Long-Term Mortality and Causes of Death in Isolated GHD, ISS, and SGA Patients Treated with Recombinant Growth Hormone during Childhood in Belgium, The Netherlands, and Sweden: Preliminary Report of 3 Countries Participating in the EU SAGhE Study
ABSTRACT The long-term mortality in adults treated with recombinant GH during childhood has been poorly investigated. Recently released data from the French part of the European Union Safety and Appropriateness of GH treatments in Europe (EU SAGhE) study have raised concerns on the long-term safety of GH treatment.
To report preliminary data on long-term vital status and causes of death in patients with isolated GH deficiency or idiopathic short stature or born small for gestational age treated with GH during childhood, in Belgium, The Netherlands, and Sweden.
Data were retrieved from national registries of GH-treated patients and vital status from National Population Registries. Causes of death were retrieved from a National Cause of Death Register (Sweden), Federal and Regional Death Registries (Belgium), or individual patient records (The Netherlands).
All patients diagnosed with isolated GH deficiency or idiopathic short stature or born small for gestational age started on recombinant GH during childhood from 1985-1997 and who had attained 18 yr of age by the end of 2010 were included. Vital status was available for approximately 98% of these 2,543 patients, corresponding to 46,556 person-years of observation.
Vital status, causes of death, age at death, year of death, duration of GH treatment, and mean GH dose during treatment were assessed.
Among 21 deaths identified, 12 were due to accidents, four were suicides, and one patient each died from pneumonia, endocrine dysfunction, primary cardiomyopathy, deficiency of humoral immunity, and coagulation defect.
In these cohorts, the majority of deaths (76%) were caused by accidents or suicides. Importantly, none of the patients died from cancer or from a cardiovascular disease.
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ABSTRACT: Treatment with recombinant human growth hormone (rhGH) has been consistently reported to induce transcriptional changes in various human tissues including peripheral blood. For other hormones it has been shown that the induction of such transcriptional effects is conferred or at least accompanied by DNA-methylation changes. To analyse effects of short term rhGH treatment on the DNA-methylome we investigated a total of 24 patients at baseline and after 4-day rhGH stimulation. We performed array-based DNA-methylation profiling of paired peripheral blood mononuclear cell samples followed by targeted validation using bisulfite pyrosequencing. Unsupervised analysis of DNA-methylation in this short-term treated cohort revealed clustering according to individuals rather than treatment. Supervised analysis identified 239 CpGs as significantly differentially methylated between baseline and rhGH-stimulated samples (p<0.0001, unadjusted paired t-test), which nevertheless did not retain significance after adjustment for multiple testing. An individualized evaluation strategy led to the identification of 2350 CpG and 3 CpH sites showing methylation differences of at least 10% in more than 2 of the 24 analyzed sample pairs. To investigate the long term effects of rhGH treatment on the DNA-methylome, we analyzed peripheral blood cells from an independent cohort of 36 rhGH treated children born small for gestational age (SGA) as compared to 18 untreated controls. Median treatment interval was 33 months. In line with the groupwise comparison in the short-term treated cohort no differentially methylated targets reached the level of significance in the long-term treated cohort. We identified marked intra-individual responses of DNA-methylation to short-term rhGH treatment. These responses seem to be predominately associated with immunologic functions and show considerable inter-individual heterogeneity. The latter is likely the cause for the lack of a rhGH induced homogeneous DNA-methylation signature after short- and long-term treatment, which nevertheless is well in line with generally assumed safety of rhGH treatment.PLoS ONE 01/2015; 10(3):e0120463. DOI:10.1371/journal.pone.0120463 · 3.53 Impact Factor
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ABSTRACT: The measurement of insulin-like growth factors (IGF-I) and insulin-like growth factor-binding protein (IGFBP-3) often serves as first-line testing in children with growth disorders. The role of acid-labile subunit (ALS) as a screening parameter for homozygous or heterozygous mutations of the ALS gene still has to be determined.Wiener Medizinische Wochenschrift 09/2014; DOI:10.1007/s10354-014-0299-4
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ABSTRACT: Biosynthetic human Growth Hormone (r-hGH) has an extremely good efficacy and safety profile. The use of r-hGH has expanded from classic GH deficiency to wider indications such as Turner Syndrome and Chronic Renal Failure. This wider use has been predicated in part by the safety profile of r-hGH. Long-term outcomes of treating children with r-hGH are lacking although concern has been raised by preliminary data linking r-hGH use with premature death (1). These observations have been extended in a paper by Poidvin et al (2) from the Safety and Appropriateness of Growth Hormone Treatments in Europe (SAGhE) French cohort.This article is protected by copyright. All rights reserved.Clinical Endocrinology 09/2014; 82(2). DOI:10.1111/cen.12611 · 3.35 Impact Factor