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Metformin Therapy during Puberty Delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height: A Randomized Study in Low-Birth-Weight Girls with Early-Normal Onset of Puberty

Endocrinology Unit (L.I.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Department of Pediatrics (K.O., D.B.D.), University of Cambridge, Cambridge CB2 2QQ, United Kingdom; Medical Research Council Epidemiology Unit (K.O.), Cambridge CB1 8RN, United Kingdom; and Department of Pediatrics (F.d.Z.), University of Leuven, 3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.

Context and Objective: Low-birth-weight (LBW) girls who enter puberty earlier (around 8–9 yr) tend to have earlier menarche, earlier growth arrest, and a shorter adult stature. At present, there is no therapy for most of these girls. In LBW girls with early puberty, hyperinsulinemic insulin resistance could underpin their rapid transit through puberty and their loss of adult stature. We explored the effects of insulin sensitization with metformin during puberty.

Setting, Design, and Patients: In an open-labeled, prospective study, 22 LBW girls (birth weight < –1.5 SD score for gestational age) with early-normal puberty (stage 2 breast development at age 8–9 yr) were randomized to remain untreated (n = 12) or to receive metformin (850 mg/d; n = 10) for 36 months (mean age at start, 9.0 yr). All girls remained untreated between 36 and 42 months.

Main Outcome Measures: Pubertal growth, body composition by absorptiometry, uterine-ovarian size by ultrasound, fasting insulin, glucose, lipids, leptin, IGF-I, and IGF-binding protein-1 were assessed.

Results: Metformin treatment resulted in a longer duration from stage 2 breast development to menarche (P < 0.01; median difference, +1.0 yr), taller near-adult height (P < 0.01), and leaner body composition (P < 0.001). Metformin was also associated with lower insulin resistance and leptin and IGF-I levels and higher SHBG and IGF-binding protein-1 levels and with a more favorable lipid profile. Bone mineral density and uterine-ovarian growth were unaffected.

Conclusion: Metformin treatment for 36 months in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls.

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