Effects of 3-year GH replacement therapy on bone mineral density in younger and elderly adults with adult-onset GH deficiency.

OBJECTIVE: Little is known of the effects of long-term GH replacement on bone mineral content (BMC) and bone mineral density (BMD) in elderly GH-deficient (GHD) adults. DESIGN/PATIENTS/METHODS: In this prospective, single-center, open-label study, the effects of 3-year GH replacement were determined in 45 GHD patients >65 years and in 45 younger control GHD patients with a mean age of 39.5 (S.E.M. 1.1) years. All patients had adult-onset disease and both groups were comparable in terms of number of anterior pituitary hormonal deficiencies, gender, body mass index, and waist:hip ratio. RESULTS: The mean maintenance dose of GH was 0.24 (0.02) mg/day in the elderly patients and 0.33 (0.02) mg/day in the younger GHD patients (P<0.01). The 3 years of GH replacement induced a marginal effect on total body BMC and BMD, whereas femur neck and lumbar (L2-L4) spine BMC and BMD increased in both the elderly and the younger patients. The treatment response in femur neck BMC was less marked in the elderly patients (P<0.05 vs younger group). However, this difference disappeared after correction for the lower dose of GH in the elderly patients using an analysis of covariance. There were no between-group differences in responsiveness in BMC or BMD at other skeletal locations. CONCLUSIONS: This study shows that GH replacement increases lumbar (L2-L4) spine and femur neck BMD and BMC in younger as well as elderly GHD patients. This supports the notion that long-term GH replacement is also useful in elderly GHD patients.

Effect of surgery on cardiac structure and function in mild primary hyperparathyroidism.

CONTEXT: The cardiovascular (CV) risk profile is worsened in primary hyperparathyroidism (PHPT), and CV mortality is related to serum calcium levels. It is unknown whether CV mortality is increased in the most common form of PHPT and whether the increased CV risk is reversible after surgery. OBJECTIVE: To investigate reversibility of echocardiographic variables in patients with mild PHPT who were randomized to observation without surgery or operation, and followed for 2 years. DESIGN/SETTING/PATIENTS: Forty-nine patients (mean age 63 ± 7 years, 8 men) who had performed the 2-year visit in a randomized study on mild PHPT (serum calcium at baseline 2·65 ± 0·09 mm) (observation) vs 2·67 ± 0·06 mm (surgery) and where echocardiography had been performed, participated in the study. RESULTS: Calcium and parathyroid hormone (PTH) levels were normalized following surgery and were stable in the observation group. PTH levels at baseline were highly correlated with ventricular mass. Detailed echocardiography revealed a minor and borderline significant treatment effect of surgery on left ventricular mass index (LVMI) compared to observation (P = 0·066) and a significant 11% reduction in diastolic dimension of the interventricular septum (IVSd-mean) in the surgery group (P<0·01), with no alterations in the observation group. CONCLUSIONS: Based on detailed echocardiographic measures over a 2-year observation period, we found only minor differences between the two groups. However, the potential treatment effect on LVMI and the within-group differences in IVSd-mean suggest that longer follow-up may yield larger and clinically important differences.

Increased neck soft tissue mass and worsening of obstructive sleep apnea after growth hormone treatment in men with abdominal obesity.

BACKGROUND: Risk factors for obstructive sleep apnea (OSA) are male gender, obesity and abnormalities in neck soft tissue mass. OSA is associated with both growth hormone (GH) excess and severe GH deficiency in adults. Adults with abdominal obesity have markedly suppressed GH secretion. AIM: To study the effect of GH treatment on OSA in abdominally obese men with impaired glucose tolerance. PATIENTS AND METHODS: Forty men with abdominal obesity and glucose intolerance were randomized in a prospective, 12-month double-blind trial to receive either GH or placebo. The treatment groups had similar BMI and waist circumference. Overnight polysomnography and computed tomography to assess muscle and fat distribution in the neck and abdomen were performed at baseline and after 12 months. RESULTS: GH treatment increased insulin-like growth-factor-1i from (mean [SD]) 168 (72) to 292 (117) microg/L, the apnea-hypopnea index from (n/h) 31 (20) to 43 (25) and oxygen-desaturation index from (n/h) 18 (14) to 29 (21) (p = 0.0001, 0.001, 0.002). Neck transverse diameter, circumference and total cross-sectional area (p = 0.007, 0.01, 0.02) increased, while abdominal visceral adipose tissue (p = 0.007) was reduced. No between-group differences in total sleep time, REM sleep, NREM sleep, and time spent in supine position were found. The Epworth sleepiness scale score was unchanged. CONCLUSIONS: GH treatment increased the severity of OSA in abdominally obese men. The possible mechanism appears to be reflected by the GH-induced increase of measures of neck volume. The present results, to some extent, argue against that low GH/IGF-I activity is a primary cause of OSA in abdominally obese men.

Effect of surgery on cardiovascular risk factors in mild primary hyperparathyroidism.

CONTEXT: Mild primary hyperparathyroidism (pHPT) seems to have a good prognosis, and indications for active treatment (surgery) are widely discussed. The extraskeletal effects of PTH, such as insulin resistance, arterial hypertension, and cardiovascular (CV) risk, may however be reversible by operation. OBJECTIVE: Our aim was to study biochemical markers of bone turnover, indices of the metabolic syndrome, and various risk markers for CV disease in patients with mild pHPT randomized to observation without surgery or operative treatment and followed for 2 yr. DESIGN/SETTING/PATIENTS: A total of 116 patients (mean age, 63 +/- 8 yr; 19 men and 97 women) who on May 1, 2008, had performed the 2-yr visit in a randomized study on mild pHPT (serum calcium at baseline, 2.69 +/- 0.11 mmol/liter) and where frozen samples were available from baseline and follow-up participated in the study. RESULTS: Calcium and PTH levels were normalized after surgery, and biochemical markers of bone turnover decreased by 35%, followed by a significant increase in BMD in the spine (2.7%; P < 0.01) and femoral neck (1.1%; P < 0.02) compared with the observation group. No significant differences were observed between the groups for blood pressure, markers of insulin resistance, detailed cholesterol metabolism, adipokines, or parameters of inflammation and CV surrogate markers. CONCLUSIONS: We observed expected effects on biochemical markers of bone turnover and bone mass after surgical treatment of mild pHPT, with stable values in the group randomized to observation. For a variety of measures of the metabolic syndrome, adipokines, and CV risk factors, no benefit of operative treatment could be demonstrated. Neither did we observe any deleterious effects of conservative management in the 2-yr perspective.

The reduction in visceral fat mass in response to growth hormone is more marked in men than in oestrogen-deficient women.

CONTEXT: Women with severe growth hormone (GH) deficiency have a less marked response to GH replacement than men. This has mostly been attributed to the attenuating effects of oestrogen replacement therapy. OBJECTIVE: To study gender related differences in the response to GH treatment in men and postmenopausal women. METHODS: Fifteen men and 15 age- and BMI-matched women with abdominal obesity (mean age: 58; range 51-64 years) were treated for one year with similar doses (0.47 vs. 0.51 mg/day) of GH. All women were postmenopausal not receiving oestrogen treatment. Insulin sensitivity was assessed using a hyperinsulinemic euglycemic clamp and body composition by computed tomography (CT) scans and from total body potassium, K(40). RESULTS: Men and women were comparable at baseline in terms of waist circumference, IGF-1 and lipid levels. After one year of GH treatment, there was a 18% reduction in visceral adipose tissue (VAT) in men and a 5% reduction in women (P=0.0001 men vs. women). Although the magnitude of the difference was small, men increased more in thigh muscle mass (P<0.0001 vs. women). A reduction in thigh intermuscular adipose tissue (IMAT) and diastolic blood pressure was seen only in men (both p<0.05 vs. baseline). A decrease in LDL cholesterol, and an increase in serum insulin, was observed only in women (both p<0.05 vs. baseline). CONCLUSION: Low dose GH treatment reduced VAT more markedly in men as compared with women. As all women were postmenopausal and oestrogen-deficient, this gender difference in responsiveness was not due to an antagonistic effect of oestrogen on peripheral GH action.

Growth hormone reduces inflammation in postmenopausal women with abdominal obesity: a 12-month, randomized, placebo-controlled trial.

CONTEXT: Abdominal obesity is associated with low GH secretion, elevated circulating markers of inflammation, and increased risk of cardiovascular disease. OBJECTIVE: The objective was to study the effect of GH treatment on inflammatory markers and vascular adhesion molecules in postmenopausal women with abdominal obesity. DESIGN: Forty women aged 51-63 yr received GH (0.67 mg/d) in a randomized, double-blind, placebo-controlled, 12-month trial. Measurements of inflammatory markers [highly sensitive C-reactive protein (CRP), IL-6, and amyloid polypeptideA] and markers of endothelial dysfunction (soluble E-selectin, vascular adhesion molecule-1, intercellular molecule-1, and matrix metalloproteinase-9) were performed at baseline and after 6 and 12 months of treatment. RESULTS: After 12 months, the mean IGF sd score was 0.9 +/- 1.5 and -0.8 +/- 0.6 in the GH and placebo groups, respectively. GH treatment reduced CRP and IL-6 levels compared with placebo (P = 0.03 and P = 0.05, respectively), whereas the markers of endothelial dysfunction were unaffected. Within the GH-treated group, a reduction was shown in CRP (4.3 +/- 4 to 3.0 +/- 3 mg/liter; P < 0.05) and in IL-6 (4.4 +/- 2 to 3.3 +/- 2 ng/liter; P < 0.01). In the GH-treated group, the decrease in CRP and IL-6 correlated with a reduction in visceral adipose tissue (r = 0.7, P < 0.001 and r = 0.5, P < 0.05, respectively). CONCLUSION: GH treatment in postmenopausal women with abdominal obesity reduced serum markers of systemic inflammation. Circulating markers of endothelial dysfunction were unaffected by treatment.

Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial.

CONTEXT: The clinical presentation of primary hyperparathyroidism (pHPT) has changed during the last half century, and the diagnosis is now more often made by chance in patients with no specific symptoms. OBJECTIVE: The present study is a randomized, controlled trial that investigates the effects of parathyroidectomy or medical observation in mild asymptomatic pHPT on morbidity and quality of life (QoL). DESIGN/SETTING/PATIENTS: A total of 191 patients (26 men) with asymptomatic pHPT [mean age 64.2 +/- 7.4 (sd) yr] were recruited in the study and randomized to medical observation (serum calcium level 2.69 +/- 0.08 mmol/liter) or surgery (2.70 +/- 0.08 mmol/liter). We here report baseline and 1 (n = 119) and 2 yr data (n = 99) on those who had completed the follow-up visits by the end of the inclusion period. RESULTS: At baseline, the patients had significantly lower QoL (SF-36) and more psychological symptoms, compared with age- and sex-matched healthy subjects. The two groups were similar at baseline, and no clinically significant changes in these parameters were seen during the observation time. Calcium and PTH normalized after surgery. The areal bone mineral density increased in the group randomized to operation, whereas the bone mineral density remained stable in the medical observation group. No change in kidney function (creatinine) or blood pressure was observed longitudinally or between the groups. CONCLUSIONS: Asymptomatic patients with mild pHPT have decreased QoL and more psychological symptoms than normal controls. No benefit of operative treatment, compared with medical observation, was found on these measures so far.

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.

Thigh intermuscular fat is inversely associated with spontaneous GH release in post-menopausal women with abdominal obesity.

CONTEXT: The metabolic syndrome is characterized by an increased accumulation of visceral adipose tissue (VAT) and blunted GH secretion. There are, however, no data on the association between GH secretion and other fat depots (in liver and muscle). OBJECTIVE/DESIGN: The aim of this cross-sectional study, which included 20 post-menopausal women with abdominal obesity, was to determine the association between GH secretion and regional adipose tissue (AT) distribution. Twelve-hour GH profiles (2000-0800 h) were performed by blood sampling every 20 min. GH was analyzed using an ultra-sensitive assay followed by approximate entropy (ApEn) and deconvolution analysis. RESULTS: In simple regression analyses, both basal and pulsatile GH secretions correlated negatively with VAT and thigh intermuscular adipose tissue (IMAT), but not with hepatic fat content. There was no correlation between ApEn and the AT depots studied. In multiple regression analysis, pulsatile GH secretion correlated inversely with thigh IMAT (B-coefficient=-0.67; P<0.01), whereas the correlation with VAT became non-significant. Furthermore, in multiple regression analysis, basal GH secretion correlated negatively with VAT (B-coefficient=-0.77; P=0.001), but not significantly with thigh IMAT. CONCLUSION: In post-menopausal women with abdominal obesity, pulsatile GH secretion demonstrated an independent, negative association with thigh IMAT, whereas basal GH secretion showed an independent, negative association with VAT. These findings suggest that the neuroendocrine association between fat mass and somatotropic axis is depot-dependent. We have identified thigh IMAT to be important in this interplay.

The GH/IGF-1 Axis in Obesity: Physiological and Pathological Aspects.

The cluster of cardiovascular risk factors-abdominal obesity, dyslipidaemia, insulin resistance and hypertension-has been recognized as the core of the metabolic syndrome. Adults with severe growth hormone (GH) deficiency have, to a large extent, features of the metabolic syndrome, and there is a strong inverse association between visceral fat accumulation and blunted GH secretion in adults. Hyposomatotropism in abdominal obesity has therefore been suggested to be of importance for its metabolic consequences. However, the underlying pathophysiological mechanisms are poorly understood. Prevalence of the metabolic syndrome is steadily increasing worldwide. Overnutrition and sedentary habits are the stigmata of modern society that predispose genetically susceptible individuals to develop central obesity and other features of the metabolic syndrome including glucose intolerance, hypertension and dyslipidemia. Although there are still no unified definitions of the syndrome, it is clear that this condition is associated with an increased risk for development of cardiovascular disease (CVD) and diabetes mellitus (DM). In this review, we discuss current evidence regarding alterations in the GH-IGF- 1 axis in abdominal obesity and its possible impact on other features of the metabolic syndrome.

Growth hormone treatment reduces abdominal visceral fat in postmenopausal women with abdominal obesity: a 12-month placebo-controlled trial.

Abdominal obesity is associated with blunted GH secretion and a cluster of cardiovascular risk factors that characterize the metabolic syndrome. GH treatment in abdominally obese men reduces visceral adipose tissue and has beneficial effects on the metabolic profile. There are no long-term data on the effects of GH treatment on postmenopausal women with abdominal obesity. Forty postmenopausal women with abdominal obesity participated in a randomized, double-blind, placebo-controlled, 12-month trial with GH (0.67 mg/d). The primary aim was to study the effect of GH treatment on insulin sensitivity. Measurements of glucose disposal rate (GDR) using a euglycemic, hyperinsulinemic glucose clamp; abdominal fat, hepatic fat content, and thigh muscle area using computed tomography; and total body fat and fat-free mass derived from (40)K measurements were performed at baseline and at 6 and 12 months. GH treatment reduced visceral fat mass, increased thigh muscle area, and reduced total and low-density lipoprotein cholesterol compared with placebo. Insulin sensitivity was increased at 12 months compared with baseline values in the GH-treated group. In the GH-treated group only, a low baseline GDR was correlated with a more marked improvement in insulin sensitivity (r = -0.68; P < 0.001). A positive correlation was found between changes in GDR and liver attenuation as a measure of hepatic fat content between baseline and 12 months (r = 0.7; P < 0.001) in the GH-treated group. In postmenopausal women with abdominal obesity, 1 yr of GH treatment improved insulin sensitivity and reduced abdominal visceral fat and total and low-density lipoprotein cholesterol concentrations. The improvement in insulin sensitivity was associated with reduced hepatic fat content.