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Submitted on October 24, 2005
Accepted on February 13, 2006
Endocrinology Unit and Hormonal Laboratory, Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Department of Pediatrics, University of Cambridge, CB2 2QQ Cambridge, UK ; Medical Research Council Epidemiology Unit, CB1 8RN Cambridge, UK; Department of Pediatrics, University of Leuven, 3000 Leuven, Belgium
* To whom correspondence should be addressed. E-mail: libanez{at}hsjdbcn.org.
Context and Objective: Low-birthweight (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 (BW below -1.5 SD Score [SDS] for gestational age) with early-normal puberty (stage 2 breast development (B2) at age 8-9 yr) were randomized to remain untreated [n = 12] or to receive metformin [850 mg/d; n = 10] for 36 mo (mean age at start = 9.0 yr). All girls remained untreated between 36 and 42 mo.
Main outcome measures: Pubertal growth, body composition by absorptiometry, uterine-ovarian size by ultrasound, fasting insulin, glucose, lipids, leptin, insulin-like growth factor-1 (IGF-1) and IGF-binding protein-1 (IGFBP-1).
Results: Metformin treatment resulted in a longer duration from B2 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, leptin and IGF-1 levels, higher SHBG and IGFBP-1 levels, and with a more favorable lipid profile. Bone mineral density and uterine-ovarian growth were unaffected.
Conclusion: Metformin treatment for 36 mo 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 co-determinant of the pubertal tempo and pubertal height gain in girls.
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