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: 6.21). 02/2012; 97(2):416-25. DOI: 10.1210/jc.2011-1995
Source: PubMed


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.

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    • "Recently, preliminary report of the French Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) study demonstrated that mortality rates were increased in adults treated with GH as children. Particularly, those who had received the highest doses showed increased bone tumors or cerebral hemorrhage but not for all cancers.25 However, these results are not yet conclusive and still in debate. "
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    ABSTRACT: Purpose It has been reported that daily recombinant human growth hormone (GH) treatment showed beneficial effects on growth in prepubertal children with idiopathic short stature (ISS). The present study aimed to validate the GH (Eutropin®) effect on growth promotion and safety after short-term GH treatment. Materials and Methods This study was an open-label, multicenter, interventional study conducted at nine university hospitals in Korea between 2008 and 2009. Thirty six prepubertal children with ISS were enrolled in this study to receive 6-month GH treatment. Yearly growth rate, height standard deviation score (SDS), and adverse events were investigated during treatment. Results After 26 weeks of GH treatment, the height velocity significantly increased by 6.36±3.36 cm/year (p<0.001). The lower end of one-sided 95% confidence interval was 5.22 cm/year, far greater than the predefined effect size. The gain in height SDS at week 26 was 0.57±0.27 (p<0.0001). Bone age significantly increased after GH treatment, however, bone maturation rate (bone age for chronological age) showed limited advancement. This 26-week GH treatment was effective in increasing serum levels of insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 from baseline (p<0.0001). Eutropin was well tolerated and there were no withdrawals due to adverse events. No clinically significant changes in laboratory values were observed. Conclusion This 6-month daily GH treatment in children with ISS demonstrated increased height velocity, improved height SDS, and increased IGF-I and IGFBP-3 levels with a favorable safety profile.
    Full-text · Article · Jan 2014 · Yonsei medical journal
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    • "It is reassuring that we observed no occurrence of new cancers in the ICOGHD group (the low-risk group). In contrast with the French SAGhE data [1], no incident case of malignant neoplasm of the bone or articular cartilage was observed in the COGHD or ICOGHD subjects in HypoCCS [1]. No case of MI was identified in either the COGHD or ICOGHD groups. "
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    ABSTRACT: The French Safety and Appropriateness of Growth Hormone treatments in Europe (SAGhE) cohort has raised concern of increased mortality risk during follow-up into adulthood in certain patients who had received growth hormone (GH) treatment during childhood. The Hypopituitary Control and Complications Study monitored mortality and morbidity of adult GH-deficient patients including those with childhood-onset GH deficiency (COGHD) who received GH treatment as children. Evaluate risk of mortality, cancer, myocardial infarction (MI) and stroke in a prospective observational study. COGHD patients [n = 1,204, including 389 diagnosed with idiopathic COGHD (ICOGHD)] had received pediatric GH treatment. Standardized mortality ratios (SMRs), and cancer standardized incidence ratios (SIRs) in patients without a prior cancer were estimated relative to reference populations. Crude incidence rates were estimated for MI and stroke. No increased mortality or cancer incidence was observed, as compared with reference populations, during a follow-up of 3.7 ± 3.3 years (mean ± SD). The overall SMR for COGHD was 1.14 [95 % confidence interval (CI) 0.55-2.10], and for ICOGHD, 0.33 (0.01-1.84). The overall cancer SIR for COGHD was 0.27 (0.01-1.50), and for ICOGHD, 0.00 (0.00-2.45). No incident case of MI was reported. The crude stroke incidence rate [181.3 per 100,000 person-years] in COGHD patients was consistent with the rates reported in reference populations. No incident case of stroke was identified in ICOGHD patients who are presumed to have no increased stroke risk factors. The results indicate no increased risk of mortality or incidence of cancer, stroke, or MI in adult GH-deficient patients who had previously received pediatric GH treatment.
    Full-text · Article · Oct 2013 · Pituitary
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    • "The recent publication of two studies stemming from SAGhE (Safety and Appropriateness of GH treatments in Europe) European consortium, which was started in 2009 and includes eight countries (France, Sweden, Belgium, the Netherlands, Switzerland, Germany, United Kingdom, and Italy), has generated confusion and controversy rather than shedding light on this delicate matter (Carel et al., 2012; Sävendahl et al., 2012). The French study reported a significant increase in both allcause mortality and specific mortality for bone tumors or cerebral hemorrhage in a cohort of about 6500 young adult subjects treated with rhGH during childhood for GH deficiency, SGA, or ISS (Table 1). "

    Full-text · Article · Sep 2012 · Frontiers in Endocrinology
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