Treatment with flutamide, metformin, and their combination added to a hypocaloric diet in overweight-obese women with polycystic ovary syndrome: A randomized, 12-month, placebo-controlled study

Context: The few controlled trials performed so far indicate that the addition of metformin and/or flutamide to a hypocaloric diet in obese women with polycystic ovary syndrome ( PCOS) effectively influences different phenotypic aspects of the syndrome. All these studies are, however, characterized by a short to medium period of treatment. Objective: Our objective was to investigate the long-term effects of these therapies. Design and Setting: We conducted a prospective, randomized, placebo-controlled trial at a medical center. Patients: Of 80 overweight-obese women with PCOS, 76 completed the study. Interventions: Patients were placed on a hypocaloric diet for the first month and then on a hypocaloric diet plus placebo, metformin ( 850 mg, orally, twice a day), flutamide ( 250 mg, orally, twice a day), or metformin plus flutamide for the subsequent 12 months ( 20 subjects in each group). Main Outcome Measures: We assessed clinical features, computerized tomography measurement of fat distribution, androgens, lipids, and fasting and glucose-stimulated glucose and insulin levels at baseline and after 6 and 12 months of treatment. Results: After 6 months, compared with placebo, flutamide further decreased visceral/sc fat mass ( P = 0.044), androstenedione ( P < 0.001), dehydroepiandrosterone sulfate ( P < 0.001), and hirsutism score ( P < 0.001), whereas metformin further increased frequency of menstruation ( P = 0.039). After 12 months, flutamide maintained the effects observed after 6 months on visceral/sc fat mass ( P = 0.033) and androstenedione ( P < 0.001), whereas it produced an additional decrease in dehydroepiandrosterone sulfate ( P = 0.020) and hirsutism score ( P = 0.019); metformin further improved the menstrual pattern ( P = 0.013). Moreover, after 12 months, flutamide improved more than placebo the menstrual pattern ( P = 0.008), glucose-stimulated glucose levels ( P = 0.041), insulin sensitivity ( P < 0.001), and low-density lipoprotein cholesterol levels ( P = 0.003), whereas metformin decreased glucose-stimulated insulin levels ( P = 0.014). The combination of the two drugs maintained the specific effect of each of the compounds, without any additive or synergistic effect. Conclusions: These findings add relevance to the usefulness of metformin and flutamide in the treatment of dieting overweight-obese PCOS women and provide a rationale for targeting different therapeutic options according to the required outcomes in the long term.