Childhood malignant disease and consequences for growth hormone secretion, intellectual function and cardiovascular risk

Abstract: In childhood onset growth hormone deficiency (GHD) a reduction in cardiac left ventricular mass (LVMi) and impairment of cardiac systolic function, as well as in glomerular filtration rate (GFR) has been shown. In study I, we showed that a low dose of GH treatment for 10 months resulted in increased LVMi and kidney size. No significant improvement in cardiac systolic function or GFR, except for a normalisation in GFR in 3 patients, was recorded. Hypopituitary patients receiving conventional hormone treatment, but without GH replacement, have an increased mortality from cardiovascular disease and a reduced insulin sensitivity. Hypothalamic-pituitary hormone insufficiencies are well known consequences of cranial radiotherapy (CRT) and CRT has previously been part of treatment regimens in childhood acute lymphoblastic leukemia (ALL) to prevent central nervous system relapses. A decline in intellectual function has been shown 4-8.5 years after treatment with18-24 Gy of CRT in childhood ALL patients, but information on longer follow-up is missing. In study II, we aimed to investigate cardiovascular risk factors in former ALL patients, and in study III to evaluated insulin sensitivity before and after 12 months of GH treatment. In study IV, we evaluated neuropsychological performance and self-rated mental well-being. All comparisons were made with matched population controls. Further, the impact of 12 months of GH treatment on neuropsychological test scores was evaluated. We have shown that, at a median 17 years after treatment with CRT and chemotherapy, the former ALL had an increase in cardiovascular risk factors, including dyslipidemia, increased fibrinogen levels, insulin resistance, increase in fat mass and decrease in lean mass, and a marked reduction in cardiac dimensions and performance. We suggested that GH deficiency (GHD), induced by CRT is a primary cause, because 91% of the former ALL patients were GHD, and strong correlations between stimulated GH secretion and several of the cardiovascular risk factors were recorded. GH treatment for 12 months had positive effects on body composition, but no significant improvement on insulin sensitivity was recorded. There was no difference in the self reported quality of life, but significantly lower scores in neuropsychological performance was recorded in former ALL patients, where early age at treatment had a strong negative impact on test scores. GH treatment for one year, in a subset on former ALL patients, did not improve neuropsychological performance. In study V, we showed that the GHRH-arginine test can not be used to rule out GHD due to its low negative predictive value (27%), but a failed GH response accurately reflects the presence of radiation induced GHD, illustrated by a high positive predictive value (91%).