Insulin Sensitization for Girls with Precocious Pubarche and with Risk for Polycystic Ovary Syndrome: Effects of Prepubertal Initiation and Postpubertal Discontinuation of Metformin Treatment
Lourdes Ibáñez,
Carme Valls,
Maria Victoria Marcos,
Ken Ong,
David B. Dunger and
Francis de Zegher
Endocrinology Unit (L.I.) and Hormonal Laboratory (C.V.), Hospital Sant Joan de Déu, University of Barcelona, 08950 Esplugues, Barcelona, Spain; Endocrinology Unit, Hospital de Terrassa (M.V.M.), 08227 Terrassa, Barcelona, Spain; Department of Pediatrics, University of Cambridge (K.O., D.B.D.), Cambridge, United Kingdom CB2 2QQ; and Department of Pediatrics, University of Leuven (F.d.Z.), 3000 Leuven, Belgium
Address all correspondence and requests for reprints to: Dr. Lourdes Ibáñez, 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.
Among girls with precocious pubarche (PP), those with low birthweight (LBW) are, even if nonobese, at risk for progressionto polycystic ovary syndrome (PCOS) including hyperinsulinemichyperandrogenism, dyslipidemia, dysadipocytokinemia, and centralfat excess. Recently, we disclosed the efficacy of insulin sensitizationwith metformin to disrupt progression from PP to PCOS in formerlyLBW girls who were postmenarche. In LBW-PP girls, we have nowextended the exploration of early insulin sensitization therapyin two directions: 1) metformin therapy was started before puberty;and 2) we assessed the effects of metformin discontinuationin girls who had started metformin treatment after menarche.Prepubertal LBW-PP girls (n = 33; mean age, 8.0 yr; body massindex, 18.5 kg/m2) were randomly assigned to remain untreatedor to receive metformin (425 mg/d) for 6 months. PostpubertalLBW-PP girls (n = 24; age, 12.4 yr; body mass index, 21.0 kg/m2)had been randomized (at –12 months) to remain untreatedor to receive metformin (850 mg/d) for 12 months, at which time(0 month) a treatment cross-over was performed for 6 months.Fasting blood glucose and serum insulin, SHBG, dehydroepiandrosteronesulfate, androstenedione, testosterone, lipid profile, IL-6,and adiponectin were assessed at 0 and 6 months, as was bodycomposition (by dual x-ray absorptiometry). In the prepubertalstudy (group A), comparisons of untreated vs. treated girlsdisclosed normalizing effects of metformin on SHBG, androstenedione,dehydroepiandrosterone sulfate, low and high density lipoproteincholesterol, triglycerides, IL-6, adiponectin, total and abdominalfat mass, and lean body mass. In the postpubertal study (groupB), treatment cross-over at 0 month was in each subgroup followedby a striking reversal in the course of the endocrine-metabolicstate, adipocytokinemia, and body composition; all changes pointedto normalizing effects of metformin treatment. In conclusion,these two studies provide the first evidence that 1) prepubertalmetformin therapy has normalizing effects on PCOS features inhigh risk girls with a combined history of LBW and PP; and 2)in adolescence, metformin’s normalizing effects are reversedas soon as metformin therapy is discontinued.
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