Metformin therapy in girls to delay progression of advanced puberty and increase the adult height: a randomized trial

Abstract

BACKGROUND: Currently, puberty takes place earlier, especially in those girls with elevated BMI, hyperinsulinism, insulin resistance and hyperleptinemia. Leptin and insulin seem to be implicated in this advanced activation of the hypothalamus-pituitary-ovarian axis, and moreover, insulin enhances the early secretion of estrogens. All this also causes a faster tempo of puberty that traduces a decreased adult height, and many psychological consequences. JUSTIFICATION: In girls with advanced puberty (8-9 years) GnRH agonists haven’t given a good response in increasing adult height, and there is a need to find an effective treatment. In LBW-PP girls, metformin has shown favourable results in delaying puberty and improve final height. Our intention is try to reproduce the results in girls without LBW or PP, but with a BMI over the mean, taking benefit of the effects of metformin in reducing weight and leptin levels, as well as insulin levels and insulin resistance, and also in reducing steroidogenesis. OBJECTIVES: Study if metformin therapy in girls with early puberty and with a BMI above the mean, can delay age of menarche and improve adult height, lipid profile and body composition indices (BMI and waist). DESIGN: Randomized double blinded clinical trial. PARTICIPANTS: Subjects will be Caucasian girls between the age of 8-9 years old in the beginning of puberty (Tanner 2 or 3) with a BMI in percentile 50 or over. 158 subjects will be selected (79 taking metformin and 79 taking placebo) according to inclusion and exclusion criteria. MAIN OUTCOME MEASURES: Primary outcome: Age of menarche. Secondary outcomes: height, BMI, waist, LDL-cholesterol, HDL-cholesterol, total cholesterol, triglycerides. INTERVENTION AND METHOD: The girls will be distributed randomly in a 1: 1 ratio to receive metformin or placebo. They will take one pill of Metformin 850 mg or placebo every day during 3 years. The total follow-up for each girl will be of 5 years. Baseline determination and visits every 6 months with new determinations in each visit will be performed. SETTING: Multicentre. The study will be performed in outpatient of three hospitals: Dr. Josep Trueta (Girona), Sant Joan de Déu (Barcelona) and Vall d’Hebrón (Barcelona)