Insulin Sensitivity and the Insulin-Like Growth Factor System in Prepubertal Boys with Premature Adrenarche

0013-7227/02/$15.00/0 Printed in U.S.A. The Journal of Clinical Endocrinology & Metabolism 87(12):5604 –5609 Copyright © 2002 by The Endocrine Society doi: 10.1210/jc.2002-020896 Insulin Sensitivity and the Insulin-Like Growth Factor System in Prepubertal Boys with Premature Adrenarche MICHELLE R. DENBURG, MIRIAM E. SILFEN, ALEXANDRA M. MANIBO, DAISY CHIN, LENORE S. LEVINE, MICHEL FERIN, DONALD J. MCMAHON, CHRISTINA GO, AND SHARON E. OBERFIELD Department of Pediatrics (M.R.D., M.E.S., A.M.M., D.C., L.S.L., C.G., S.E.O.), Division of Pediatric Endocrinology, Columbia University, College of Physicians and Surgeons, New York, New York 10032; Department of Obstetrics and Gynecology (M.F.), Columbia University, New York, New York 10032; and Information Sciences Division (D.J.M.), Nathan Kline Institute for Psychiatric Research, Orangeburg, New York 10962 Girls with premature adrenarche (PA), similar to women with polycystic ovarian syndrome, display alterations in the IGF system, may have impaired insulin sensitivity, and demonstrate unfavorable lipid profiles. Girls with PA are also at increased risk for functional ovarian hyperandrogenism. Metabolic studies in boys with PA, however, are limited. The objective of this study was to determine whether boys with PA show alterations in insulin sensitivity and the IGF system. We studied an ethnically heterogeneous group of 19 prepubertal boys: 11 with PA (age, 8.2 ⴞ 0.7 yr; body mass index (BMI)-Z score, 1.8 ⴞ 1.1) and 8 controls (age, 7.9 ⴞ 0.8 yr; BMI-Z score, 1.2 ⴞ 1.0). Fasting levels of glucose, insulin, proinsulin (P0), hemoglobin A1c, testosterone, SHBG, ⌬4-androstenedione, dehydroepiandrosterone sulfate, LH, FSH, IGF-I, IGF-binding protein-1, IGF-binding protein-3, free IGF-I, and lipids were measured. Ten of 11 boys with PA and six of eight controls underwent standard oral glucose tolerance testing. The insulin response to this test was measured by the insulin area P REMATURE ADRENARCHE (PA) is defined as the appearance of pubic hair and/or axillary hair in the absence of thelarche or testicular development, associated with increased adrenal androgen production, before the age of 8 yr in girls and 9 yr in boys. This condition occurs more commonly in girls than boys with an unexplained sex ratio of nearly 10:1. Adrenal androgens are usually elevated for chronological age but within the range expected for the stage of pubic hair (1). Decreased levels of SHBG, hyperinsulinemia, insulin resistance, and unfavorable lipid profiles have been demonstrated in girls with PA (2–5). PA does not significantly impact the onset and progression of puberty or final height (1). Postpubertally, girls with PA are at increased risk for the development of anovulation and functional ovarian hyperandrogenism, including polycystic ovarian syndrome (PCOS) (6, 7). Reduced fetal growth has been assoAbbreviations: BMI, Body mass index; ⌬4-A, ⌬4-androstenedione; DHEAS, dehydroepiandrosterone sulfate; DM, type 2 diabetes mellitus; FGIR, fasting glucose/insulin ratio; G0, basal level of glucose; HDL, high-density lipoprotein; HgA1c, hemoglobin A1c; IAUC120, insulin area under the curve in response to glucose challenge; IGFBP-1, IGF-binding protein-1; I0, basal level of insulin; ISI(composite), composite wholebody insulin sensitivity index; LDL, low-density lipoprotein; OGTT, oral glucose tolerance test; PA, premature adrenarche; PCOS, polycystic ovarian syndrome; P0, basal level of proinsulin; QUICKI, quantitative insulin sensitivity check index. under the curve. Measures of insulin sensitivity were calculated as the fasting glucose to insulin ratio, quantitative insulin sensitivity check index, and composite insulin sensitivity index. All values were adjusted for BMI-Z score. Total IGF-I, P0, ratio of P0 and fasting insulin level, and log insulin area under the curve were higher, and SHBG was lower in the boys with PA, compared with controls. Decreased insulin sensitivity was suggested by decreased composite insulin sensitivity index. A trend toward greater triglycerides was observed in the boys with PA, compared with the controls. Prepubertal boys with PA show differences in the IGF system and decreased insulin sensitivity, independent of obesity, as observed in girls with PA. These findings suggest that both boys and girls with PA should be monitored for the development of insulin resistance and associated complications, including diabetes mellitus and cardiovascular disease. (J Clin Endocrinol Metab 87: 5604 –5609, 2002) ciated with additional risk for these endocrine/metabolic disturbances during or after puberty (8, 9). PCOS is characterized by hyperandrogenism and chronic anovulation, and its complications include hyperinsulinemia, insulin resistance, early onset of type 2 diabetes mellitus (DM), dyslipidemia, cardiovascular disease, and infertility (10, 11). Recently increased plasminogen activator-inhibitor type 1 activity, an early marker of cardiovascular risk in PCOS, was demonstrated in girls with PA (12). A significantly increased prevalence of impaired glucose tolerance and type 2 DM has also been found among first-degree relatives of girls with PA (13). Both in vitro and in vivo studies have implicated a dysregulation of the IGF system in the pathophysiology of PA and PCOS. IGF-I and insulin have been shown to potentiate LH-stimulated androgen synthesis in theca-interstitial cells (14) and were also found to stimulate the proliferation of these ovarian cells (15). High concentrations of insulin alone induce androgen accumulation in cultures of ovarian stromal tissue obtained from hyperandrogenic women (16). Insulin and IGF-I have been shown to suppress production of SHBG in a human hepatoma cell line (17), and physiological levels of insulin and IGF-I also induce steroidogenic enzymes in cultured human adrenocortical cells (18, 19). Reduced concentrations of IGF-binding protein-1 (IGFBP-1) have been 5604 Denburg et al. • Insulin/IGF-I in Boys with PA demonstrated in women with PCOS and girls with PA; IGFBP-1 levels are inversely correlated with fasting serum insulin levels (3, 20 –24) and ACTH-stimulated adrenal hormone levels in girls with PA (20). Elevated total IGF-I has been reported in prepubertal girls with PA (3), and elevated free IGF-I levels have been noted in subjects with PCOS (23, 24). Our group has recently demonstrated elevated total and free IGF-I levels in prepubertal Hispanic girls with PA (25). Studies in boys with PA are very limited. Potau et al. (26) found levels of IGF-I, IGFBP-1 and -3, and SHBG as well as measures of the glucose and insulin response to an oral glucose load to be comparable in boys with PA and controls. In a preliminary report, higher concentrations of IGF-I were demonstrated in boys with PA (27). The primary purpose of our study was to compare parameters of the insulin/IGF system in prepubertal boys with PA and matched controls. An additional aim of the study was to identify cardiov (...truncated)