Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism after precocious pubarche

Precocious pubarche in girls is often preceded by low weight at birth and f ollowed by hirsutism, ovarian hyperandrogenism; and oligomenorrhea in adole scence, the latter usually being accompanied by dyslipidemia and hyperinsul inism, which are, in turn, two major risk factors for cardiovascular diseas e in later life. We hypothesized that insulin resistance may be a key patho genetic factor in this sequence. We tested the hypothesis by assessing the effects of an insulin-sensitizing agent, metformin, given at a daily dose of 1275 mg for 6 months to 10 nono bese adolescent girls (mean age, 16.8 yr; body mass index, 21.9 kg/m(2); bi rth weight, 2.7 kg) with hirsutism, ovarian hyperandrogenism (diagnosis by GnRH agonist test), oligomenorrhea, dyslipidemia, and hyperinsulinemia afte r precocious pubarche. Before the metformin trial, longitudinal studies in these girls had shown that hyperinsulinism was present at prepubertal diagn osis of precocious pubarche, and that it increased markedly in late puberty or early postmenarche. Metformin treatment was well tolerated and was accompanied by a marked drop in hirsutism score, insulin response to oral glucose tolerance test, free androgen index, and baseline testosterone, androstenedione, dehydroepiandro sterone, and dehydroepiandrosterone sulfate levels (all P < 0.01). During m etformin treatment, the LH and 17-hydroxyprogesterone hyperresponses to GnR H agonist were attenuated (P < 0.01); serum triglyceride, total cholesterol , and low density lipoprotein cholesterol levels decreased; and high densit y lipoprotein cholesterol rose. All girls reported regular menses within 4 months. Withdrawal of metformin treatment was followed. within 3 months, by a consistent reversal toward pretreatment conditions. In conclusion, metformin treatment reduced hyperinsulinemia, hirsutism, and hyperandrogenism; attenuated the LH and 17-hydroxyprogesterone hyperrespon ses to GnRH agonist; improved the atherogenic lipid profile; and restored e umenorrhea in nonobese adolescent girls with a history of precocious pubarc he. These observations corroborate the idea that insulin resistance may ind eed be a prime factor underpinning the sequence from reduced fetal growth, through precocious pubarche, to adolescent endocrinopathies that are remini scent of so-called polycystic ovary syndrome.