Serum Insulin-Like Growth Factor-I, IGF Binding Protein-3 and IGFBP-3 Protease Activity after Cranial 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.

The Predictive Value of Insulin-Like Growth Factor 1 in Irradiation-Dependent Growth Hormone Deficiency in Childhood Cancer Survivors

“…These data support the hypothesis that IGF-1 is not suitable for screening purposes in irradiated patients and confirm on a wider sample the conclusions drawn by Tillmann et al [8, 9]. …”

“…Conversely, in CCS with irradiation-dependent GHD, the diagnostic accuracy of IGFBP-3 levels <–2 SDS was found to be extremely poor [8, 9, 12], and our analysis supports this outcome (sensitivity in the RT-NHP cohort 7.37%). We are unable to provide an explanation for the poorer sensitivity of IGFBP-3 in irradiated patients.…”

“…Conversely, in two studies performed by Tillmann et al [8, 9] on small cohorts of respectively 12 and 15 irradiated CCS diagnosed with GHD, IGF-1 levels <–2 SDS had a sensitivity of 28 and 47%; these data support the contention that IGF-1 is not suitable for predictive screening purposes in irradiated patients. Despite a similar specificity, IGF-1 sensitivity was found to be lower than that reported in other studies where most patients had idiopathic GHD [20, 21].…”

Craniopharyngioma

“…Provocative testing protocols use multiple blood draws, which can be uncomfortable for children (Hua et al, 2012). As an alternative, many centers use the serum insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3), though these screening tests are significantly less sensitive for the detection of RT-induced GHD than provocative testing (Sklar et al, 1993;Tillmann et al, 1998;Hua et al, 2012). Both IGF-1 and IGFBP-3 are affected by age, gender, pubertal status, and obesity, which can lead to an overestimation of GHD (Sklar et al, 1993).…”

Endocrine Complications Following Radiotherapy and Chemotherapy for Nasopharyngeal Carcinoma

“…It is to be noted, however, that age and gender-corrected IGF-I and/or IGFBP-3 levels are frequently normal in patients with documented radiation-induced GH deficiency defined by physiological and/or pharmacological tests (Achermann et al, 1998;Cicognani et al, 1999;Tillmann et al, 1998). Thus, it had been thought that neither of these markers can be used as a reliable index of the development of radiation-induced GH deficiency.…”