The fasting insulin resistance index, mean blood glucose, mean serum insulin (MSI), early insulin response to glucose, glucose uptake rate in peripheral tissues, and insulin sensitivity indexes in response to a standard oral glucose tolerance test; serum insulin-like growth factor I (IGF-I), IGF-binding protein-1 (IGFBP-1), IGFBP-3, and sex hormone binding-globulin (SHBG) levels; and the free androgen indexes were evaluated in 98 girls with premature pubarche [PP; prepubertal (B1; n = 32), early pubertal (B2; n = 27), midpubertal (B3; n = 23), and postmenarcheal (B5; n = 16)] and in 86 Tanner stage- and bone age-matched controls. We ascertained whether hyperinsulinemia is already present in PP girls before or during pubertal development and whether these patients show a similar pattern of growth factor secretion as normal girls. Body mass indexes did not differ significantly between patients and controls within the same pubertal stage. MSI levels showed a significant increase with pubertal onset in all subjects, as expected. Patients showed significantly higher MSI values than controls at all Tanner stages (P < 0.03, P = 0.03, P = 0.03, and P < 0.05 for B1, B2, B3, and B5, respectively); higher insulin response to glucose at B1, B2, and B3 (P < 0.03, P = 0.03, and P < 0.05, respectively); higher glucose uptake rate in peripheral tissues at B1 and B2 (P < 0.04 and P = 0.02, respectively); and a later rise in insulin sensitivity compared to controls. PP girls also showed lower IGFBP-1 levels at B1 and B5 (P < 0.01 and P = 0.02, respectively), lower SHBG concentrations at B5 (P < 0.0005), and higher free androgen indexes at B1, B3, and B5 (P < 0.01, P < 0.05, and P < 0.001, respectively) compared to controls. Among others, significant correlations between SHBG and MSI levels (r = -0.49; P < 0.0001) and between SHBG and IGFBP-1 levels (r = 0.41; P < 0.0001) were found in all subjects. Hyperinsulinemia, increased early insulin responses to glucose, increased glucose uptake rate in peripheral tissues, elevated free androgen indexes, and decreased SHBG and IGFBP-1 levels are present in most girls with PP from childhood. These findings lend strong support to the concept that PP is not a benign condition, and long term follow-up of these patients into adulthood is recommended. The possible causal role of hyperinsulinemia in adrenal and/or ovarian androgen hypersecretion remains to be established.

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