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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 Adrenarche¹

Department of Pediatrics, Division of Pediatric Endocrinology, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, New York 10467; and the Department of Pediatrics, Oregon Health Sciences University (R.G.R.), Portland, Oregon 97201-3042

Address all correspondence and requests for reprints to: Joan DiMartino-Nardi, M.D., Division of Pediatric Endocrinology, Albert Einstein College of Medicine Montefiore Medical Center, 111 East 210th Street, Bronx, New York 10467. E-mail: jdpedendo{at}aol.com

Recent reports indicate that girls with premature adrenarche are at risk of developing functional ovarian hyperandrogenism and polycystic ovarian syndrome (PCOS). As insulin and insulin-like growth factors (IGFs) have been implicated in the pathogenesis of PCOS, we hypothesize that they may also have a role in the hyperandrogenism of premature adrenarche. Thirty-five prepubertal girls (23 Caribbean Hispanics and 12 Black African-Americans) underwent a 60-min ACTH and LH-releasing hormone test. Insulin sensitivity (S_I) was assessed using the frequently sampled iv glucose tolerance test with tolbutamide. Fasting levels of IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, sex hormone-binding globulin, and free testosterone (T) were also obtained.

The mean age of the patients was 6.8 yr, and bone age was 8.0 yr. Twenty-five 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/µU·mL (normal prepubertal S_I, 6.5 ± 0.54 x 10^-4 min^-1·µU^-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 children. 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-hydroxypregnenolone (17OHPreg), dehydroepiandrosterone (DHEA), androstenedione (AS), 17-hydroxyprogesterone (17OHP), and T and the ACTH-stimulated ratios of 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 (group I, 760 ± 87.84 ng/dL; group II, 428.9 ± 46.28 ng/dL; P = 0.002), 17OHPreg/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 S_I correlated inversely with ACTH-stimulated levels of 17OHPreg, DHEA, and AS and the ACTH-stimulated 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 correlated 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-stimulated levels of 17OHPreg (r = -0.38; P < 0.05) and DHEA (r = -0.36; P < 0.05).

To summarize, the ACTH-stimulated ⁵-steroid levels were higher in prepubertal girls with premature adrenarche and reduced S_I. There was a significant 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. Hence, in certain girls with premature adrenarche, hyperandrogenism may be the first presentation of PCOS and/or insulin resistance.

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