Evolution of growth hormone neurosecretory disturbance after cranial irradiation for childhood brain tumours: a prospective study

Abstract

To determine the aetiopathology of post-irradiation growth hormone (GH) deficiency, we performed a mixed longitudinal analysis of 56 24 h serum GH concentration profiles and 45 paired insulin-induced hypoglycaemia tests (ITT) in 35 prepubertal children, aged 1.5-11.8 years, with brain tumours in the posterior fossa (n = 25) or cerebral hemispheres (n = 10). Assessments were made before (n = 16), 1 year (n = 25) and 2 to 5 years (n = 15) after a cranial irradiation (DXR) dose of at least 30 Gy. Fourier transforms, occupancy percentage, first-order derivatives (FOD) and mean concentrations were determined from the GH profiles taken after neurosurgery but before radiotherapy (n = 16) and in three treatment groups: Group 1: neurosurgery only without DXR (n = 9); Group 2: > or = 30 Gy DXR only (n = 22); Group 3: > or = 30 Gy DXR with additional chemotherapy (n = 9). Results were compared with those from 26 short normally growing (SN) children. Compared with SN children, children with brain tumours had faster GH pulse periodicities (200 min vs 140 min) and attenuated peak GH responses to ITT (24.55 (19.50-30.20) vs 8.32 (4.57-15.14) mU/l) after neurosurgery, before radiotherapy. However, spontaneous GH peaks (19.05 (15.49-23.44) vs 14.13 (9.12-21.38) mU/l), 24 h mean GH (5.01 (4.37-5.62) vs 3.98 (2.63-5.89) mU/l) and FODs (1.43 (1.17-1.69) vs 1.22 (0.88-1.56) mU/l per min) were similar. The abnormalities present before radiotherapy persisted in group 1 children at 1 year when 24 h mean GH (2.45 (1.17-5.01) mU/l) and FODs (0.73 (0.26-1.20) mU/l per min) were additionally suppressed, although partial recovery was evident by 2 years. With time from radiotherapy, there was a progressive increase in GH pulse periodicity (Group 2: 200 min at 1 year, 240 min at > or = 2 years; Group 3: 140 min at 1 year, 280 min at > or = 2 years) and a decrease in 24 h mean GH (Group 2 vs Group 3 at > or = 2 years: 2.45 (1.70-3.47) vs 1.86 (1.32-2.69) mU/l) and FODs (Group 2 vs Group 3 at > or = 2 years; 0.56 (0.44-0.69) vs 0.44 (0.27-0.61) mU/l per min). Initial discrepancies between measures of spontaneous and stimulated (ITT) GH peaks were lost by 2 or more years (spontaneous vs ITT; Group 2: 7.76 (5.89-9.77) vs 3.80 (0.91-15.84) mU/l; Group 3: 6.03 (4.27-8.32) vs 3.80 (0.31-46.77) mU/l). After cranial irradiation, a number of changes evolved within the GH axis: faster GH pulse periodicities and discordance between physiological and pharmacological tests of GH secretion before irradiation gave way to a slow GH pulse periodicity, decreased GH pulse amplitude and rate of GH change (FOD) and, with time, eventual concordance between physiological and pharmacological measures. The evolution of these disturbances may well reflect differential pathology affecting hypothalamic GH-releasing hormone and somatostatin.

Endocrine Outcome in Long-Term Survivors of Childhood Brain Tumors

“…GH neurosecretory dysfunction has been described by others following radiation injury to the hypothalamic-pituitary axis [13]. It is characterized first by diminished spontaneous secretion of GH in the presence of preserved peak GH responses to provocative tests [14] and then by a decreased response on provocative tests.…”

“…These patients were treated with brain neurosurgery or chemotherapy. Although there is no conclusive evidence that chemotherapy alone results in neuroendocrine dysfunction, it may play a role [13]. …”

“…Growth in the first 4 years after treatment with craniospinal radiation was found to be more profoundly affected in children who also received adjuvant chemotherapy, suggesting a potentiation of radiation-induced growth failure by chemotherapy [38]. Some authors hypothesized that cytotoxic drugs may amplify the radiation-induced damage to the hypothalamic-pituitary axis [13], directly affect the production of insulin-like growth factor-I by the liver [39] and/or impair the action of insulin-like growth factor-I on the growth plate. …”

Long-Term Effects on Bone Mineral Density of Different Therapeutic Schemes for Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma during Childhood

“…In addition to the known direct toxic effects of spinal irradiation on longitudinal growth, the main mechanism accounting for bone loss induced by cerebral irradiation is related to the subsequent neuroendocrine abnormalities leading in turn to multiple anterior pituitary hormone deficiencies [40]. Furthermore, these alterations might be amplified by prior administration of cytotoxic drugs [41]. The GH axis is the most sensitive to irradiation [40] and GHD is associated with a reduced bone mass in both adults and adolescents [42].…”

Hypothalamo‐pituitary‐adrenal axis integrity after cranial irradiation for childhood posterior fossa tumours

“…With the exception perhaps of GH, where the few longitudinal studies of stimulated [23][24][25] and spontaneous 24 hr GH secretion [25] suggest subtle and persisting post-operative neuroregulatory disturbances, compounded by irradiation, chemotherapy and time [25,26], the independent neurotoxic effect of cranial irradiation, as distinct from any tumour, surgical or other treatment effect, remains unclear. Although the selection criteria in our study bias our results in favour of the high prevalence of GH deficiency we document, long-term cohort studies in treated children confirm the high incidence and permanence of GH deficiency after cranial irradiation (>85%) for posterior fossa tumours [25,26] and support our findings.…”