Metabolic effects and long-term safety of childhood growth hormone treatment

The overall aim of this thesis was to investigate the metabolic effects and long-term safety of childhood growth hormone (GH) treatment. In order to achieve this aim, the different projects consist of a two-part clinical trial on metabolic features linked to GH physiology and GH treatment as well as two large population-based cohort studies with focus on the long-term cardiovascular and cancer risks in previously GH-treated patients. In study I, the metabolic profile of 35 prepubertal children of short stature, between 7 and 10 years of age, with stimulated peak GH levels in the lower normal range (7-14 µg/L) was compared to 12 age- and sex-matched control children of normal height and weight. The groups were compared using blood samples of fasting glucose and insulin, HbA1c, insulin-like growth factor I (IGF-I), insulin sensitivity using both homeostasis model assessment of insulin resistance (HOMA-IR) and frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy x-ray absorptiometry (DEXA), microdialysis and stable isotope examination of glucose production and lipolysis. Few differences between the groups were found but the subgroup of children with the lowest GH peak levels demonstrated lower fasting insulin levels and signs of increased insulin sensitivity. In study II, the 35 short children from study I were subsequently randomized to three different doses of recombinant human GH (rhGH) treatment; low dose (11 µg/kg/d), standard dose (33 µg/kg/d) or high dose (100 µg/kg/d), and followed for two years. The doses were blinded to both patients and the study investigators. The metabolic effects of the different treatment doses were analyzed by the same methods as in study I and a clear dose-dependent metabolic effect could be demonstrated, in particular for the high dose group regarding fasting insulin and different measures of insulin sensitivity. In study III, the long-term cardiovascular morbidity in childhood rhGH-treated Swedish patients between 1985 and 2010, due to isolated GH deficiency (GHD), small for gestational age (SGA) or idiopathic short stature (ISS), was investigated. Data on cardiovascular outcomes and important covariates were gathered for a total of 3,408 patients and 50,036 randomly selected controls matched on sex, age and county. Time to first cardiovascular event was analyzed by Cox proportional-hazard regression models and the study showed increased adjusted hazard ratios for the patients compared to the controls. In study IV, the long-term cancer incidence and mortality in a large meta-cohort of approximately 24,000 previously childhood rhGH-treated patients from eight European countries were investigated. The results did not support an overall carcinogenic effect of rhGH treatment but the significant trend of increased cancer mortality risk in relation to rhGH dose in patients with previous cancer and the indication of possible effects on bone cancer, bladder cancer and Hodgkin’s lymphoma requires further vigilance

Cancer risks in patients treated with growth hormone in childhood: the SAGhE European cohort study.

Context: Growth hormone (GH) is prescribed for an increasing range of indications, but there has been concern that it might raise cancer risk. Published data are limited. Objective: To examine cancer risks in relation to GH treatment. Design: Cohort study. Setting: Population-based. Patients: Cohort of 23,984 patients treated with recombinant human GH (r-hGH) in eight European countries since this treatment was first used in 1984. Cancer expectations from country-specific national population statistics. Main Outcome Measures: Cancer incidence and cancer mortality. Results: Incidence and mortality risks in the cohort were raised for several cancer sites, largely consequent on second primary malignancies in patients given r-hGH after cancer treatment. There was no clear raised risk in patients with growth failure without other major disease. Only for bone and bladder cancers was incidence significantly raised in GH-treated patients without previous cancer. Cancer risk was unrelated to duration or cumulative dose of r-hGH treatment, but for patients treated after previous cancer, cancer mortality risk increased significantly with increasing daily r-hGH dose (P trend < 0.001). Hodgkin lymphoma (HL) incidence increased significantly with longer follow-up (P trend = 0.001 for patients overall and 0.002 for patients without previous cancer). Conclusions: Our results do not generally support a carcinogenic effect of r-hGH, but the unexplained trend in cancer mortality risk in relation to GH dose in patients with previous cancer, and the indication of possible effects on bone cancer, bladder cancer, and HL risks, need further investigation

Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study

Background: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. Methods: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). Findings: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. Interpretation: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance

DataSheet_1_Long-term risk of neoplastic events after childhood growth hormone treatment: a population-based cohort study in Sweden.pdf

BackgroundIncreased risk of neoplastic events after recombinant human growth hormone (rhGH) treatment in childhood has been an ongoing concern but long-term safety data are limited.MethodsA nationwide population-based cohort study in Sweden of patients treated with rhGH during childhood between 1985-2010, due to isolated growth hormone deficiency (GHD), small for gestational age (SGA) and idiopathic short stature (ISS). The comparison group consisted of 15 age-, sex-, and region-matched controls per patient, randomly selected from the general population. Data on neoplastic events and covariates, such as gestational age, birth weight, birth length, socioeconomic status, and height at study start, were collected through linkage with population-based registers. The cohort was followed for neoplastic events until the end of 2020.Results53,444 individuals (3,408 patients; 50,036 controls) were followed for up to 35 years, with a median follow-up of 19.8 years and a total of 1,050,977 person-years. Patients showed a moderately increased hazard ratio (HR) for neoplastic events overall compared to controls (HR 1.28, 95% CI: 1.12-1.46), but only significant for males (HR 1.39, 95% CI: 1.17-1.66) and not females (HR 1.15, 95% CI: 0.94-1.41). Longer treatment duration was associated with an increased HR, but no association was found between neoplastic events and mean or cumulative dose. No increased risk of malignant neoplasms was observed for the patients compared to matched controls (HR 0.91 95% CI: 0.66-1.26).ConclusionNo association was found between rhGH treatment during childhood for GHD, SGA, or ISS and malignant neoplastic events in early to mid-adulthood. A moderate increase in overall neoplastic events was observed due to an increased number of events in male patients.</p

Risk of meningioma in European patients treated with growth hormone in childhood: results from the SAGhE cohort.

There has been concern that growth hormone (GH) treatment of children might increase meningioma risk. Results of published studies have been inconsistent and limited. To examine meningioma risks in relation to GH treatment. Cohort study with follow-up via cancer registries and other registers. Population-based. A cohort of 10,403 patients treated in childhood with recombinant GH (r-hGH) in 5 European countries since this treatment was first used in 1984. Expected rates from national cancer registration statistics. Risk of meningioma incidence. During follow-up 38 meningiomas occurred. Meningioma risk was greatly raised in the cohort overall (SIR=75.4; 95% confidence interval (CI) 54.9-103.6), as a consequence of high risk in subjects who had received radiotherapy for underlying malignancy (SIR= 658.4; 95% CI 460.4-941.7). Risk was not significantly raised in patients who did not receive radiotherapy. Risk in radiotherapy-treated patients was not significantly related to mean daily dose of GH, duration of GH treatment or cumulative dose of GH. Our data add to evidence of very high risk of meningioma in patients treated in childhood with GH after cranial radiotherapy, but suggest that GH may not affect radiotherapy-related risk, and that there is no material raised risk of meningioma in GH-treated patients who did not receive radiotherapy

Long-term mortality after childhood growth hormone treatment: the SAGhE cohort study.

BACKGROUND Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis. METHODS This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs). FINDINGS The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups. INTERPRETATION In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance. FUNDING European Union