ORIGINAL STUDIES Endocrine Abnormalities and Impaired Growth in Human Immunodeficiency Virus–Infected Children Caroline J. Chantry, MD,* Margaret M. Frederick, PhD,† William A. Meyer III, PhD,‡ Edward Handelsman, MD,§ Kenneth Rich, MD, Mary E. Paul, MD,¶ Clemente Diaz, MD,# Ellen R. Cooper, MD,** Marc Foca, MD,†† Samuel K. Adeniyi-Jones, MD, PhD,‡‡ and Jack Moye, MD§§ Objectives: Identify endocrine differences between human immu- nodeficiency virus– (HIV) infected versus uninfected children and evaluate associations of growth and body composition with endo- crine measures. Study Design: Nested case-control study in 21 HIV-infected and 46 age- and sex-matched uninfected children in the Women and Infant Transmission Study. Plasma specimens from children between 2.5 to 7.0 years of age, taken during 3– 4 visits, were tested for insulin-like growth factor binding protein-3 (IGFBP-3), cortisol, dehydroepiandrosterone (DHEA), growth hormone and thyroid studies. Longitudinal mixed and generalized estimating equation models compared group means and examined effects of endocrine measures on growth and body composition, respectively. Results: HIV-infected children had lower IGFBP-3 than uninfected children (1.96  0.09 mg/L versus 2.34  0.06 mg/L, P  0.001). In infected but not in uninfected children, IGFBP-3 values and DHEA:cortisol ratios were associated with weight- and body mass index–for-age z scores (WAZ P = 0.019, .001 respectively, and BMZ P = 0.029, 0.038). DHEA concentration was associated with height-for-age z score (P = 0.049). Conclusions: In these HIV-infected children compared with their uninfected counterparts, IGFBP-3 concentration was different be- tween groups. Infected children had multiple endocrine associations with growth and body composition not found in their uninfected peers. We hypothesize that in HIV-infected children, growth hor- mone resistance and shunting of precursors from adrenal androgen to cortisol production contributes to altered body composition and stunting. Key Words: Growth, body composition, HIV, children, thyroid, growth hormone, insulin-like growth factor binding protein-3, DHEA, cortisol (Pediatr Infect Dis J 2007;26: 53– 60) H uman immunodeficiency virus (HIV) –associated wast- ing syndrome, a leading manifestation of progressive disease in HIV-infected U.S. children, was recently reported as the fourth most common acquired immunodeficiency syn- drome (AIDS) indicator condition in children. 1 Poor linear growth is also a common manifestation of pediatric HIV infection. 2–4 Weight, length, and head circumference are all affected in HIV-infected children; decrements in attained ponderal and linear growth are early and progressive. 2 The significance of poor growth in this population is underscored by the report that height growth velocity was associated with survival, independent of viral load and CD4 + T-cell lympho- cyte count in symptomatic children in the era preceding highly active antiretroviral therapy (HAART). 5 HAART pre- serves or restores growth according to findings reported in most, 6–9 but not all, 10 studies. Determinants of growth failure and wasting in HIV-infected children are poorly understood and are likely to be multifactorial. Endocrine derangements have been suspected in asso- ciation with the growth impairment observed in pediatric HIV disease, but available data are limited and inconclusive. 11–22 The growth hormone (GH) axis is affected in some HIV- infected patients with altered growth and/or metabolism. Classic GH deficiency has been described in HIV-infected children, 13,16 as well as reduced insulin-like growth factor-1 (IGF-1), particularly in patients with failure to thrive. 17,18 HIV-infected adolescents or adults with lipodystrophy have demonstrated impaired GH secretion. 19,23 Catabolic children with AIDS have increased proteolysis and diminished serum insulin-like growth factor binding protein-3 (IGFBP-3) 15 and diminished growth. Frank hypothyroidism has also been described in asso- ciation with poor growth in HIV-infected children, 11,20 but is not consistently present. Adrenal dysfunction may be related to poor growth in HIV-positive children. Adrenal insufficiency has been ob- served in wasting syndrome 14 and HIV-associated failure to thrive 21 in children. In HIV-infected adults, adrenal dysfunc- Accepted for publication September 14, 2006. From the *University of California, Davis, Medical Center, Sacramento, CA; †Clinical Trials & Surveys Corp., Baltimore, MD; ‡Quest Diagnostics Incorporated, Baltimore, MD; §State University of New York, Brooklyn, NY; University of Illinois at Chicago School of Medicine, Chicago, IL; ¶Baylor College of Medicine, Houston, TX; #University of Puerto Rico, San Juan, PR; **Boston Medical Center, Boston, MA; ††Columbia- Presbyterian Medical Center, New York, NY; ‡‡NIH, NIAID, DHHS, Bethesda, MD; and the §§NIH, NICHD, DHHS, Bethesda, MD. Address for correspondence: Caroline J. Chantry, MD, Department of Pediatrics, UCDMC, 2516 Stockton Blvd., Sacramento, CA 95817. E-mail caroline.chantry@ucdmc.ucdavis.edu. Copyright © 2006 by Lippincott Williams & Wilkins ISSN: 0891-3668/07/2601-0053 DOI: 10.1097/01.inf.0000247131.76584.af The Pediatric Infectious Disease Journal • Volume 26, Number 1, January 2007 53