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

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.