Effect of flutamide and metformin administered alone or in combination in dieting obese women with polycystic ovary syndrome

BACKGROUND Hyperandrogenism, hyperinsulinaemia and obesity play a key and coordinating roles in the pathogenesis of polycystic ovary syndrome (PCOS), contributing in different ways to the clinical expression of the syndrome. Weight loss is beneficial, but the additional administration of insulin-lowering drugs, such as metformin, and antiandrogens may produce further benefits, due to their different spectrum of action. The effects of long-term metformin and flutamide, an antiandrogen drug, added alone or in combination with a low-calorie diet, on body weight and fat distribution, androgens, metabolic parameters and clinical status in obese women with PCOS were investigated. METHODS Forty obese women with PCOS were enrolled in the study. After a 1-month diet, according to single-blind design, the patients were allocated to treatment with placebo, metformin (850 mg/orally, twice daily), flutamide (250 mg/orally, twice daily) or metformin (850 mg/orally, twice daily) + flutamide (250 mg/orally, twice daily) for the following 6 months, while continuing hypocaloric dieting. At baseline and at the end of the study, sex hormone, SHBG, lipid, insulin and insulin sensitivity determinations were evaluated. At the same time, clinical parameters such as anthropometry, total (TAT), visceral (VAT) and subcutaneous (SAT) adipose tissue, hirsutism and menses were also measured. RESULTS We found that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment had some specific additional favourable effects with respect to the low-calorie diet alone. In particular, flutamide treatment seemed to add a significant effect in decreasing visceral fat, androstenedione, DHEA-S, total and low density lipoprotein (LDL) cholesterol and in improving hirsutism. Conversely, metformin had significant benefits on the menstrual status. The two drugs showed an additive effect in reducing testosterone concentrations and a synergistic effect in increasing high density lipoprotein (HDL) cholesterol and SHBG levels. Improvement of insulin sensitivity and hyperinsulinaemia appeared to depend on hypocaloric diet, without any further significant effect of the pharmacological treatments, either alone or in combination. CONCLUSIONS We conclude that, in obese PCOS women, following a hypocaloric diet the addition of metformin, flutamide or the combined metformin + flutamide treatment appears to have a more favourable outcome on body fat distribution, androgens, lipids, hirsutism and menses. However, our data emphasize the dominant role of hypocaloric dieting in improving insulin resistance and hyperinsulinaemia. Therefore, this study provides a rationale for specifically targeting different therapeutical options for PCOS according to the required outcomes.