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.

We report a strong relationship between hemorrhagic stroke and GH treatment in childhood for isolated growth hormone deficiency or childhood short stature. Patients treated with GH worldwide should be advised about this association and further studies should evaluate the potentially causal role of GH treatment in these findings.

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Background: The long-term safety of growth hormone treatment is uncertain. Raised risks of death and certain cancers have been reported inconsistently, based on limited data or short-term follow-up by pharmaceutical companies. Patients and Methods: The SAGhE (Safety and Appropriateness of Growth Hormone Treatments in Europe) study assembled cohorts of patients treated in childhood with recombinant human growth hormone (r-hGH) in 8 European countries since the first use of this treatment in 1984 and followed them for cause-specific mortality and cancer incidence. Expected rates were obtained from national and local general population data. The cohort consisted of 24,232 patients, most commonly treated for isolated growth failure (53%), Turner syndrome (13%) and growth hormone deficiency linked to neoplasia (12%). This paper describes in detail the study design, methods and data collection and discusses the strengths, biases and weaknesses consequent on this. Conclusion: The SAGhE cohort is the largest and longest follow-up cohort study of growth hormone-treated patients with follow-up and analysis independent of industry. It forms a major resource for investigating cancer and mortality risks in r-hGH patients. The interpretation of SAGhE results, however, will need to take account of the methods of cohort assembly and follow-up in each country.

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A total of 130 short children were included in a French multicentre study and randomized between a control group (group A) and two groups treated with daily subcutaneous injections of GH at doses of 0.7 IU/kg/week (group B) and 1.4 IU/kg/week (group C) for 2 years. Height velocity was significantly increased (p<0.0005) in groups B and C, with a greater increase in group C than in group B (p< 0.001). The benefit after 2 years compared with controls was 4.3 cm in group B and 5.9 cm in group C. The rate of bone maturation was not affected by GH therapy. These results led to the conclusion that 2 years of treatment with GH improves final height prognosis in children with short stature secondary to IUGR, and that this effect is dose dependent. The effect on final height has still to be demonstrated.

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GH, 0.1 IU/kg/day 6 days/week, was given to 30 early pubertal short patients for 3 years. There were 16 males, aged 14.4 ± 0.8 years, and 14 females, aged 12.2 ± 1.2 years, at pubertal stage 2 or 3 with slow growth (4.2 ± 1.2 cm/year) and no detected GH insufficiency or other cause for short stature. They were randomized in 2 groups: group A with GH alone, and group B with GH and a gonadotropin-releasing hormone agonist during the first 2 years. 28 of the 30 patients completed 3 years of treatment. The annual growth rate increased during the 1st year in both groups and sexes, the increase being significant (p < 0.01) in group A only. Patients of group A kept an improved growth velocity in the 2nd year, then returned to pretreatment growth rate in the 3rd year, while completing their sexual development and bone maturation. Their height, expressed as standard deviation score (SDS) for bone age, improved in the first 2 years, but decreased thereafter. Group B patients returned to pretreatment growth velocity in the 2nd year, and had no significant improvement in growth rate in the 3rd year with GH alone. Their bone maturation, slow when on the GnRH agonist, accelerated when sexual development resumed. At the end of the 3 years, height, expressed as SDS for age, improved in group A from -2.5 ± 0.6 to -1.5 ± 0.4 in males (p < 0.05) and from -2.8 ± 0.5 to -2.1 ± 0.9 in females (NS). In group B there was no significant progress in height for age at any time. Mean height SDS for bone age slightly improved in males (NS) but not in females. In both groups, the mean predicted height according to Bayley and Pinneau was slightly, nonsignificantly increased at the end of 3 years on GH, with a gain of 2-5 cm on average, depending on the group. There was a wide interindividual variability in these results within each group. Looking for possible correlations of results with pretreatment characteristics of the patients did not account for such differences. The only correlations found were within group A, one negative between total height gain in 3 years and the patient’s height at the onset of treatment, and one positive between growth rates in years 2-3 and year 1 of the study. The annual measurement of plasma IGF₁ showed different degrees of increase, not correlated with the growth changes. The most certain conclusion of this study is that inhibiting sexual development in constitutionally short pubertal subjects has no advantage and must be avoided. The other possible conclusion is that GH alone can accelerate growth for 2 years, and slightly improve the predicted height in relation to the result of the first year of treatment. The expected results cannot be overestimated. The present data cannot be considered as an opening for the possible routine use of GH in endocrinologically normal short adolescents.