Early Metformin Therapy (Age 8-12 Years) in Girls with Precocious Pubarche to Reduce Hirsutism, Androgen Excess, and Oligomenorrhea in Adolescence

Context: Girls with a combined history of low(-normal) birth weight (LBW) and precocious pubarche (PP) are at high risk to develop polycystic ovary syndrome (PCOS). Objective: The objective of the study was to compare the capacity of early vs. late metformin treatment to prevent adolescent PCOS. Design: This was a randomized, open-label study over 7 yr. Setting: The study was conducted at a university hospital. Patients: Thirty-eight LBW-PP girls were followed up from the mean age 8 until age 15 yr. Intervention: Early metformin (study yr 1-4; age 8-12 yr) vs. late metformin (yr 6; age 13-14 yr). Main Outcome Measures: Measures included height; weight; hirsutism score; menstrual cycle; endocrine-metabolic screening (fasting; follicular phase); C-reactive protein; body composition (absorptiometry); abdominal fat partitioning (magnetic resonance imaging); ovarian morphology (ultrasound); PCOS (National Institutes of Health and Androgen Excess Society definitions) after yr 7 (all girls thus untreated for at least 1 yr). Results: None of the girls dropped out of the study. At age 15 yr, early-metformin girls were taller (4 cm), were in a less proinflammatory state, and had less central fat due to reductions in visceral and hepatic fat. Hirsutism, androgen excess, oligomenorrhea, and PCOS were between 2- and 8-fold more prevalent in late-than early-treated girls. Abdominal adiposity was the first variable to diverge (at age 8-10 yr) between girls without vs. with PCOS at age 15 yr. Conclusions: In LBW-PP girls, early metformin therapy was found to prevent or delay the development of hirsutism, androgen excess, oligomenorrhea, and PCOS more effectively than late metformin. The time window of late childhood and early puberty may be more critical for the development, and thus for the prevention, of adolescent PCOS than the first years beyond menarche. (J Clin Endocrinol Metab 96: E1262-E1267, 2011)