Baseline characteristics and the effects of two years of growth hormone (GH) replacement therapy in adults with GH deficiency previously treated for acromegaly

CONTEXT: The effects of GH replacement in GH-deficient (GHD) adults previously treated for acromegaly are not well known. OBJECTIVE, DESIGN, AND PATIENTS: In this single-center, open-labeled, prospective study, 10 consecutive GHD adults with cured acromegaly (A group) and 10 matched GHD adults with previous nonfunctioning hypopituitary disease (NF group) were included. Comparisons were made at baseline and in the responses in body composition, muscle strength, bone mass, and metabolic indices during 2 yr of GH replacement. RESULTS: At baseline, upper leg local muscle endurance and serum low-density lipoprotein-cholesterol concentration were more impaired in the A group. The A group contained three patients with hypertension, one with diabetes mellitus type 2, and one with hyperlipidemia. The NF group had only one patient with hypertension. There were no significant between-group differences in the responses to the GH therapy. Body composition and serum lipid pattern improved in both groups without any deterioration of glucose homeostasis. At study end, no difference remained between the two groups in any variable. During the 2-yr treatment, one patient had a myocardial infarction and two had cerebral infarctions in the A group, whereas no vascular event occurred in the NF group. CONCLUSIONS: GHD patients with previous acromegaly have an impaired cardiovascular risk profile and decreased local muscle endurance as compared with other GHD patients. Two-year GH replacement eliminated these differences, but vascular events occurred more frequently in the A group. Therefore, GHD patients with cured acromegaly will benefit from GH replacement, but careful monitoring of cardiovascular status is needed.     

Baseline characteristics and the effects of two years of growth hormone replacement therapy in adults with growth hormone deficiency previously treated for Cushing's disease

OBJECTIVE: To determine baseline characteristics and the effects of 2 years of GH replacement therapy on body composition, muscle strength, bone mass, and metabolic indices in GH-deficient (GHD) adults previously treated for pituitary-dependent Cushing's disease. DESIGN: A single-centre, open-labelled, prospective study. PATIENTS: Fifteen consecutive GHD adults previously treated for pituitary-dependent Cushing's disease (CD group) and 15 closely matched GHD adults with previous nonfunctioning hypopituitary disease (NF group) were included. All patients had adult-onset GH deficiency. RESULTS: The mean dose of GH was similar in both study groups during the 2-year treatment. At baseline, diastolic blood pressure was higher, and lumbar (L2-L4) bone mineral density (BMD) was lower, in the CD group than in the NF group. The increase in lean mass in response to GH therapy, as measured by dual-energy X-ray absorptiometry (DEXA), was less marked in the CD group. GH replacement therapy reduced diastolic blood pressure only in the CD group. The patients in the CD group had greater treatment response in lumbar (L2-L4) spine BMD and in isometric and isokinetic knee extension strength than the patients in the NF group. At study end, no difference remained between the two study groups. CONCLUSIONS: This study revealed differences in the baseline characteristics between GHD patients previously treated for Cushing's disease as compared with closely matched GHD patients with previous nonfunctioning hypopituitary disease. The 2-year GH replacement therapy eliminated all the differences between the two study groups.     

Baseline characteristics and effects of growth hormone therapy over two years in younger and elderly adults with adult onset GH deficiency

CONTEXT: The effects of GH replacement in elderly GH-deficient (GHD) adults are not well known. OBJECTIVE/DESIGN/PATIENTS: In this prospective, single-center, open-label study, baseline characteristics and the effects of 2-yr GH replacement were determined in 24 GHD adults above 65 yr of age and in 24 younger GHD patients (mean age, 37 yr; range, 27-46 yr). All patients had adult onset disease, and both groups were comparable in terms of the number of pituitary hormonal deficiencies, gender, body mass index, and waist/hip ratio. Duration of hypopituitarism was, however, longer in the elderly patients. RESULTS: The mean maintenance dose of GH was 0.31 (sem, 0.03) mg/d in the elderly GHD patients and 0.44 (0.04) mg/d in the younger patients. The less marked response in IGF-I sd score, total body fat, and extracellular water in the elderly patients lost significance when the dose of GH was accounted for in the statistical analyses. Despite the lower dose in the elderly GHD group, these patients had a more marked reduction in waist/hip ratio and serum low-density lipoprotein-cholesterol level, and these differences remained also after correction for duration of hypopituitarism. There was no difference at baseline or in responsiveness in lean mass, bone mineral density, and glucose homeostasis. CONCLUSIONS: This study identifies elderly GHD adults as a GH-sensitive group in whom a low dose of GH can improve body composition and serum lipid profile without any significant impairment of glucose metabolism. GH replacement should therefore be considered in elderly GHD adults.     

Amino acid profiles in adults with growth hormone (GH) deficiency before and during GH replacement therapy

ObjectiveGH replacement to growth hormone deficient (GHD) adults improves body composition. In a subset however, lean body mass (LBM) fails to increase despite normalization of IGF-I and amino acid availability could be of importance. We analyzed amino acid (AA) profiles in plasma and erythrocytes (RBC) and associations with LBM, serum IGF-I and IGFBP-1 before and during GH replacement.Design and methodsExaminations were performed in 15 GHD patients (six women), aged 34–61 yrs before and after 12 months of GH therapy and in a control group of 20 healthy males aged 31–68 yrs. LBM was measured by dual energy X-ray absorptiometry (DXA), free AAs in plasma and RBC by high performance liquid chromatography and serum IGF-I and IGFBP-1 by in-house RIAs.SettingTertiary care referral centre.ResultsAt baseline, female GHD patients tended to have lower concentrations of the essential branched – chain AAs isoleucine and leucine, total essential AAs, and of the non-essential AA glutamine than the male patients. Male GHD patients tended to have higher plasma and RBC glutamate than controls. At 12 months, IGF-I had normalized in all but one patient and mean LBM gain was 1.9 ± 0.4 kg. AA levels were unchanged. The change in LBM at 12 months was positively correlated to the ratio between the sum of isoleucine, leucine and valine and baseline LBM kg/m² (r = 0.76, p = 0.001, n = 15).ConclusionOur results suggest that the essential branched-chain amino acids in plasma are important for the LBM response to GH substitution. Our finding has to be confirmed in larger groups of GHD adults before making a proper selection of AAs to be measured in plasma and added as dietary supplement during GH therapy. GH administration did not change AA levels and measurements are not useful for monitoring of GH therapy at the time being.     

Effects of 5 years of growth hormone (GH) replacement therapy on cardiac parameters and physical performance in adults with GH deficiency

The purpose of this study was to evaluate the effects of 5 years of GH substitution on cardiac structure and function, physical work capacity and blood pressure levels in adults with GH deficiency (GHD). Fourteen patients were clinically assessed every 3 months for 5 years. Transthoracic echocardiography and exercise test were performed at baseline, 24, 48 and 60 months. Blood pressure (BP) was measured by means of ambulatory monitoring of blood pressure at baseline, 6, 12, 24 and 60 months. Left ventricular mass and its index increased progressively during the 5 years of GH substitution (P = 0.008 and 0.007, respectively). There were no significant changes in all others cardiac parameters evaluated. It was observed a significant improve in functional capacity (P < 0.001) and maximal oxygen uptake (P = 0.006) during the treatment. Diurnal systolic BP increased by 15 mmHg (P = 0.024) and diurnal diastolic BP by 4.5 mmHg (P = 0.037). There was no change in dirnal systolic pressure load but a considerable but non-statistically significant reduction in diurnal diastolic pressure load was observed during the study. During the night diastolic BP increased by 4 mmHg (P = 0.012) despite a substantial but non-statistically significant reduction in diastolic pressure load. We observed an increase in the proportion of persons with a non-physiological nocturnal fall (non-dippers) throughout the study (from 36.4% at baseline to 54.6% after 60 months of therapy). We concluded that 5 years of GH replacement promoted positive effects on exercise capacity and maximum oxygen uptake in spite of a modest increase in BP levels and left ventricular mass. Continuous monitoring is mandatory to arrive at further conclusions concerning the effects of GH substitution in adults on cardiovascular parameters with respect to possible unfavorable long term effects.     

Congenital growth hormone (GH) deficiency and atherosclerosis: effects of GH replacement in GH-naive adults

BACKGROUND: GH deficiency (GHD) in adults is associated with increased abdominal adiposity and systolic blood pressure, total and low-density lipoprotein cholesterol, and C-reactive protein. METHODS: We have studied the effects of 6-month GH replacement therapy in 20 adult members of a large Brazilian kindred with lifelong severe and isolated GHD due to a homozygous mutation in GHRH receptor gene (46 +/- 14.5 yr; 122 +/- 7.7 cm; 36.7 +/- 5.4 kg; 10 men). Subjects were studied at baseline, after 6-month bimonthly depot GH injections (Nutropin Depot; Genentech, Inc., South San Francisco, CA) [post GH (pGH)], and after 6- and 12-month washout. RESULTS: Despite modest trough serum IGF-I increase, GH replacement therapy caused a decrease in skinfolds and in waist-hip ratio, with a rebound increase at 12 months. Total and low-density lipoprotein cholesterol were reduced pGH and returned to baseline at 6 months. High-density lipoprotein cholesterol increased pGH, but at 12 months was lower than baseline. A progressive increase in left ventricular mass index, posterior wall, and septum thickness occurred from pGH to 12 months, and of carotid intima-media thickness, from 6 to 12 months. Individuals were 6, 16, and 52 times more likely to have an atherosclerotic carotid plaque at pGH, 6 and 12 months, respectively, when compared with baseline. CONCLUSION: In patients with lifetime isolated GHD, 6-month treatment with GH has reversible beneficial effects on body composition and metabolic profile, but it causes a progressive increase in intima-media thickness and in the number of atherosclerotic carotid plaques.     

Epicardial fat thickness significantly decreases after short-term growth hormone (GH) replacement therapy in adults with GH deficiency

Background and AimGrowth Hormone Deficiency (GHD) is characterized by increased visceral fat accumulation. Echocardiographic epicardial fat thickness is a new marker of visceral adiposity. Aim of the present study was to evaluate whether epicardial fat thickness can significantly change and therefore serve as a marker of visceral fat reduction after short-term rhGH replacement therapy in patients with adult-onset GHD.Methods and ResultsEchocardiographic epicardial fat thickness was measured in 18 patients (10 M, 8 F, age 48 ± 11.8 yrs, BMI 29 ± 5.9 kg/m²) with adult-onset GHD, at baseline and after 6 and 12 months of rhGH therapy and in 18 healthy matched controls, at baseline. Echocardiographic epicardial fat thickness, conventional anthropometric and metabolic parameters, body fat percentage and quality of life were also evaluated. Epicardial fat thickness in adult GHD patients was higher than in controls (9.8 ± 2.8 vs 8 ± 3 mm, p < 0.05). Epicardial fat thickness significantly decreased after 6-months of rhGH replacement therapy (from 9.8 ± 2.8 to 7.0 ± 2.3 mm, P < 0.01, i.e. ?29% from baseline). After 12 months of rhGH replacement therapy, epicardial fat thickness showed a further significant decrease (from 7.0 ± 2.3 to 5.9 ± 3.1 mm, P < 0.01, i.e. ?40% from baseline). No significant changes in BMI or waist circumference after 6 or 12 months of rhGH therapy were observed.ConclusionsEchocardiographic epicardial fat thickness may represent a valuable and easy marker of visceral fat and visceral fat changes during rhGH replacement treatment in patients with adult-onset growth hormone deficiency.     

Baseline characteristics and the effects of five years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset: a comparative, prospective study

The consequences of GH deficiency may differ if the disease is childhood onset or adulthood onset. In this single-center, prospective study, 21 consecutive adults with childhood onset GH deficiency and 21 adults with adulthood onset GH deficiency, matched for age, gender, body mass index, and number of anterior pituitary hormonal deficiencies, were included. Baseline differences and differences in the responses in body composition, muscle strength, bone mass, and metabolic indices during 5-yr GH replacement were determined. The duration of GH deficiency was longer and serum IGF-I level and body height were lower in the childhood onset patients than in the adulthood onset patients. Body fat (observed/predicted ratio) was increased, and lean mass and muscle strength were decreased, in the childhood onset patients. Total body and lumbar (L2-L4) bone mineral content and bone mineral density were lower in the childhood onset patients. Serum total cholesterol level was higher in the adulthood onset patients. The childhood onset and adulthood onset patients received a similar dose of GH. After adjustment for body weight, however, the dose of GH was higher in the childhood onset patients. The treatment responses were more marked in the childhood onset patients in lean mass, knee extensor strength, left-hand grip strength, and in total body and lumbar (L2-L4) bone mineral content and bone mineral density. The reduction in serum total cholesterol concentration was more marked in the adulthood onset patients. At study end, no differences remained between the two study groups after the correction for body height in the statistical analysis. In conclusion, the baseline analysis suggests more decreased lean mass, muscle strength, and bone mass in the childhood onset patients whereas the lipid profile was more disturbed in the adulthood onset patients. The 5-yr GH replacement eliminated all the anthropodometric and metabolic differences between the two groups.     

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.     

Short- and long-term effects of growth hormone (GH) replacement on protein metabolism in GH-deficient adults

Reduced fat-free mass (FFM) in GH-deficient (GHD) adults is improved by GH replacement, but the protein metabolic changes are unclear. Using iv [(2)H(3)]leucine and oral l-[(13)C(1)]leucine infusions and dual emission x-ray absorptiometry, we compared leucine kinetics and body composition in eight GHD adults and eight healthy controls in the fasted and fed states, before and after 2 wk and 6 months of GH replacement. Leucine kinetics were not different between pretreatment GHD subjects and controls. After 2 wk of GH treatment, leucine oxidation decreased in the GHD subjects compared with baseline values [fasted, 41 +/- 6 vs. 30 +/- 5 micromol/kg FFM.h (P < 0.01); fed, 49 +/- 3 vs. 41 +/- 3.6 micromol/kg FFM.h (P < 0.05)], leucine balance improved [fasted, -14 +/- 4 vs. -3.5 +/- 3 micromol/kg FFM.h (P < 0.01); fed, 65 +/- 10 vs. 72 +/- 7 micromol/kg FFM.h (P = 0.07)], and protein synthesis increased [fasted, 116 +/- 5 vs. 131 +/- 6 micromol/kg FFM.h (P < 0.05); fed, 103 +/- 6 vs. 116 +/- 6 micromol/kg FFM.h (P < 0.05)]. After 6 months of GH treatment, these changes were not maintained in the fed state. The five GHD subjects with decreased FFM at baseline showed a significant increase after 6 months of GH treatment (P < 0.05). GH replacement in GHD acutely improves protein balance by stimulating synthesis and inhibiting catabolism. After 6 months, protein kinetics reached a new homeostasis to maintain the net gain in FFM.     

Long-term effects of growth hormone (GH) replacement in men with childhood-onset GH deficiency.

Short term GH replacement therapy has been shown to improve body composition and exercise capacity. It is not yet known whether GH replacement remains beneficial over the long term. We assessed the effects of long term GH replacement on body composition, bone mineral density, and cardiac function. Thirty-eight men with childhood-onset GH deficiency were studied for a period of 3-5 yr. Measurements included anthropometry, computed tomographic scanning of abdomen and upper leg, bone densitometry, echo cardiography, and bicycle ergometry. The initial GH dose of 1-3 IU/m2 x day (9-27 microg/kg) was gradually tapered to 1.30+/-0.38 IU/m2 x day (11 g/kg), aiming at physiological insulin-like growth factor I levels. During the study, leg muscle mass progressively increased by 28.7% (P<0.001). Subcutaneous and intraabdominal fat decreased by 30.9% and 46.0%, respectively, after 1 yr (both P<0.001), but demonstrated a partial regain thereafter. Bone mineral density at the lumbar spine, femoral neck, and trochanter gradually increased by 9.6%, 11.1%, and 16.2%, respectively (all P<0.001). Left ventricular mass exceeded baseline values by 14.1% after 1 yr (P<0.001), but returned to pretreatment values thereafter. Stroke volume and cardiac output increased by 16.3% (P = 0.002) and 33.4% (P<0.001), respectively. Maximal work load increased from 189+/-30 to 232+/-41 watts (P<0.001). Thus, long term GH replacement is safe and beneficial. It improves cardiac performance without inducing left ventricular hypertrophy and progressively increases bone mineral density.     

Baseline characteristics and response to 2 years of growth hormone (GH) replacement of hypopituitary patients with GH deficiency due to adult-onset craniopharyngioma in comparison with patients with nonfunctioning pituitary adenoma: data from KIMS (Pfizer International Metabolic Database)

OBJECTIVE: In epidemiological studies, hypopituitary adults show increased mortality compared with population controls. Patients with hypopituitarism caused by a craniopharyngioma (CP) and/or its treatment have a higher mortality than patients with other etiologies, such as a nonfunctioning pituitary adenoma (NFPA). To analyze this difference, we used the KIMS database (Pfizer International Metabolic Database) comparing CP and NFPA patients in terms of baseline characteristics and responses to GH replacement. PATIENTS: Baseline characteristics were studied in 351 CP patients (189 men and 162 women; mean age, 42.5 yr) and compared with 370 NFPA patients, matched for age and sex (185 men and 185 women; mean age, 42.5 yr). The effects of 2 yr of GH replacement were analyzed in a subgroup of 183 CP and 209 NFPA patients. RESULTS: At baseline, both CP and NFPA patients had characteristic features of GH deficiency, with low serum IGF-I, increased body fat, dyslipidemia, and reduced quality of life. Male CP patients were significantly more obese (30.0 vs. 28.2 kg/m2; P = 0.0003) compared with NFPA patients, had a higher waist/hip ratio (P = 0.004), higher triglycerides (P = 0.003), and lower high-density lipoprotein cholesterol (P = 0.03). Similar, but much smaller, differences were seen in female CP compared with NFPA patients, only reaching significance for waist/hip ratio (P = 0.05) and triglycerides (P = 0.0004). CP patients had more often undergone surgery by the transcranial route (68.8% vs. 30.9%; P < 0.0001), and panhypopituitarism was more prevalent in CP than in NFPA patients (58.7% vs. 19.8%; P < 0.0001). The incidence of previous fractures, hypertension, coronary heart disease, claudication, and diabetes mellitus was high, but not different, between CP and NFPA patients. After 2 yr of GH replacement therapy, similar significant improvements were evident in both groups in fat-free mass, total and low-density lipoprotein cholesterol, and Quality-of-Life-Assessment in GH Deficient Adults score compared with baseline. In contrast to NFPA patients, CP patients had no significant decrease in body fat with GH therapy. CONCLUSIONS: In the KIMS database, patients with CP have more often undergone surgery by the transcranial route than patients with NFPA, have a higher prevalence of pituitary deficiencies, are more obese (predominantly males), and have more dyslipidemia. This could provide an explanation, at least in part, for the higher mortality rate in CP patients observed in epidemiological studies. CP patients respond equally well to GH therapy in fat-free mass, lipids, and quality of life, but are less likely to lose body fat. We assume that this difference in response merely reflects the stronger tendency of CP patients to accumulate fat over time.