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Submitted on October 11, 2005
Accepted on July 13, 2006
Division of Endocrinology, Dept. of Internal Medicine, and Center for Applied Biomedical Research (C.R.B.A.), S. Orsola-Malpighi Hospital, University of Bologna, Italy
* To whom correspondence should be addressed. E-mail: renato.pasquali{at}unibo.it.
Context
The few controlled trials performed so far indicate that the addition of metformin and/or flutamide to hypocaloric diet in obese women with PCOS effectively influences different phenotypic aspects of the syndrome. All these studies are, however, characterized by a short-medium period of treatment.
Objective
To investigate the long-term effects of these therapies.
Design
Prospective, randomized, placebo-controlled trial.
Setting
Medical center.
Patient(s)
Eighty overweight-obese women with PCOS. Seventy-six completed the study.
Intervention(s)
Hypocaloric diet for the first month; hypocaloric diet plus placebo, or metformin (850 mg, orally, twice a day), or flutamide (250 mg, orally, twice a day), or metformin+flutamide for the subsequent 12 months (20 subjects in each group).
Main outcome measure(s)
Clinical features, computerized tomography measurement of fat distribution, androgens, lipids, fasting and glucose-stimulated glucose and insulin levels at baseline, 6 months 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), DHEA-S (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 a further decrease in DHEA-S (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 (glucoseAUC, P = 0.041), insulin sensitivity (ISI, P < 0.001) and LDL cholesterol levels (P = 0.003), whereas metformin decreased glucose-stimulated insulin levels (insulinAUC, 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 therapeutical options according to the required outcomes in the long-term.
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