Inaccuracy of IGFBP-3 Assessment in the Diagnosis of Growth Hormone Deficiency (GHD) from Childhood to Young Adulthood: Association to Low GH-Dependency of IGF-II and Presence of Circulating IGFBP-3 18 kD 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.