Does growth hormone replacement therapy reduce mortality in adults with growth hormone deficiency? Data from the Dutch National Registry of Growth Hormone Treatment in adults.

CONTEXT: Adults with GH deficiency (GHD) have a decreased life expectancy. The effect of GH treatment on mortality remains to be established. OBJECTIVE: This nationwide cohort study investigates the effect of GH treatment on all-cause and cause-specific mortality and analyzes patient characteristics influencing mortality in GHD adults. DESIGN, SETTING, AND PATIENTS: Patients in the Dutch National Registry of Growth Hormone Treatment in Adults were retrospectively monitored (1985-2009) and subdivided into treatment (n = 2229), primary (untreated, n = 109), and secondary control (partly treated, n = 356) groups. MAIN OUTCOME MEASURES: Standardized mortality ratios (SMR) were calculated for all-cause, malignancy, and cardiovascular disease (CVD) mortality. Expected mortality was obtained from cause, sex, calendar year, and age-specific death rates from national death and population counts. RESULTS: In the treatment group, 95 patients died compared to 74.6 expected [SMR 1.27 (95% confidence interval, 1.04-1.56)]. Mortality was higher in women than in men. After exclusion of high-risk patients, the SMR for CVD mortality remained increased in women. Mortality due to malignancies was not elevated. In the control groups mortality was not different from the background population. Univariate analyses demonstrated sex, GHD onset, age, and underlying diagnosis as influencing factors. CONCLUSIONS: GHD men receiving GH treatment have a mortality rate not different from the background population. In women, after exclusion of high-risk patients, mortality was not different from the background population except for CVD. Mortality due to malignancies was not elevated in adults receiving GH treatment. Next to gender, the heterogeneous etiology is of influence on mortality in GHD adults with GH treatment.

The GH/IGF-I Axis and Cognitive Changes across a 4-Year Period in Healthy Adults.

After the age of 40, the amount of growth hormone in humans decreases. The reduced activity of the GH-IGF axis may play a role in age-related cognitive impairments. In the present study, mood and cognition of 30 healthy subjects (7 males, 23 females, aged 41-76 yr, mean age 60.9 ± 9.0) were examined twice. At baseline, we determined fasting blood levels of GH and IGF-I. Mood and cognitive status were assessed at baseline and after, on the average, 3 years and 9 months of followup. Working memory performance decreased over the years in the low IGF-group (P = .007), but not the high IGF-I group. Higher levels of GH were related with a better working memory at the second test (r = 0.42, P = .01) while higher levels of IGF-I tended to be related with a better working memory (r = 0.3, P = .06). The results suggest that higher serum levels of GH and IGF-I preserve the quality of working memory functions over the years.

Impaired quality of life in hypopituitary adults with growth hormone deficiency : can somatropin replacement therapy help?

It is generally known that growth hormone (GH)-deficient patients experience emotional instability, reduced energy, sleep disturbances, and problems with (sexual) relationships. GH and insulin-like growth factor-1 (IGF-I) may affect mood parameters by their actions at binding sites in specific brain areas and/or by their effects on dopamine turnover in the brain. Indeed, there is substantial evidence that somatropin (growth hormone) treatment improves the quality of life (QOL) of GH-deficient patients.However, the variety of instruments used makes it questionable whether QOL in particular is affected by somatropin therapy. The measurement of QOL is subject to methodologic difficulties and is frequently not properly distinguished from health status and well-being. QOL ratings are characterized by an emphasis on mental health and health status by an emphasis on physical function, while well-being is concerned with depression, anxiety, and energy levels. Examples of instruments used to measure QOL, health status, and well-being in GH-deficient patients are the Quality of Life-Assessment of Growth Hormone Deficiency in Adults, the Short-Form Health Survey, and the Psychological General Well-Being Schedule, respectively. One additional problem in establishing the effects of somatropin treatment on QOL is that the QOL effects of somatropin treatment may be different for patients with isolated GH deficiency (GHD) and those with multiple pituitary hormone deficiencies.Previously, in order to answer the question of whether somatropin therapy improves mood status in GH-deficient patients, we conducted a meta-analysis comparing somatropin treatment effects relative to baseline and placebo. At 3, 6, and 12 months of somatropin replacement the mood status of GH-deficient patients improved with decreasing effect sizes over time (d = 0.81, 0.55, and 0.29, respectively) from baseline. However, the median somatropin treatment period of 6 months did not improve mood status more than placebo. In a second analysis we classified the questionnaires into those on QOL, those on health status, and those on well-being, respectively, and analyzed the separate effects of pooled treatment durations of about 9 months. Somatropin replacement improved QOL with a small effect size (d = 0.18), well-being with a medium effect size (d = 0.47), and health status with a small effect size (d = 0.26).Although the separate effects of somatropin on QOL, health status, and well-being could not be compared to placebo, we concluded that somatropin treatment most likely plays a role in improving the well-being of patients with GHD. This conclusion is based on correlations that have been found between IGF-I levels and parameters of well-being, such as anxiety and depression.

Effects of growth hormone substitution therapy on cognitive functioning in growth hormone deficient patients: a functional MRI study.

Patients with childhood-onset growth hormone (GH) deficiency (GHD) show impairments in mood and cognitive functioning which may resolve following GH substitution. Brain functional magnetic resonance imaging (fMRI) during performance of a memory task was used to assess the cerebral activity of such patients. Thirteen childhood-onset GHD patients (mean age 27.3 +/- 6.9 years) were included in a double-blind, placebo-controlled study. The effects of 6 months of GH replacement or placebo therapy were studied using neuropsychological tests and fMRI. One patient was excluded from the study due to noncompliance with the protocol. Six months of GH substitution in these GHD patients resulted in improved memory functioning, both for long-term and working memory. fMRI showed activations during the working memory task in prefrontal, parietal, motor, and occipital cortices, as well as in the right thalamus and anterior cingulate cortex. Decreased activation in the ventrolateral prefrontal cortex was observed after GH treatment as compared with placebo treatment, indicating decreased effort and more efficient recruitment of the neural system involved. It can be concluded that GH treatment for 6 months improved the long-term as well as the working memory in patients with GHD, and this was associated with decreased brain activation in the ventrolateral prefrontal cortex. GH substitution in GHD patients is beneficial for cognitive functioning, the effects of which can be visualized by means of neuroimaging.

Growth hormone deficiency and memory functioning in adults visualized by functional magnetic resonance imaging.

Cognitive functioning, especially memory performance, is known to be impaired in patients with childhood-onset growth hormone deficiency (CO-GHD), and growth hormone substitution has been found to counteract this memory impairment. Neuropsychological and functional magnetic resonance imagining (fMRI) data acquired during a working memory task in 13 childhood-onset GH-deficient patients were compared with 13 age, sex and education level matched healthy controls. Results demonstrated that there is no difference in the quality of the performance in the working memory task between GH-deficient patients and control subjects. However, memory speed was found to be subnormal in patients. Concerning mood, patients reported more complaints of fatigue, and less vigor. Imaging data showed that patients had increased activity in dorsolateral/ventrolateral prefrontal cortex, anterior cingulate cortex, parietal cortex, supplementary motor and motor cortex, as well as in the thalamus and precuneus area. Increasing task load was also associated with an increase in brain activity in similar areas in patients compared to control subjects. In conclusion, this fMRI study shows that GH-deficient patients have a subnormal memory speed, but no impaired quality of memory performance, which may be due to compensatory recruitment of dorsal prefrontal brain regions. These findings indicate that the GH-IGF-1 axis contributes to prefrontal functioning in patients with CO-GHD.

Differential effect sizes of growth hormone replacement on Quality of Life, well-being and health status in growth hormone deficient patients: a meta-analysis.

BACKGROUND: Patients with growth hormone deficiency (GHD) frequently report to suffer from an impaired Quality of Life (QoL) and growth hormone (GH) substitution is found to improve this. However, the same test may be used for measuring QoL, well-being or health status in different studies. QoL has been defined as the subjective appraisal of one's current life based primarily on psychological function. The most important in the appraisal of well-being is mental function and concerning health status patients evaluate physical function as most important. To differentiate the effects of GH replacement on psychological variables in patients with GHD we carried out a number of meta-analyses, classifying questionnaires into instruments measuring QoL, psychological well-being and health status. METHODS: We searched the electronic databases PUBMED and PiCarta from 1985 to 2004. Studies were included that evaluated the effect of GH on patient-reported outcomes in adults with GHD (aged 18 years and above). According to generally accepted definitions we classified the questionnaires as instruments measuring QoL, well-being and health status. By means of meta-analyses the average effect size (d) for QoL, well-being and health status was calculated. RESULTS AND DISCUSSION: Based on open studies GH replacement is found to improve QoL with a small effect size (d = 0.18), well-being with a medium effect size (d = 0.47) and health status with a small effect size (d = 0.26). As the effect size of well-being is most pronounced the generally reported effects of GH replacement on QoL may be overestimated and actually reflect the effect on well-being. CONCLUSION: To get more insight in the specific psychological effects of GH treatment it is recommended that instruments selected for these studies should be more consistently classified as instruments measuring QoL, well-being or health status.

Effects of 10 years of growth hormone (GH) replacement therapy in adult GH-deficient men.

OBJECTIVE: GH-deficient adults have changes in body composition, bone mineral density (BMD) and lipid profile that can be altered by GH substitution. However, long-term data on GH substitution (up to 10 years of follow-up) are limited. DESIGN: The effects of 10 years of GH replacement therapy on BMD, body composition, bone parameters, serum lipids and glucose metabolism were studied. PATIENTS: Twenty-three childhood-onset GH-deficient men (mean age at baseline 28.6 years) were studied during 10 years of GH substitution therapy. A group of 19 age-matched healthy men served as a control group for BMD measurements at baseline and after 10 years. RESULTS: BMD of the lumbar spine increased during the 10 years of GH therapy. Bone markers and BMD in the hip increased during the first 5 years of GH therapy, but were not different from baseline after 10 years. BMD changes over time in the lumbar spine and femoral neck were significantly different in the patients compared to the controls. After 10 years the difference between the groups had decreased, but BMD was still higher in the controls than in the patients. Lipid profile had improved after 10 years of GH therapy, but body mass index (BMI), waist-hip ratio (WHR), fasting glucose and glycosylated haemoglobin (HbA1c) had increased compared to baseline. CONCLUSIONS: This long-term follow-up study found that 10 years of GH substitution in GH-deficient men causes sustained improvements in BMD in the lumbar spine and lipid profile but not in body composition.

Memory performance and the growth hormone/insulin-like growth factor axis in elderly: a positron emission tomography study.

The relationship between the growth hormone/insulin-like growth factor (GH-IGF)-I status and memory performance is studied in 24 elderly males and females, aged 75-85 years. Positron emission tomography (PET) was used to measure differences in regional cerebral blood flow during the performance of a delayed-non-match-to-sample (DNMTS) working memory task. Quality and speed of performance on the DNMTS task were measured separately for the easy items (3, 4 and 5 letters) and difficult items (6, 7 and 8 letters). Results were analyzed in two different groups based on the IGF-I level of the subjects (low or high IGF-I). Error rates on the working memory task were not different, but the high IGF-I group had shorter reaction times on the easy items. The high IGF-I group showed a significantly greater increase in cerebral blood flow in the left premotor cortex (easy items) and left dorsolateral prefrontal cortex (difficult items) compared to the low IGF-I group. It is concluded that elderly with high IGF-I levels are capable of faster working memory performance and increased recruitment of task-associated prefrontal regions.

Long-term growth hormone treatment preserves GH-induced memory and mood improvements: a 10-year follow-up study in GH-deficient adult men.

Growth hormone (GH) replacement therapy with duration of several years is known to be safe and beneficial in GH-deficient adult patients. However, long-term follow-up data on GH substitution, cognition, and well-being are scarce. The purpose of this study was to investigate whether the benefits of GH replacement in psychological functioning found in previous studies lasting up to 2 years are preserved over a 10-year follow-up period. Twenty-three men (mean age at baseline 28.6 years) with childhood-onset GH deficiency were studied during a 10-year period of GH substitution. Memory tasks, mood questionnaires, and IGF-I values were obtained at baseline and after 0.5, 1, 2, 3, 5, and 10 years of GH substitution. Both mood and memory improved during GH therapy. After 6 months of treatment, anxiety and tension were reduced and vigor had improved. Memory improved after 1 year of substitution. These improvements were maintained during the 10-year follow-up period. Higher intra-subject IGF-I levels were associated with better mood (anxiety, tension, vigor). This study shows that 10 years of GH therapy is beneficial in terms of well-being and cognitive functioning in childhood-onset GH-deficient men. It may be concluded that once the decision to start GH treatment has been taken, this may imply that GH therapy has to be continued for a long period to maintain the psychological improvements and to prevent a relapse.