The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche

Recent reports indicate that girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism and polycystic ovarian synd rome (PCOS). As insulin and insulin-like growth factors (IGFs) have been im plicated in the pathogenesis of PCOS, we hypothesize that they may also hav e a role in the hyperandrogenism of premature adrenarche. Thirty-five prepu bertal girls (23 Caribbean Hispanics and 12 Black African-Americans) underw ent a 60-min ACTH and LH-releasing hormone test. Insulin sensitivity (S-I) was assessed using the frequently sampled iv glucose tolerance test with to lbutamide. Fasting levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP- 3, sex hormone-binding globulin, and free testosterone (T) were also obtain ed. The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-fi ve patients had a family history of noninsulin-dependent diabetes mellitus and 19 patients had acanthosis nigricans. The mean S-I for the entire group was 6.78 +/- 5.21 x 10(-4) min/mu U.mL (normal prepubertal S-I, 6.5 +/- 0. 54 x 10(-4) min(-1).mu U-1.mL(-1)). However, 15 of the 35 girls had an S-I that was more than 2 SD below the mean reported for normal prepubertal chil dren. Of these 15 patients, 13 were obese, and 14 had acanthosis nigricans. For the entire group of girls, the mean ACTH-stimulated levels of 17-hydro xypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione ( AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios o f 17OHPreg/17OHP, 17OHPreg/DHEA, 17OHP/AS, and DHEA/AS did not differ from the levels reported for Tanner stage II-III pubertal girls. The girls were divided into two groups based on their S-I (group I, S-I >2 SD below the mean for age; group II, normal S-I). The group I girls with a reduced S-I had significantly higher ACTH-stimulated levels of 17OHPreg (gr oup I, 760 +/- 87.84 ng/dL; group II, 428.9 +/- 46.28 ng/dL; P = 0.002), 17 OHPreg/17OHP ratio (group I, 3.95 +/- 0.36; group II, 2.96 +/- 0.35; P = 0. 05), 17OHPreg/DHEA(group I, 2.06 +/- 0.21; group II, 1.4 +/- 0.13; P = 0.01 ), and free T (group I, 1 +/- 0.23 ng/dL; group II, 0.49 +/- 0.19 ng/dL; P = 0.014). Levels of sex hormone-binding globulin were lower in the group I girls. Furthermore, for the entire group of girls, the SI correlated invers ely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stim ulated ratio of 17OHPreg/17OHP. IGF-I correlated inversely with S-I (r = -0 .94; P < 0.001) and correlated directly with the ACTH-stimulated levels of 17OHPreg (r = 0.8; P < 0.001) and AS (r = 0.63; P < 0.05). IGF-I also corre lated with the ACTH-stimulated ratios of 17OHPreg/17OHP (r = 0.61; P < 0.05 ), 17OHPreg/DHEA (r = 0.9; P < 0.001), 17OHP/AS (r = 0.79; P < 0.001), and DHEA/AS (r = 0.96; P < 0.001). IGFBP-1 correlated inversely with the ACTH-s timulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05). To summarize, the ACTH-stimulated Delta(5)-steroid levels were higher in pr epubertal girls with premature adrenarche and reduced S-I. There was a sign ificant inverse correlation among ACTH-stimulated hormone levels, S-I, and IGFBP-1, whereas IGF-I correlated directly with ACTH-stimulated androgens. These findings support the hypothesis that insulin and IGFs may have a role in the hyperandrogenism of premature adrenarche just as they do in PCOS. H ence, in certain girls with premature adrenarche, hyperandrogenism may be t he first presentation of PCOS and/or insulin resistance.