Increased frequency of the G972R variant of the insulin receptor substrate-1 (IRS-1) gene among girls with a history of precocious pubarche

Objective: To test the hypothesis that lower sex hormone-binding globulin (SHBG) concentrations are associated with heterozygosity for the G972R variant of the IRS-1 gene among adolescent girls with a history of precocious pubarche (PP) and hyperinsulinemic ovarian hyperandrogenism. Design: Association study. Setting: Academic research environment. Patient(s): Adolescent girls with a history of PP and healthy adolescent female control subjects. Intervention(s): Determine body mass index; measure serum androgen, insulin-like growth factor (IGF)-binding protein 1, lipids, IGF-1, and SHBG concentrations; perform glucose tolerance tests; and assay for G972R variant of the IRS-1 gene. Main Outcome Measure(s): Serum androgen, IGFBP-1, and SHBG concentrations; IRS-1 genotypes. Result(s): Twenty-five of 54 (45%) girls with a history of PP developed hyperinsulinemic ovarian hyperandrogenism at adolescence. Frequency of heterozygosity for G972 was 31% among girls with a history of PP, 40% among girls with hyperinsulinemic ovarian hyperandrogenism, and 19% among healthy control subjects. Sex hormone-binding globulin concentrations were lower among girls heterozygous for G972R variant. Predictors of progression from PP to hyperinsulinemic ovarian hyperandrogenism included chronological age, insulin, low-density lipoprotein cholesterol, and IGFBP-1 concentrations. Conclusion(s): The low mean SHBG concentration found among G972R carriers suggests that this variant may be a minor locus associated with development of hyperinsulinemic insulin resistance and ovarian androgen excess in girls with a history of PP.