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Free/Dissociable Insulin-Like Growth Factor (IGF)-I, Not Total IGF-I, Correlates with Growth Response during Growth Hormone Treatment in Children Born Small for Gestational Age

Department of Pediatrics (E.M.N.B., A.C.S.H.-K.), Division of Endocrinology, and Department of Epidemiology and Biostatistics (P.G.H.M.), Erasmus MC-Sophia Children’s Hospital, 3015 GJ Rotterdam, The Netherlands; and Department of Metabolic and Endocrine Diseases (J.v.D.), University Medical Center, Wilhelmina Children’s Hospital, 3508 AB Utrecht, The Netherlands

Address all correspondence and requests for reprints to: Anita C. S. Hokken-Koelega, M.D., Erasmus MC-Sophia Children’s Hospital, Department of Pediatrics, Division of Endocrinology, Dr. Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands. E-mail: a.hokken{at}erasmusmc.nl.

Context: IGF-I plays an important role in pre- and postnatal growth. Its serum levels are regulated by metabolic and genetic factors. Mean total IGF-I in short, small for gestational age (SGA) children is reduced, but within the normal range. Free/dissociable IGF-I is the bioactive form of IGF-I.

Objectives: The aim of the study was to investigate changes in free IGF-I during GH treatment in short SGA children and to evaluate whether free IGF-I levels contribute to predicting first-year growth response and/or adult height.

Design, Setting, and Intervention: We conducted a randomized, double-blind GH dose-response study with a GH dose of either 1 mg/m²·d (group A) or 2 mg/m²·d (group B). Free IGF-I, total IGF-I, and IGF binding protein (IGFBP)-3 were determined at baseline, after 1 and 5 yr, at stop, and 6 months after GH discontinuation.

Patients: We studied 73 (46 male) short SGA children (36 group A) with a baseline mean age of 7.7 (2.2) yr and a mean GH duration of 8.2 (2.1) yr.

Main Outcome Measures: Untreated SGA children had a mean free IGF-I SD score (SDS) of –0.2 (1.2), not related to total IGF-I. During GH therapy, free IGF-I significantly increased to 1.6 (0.7) SDS, as did total IGF-I and IGFBP-3 [2.0 (0.8) and 1.3 (0.9), respectively]. Multiple regression analysis showed that baseline free IGF-I and IGFBP-3 were negatively correlated with adult height SDS, whereas baseline bone age delay, target height SDS, baseline height SDS, and GH dose were positively correlated. Free IGF-I was also negatively correlated with first-year growth response.

Conclusions: Circulating baseline free IGF-I and IGFBP-3 were better predictors for adult height in GH-treated SGA children than total IGF-I, or total IGF-I to IGFBP-3 ratio. This suggests a possible role for free IGF-I measurement in predicting the effect of GH therapy in short SGA children.