No abstract

Young adults who receive cranial irradiation in childhood are prone to GH deficiency and hyperleptinaemia. The pathophysiological significance of the hyperleptinaemia remains to be established but it has occurred either as a consequence of radiation induced hypothalamic damage or GH deficiency.

The most profound GH release is seen after insulin-induced hypoglycaemia. Glucagon appears to be more effective at inducing GH release than arginine. Clonidine at a dose of 100 or 200 micrograms is no more effective than placebo.

Bone mineral density (BMD), serum osteocalcin and type I collagen C-telopeptide (ICTP) were assessed in a cohort of 31 (16 males) adults who had received cranial irradiation in childhood as part of their treatment for acute lymphoblastic leukaemia (ALL). Markers of bone turnover were compared with those of 35 age and body mass index (BMI) matched young adults (18 male). Growth hormone status had previously been determined using an insulin tolerance test and arginine stimulation test. Eight patients were classified as severe growth hormone deficiency (group 1), 12 patients as growth hormone insufficient (group 2) and 11 patients as normal (group 3). Vertebral trabecular BMD, lumbar spine and femoral neck integral BMD and forearm cortical bone mineral content (BMC) was measured 17.8 (6.8–28.6) years after cranial irradiation and was expressed as Z (standard deviation) scores. There was a significant reduction in vertebral trabecular BMD (median Z score –1.25, P < 0.001), in lumbar spine integral BMD (median Z score –0.74, P = 0.001), in forearm cortical BMC (median Z score –1.35, P < 0.001), and less so in femoral neck integral BMD (median Z score –0.43, P = 0.03). There was no difference among the growth hormone status groups for the following BMD measurements: vertebral trabecular BMD, lumbar spine integral BMD or femoral neck integral BMD ( P = 0.8, P = 0.96 and P = 0.4 respectively). There was only a marginal significant difference for BMD at the wrist between growth hormone status groups ( P = 0.04). There was no correlation between the BMD measurements with time since or age at diagnosis and no difference in markers of bone turnover between patients and controls; median serum osteocalcin 13.3 and 12.0 ng ml ( P = 0.7), respectively, and for ICTP 5.0 and 4.9 μg L ( P = 0.67) respectively. In conclusion, there is a highly significant reduction in BMD in young adults following treatment for ALL in childhood. The reduction in BMD affects both trabecular and cortical bone but did not seem to be related to time since diagnosis, age at diagnosis, or current growth hormone status. Possible explanations include a direct effect of chemotherapy, steroids or both on bone during childhood and hence an effect on the accretion of bone mass. In view of the risk of fractures in patients with osteopenia, adults treated for ALL in childhood may be at an increased risk of bone fractures later in life irrespective of the underlying cause of the osteopenia and thus intervention should be considered. © 1999 Cancer Research Campaign

These data suggest that a significant proportion of adults treated with cranial XRT in childhood with irradiation doses between 18-25 Gy, as part of their treatment for ALL, are severely GH deficient now and should be considered for GH replacement. Changes in GH secretion evolve with time following irradiation-induced damage to the hypothalamic-pituitary axis; therefore long-term surveillance will be required in those remaining patients, in whom GH status is considered currently to be insufficient or even normal.

Baseline QOL as assessed by self-rating questionnaires is influenced by the age of onset of the GH deficiency, adult onset patients expressing the greater distress. Improvements in QOL scores are influenced by both baseline score and to a lesser extent the age of onset of GHD, the greater improvement being observed in childhood onset patients. The degree of improvement was observed to be independent of gender, pathology and number of pituitary hormone deficits. In a cohort selected by subjectively impaired QOL, we have demonstrated childhood onset GHD patients perceive themselves to have less impairment of QOL pretreatment. In contrast to previous data in unselected cohorts, however, we have shown that those childhood onset GHD patients in whom QOL is significantly reduced, show a capacity for improvement that is equal to, if not greater, than that seen in adult onset-GHD patients.

Our study suggests that all children who have received GH replacement therapy in childhood should undergo reassessment of GH status in young adult life. Between 40 and 60% of such patients merit consideration for GH therapy in adult life depending on the definition of severe GH deficiency in use. Patients with isolated GH deficiency should undergo two provocative tests of GH secretion, but those with additional anterior pituitary hormone deficiencies require only one test at reassessment.

Hypovitaminosis D remains a major public health issue in the Asian population and is exaggerated in patients with T2DM. The fact that vitamin D deficient women had higher HbA1c levels raises the possibility that vitamin D replacement may improve glycaemic control.