Source: Ibáñez L, Ong K, Ferrer A, et al. Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism. J Clin Endocrinol Metab. 2003;88:2600–2606.Thirty adolescent girls (age 13.6 to 18.6 years) with polycystic ovary syndrome (PCOS) or hyperinsulinemic ovarian hyperandrogenism confirmed by serum hormonal measurements participated in a 1-year study of flutamide, an antiandrogen (125mg/day), plus metformin (1,275mg/day), conducted in Barcelona, Spain, by researchers from Barcelona, United Kingdom, and Belgium. Patients were excluded if diagnosed with other endocrine processes such as hypothyroidism or Cushing’s syndrome. Outcome measures included body composition, overnight growth hormone and luteinizing hormone, pulse levels, insulin sensitivity, and ovulation (weekly progesterone levels). The girls had symptoms of menstrual irregularity, acne, seborrhea, hirsutism, and male pattern hair loss, and the potential for long-term complications, including infertility, obesity, diabetes, and cardiovascular disease.No changes were observed during a 3-month control (off-treatment) period. During 9 months of therapy with low-dose flutamide and metformin, patients experienced reductions in insulin, androgen, lipids, and waist-hip ratio. There were no changes in liver function. The percent of girls with ovulation increased from 7% to 87%. Fat mass decreased 10% (20% decrease in abdominal fat mass) and lean body mass increased, resulting in minimal net change in weight. The authors concluded that low-dose flutamide-metformin therapy attenuated a wide spectrum of abnormalities, including excess fat mass and reduced lean mass.In the current epidemic of obesity, the incidence of PCOS is also increasing through the physiologic mechanism of insulin resistance and hyperinsulinism, which affect ovarian function. Overweight adolescents develop amenorrhea, acne, and facial hair;1 overweight children develop early pubic hair, body odor, and acne.2 Of course, the most effective cure for overweight-induced PCOS is to lose weight and thereby improve insulin sensitivity and lessen symptoms of hyperandrogenism. In patients who are making reasonable lifestyle changes and yet are still developing hyperandrogenism, pharmacologic intervention may be beneficial.This study addresses the potential of combining lifestyle changes (diet and exercise) designed to control weight with pharmacotherapy targeting the insulin resistance and androgen effects that underlie PCOS. Metformin serves to improve sensitivity to insulin. As a result, insulin levels decline and the consequences of hyperinsulinism (ovarian androgen production, hyperlipidemia, acanthosis nigricans) decrease.3 Flutamide can cause hepatotoxicity at high doses.4 The flutamide dose in the current study has minimal benefit when used alone, but when used in combination with metformin, it magnifies the benefits of metformin. 5 Flutamide-metformin therapy, as described in the above study, may serve as an adjunct in diabetes prevention.