Anovulation in Eumenorrheic, Nonobese Adolescent Girls Born Small for Gestational Age: Insulin Sensitization Induces Ovulation, Increases Lean Body Mass, and Reduces Abdominal Fat Excess, Dyslipidemia, and Subclinical Hyperandrogenism

Adolescent girls born small for gestational age (SGA) are at risk for anovulation, hyperinsulinism, subclinical hyperandrogenism, dyslipidemia, and central adiposity. Hyperinsulinemic insulin resistance has been proposed as a key pathogenetic factor underpinning these associations. We have tested this hypothesis in an intervention study by assessing the effects of insulin sensitization (metformin treatment, 850 mg/d for 3 months) in eumenorrheic, nonobese, anovulatory SGA adolescents [n = 13; mean birth weight, 2.3 kg; age, 15 yr; body mass index (BMI), 20.5 kg/m2; ≥3 yr post-menarche] who were in a steady state (over ∼6 months) for BMI, hyperinsulinism, subclinical hyperandrogenism, and dyslipidemia, and who presented a deficit of lean body mass and an excess of (truncal and abdominal) fat mass. Metformin treatment was accompanied by a drop in fasting insulin and serum androgens and by a less atherogenic lipid profile (all P ≤ 0.01). After 3 months on metformin, all identified aberrations in body composition were attenuated, the most marked changes (P < 0.0001) being a reduction of the excess in abdominal fat and of the deficit in lean body mass; BMI remained unaltered. Finally, 6 of 13 girls became ovulatory after about 6 wk on metformin, and 9 of 13 (69%) ovulated within 11 wk on metformin. In conclusion, these observations corroborate the notion that anovulation, an excess of abdominal fat mass, and a deficit of lean mass in nonobese SGA adolescents are essentially underpinned by hyperinsulinemic insulin resistance, and that sensitization to insulin is an effective approach to correct these abnormalities and, conceivably, to prevent them.