Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy☆

Abstract Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% ( P = .04) and the waist to hip ratio (WHR) decreased 2.8% ( P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% ( P = .04), and the insulin area to glucose area ratio decreased 31% ( P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased ( P = .04) and apo A-1 increased ( P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T ( P = .0001), androstenedione ( P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04). The change (decrease) in IA on Metformin was a significant independent positive determinant of the reduction in total T ( R 2 = 22%, P = .03), free T ( R 2 = 30%, P = .01), and FAI ( R 2 = 29%, P = .01). Three spontaneous pregnancies occurred during treatment. Those seven patients who continued Metformin therapy all resumed normal menstrual cycles. In PCOS, hyperinsulinemia favors hyperproduction of androgens with subsequent alterations in secretion of gonadotropins, depression of apo A-1, and elevation of SBP, metabolic changes that increase coronary heart disease risk. Most of the metabolic abnormalities of PCOS can be reversed by Metformin, with the additional benefit of enough normalization of the endocrine milieu to allow regular menstrual cycles, reversal of infertility, and spontaneous pregnancy.