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Inaccuracy of Insulin-Like Growth Factor (IGF) Binding Protein (IGFBP)-3 Assessment in the Diagnosis of Growth Hormone (GH) Deficiency from Childhood to Young Adulthood: Association to Low GH Dependency of IGF-II and Presence of Circulating IGFBP-3 18-Kilodalton Fragment

Department of Public Health and Cell Biology (S.C., A.L., D.G.), Tor Vergata University, 00133 Rome, Italy; Division of Nuclear Medicine (S.B.), San Eugenio Hospital, 00144 Rome, Italy; Department of Pediatrics (M.M.), Istituto di Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, University of Pavia, 27100 Pavia, Italy; University of Modena and Reggio Emilia (L.I.), 41100 Modena, Italy; University of Messina (M.W.), 98100 Messina, Italy; University of Parma (M.E.S.), 43100 Parma, Italy; University of Bologna (S.Z.), 40100 Bologna, Italy; and Department of Internal Medicine (G.A.), University of Turin, 10100 Turin, Italy

Address all correspondence and requests for reprints to: Stefano Cianfarani, M.D., Rina Balducci Center of Pediatric Endocrinology, Department of Public Health and Cell Biology, Room E-178, Tor Vergata University, Via Montpellier 1, 00133 Rome, Italy. E-mail: stefano.cianfarani{at}uniroma2.it.

Context: Poor sensitivity of IGF binding protein (IGFBP)-3 assessment in the work-up of GH deficiency (GHD) has been ascribed to the equal affinity of IGFBP-3 for IGF-I and IGF-II and to IGFBP-3 proteolysis.

Objective: The objective of this study was to determine the IGF-II GH dependency and IGFBP-3 proteolysis in patients with GHD from childhood to young adulthood.

Design: This study was cross-sectional.

Setting: This was a national multicenter study performed in university hospitals.

Patients: One hundred thirty-one subjects (chronological age, 1.3–25 yr), 72 patients with GHD and 59 subjects with idiopathic short stature, were studied.

Interventions: IGF-I, IGF-II, and IGFBP-3 serum concentrations were measured by immunoradiometric assay. IGFBP-3 circulating forms were assessed by Western immunoblot (WIB) analysis.

Main Outcome Measures: Main outcome measures were sensitivity and specificity of IGF-I, IGF-II, and IGFBP-3 measurements.

Results: Sensitivity and specificity of IGFBP-3 measurement were 27 and 100%, respectively. IGFBP-3 sensitivity was 46% in young adulthood. Sensitivity and specificity of IGF-I were 69 and 81%, respectively. Sensitivity and specificity of IGF-II assessment were 23 and 97%, respectively. IGFBP-3 WIB revealed the presence of the intact form and the major 29-kDa fragment in both GHD and subjects with idiopathic short stature. In patients with GHD, WIB showed the presence of an additional smaller IGFBP-3 fragment migrating at approximately 18 kDa.

Conclusions: Our results suggest that in children and young adults with GHD, the low GH dependency of IGF-II together with IGFBP-3 proteolytic activity yielding the 18-kDa fragment concur to reduce the sensitivity of IGFBP-3 assessment, ultimately making it too inaccurate as a screening test in the work-up of GHD.

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