Long-Term Mortality after Recombinant Growth Hormone Treatment for Isolated Growth Hormone Deficiency or Childhood Short Stature: Preliminary Report of the French SAGhE Study

Department of Pediatric Endocrinology and Diabetology, Institut National de la Santé et de la Recherche Mdicale CIE5, Paris, France.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.31). 02/2012; 97(2):416-25. DOI: 10.1210/jc.2011-1995
Source: PubMed

ABSTRACT Little is known about the long-term health of subjects treated with GH in childhood, and Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) is a study addressing this question.
The objective of the study was to evaluate the long-term mortality of patients treated with recombinant GH in childhood in France.
This was a population-based cohort study.
The setting of the study was a French population-based register.
A total of 6928 children with idiopathic isolated GH deficiency (n = 5162), neurosecretory dysfunction (n = 534), idiopathic short stature (n = 871), or born short for gestational age (n = 335) who started treatment between 1985 and 1996 participated in the study. Follow-up data on vital status were available in September 2009 for 94.7% of the patients.
All-cause and cause-specific mortality was measured in the study.
All-cause mortality was increased in treated subjects [standardized mortality ratio (SMR) 1.33, 95% confidence interval (CI) 1.08-1.64]. In a multivariate analysis adjusted for height, the use of GH doses greater than 50 μg/kg · d was associated with mortality rates using external and internal references (SMR 2.94, 95% CI 1.22-7.07, hazard ratio 2.79, 95% CI 1.14-6.82). All type cancer-related mortality was not increased. Bone tumor-related mortality was increased (SMR 5.00, 95% CI 1.01-14.63). An increase in mortality due to diseases of the circulatory system (SMR 3.07, 95% CI 1.40-5.83) or subarachnoid or intracerebral hemorrhage (SMR 6.66, 95% CI 1.79-17.05) was observed.
Mortality rates were increased in this population of adults treated as children with recombinant GH, particularly in those who had received the highest doses. Specific effects were detected in terms of death due to bone tumors or cerebral hemorrhage but not for all cancers. These results highlight the need for additional studies of long-term mortality and morbidity after GH treatment in childhood.

  • Source
    [Show abstract] [Hide abstract]
    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 03/2015; 10(3):e0120463. DOI:10.1371/journal.pone.0120463 · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Growth hormone (GH) treatment has been increasingly widely used for children with GH deficiencies as the survival rate of pediatric patients with malignancies has increased. Both GH and insulin-like growth factor-I have mitogenic and antiapoptotic activity, prompting concern that GH treatment may be associated with tumor development. In this review, the authors examined the relationship between GH treatment and cancer risk in terms of de novo malignancy, recurrence, and secondary neoplasm. Although the results from numerous studies were not entirely consistent, this review of various clinical and epidemiological studies demonstrated that there is no clear evidence of a causal relationship between GH treatment and tumor development. Nonetheless, a small number of studies reported that childhood cancer survivors who receive GH treatment have a small increased risk of developing de novo cancer and secondary malignant neoplasm. Therefore, regular follow-ups and careful examination for development of cancer should be required in children who receive GH treatment. Continued surveillance for an extended period is essential for monitoring long-term safety.
    Korean Journal of Pediatrics 02/2015; 58(2):41-6. DOI:10.3345/kjp.2015.58.2.41
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Patients treated with biosmilar growth hormone (BGH) is increasing since its approval by the EMA. The purpose of this study is to evaluate the effects of BGH in hydrocarbonate and lipidic metabolism as well as thyroid function, in children small for gestational age (SGA) and growth hormone deficiency (GHD). Method: We carried out a retrospective study 18 children (4 GHD and 14 SGA) treated for at least 6 months. We analize anthropometric and laboratory parameters, and other adverse events or GH disruption. Results: The height went up from -3,8 standard deviation (SD) to – 2.43 SD, -2.39 SD and -2 SD at 6, 12 and 24 months of treatment (p <0.05). There was a significant rise of the type 1 insulin growth factor (IGF-1) levels; average at start 115.4 ng/ml vs 250.2 ng/ml at 6 months (p < 0.05). There was no difference in colesterol, triglycerides, hemoglobin A1c and TSH levels before and after 6, 12 and 24 months. Free T4 average decreased after 6, 12 and 24 months from 1.2 ng/dl to 1, 0.8 y 0.9 ng/dl (p < 0.05). Conclusions: Children SGA represent the large group in GH therapy. BGH is effective in treating children DGH and SGA, with a suitable safety profile in hydrocarbonate-lipidic metabolism and thyroid function.