Nele Friedrich1, Ole D Wolthers, Ayman M Arafat, Rebecca T Emeny, Joachim Spranger, Josefine Roswall, Jürgen Kratzsch, Hans J Grabe, Christoph Hübener, Andreas F H Pfeiffer, Angela Döring, Maximilian Bielohuby, Jovanna Dahlgren, Jan Frystyk, Henri Wallaschofski, Martin Bidlingmaier. 1. Metabolic Center (N.F., H.W.), Institute of Clinical Chemistry and Laboratory Medicine, and Department of Psychiatry and Psychotherapy (H.J.G.), University Medicine Greifswald, D-17475 Greifswald, Germany; Department of Psychiatry and Psychotherapy (H.J.G.), Helios Hospital Stralsund, D-18437 Stralsund, Germany; Children's Clinic Randers (O.D.W.), DK-8900 Randers, Denmark; Department of Endocrinology, Diabetes, and Nutrition (A.M.A., J.S., A.F.H.P.) and Center for Cardiovascular Research (A.M.A., J.S.), Charité-University Medicine Berlin, D-10117 Berlin, Germany; Department of Clinical Nutrition (A.M.A., A.F.H.P.), German Institute of Human Nutrition Potsdam-Rehbruecke, D-14558 Nuthetal, Germany; Helmholtz Zentrum Muenchen-German Research Center for Environmental Health (R.T.E., A.D.), Institute of Epidemiology II, D-85764 Neuherberg, Germany; Experimental and Clinical Research Center (J.S.), Charité-University Medicine Berlin and Max-Delbrück Centre Berlin-Buch, D-13125 Berlin, Germany; Göteborg Pediatric Growth Research Center (J.R., J.D.), The Sahlgrenska Academy at University of Gothenburg, SE-41685 Gothenburg, Sweden; Institut für Laboratoriumsmedizin (J.K.), Klinische Chemie, Molekulare Diagnostik, University of Leipzig, D-04103 Leipzig, Germany; Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe-Großhadern (C.H.), Klinikum der Universität München, D-81377 Munich, Germany; Endocrine Research Laboratories (M.B., M.B.), Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, D-80336 Munich, Germany; and Medical Research Laboratory (J.F.), Department of Clinical Medicine, Faculty of Health, Aarhus University, and Department of Endocrinology and Internal Medicine (J.F.), Aarhus University Hospital, DK-8000 C Aarhus, Denmark.
Abstract
CONTEXT: Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. OBJECTIVE: The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. SETTING: This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. PARTICIPANTS: A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. MAIN OUTCOME MEASURES: Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. RESULTS: Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. CONCLUSIONS: We present an extensive set of assay-specific age- and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.
CONTEXT: Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. OBJECTIVE: The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. SETTING: This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. PARTICIPANTS: A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. MAIN OUTCOME MEASURES: Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. RESULTS: Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. CONCLUSIONS: We present an extensive set of assay-specific age- and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span.
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