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Serum insulin-like growth factor-I, IGF binding protein-3 and IGFBP-3 protease activity after cranial irradiation
V Tillmann1, S M Shalet, D A Price
1Royal Manchester Children's Hospital, Manchester, UK.
Insights
Childhood cancer survivors treated with CNS irradiation may develop growth hormone deficiency (GHD). However, serum insulin-like growth factor I (IGF-I) and IGF-I binding protein 3 (IGFBP-3) are unreliable indicators of radiation-induced GHD.
Area of Science:
- Pediatric Endocrinology
- Radiation Oncology
- Biochemistry
Background:
- Cranial irradiation for central nervous system (CNS) tumors or leukemia prophylaxis can impact pituitary function in children and adolescents.
- Growth hormone (GH) deficiency (GHD) is a potential long-term consequence of such treatments.
- Assessing pituitary function relies on evaluating GH, IGF-I, and IGFBP-3 levels.
Purpose of the Study:
- To investigate the relationship between peak GH, IGF-I, IGFBP-3, and IGFBP-3 protease activity in pediatric patients post-CNS irradiation.
- To determine if IGF-I or IGFBP-3 can reliably predict radiation-induced GHD.
- To explore the role of IGFBP-3 protease activity in maintaining normal IGFBP-3 levels.
Main Methods:
- Study included 28 children and adolescents 0.4-14.2 years post-CNS irradiation.
- Peak GH was measured via stimulation tests; GHD defined as peak GH <7.5 ng/ml.
- Serum IGF-I, IGFBP-3 (by RIA), and IGFBP-3 protease activity (by Western ligand blot) were analyzed.
Main Results:
- Seven of 15 patients with GHD had low IGF-I SDS (< -2).
- No patients had IGFBP-3 levels <-1.5 SDS; IGFBP-3 levels correlated with Western ligand blot density (r=0.71).
- IGFBP-3 protease activity negatively correlated with IGFBP-3 levels (r=-0.55 and r=-0.51). Twenty-two patients had normal protease activity, suggesting it doesn't explain normal IGFBP-3 levels.
Conclusions:
- Low serum IGF-I is observed in some patients with radiation-induced GHD.
- Serum IGFBP-3 concentrations remain normal in the majority of patients post-CNS irradiation, irrespective of GHD status.
- Neither serum IGF-I nor IGFBP-3 are reliable biomarkers for detecting radiation-induced GHD in pediatric patients after CNS irradiation.
Abstract:
The relationship between peak growth hormone (GH), insulin-like growth factor I (IGF-I), IGF-I binding protein 3 (IGFBP-3) and IGFBP-3 protease activity was studied in 28 children and adolescents undergoing investigation of pituitary function 0.4-14.2 years after cranial or craniospinal irradiation for the treatment of CNS tumours distant from the hypothalamic-pituitary axis (n = 16) or prophylaxis against CNS leukaemia (n = 12). Seven out of 15 patients with GH deficiency (GHD) (defined as a peak GH concentration <7.5 ng/ml in a stimulation test) had IGF-I <-2 standard deviation score (SDS). None of the 28 patients had serum IGFBP-3 concentrations measured by radioimmunoassay (RIA) <-1.5 SDS with no difference between those with and without GHD. IGFBP-3 concentrations measured by RIA were strongly correlated to IGFBP-3 band density on Western ligand blot (WLB) (r = 0.71; p < 0.0001). IGFBP-3 protease activity was negatively correlated to IGFBP-3 by RIA (r = -0.55; p < 0.01) and to IGFBP-3 by WLB (r = -0.51; p < 0.01). Twenty-two patients had normal IGFBP-3 protease activity (<30% of the activity in pregnancy serum) indicating that serum IGFBP-3 protease activity does not account for the normal levels of IGFBP-3 in RIA. Low serum IGF-I but normal IGFBP-3 concentrations and in the majority normal IGFBP-3 protease activity was found in patients in the years after CNS irradiation. Neither serum IGF-I nor IGFBP-3 can be used as a reliable index of the development of radiation-induced GHD.