One-year follow-up of quality of life in adults with untreated growth hormone deficiency

OBJECTIVE: The aim of the study was to evaluate the impact on health-related quality of life (HRQoL) in untreated GHD patients using the disease-specific Assessment of Growth Hormone Deficiency in Adults (AGHDA) questionnaire. DESIGN AND PATIENTS: A cohort of 356 consecutive adult GHD patients, diagnosed after the age of 18 years, from the endocrinology units of 37 Spanish hospitals were included over a 6-month period in a longitudinal observational quality-of-life study. In addition, patients' HRQoL scores were compared to those obtained from a random sample of 963 subjects from the general population recruited by trained interviewers in a 6-month period and matched by age and sex to figures of the 1991 Spanish census. MEASUREMENTS: Patients were evaluated at baseline and after 12-months. Socio-demographic and health variables such as age, sex, level of education, income level, number of chronic diseases and self-reported health status were recorded at baseline and follow-up visits. Patients underwent physical and analytical examination and completed the AGHDA questionnaire. A survey including socio-demographic, self-reported health status and the AGHDA questionnaire was administered at the individuals' homes. RESULTS: Mean score for patients at baseline was 9.4 (CI = 8.4-10.4) and at 12 months 10 (CI = 8.8-11). HRQoL was worse in the case of older patients with a low level of education, lower income levels, reporting having an associated chronic disease and poor self-reported health status (P < 0.01). Untreated GHD patients maintain or slightly worsen their HRQoL after 12 months of follow-up, with high individual variability. Although AGHDA scores worsened during the observation period, differences were not statistically significant. AGHDA mean score in controls was 5.49 (CI = 5.27-5.71). Comparison of the mean AGHDA scores between patients and controls previously standardized by level of education and age were statistically different (P < 0.01), indicating that patients declared a worse HRQoL than the general population except for those aged 60-69 years. GHD patients presented a deterioration in HRQoL almost double that of the general population. CONCLUSIONS: These results permit comparison of patients' scores against reference scores with regard to the desirable effect of treatment. Future use of the AGHDA questionnaire in clinical trials should try to establish a relationship between biological and HRQoL changes.     

The effects of 12 months of growth hormone replacement therapy on cardiac autonomic tone in adults with growth hormone deficiency

OBJECTIVES: Growth hormone deficiency (GHD) in adults is associated with a cluster of cardiovascular risk factors. Some abnormalities of cardiac structure and function have been reported in adult patients with GHD, but there are few data related to cardiac autonomic tone. Non-invasive assessment of cardiac autonomic status can be achieved by heart rate variability (HRV), which can be measured by using time-domain or frequency-domain variables. To our knowledge, short-term (6 months) effects of GH replacement therapy (GHRT) on HRV in a limited number of patients have been evaluated prospectively in only two previous studies. The present study was therefore designed to investigate the effects of GHD and 12 months of GHRT on cardiac autonomic tone in a larger number of adult patients with severe GHD. PATIENTS AND METHODS: HRV measurement, by using time-domain variables, was performed in 22 patients with GHD (eight men, 14 women; mean age 45.4 +/- 2.4 years) and 22 healthy controls (nine men, 13 women; mean age 40.8 +/- 1.8 years) at baseline. The time-domain variables (sympathetically influenced parameters SDNN and SDANN and parasympathetically influenced parameters RMSSD and PNN50) were derived from 24-h electrocardiogram (ECG) recordings. In the patient group, cardiac autonomic tone was re-evaluated after 6 and 12 months of GHRT. RESULTS: Mean baseline values of SDNN and SDANN were significantly higher (higher values mean lower sympathetic activity) in GHD patients than in healthy controls (P < 0.05), but mean baseline values of RMSSD and PNN50 did not differ significantly in healthy controls and patients. After 6 and 12 months of GHRT, mean SDNN and SDANN were decreased significantly when compared with the baseline values before GHRT (P < 0.05). However, mean RMSSD and PNN50 did not differ significantly from baseline. When SDNN and SDANN measurements were evaluated individually for each patient, after 12 months of GHRT both of the sympathetically influenced parameters decreased in 90% of the patients. CONCLUSIONS: These data indicate that sympathetic tone is decreased in adult patients with severe GHD. Additionally, an increment in sympathetic activity and normalization of sympathovagal balance have been demonstrated after 6 and 12 months of GHRT. This result suggests that, at least at the doses used in this study, GHRT improves sympathetic tone, without an obvious arrhythmogenic effect.     

Effect of growth hormone replacement on bone mass in adults with adult onset growth hormone deficiency

OBJECTIVE Previous studies of the effect of GH replacement on bone mass in adults with GH deficiency have produced conflicting results. We have studied the effect of 6 and 12 months of GH replacement on bone mass in adults with adult onset GH deficiency. DESIGN Double blind placebo controlled study of GH replacement (0.125 IU/kg/week for the first month and 0.25 IU/kg/week thereafter) for 6 months and an open study for a further 6 or 12 months. PATIENTS Twenty-two adults (10 men, 12 women), aged 41.5±2.1 years (mean ± SE, range 23.6–59.5), with adult onset GH deficiency. MEASUREMENTS Single-energy quantitative computed tomography was used to measure vertebral trabecular bone mineral density (BMD), single-photon absorptiometry (SPA) was used to measure forearm cortical and integral bone mineral content and BMD and dual-energy X-ray absorptiometry (DXA) was used to measure lumbar spine, femoral neck, trochanteric and Ward's triangle Integral BMD. RESULTS After 6 months of GH replacement (n=21) there was a significant decrease In forearm cortical BMD (SPA: median change ?0.009g/cm², P=0.01), forearm Integral BMD (SPA: median change ?0.016g/cm², P=0.03), lumbar spine BMD (DXA: median change ?0.022g/cm²; P=0.003) and femoral neck BMD (DXA: median change ?0.029g/cm², P=0.006). After 12 months of GH replacement (n=13) there was a significant decrease in lumbar spine BMD (DXA: median change ?0.035 g/cm², P=0.002) from baseline. There was no significant Increase in bone mass at any site after 6 or 12 months of GH replacement. Change In bone mass was not influenced by sex of the patient or by presence or absence of additional pituitary hormone deficiencies. CONCLUSION The response of bone mass to 6 and 12 months of GH replacement in adults with adult onset GH deficiency is disappointing. Longer-term studies are required to determine whether prolonged GH replacement has a beneficial effect on bone mass.     

The influence of growth hormone replacement on heart rate variability in adults with growth hormone deficiency

OBJECTIVE: Growth hormone (GH) deficiency is associated with increased cardiovascular morbidity and mortality. Abnormalities in heart rate variability (HRV), a surrogate marker of cardiac autonomic tone, have also been found in untreated growth hormone deficient (GHD) patients. Similar abnormalities have been found in patients with complications postmyocardial infarction. DESIGN AND MEASUREMENTS: This study was designed to investigate whether GH treatment leads to normalization of cardiac autonomic tone. HRV measurements were obtained from 15 minute resting ECG recordings in 11 untreated adult GHD patients (7 females; mean age 39.2 years), 10 GHD patients (6 females; mean age 46.2 years) reCENving GH replacement (mean duration, 52.7 months) and 12 healthy controls (7 females; mean age 44.6 +/- 2.9 years) who were all of similar age, weight and BMI. The untreated GHD patients were then commenced on GH and HRV measurements repeated after 3 and 6 months of treatment. RESULTS: In accord with our previous findings, HRV analysis using Fast Fourier Transform (FFT) showed a distinct pattern of abnormality in GHD patients compared with controls. Specifically, there was an increase in nHF power (P = 0.04) and a reduction in nLF power (P = 0.04) (representing parasympathetic and sympathetic activity, respectively), a reduction in nVLF power (P = 0.03) and a 50% reduction in LF/HF ratio (P = 0.02) (a measure of sympathovagal balance) in GHD patients when compared with controls. HRV results in patients who have been on long-term GH replacement were indistinguishable from controls. After 3 months GH replacement in the untreated GHD patient group, nVLF power had increased by 28% (P = 0.03) at 3 months and this was sustained at 6 months. However, no significant changes in LF and HF power were seen. CONCLUSIONS: These results suggest that abnormalities of the cardiac autonomic system in GHD patients may be correctable. Longer duration of prospective follow-up will be required to determine at what time point improvements in the other frequency bands occur.     

Growth hormone replacement therapy in adults with growth hormone deficiency improves vascular reactivity.

OBJECTIVE: Patients with adult growth hormone (GH) deficiency are thought to be of increased risk of cardiovascular disease. Impaired vascular reactivity to endothelium derived nitric oxid (NO) is an early event in the development of atherosclerosis. In order to detect a possible effect of GH on vascular endothelium we examined forearm vasodilator responses in 8 patients with adult GH-deficiency before and after 3 months GH replacement therapy. METHODS: Forearm blood flow studies were performed using venous occlusion plethysmography. Blood flow was measured at baseline and during intra-arterial infusions of 3 cumulative doses (7.5, 15 and 30 microg/minutes) of acetylcholine chloride and of sodium nitroprusside (1, 3 and 10 microg/minutes). Fasting blood samples were collected for measurement of lipid profile, Haemoglobin A1C (HbA1C), glucose, IGF-I and insulin. RESULTS: GH replacement therapy significantly increased IGF-I concentrations and tended to increase fasting insulin concentrations (IGF-I: 72.7 +/- 12.4 vs. 130.8 +/- 18.5 microg/l, P < 0.001; fasting insulin: 14.3 +/- 3.4 vs. 32.9 +/- 18.6, mU/l, P = 0.06). Fasting lipid profile, glucose and HbA1C did not significantly change. Blood flow responses to acetylcholine were significantly greater after GH replacement therapy (10.3 +/- 1.0 vs. 17.6 +/- 2.5 ml/minutes/100 ml for the highest dose, P < 0.03). There was a strong tendency to increased blood flow response to nitroprusside after GH therapy (10.7 +/- 1.2 vs. 17.5 +/- 1.7 ml/minutes/100 ml for the highest dose, P = 0.06). CONCLUSION: These findings suggest that GH replacement therapy may have a beneficial effect on endothelium function which is independent of quantitative changes in fasting lipid profile.     

The influence of long-term growth hormone replacement therapy on body composition, bone tissue and some metabolic parameters in adults with growth hormone deficiency

A syndrome of growth hormone deficiency in adults (GHDA) is a syndrome characterised by metabolic deviations, body composition abnormalities, fatigue, decreased quality of life and some cardiovascular changes. The aim of the study was to assess the influence of the growth hormone (GH) replacement therapy on body composition, bone changes, serum lipids levels and some parameters of sugar metabolism in the course of 7-year monitoring. We followed 34 individuals of mean age of 41.73 +/- 2.49 years (mean +/- SE). Severe deficiency of GH was demonstrated by performing stimulation insulin tolerance test. Duration of treatment was 4.13 +/- 0.36 years (mean +/- SE). Patients were examined before the initiation of replacement therapy, after 6 months and further in yearly visits. To determine a statistical level of significance in individual parameters we compared initial baseline status (before drug administration) with the status in individual time intervals. The body composition was examined by anthropometric methods, bioelectric impedance and by densitometry, bone changes were examined by means of DEXA. There were no statistically significant changes of weight, but the waist circumference significantly decreased (p < 0.05), as well as the sum of skinfold thickness (p < 0.05) within the whole treatment period. The percentage of body fat mass measured by the BIA method was significantly changed after the period of 3 years (p < 0.05). Upon the densitometrical measurement of the body composition a significant decrease in kilograms of body fat mass (FM) occurred in the first year of the treatment (p < 0.05) and an increase in lean body mass (LBM) in kilograms during our complete monitoring (p < 0.05). A statistically significant increase in bone density was found in the whole-body BMD and BMC after the first year of the treatment. In the examination of peripheral bone changes a statistically significant increase in BMD occurred (expressed as a Z score) in the area of proximal femur after the first year and collum femoris after three years (p < 0.05), there was a significant increase in BMD of the lumbar spine already after one year of the treatment (p < 0.05) and changes were significant also in further four years. There were found no statistically significant changes related to the sugar metabolism. In the field of lipid metabolism a decrease of total and LDL cholesterol occurred already after a half of the year of the treatment (p < 0.05), changes were significant also in further four years. HDL cholesterol levels have had a progressive tendency, but they were not statistically significant. Positive changes of body composition, an increase in bone density and a decrease of total and LDL cholesterol were demonstrated in the course of the growth hormone replacement therapy.     

Growth hormone replacement in adults with growth hormone deficiency: assessment of current knowledge.

The recent availability of recombinant human growth hormone (GH) has led to intense investigation of the consequences of adult GH deficiency (GHD) and the effects of GH replacement. These studies have led to the identification of a characteristic syndrome of GHD consisting of decreased mood and well-being, with alterations in body composition and substrate metabolism. In both placebo-controlled and open studies, GH replacement therapy has consistently been shown to reverse or correct these features. Whether long-term GH replacement will result in a reduction of osteoporotic fractures, cardiovascular morbidity and mortality is not yet known. To date, no permanent serious adverse effects have been associated with GH replacement in GHD, and although currently expensive, it is anticipated that GH replacement will become routine in the treatment of the severely hypopituitary adult.     

Cardiovascular effects of prolonged growth hormone replacement in adults

Abstract. Objectives . To study the cardiovascular effects of human growth hormone (GH) replacement therapy in adults. Intervention . Biosynthetic human GH given in a daily dose of 0.04 ± 0.01 IU kg^?1 for 6–18 months in an open trial. Patients . Thirty-four GH-deficient hypopituitary patients on conventional replacement therapy, aged 19–67 years and with a body mass index of 18.0–410.0 kg/m². Measurements . Resting blood pressure, exercise tolerance, renal function and routine blood counts were assessed every 6 months. Two-dimensional echocardiography and Doppler ultrasound scanning were performed at 0, 6 and 12 months of GH therapy. Results . Exercise time increased significantly on GH from 9.37 ± 2.64min at the start to 10.39 ± 2.86 min (P < 0.001), 10.90 ± 2.48 min (P < 0.001) and 11.11 ± 0.70 min (P < 0.001) at 6, 12 and 18 months respectively. There was no change in the heart rate or in the blood pressure at rest nor at the peak of exercise. No significant changes were observed in measures of cardiac structure (left ventricular mass index, left ventricular posterior wall thickness and interventricular septal thickness), ejection fraction nor in cardiac output. Isovolumic relaxation time, a marker of diastolic function, decreased in 24 patients after 6 months on GH (from 98.6 ± 15.9 to 89.6 ± 15.2 ms; P < 0.03) but it was not different from baseline in the 18 patients who were restudied at 12 months. There was no significant change in the left ventricular filling neither at 6 nor at 12 months. No significant changes were observed in plasma electrolytes, creatinine nor in blood count on GH treatment. Conclusions . Growth hormone replacement therapy in hypopituitary adults for 6–18 months produced sustained increase in exercise tolerance but was not associated with changes in cardiac structure or systolic function.     

Psychological effects of withdrawal of growth hormone therapy from adults with growth hormone deficiency

OBJECTIVE: Growth hormone (GH) is known to be required for physical well-being. Although it is also widely believed to be important for quality of life (QoL) and psychological health, there is less supportive evidence. The objective of this study was to investigate the psychological effects of discontinuation of GH replacement from adults with severe GH deficiency (GHD). DESIGN: A double-blind, placebo-controlled trial in which GH replacement therapy was discontinued for 3 months from 12 of 21 GH-deficient adults, where nine continued with GH replacement. PATIENTS: GH-treated adults (10 men, 11 women), all with severe GHD (peak GH < 7.7 mU/l on provocative testing), mean age 44.9 years (range 25-68 years). MEASUREMENTS: Semi-structured interviews were given at baseline and end-point plus questionnaires that included a new hormone-deficiency specific, individualized, QoL questionnaire (HDQoL), the General Well-being Index (GWBI), the Well-being Questionnaire (W-BQ12), the Short-Form 36 health status questionnaire (SF-36), the Nottingham Health Profile (NHP) and the General Health Questionnaire (GHQ). RESULTS: Three months after baseline the serum total IGF-I of placebo-treated patients fell from normal, age-related levels (mean 26.6 +/- 13.2 nmol/l) to levels indicative of severe GHD (11.6 +/- 6.6 nmol/l) (P<0.001). Psychological symptoms of GH withdrawal, reported in interviews at end-point by placebo-treated patients, included decreased energy, and increased tiredness, pain, irritability and depression. Patients who believed they knew which treatment they had received correctly identified the treatment (GH or placebo) at end-point (chi2=11.25, P<0.01). Significant between-treatment-group differences in change scores were found for SF-36 General Health (P<0.01), W-BQ12 Energy (P<0.01) and HDQoL do physically (P<0.05), indicating reduced general health, reduced energy and greater perceived impact of hormone deficiency on physical capabilities in the placebo-treated group at end-point relative to GH-treated patients. CONCLUSION: Withdrawal of GH treatment from adults with severe GH deficiency has detrimental psychological effects.