Nonparallel changes of growth hormone (GH) and insulin-like growth factor-I, insulin-like growth factor binding protein-3, and GH-binding protein, after craniospinal irradiation and chemotherapy.

Abstract

We studied the GH-insulin-like growth factor-I (IGF-I) axis serially over 24-36 months in six patients with medulloblastoma who underwent surgical removal of the tumor followed by craniospinal irradiation therapy for 6 weeks and then chemotherapy for 42 weeks. Eighteen and 24 months after beginning irradiation there was a decline in the peak GH secretory response to acute stimulation with arginine/insulin hypoglycemia. Six months after irradiation and during chemotherapy there was a transient decline in IGF-I, IGF binding protein-3 (IGFBP-3), and GH-BP values (respective mean values of 56.1 +/- 9.0 ng/mL, 1.1 +/- 0.2 microgram/mL, and 7.6 +/- 3.3% of radioactivity as compared to time 0 values: 13%%o/- 15 ng/mL, 2.2 +/- 0.2 micrograms/mL, and 20.0 +/- 4.0%, P < 0.001), although provoked GH secretion was normal at this time. The IGF-I, IGFBP-3, and GH-BP returned to pretreatment ranges by 12-36 months after initiation of the study. There was also a decline in body mass index and serum protein values at 6 months, suggesting suboptimal nutrition during this period. Six months after irradiation in ligand and immunoblot analysis there was a decline in IGFBP-3 and an abnormal electrophoretic mobility of IGFBP-2 that were both normalized at 36 months. In one patient we observed a high level of IGFBP-3 proteolysis at this time. This study demonstrates that before the decrease of GH secretion in patients receiving cranial irradiation there is a transient phase of GH insensitivity that may be characteristic of the acute therapeutic phase including the chemotherapy. This partial insensitivity may explain the early growth retardation observed in these patients.

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

“…Recently, a wide meta-analysis by Shen et al [19] found that IGF-1 levels <–2 SDS had a pooled sensitivity of 66% and a pooled specificity of 69%, and the authors concluded that IGF-1 is a useful screening tool in patients at risk of developing GHD. Most studies did not focus on radiation-dependent GHD, and specific figures about the role of low IGF-1 in irradiated CCS were drawn from small samples of patients [8, 10-12] and provided conflicting outcomes.…”

“…In the latter, IGF-1 sensitivity at –2 SDS rose to 43.55% in patients with severe GHD. A longitudinal study by Nivot et al [10] about irradiated CCS suggests non-parallel changes in IGF-1 levels and GH peak achieved, with unchanged IGF-1 levels 2 years after irradiation and a progressive decrease in GH peaks achieved after stimulation tests. Conversely, we found a statistically significant positive correlation between IGF-1 levels and GH peaks in patients with irradiation-dependent GHD.…”

“…However, conflicting evidence has been reported about the value of low IGF-1 levels in predicting radiation-induced GHD in CCS, with some studies supporting a poor diagnostic impact in this specific population [8-10] and others demonstrating a satisfactory role as a screening tool also in irradiated CCS [11, 12]. Most of these outcomes are drawn from small samples of patients and do not provide specific figures about the distribution of IGF-1 values in relation to the severity of GHD and the radiation exposure of the HP area.…”

The relationship between the growth hormone and insulin‐like growth factor axis in long‐term survivors of childhood brain tumours

“…Most studies to date have focussed on short-term changes in IGF-1 and IGFBP3 in children receiving radiotherapy and chemotherapy for brain tumours. For example, Nivot et al (1994) showed a transient decline in serum IGF-1 and IGFBP3 concentrations six months after treatment, which mirrored changes in body mass index and plasma proteins and was thought to reflect nutritional status and the effects of chemotherapy. A progressive decline in IGF-1 concentrations with increasingly severe GH insufficiency has been reported in prospective studies of children in the first two years after radiotherapy (Brauner et al 1989;Spoudeas et al, 1996), but short-term changes in serum concentrations of IGFBP3 with postirradiation GH insufficiency have been less severe.…”

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

“…Although the increased proteolytic activity is more pronounced at the time of diagnosis, some patients can have high protease activity many years after cranial irradiation [10, 26]. To assess whether this might account for the normal IGFBP-3 levels in our patients, we measured serum IGFBP-3 protease activity.…”