who present with hyperandrogenemia, hyperinsulinemia, and insulin resistance appear to be at high risk of cardiovascular disease. Elevated levels of endothelin-1, a marker of vasculopathy, have been reported in insulin-resistant subjects with endothelial dysfunction. Male gender also seems to be an aggravating factor for cardiovascular disease. In this study we investigated endothelin-1 levels in women with polycystic ovary syndrome, and we evaluated the effect of an insulin sensitizer, metformin, on endothelin-1 levels. Plasma endothelin-1 levels were measured in 23 obese (mean age, 24.3 +/- 4.6 yr; body mass index, 35 +/- 5.6 kg/m(2)) and 20 nonobese women with polycystic ovary syndrome (24.1 +/- 3.6 yr; body mass index, 21.8 +/- 2.5 kg/m(2)) as well as in 7 obese and 10 nonobese healthy, normal cycling, age-matched women. Additionally, endothelin-1 levels were evaluated in a subgroup of women with polycystic ovary syndrome (10 obese and 10 nonobese) 6 months postmetformin administration (1700 mg daily). Our results showed that obese and nonobese women with polycystic ovary syndrome had higher levels of endothelin-1 compared with the controls [obese, 2.52 +/- 1.87 vs. 0.44 +/- 0.23 pmol/liter (by analysis of covariance, P < 0.02); nonobese, 1.95 +/- 1.6 vs. 0.43 +/- 0.65 pmol/liter (P < 0.009)]. All of the participating women with polycystic ovary syndrome (n = 43) when compared with the total group of controls (n = 17) demonstrated hyperinsulinemia (polycystic ovary syndrome, 24.5 +/- 19.6; controls, 11.2 +/- 3.4 U/liter; P < 0.03), lower glucose utilization (M40) during the hyperinsulinemic euglycemic clamps (3.4 +/- 2.4 vs. 5.6 +/- 1.75 mg/kg.min; P < 0.045, by one-tailed test), and higher levels of endothelin-1 (polycystic ovary syndrome, 2.52 +/- 1.87; controls, 0.44 +/- 0.23 pmol/liter; P < 0.02, analysis of covariance covariate for body mass index). A positive correlation of endothelin-1 with free T levels was also shown (r = 0.4, P = 0.002) as well as a negative correlation of endothelin-1 with glucose utilization (r = -0.3; P = 0.033) in the total studied population. Finally, after metformin therapy, endothelin-1 levels were significantly reduced in obese (endothelin-1 before, 3.25 +/- 2.2; endothelin-1 after, 1.1 +/- 0.9 pmol/liter; P < 0.003) and nonobese (endothelin-1 before, 2.7 +/- 2; endothelin-1 after, 0.7 +/- 0.4 pmol/liter; P < 0.01) women with polycystic ovary syndrome, with no change in body mass i