Flutamide-metformin therapy to reduce fat mass in hyperinsulinemic ovarian hyperandrogenism: effects in adolescents and in women on third-generation oral contraception.

Adolescents and young women with menstrual irregularities and hyperinsulinemic hyperandrogenism, so-called polycystic ovary syndrome, have abnormalities in body composition, even when nonobese. The combination of flutamide (125-250 mg/d) and metformin has additive benefits on endocrine- metabolic indices in women with polycystic ovary syndrome. However, it is unknown whether this combination also reverses the abnormalities in body composition in this population, especially if the flutamide dose is further reduced, the combination is given at a young age, and an oral contraceptive (OC) is added. Two randomized 3-month studies with flutamide-metformin were conducted in nonobese patients (n = 45) with hyperinsulinemic ovarian hyperandrogenism. In teenagers [n = 21; approximately 15 yr; no use of OC (OC-)], we determined whether a minidose combination (flutamide 62.5 mg/d) improved body composition and endocrine-metabolic indices, and in young women (n = 24; approximately 18 yr; OC+), we determined whether the addition of the minidose combination to a gestodene-containing OC exerted additive effects on the same variables. In OC- teenagers, flutamide-metformin improved fasting insulin/glucose ratio; serum IGF-binding protein-1, testosterone, SHBG, androstenedione, triglycerides, low- density lipoprotein and high-density lipoprotein cholesterol; lean mass, total fat, and abdominal fat (all P < 0.01). In OC+ women, the addition of flutamide-metformin was associated with gain of lean mass and loss of total fat (P < 0.01 vs. OC alone), but the addition failed to reduce abdominal fat. In conclusion, in nonobese adolescents with hyperinsulinemic ovarian hyperandrogenism, minidose flutamide-metformin reversed endocrine-metabolic anomalies and the excess of fat, including abdominal fat; in women, adding flutamide- metformin to a third-generation OC was also effective in improving body composition, but abdominal adiposity was not improved.