Recombinant human insulin-like growth factor I has significant anabolic effects in adults with growth hormone receptor deficiency: studies on protein, glucose, and lipid metabolism

The physiological effects of insulin-like growth factor I (IGF-I) on intermediate metabolism of substrates have been extensively studied in a variety of experimental situations in man, and its effects on linear growth of children with GH receptor mutations have proven beneficial. However, there is a paucity of data on the metabolic effects of IGF-I as replacement therapy in adults with GH receptor deficiency (Laron's syndrome). We designed these studies to investigate the in vivo effects of 8 weeks of therapy with recombinant human IGF-I (rhIGF-I) in a unique group of 10 adult subjects with profound IGF-I deficiency due to a mutation in the GH receptor gene (mean +/- SEM age, 29.2 +/- 2.0 yr; 4 males and 6 females). At baseline, patients had infusions of stable tracers, including L-[13C]leucine, [2H2]glucose, and d5-glycerol, as well as indirect calorimetry, assessment of body composition (dual energy x-ray absortiometry), and measurements of growth factor concentrations. Patients were then discharged to receive twice daily rhIGF-I (60 microg/kg, sc) for the next 8 weeks when the studies were repeated identically. Plasma IGF-I concentrations increased during rhIGF-I treatment from 9.3 +/- 1.5 microg/L to 153 +/- 23 (P = 0.0001). There was no change in weight during these studies, but a significant change in body composition was observed, with a decrease in percent fat mass (P = 0.003) and an increase in lean body mass (P = 0.001). These were accompanied by increased rates of protein turnover, decreased protein oxidation, and increased rates of whole body protein synthesis, as measured by leucine tracer methods (P < 0.01). These results are similar to those observed in GH-deficient subjects treated with GH. All measures of lipolytic activity and fat oxidation increased during treatment, with an 18% increase in the glycerol turnover rate (P = 0.04), an increase in free fatty acid and beta-hydroxybutyrate concentrations, and a significant increase in fat oxidation, as measured by indirect calorimetry (P = 0.04). There were significant decreases in insulin concentrations (P = 0.01) and a reciprocal increase in glucose production rates (P = 0.04) during rhIGF-I, yet plasma glucose concentrations remained constant, suggestive of a significant insulin-like action of this peptide. RhIGF-I was well tolerated by all patients. In conclusion, 8 weeks of treatment with rhIGF-I had significant positive effects on body composition and measures of intermediate metabolism independent of GH. These results suggest that, similar to GH treatment of adults with GH deficiency, rhIGF-I may be beneficial as long term replacement therapy for the adult patient with Laron's syndrome.     

The effects of Xanthigen™ in the weight management of obese premenopausal women with non-alcoholic fatty liver disease and normal liver fat

Aim: To investigate the effects of Xanthigen (brown marine algae fucoxanthin + pomegranate seed oil (PSO)) on body weight, body fat, liver lipids, and blood biochemistry; and Xanthigen and its individual components on resting energy expenditure (REE) in obese, non-diabetic female volunteers with non-alcoholic fatty liver disease (NAFLD) and normal liver fat (NLF) content.
Methods: Sixteen-week, double-blind, randomized, placebo-controlled study. Food record data, body composition, REE (only 41 volunteers with NAFLD) and blood sample analysis were assessed weekly for 16 weeks in 151 non-diabetic, obese premenopausal women with liver fat content above 11% (NAFLD) n = 113, and below 6.5% (NLF) n = 38.
Results: Xanthigen-600/2.4 mg (300 mg PSO + 300 mg brown seaweed extract containing 2.4 mg fucoxanthin) resulted in statistically significant reduction of body weight (5.5 ± 1.4 kg NAFLD group and 4.9 ± 1.2 kg NLF group, p < 0.05), waist circumference (NAFLD group only), body (3.5 ± 1.9 kg NAFLD group, p < 0.001; 3.6 ± 0.7 kg NLF group, p < 0.05) and liver fat content, liver enzymes (NAFLD group only), serum triglycerides and C-reactive protein. Weight loss and reduction in body and liver fat content occurred earlier in patients with NLF than in patients with NAFLD. Fucoxanthin ( > 2.4 mg) and Xanthigen-400/1.6 mg (200 mg PSO + 200 mg brown seaweed extract containing 1.6 mg fucoxanthin) significantly increased REE in NAFLD subjects compared to placebo.
Conclusions: Xanthigen promoted weight loss, reduced body and liver fat content, and improved liver function tests in obese non-diabetic women. Xanthigen and Fucoxanthin also increased REE. This product may be considered a promising food supplement in the management of obesity.     

Interrelationships of spontaneous growth hormone axis activity, body fat, and serum lipids in healthy elderly women and men

Aging is associated with decreased growth hormone (GH) secretion and plasma insulin-like growth factor-I (IGF-I) levels, increased total and abdominal fat, total and low-density lipoprotein (LDL) cholesterol, and triglycerides, and reduced high-density lipoprotein (HDL) cholesterol. Similar changes in lipids and body composition occur in nonelderly GH-deficient adults and are reversed with GH administration. To examine whether GH/IGF-I axis function in the elderly is related to the lipid profile independently of body fat, we evaluated GH secretion, serum IGF-I and IGF binding protein-3 (IGFBP-3) levels, adiposity via the body mass index (BMI), waist to hip ratio (WHR), dual-energy x-ray absorptiometry (DEXA), and magnetic resonance imaging (MRI), and circulating lipids in 101 healthy subjects older than 65 years. Integrated nocturnal GH secretion (log IAUPGH) was inversely related (P < .005) to DEXA total and abdominal fat and MRI visceral fat in both genders. Log IAUPGH was inversely related to visceral fat in women (P < .005) and men (P < .0001), but was not significantly related to total fat in either gender. In women, log IAUPGH was related inversely to total and LDL cholesterol and positively to HDL cholesterol (P < .008). In men, log IAUPGH was inversely related to total cholesterol and triglycerides (P < .005). In women, HDL cholesterol was inversely related to the WHR (P < .005). In men, triglycerides were positively related (P < .001) to the WHR and DEXA abdominal and MRI visceral fat. Multivariate regression revealed log IAUPGH, but not DEXA total body fat, to be an independent determinant of total (P < .001 for women and P = .01 for men) and LDL (P < .007 and P = .05) cholesterol in both sexes and of HDL cholesterol (P < .005) and triglycerides (P < .03) in women. Log IAUPGH, but not DEXA abdominal fat, was related to total (P < .005 and P < .03) and LDL (P < .03 and P = .05) cholesterol in both genders and to HDL in women (P < .05). Log IAUPGH, but not MRI visceral fat, was related to total cholesterol (P < .03 and P = .05) in women and men. Age, IGF-I, and IGFBP-3 were not significantly related to any body fat or lipid measures, except for a positive correlation of IGF-I with triglycerides in men. Thus, endogenous nocturnal GH secretion predicts total, LDL, and HDL cholesterol levels independently of total or abdominal fat, suggesting that it is an independent cardiometabolic risk factor in healthy elderly people.     

Characterization of the metabolic phenotypes of Cushing's syndrome and growth hormone deficiency: a study of body composition and energy metabolism

OBJECTIVE: A comparison of the severity and distribution of perturbations in body composition and their relationship to energy metabolism in glucocorticoid excess and GH deficiency (GHD) has not been undertaken before. The aim of this study was to investigate the impact of Cushing's syndrome (CS) and GHD on whole and regional body composition and energy metabolism. DESIGN: Cross-sectional study design. PATIENTS: Eighteen subjects with CS (12 women, aged = 41.5 +/- 3.0 years, 24-h urinary free cortisol = 1601 +/- 361 nmol/day, normal < 300 nmol/day), 22 subjects with GHD (14 women, age = 42.9 +/- 2.9 years) and 18 normal subjects (11 women, age = 46.8 +/- 2.8 years). MEASUREMENTS: Lean body mass (LBM), fat mass (FM) and regional body composition were assessed by dual-energy X-ray absorptiometry (DEXA). Resting energy expenditure (REE) and fat oxidation (Fox) were assessed by indirect calorimetry. RESULTS: Mean percentage FM was significantly greater by 30% in CS (P = 0.002) and 22% in GH-deficient subjects (P = 0.014) than in normal subjects. LBM was significantly lower by 15% in CS (P = 0.002) and 11% in GHD (P = 0.013). In CS, the proportion of lean tissue in the limbs was 12% less than in normal (P = 0.001) and GH-deficient subjects (P = 0.0005). Truncal fat represented a greater proportion of total FM in CS (52.5 +/- 1.8%vs. 46.9 +/- 1.3%, P = 0.014) than in normal subjects, but not in GHD. REE and Fox, corrected for LBM, were significantly lower in GHD (P < 0.02 for both vs. normal) but not in CS. CONCLUSION: FM was higher and LBM lower in both CS and GHD. However, there is a greater abnormality of regional body composition in patients with CS who exhibit a lower limb lean mass and a greater truncal fat. Reduced REE and Fox contribute to increased adiposity in GHD. As REE and Fox are not perturbed in CS, other mechanisms must explain the marked gain in truncal and total fat.     

Effects of growth hormone on pulmonary function,sleep quality,behavior, cognition,growth velocity,body composition,and resting energy expenditure in Prader-Willi syndrome

The objective of this study was to investigate the effects of GH administration on pulmonary function, sleep, behavior, cognition, linear growth velocity, body composition, and resting energy expenditure (REE) in children with Prader-Willi syndrome. The study used a 12-month, balanced, randomized, double-blind, placebo-controlled, cross-over experimental design. Twelve subjects were randomized to GH (0.043 mg/kg x d) or placebo intervention for 6 months and then crossed over to the alternate intervention for 6 months. Differences in outcome variables were determined by paired t tests. Peak flow rate, percentage vital capacity, and forced expiratory flow rate improved and number of hypopnea and apnea events and duration of apnea events trended toward improvement after GH intervention. The only difference in cognition or behavior was an increase in hyperactivity scale on the Behavior Assessment System for Children after GH intervention. Linear growth velocity, REE, and lean mass were higher (67%, 19%, and 7.6%, respectively), and fat mass and percentage body fat were lower (10.3% and 8.1%, respectively) after GH intervention. GH administration did not change mean fasting ghrelin concentration. GH intervention improved body composition and REE and may contribute to better sleep quality and pulmonary function. GH administration did not impact fasting ghrelin concentration.     

Growth hormone (GH) status is an independent determinant of serum levels of cholesterol and triglycerides in healthy adults

OBJECTIVE: Both severe growth hormone (GH) deficiency in hypopituitary adults and physiological ageing are associated with an increase in fat mass, dyslipidaemia, and an increased incidence of cardiovascular disease. Ageing is also associated with a physiological decrease in spontaneous as well as stimulated GH secretion. We wished to evaluate the effects of endogenous GH status on circulating lipoproteins. DESIGN: A cross-sectional study. SUBJECTS: Forty-two healthy nonobese adults of both sexes (20 M + 22 F) aged 27-59 years. MEASUREMENTS: Twenty-four hour GH secretion, arginine-stimulated GH secretion, and fasting values of lipoproteins and triglycerides. Body composition was measured by CT-scan and whole body DXA-scan. VO2-max was measured on an ergometer bicycle. RESULTS: GH secretion decreased with age and was lower in males. Older subjects had more total body fat, subcutaneous abdominal fat, and intra-abdominal fat than younger ones, and their VO2-max was decreased. Men had more intra-abdominal and subcutaneous abdominal fat but less total body fat than women. There was no sex difference in VO2-max. Total cholesterol (TC) and LDL-C (mmol/l) were higher in older than in the younger subjects (TC: 5.32 (95% CI = 0.49) vs. 4. 17 (95% CI = 0.28), P < 0.001; LDL-C: 3.66 (95% CI = 0.52) vs. 2.54 (95% CI = 0.37), P = 0.001) without sex differences. HDL-C did not show any difference with age or between sexes. Triglycerides (mmol/l) were higher in older subjects and in males (older: 1.36 (95% CI = 0.19) vs. younger: 1.02 (95% CI = 0.20), P = 0.015; M: 1. 34 (95% CI = 0.24) vs. F: 1.03 (95% CI = 0.16), P = 0.03). There was no age-difference in lipoprotein (a), but concentrations were higher in women (M: 4.35 (2.95-8.30) vs. F: 19.40 (4.10-32.80), P = 0.03). TC, LDL-C, and triglycerides correlated positively with age and indices of adiposity, and inversely with VO2-max. TC, LDL-C, and triglycerides also correlated significantly and negatively with arginine-stimulated GH secretion (peak GH) (TC vs. peak GH (r = - 0. 395, P = 0.01); LDL-C vs. peak GH (r = - 0.365, P = 0.017); triglycerides vs. peak GH (r = - 0.386, P = 0.01)). Multiple linear regression analysis showed GH status to be an independent predictor of both TC, LDL-C, and triglycerides. CONCLUSION: We hypothesize that GH may exert direct effects on lipid metabolism.     

The relationship between insulin-like growth factor-I, adiposity, and aging

Aging is associated with both a relative accumulation of body fat and a reduction in growth hormone (GH) secretion. This study was devised to investigate the relationship between plasma insulin-like growth factor-I (IGF-I), an index of GH secretion, and anthropometric indices of body fat in normal subjects of various ages. Somatic and biochemical indices of nutrition were assessed in 107 subjects between the ages of 17 and 83 years who attended an outpatient clinic for general health supervision. Plasma IGF-I correlated negatively with age in both males (r = -.44, P = .001) and females (r = -.40, P = .005). In addition, plasma IGF-I correlated negatively with body mass index (BMI) (r = .35, P = .006), percentage of standard triceps skinfold (TSF) (r = -.26, P = .05), and percentage of standard weight (r = -.35, P = .006) in males, but not in females. Multiple regression analysis indicated that in males, BMI and percentage of standard weight correlated with plasma IGF-I independent of the effect of age. We conclude that adiposity and aging are independently associated with decreased plasma IGF-I concentrations. The negative correlations between indices of adiposity and IGF-I were observed only in males, whereas the age-associated decline in IGF-I was present in both males and females. We speculate that sex differences in the gonadal steroid milieu, combined with declining GH secretion in both sexes, may contribute to the age-associated development of obesity in males.     

Lack of reduction in body fat after treatment with insulin-like growth factor-I in two children with growth hormone gene deletions

Two patients with growth hormone (GH) gene deletions were treated with recombinant insulin-like growth factor-I (IGF-I) (80-240 (microg/kg/day) and the effects on bone mass and body composition were compared to administration of GH (0.075 U/kg/day) to 8 patients with idiopathic GH deficiency. Bone mass and body composition were measured by dual photon X-ray absorptiometry (DEXA ) before and 3 and 6 months after treatment with GH or IGF-I. Similar increases in growth velocities were observed after GH and IGF-I treatment. Treatment with GH resulted in prompt and significant reduction in body fat percentage (basal, 3 and 6 months: 22+/-10, 17+/-9, and 16+/-9%) whereas body fat percentage remained unchanged after IGF-I therapy (basal, 3 and 6 months: 49, 52 and 48% in patient 1 and 45, 42 and 43% in patient 2, respectively). Fat percentage remained elevated after 18 months of IGF-I treatment in patients 1 (51%) and 2 (44%), respectively. Lean mass and bone mineral content increased with GH and IGF-I therapies. We conclude that reduction of body fat measured by DEXA, observed after administration of GH but not after IGF-I treatment in these children with GH deficiency, suggests that the GH effect on body fat mass is not mediated by circulating IGF-I.     

Body composition during GH replacement in adults - methodological variations with respect to gender

OBJECTIVE: Men with growth hormone deficiency (GHD) may be more sensitive to GH treatment than women in terms of changes in body composition. We have studied whether age, body-mass index (BMI) and the different types of methodology used to assess body composition may explain these differences. DESIGN: Forty-four men and forty-four women with GHD, closely matched for age and BMI, were studied before and after 6 months of GH replacement. The dose of GH was individually adjusted. Body composition was assessed by measurements of potassium-40, total body nitrogen (TBN), tritiated water dilution, dual-energy X-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA). Four- and five-compartment models for body composition were also calculated. RESULTS: The total daily dose of GH was similar in men and women at 6 months. Serum insulin-like growth factor-I (IGF-I) was higher in men than women at baseline and after 6 months of treatment (P = 0.01, paired t-test). The increment was, however, similar. In women, GH treatment reduced body weight and increased TBN. In both men and women, total body water and body cell mass increased, while total body fat (BF) mass decreased. At baseline, mean total BF varied considerably depending on the methodology used, with the highest value obtained from DXA. The changes in BF were, however, less dependent on the methodology, but DXA and BIA demonstrated the largest inconsistency between men and women. CONCLUSIONS: These results suggest that gender differences in body composition in response to GH treatment are small, if adjustments are made for baseline factors such as age, BMI and dose of GH. Different methods of body composition measurements produce different results, but changes in response to GH administration are less inconsistent.     

Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study

Obesity, poor growth, and hypotonia in children with Prader-Willi syndrome (PWS) are accompanied by abnormal body composition resembling a GH-deficient state. Hypothalamic dysfunction in PWS includes decreased GH secretion, suggesting a possible therapeutic role for GH treatment. While short-term benefits of treatment with GH have been shown, whether these beneficial effects are dose dependent and persist or wane with prolonged therapy remains uncertain. Effects of 24 additional months of GH treatment at varying doses (0.3, 1.0, and 1.5 mg/m(2).d) on growth, body composition, strength and agility, pulmonary function, resting energy expenditure (REE), and fat utilization were assessed in 46 children with PWS, who had previously been treated with GH therapy (1 mg/m(2).d) for 12-24 months. Percent body fat, lean muscle mass, and bone mineral density (BMD) were measured by dual x-ray absorptiometry. Indirect calorimetry was used to determine REE and to calculate respiratory quotient. A modified Bruininks-Oseretski test of physical performance evaluated strength and agility. During months 24-48 of GH therapy, continued beneficial effects on body composition (decrease in fat mass and increase in lean body mass), growth velocity, and REE occurred with GH therapy doses of 1.0 and 1.5 mg/m(2).d (P < 0.05), but not with 0.3 mg/m(2).d. BMD continued to improve at all doses of GH (P < 0.05). Prior improvements in strength and agility that occurred during the initial 24 months were sustained but did not improve further during the additional 24 months regardless of dose. Salutary and sustained GH-induced changes in growth, body composition, BMD, and physical function in children with PWS can be achieved with daily administration of GH doses > or =1 mg/m(2). Lower doses of GH, (0.3 mg/m(2).d) effective in improving body composition in GHD adults, do not appear to be effective in children with PWS at sustaining improvement in body composition.     

Serum Sex Hormones,IGF-1, and IGFBP3 Exert a Sexually Dimorphic Effect on Lean Body Mass in Aging

BACKGROUND: Endogenous and exogenous sex hormones affect changes in body composition during aging via independent and dependent effects on the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis and associated binding proteins (BP). METHODS: Fasting serum IGF-1, IGFBP3, testosterone, estrone, and sex hormone binding globulin were analyzed in 48 women on hormone replacement (HRT) (unopposed oral estrogen, HRT+, 74.0 +/- 6 years), 135 women not on HRT (HRT-, 77.3 +/- 7 years), and 128 healthy men (men, ). Total lean body mass (LBM) and total fat were measured by dual energy X-ray absorptiometry. RESULTS: Total LBM decreased with age in all groups (p = .05). LBM was greater, and IGF-1, IGFBP3, and testosterone were lower in HRT+ versus HRT- women (p = .02, p = .01, p = .04, and, respectively). LBM in men was positively related to IGF-1 (p = .02) and testosterone (p < .01), whereas LBM was associated with IGFBP3 (p = .04) and total fat (p < .001) in female HRT+ and total fat (p < .01) in HRT- women. IGF-1 decreased with age in men and HRT- women (p < .01) but did not decrease in HRT+ women. Total fat significantly decreased across age (p < .05). Controlling for age and HRT, the rate of decrease in fat was slower in men versus women (p = .02). IGFBP3 decreased in all groups across age (p < .01), and the ratio of IGF-1 to IGFBP3 decreased faster in men compared to HRT+ and HRT- women (p = .02). CONCLUSIONS: Our data indicate divergent influences of sex steroids, IGF-1, and IGFBP3 on age-related changes in LBM in healthy elderly men and women.     

Supraphysiological growth hormone: less fat, more extracellular fluid but uncertain effects on muscles in healthy, active young adults

OBJECTIVES: To study the effects on body composition after 1 month's administration of supraphysiological doses of growth hormone (GH) in healthy, active young adults with normal GH-IGF-I axis. SUBJECTS AND METHODS: Thirty healthy, physically active volunteers (15 men and 15 women), mean age 25.9 years (range 18-35), participated in this study, designed as a randomized, double-blind, placebo-controlled, parallel study with three groups (n = 10: five men and five women in each group). The groups comprised the following: placebo (P), GH 0.1 IU/kg/day [0.033 mg/kg/day] (GH 0.1) and GH 0.2 IU/kg/day [0.067 mg/kg/day] (GH 0.2). RESULTS: In the pooled group with active GH treatment (n = 20) the results showed significant increases: IGF-I increased by 134% (baseline vs. after 1 month), body weight by 2.7%, fat free mass by 5.3%, total body water by 6.5% and extracellular water (ECW) by 9.6%. Body fat decreased significantly by 6.6%. No significant change in intracellular water was detected. The observed increase in fat free mass by 5.3% was explained by the ECW increase, indicating limited anabolic effects of the supraphysiological GH doses. Changes were noticeable in both genders, although more prominent in the male subjects. Fluid retention symptoms occurred in the majority of individuals. CONCLUSIONS: This is, to our knowledge, the first placebo-controlled trial to show the effects of supraphysiological GH doses on body composition and IGF-I levels in physically active and healthy individuals of both genders; the results indicate limited anabolic effects of GH with these supraphysiological doses. The role of GH as an effective anabolic doping agent is questioned.     

Serum lipid and leptin concentrations in hypopituitary patients with growth hormone deficiency

OBJECTIVE: To investigate the effects of growth hormone (GH) deficiency on serum lipid and leptin concentrations in hypopituitary patients taking conventional replacement therapy and to determine the relations between leptin and gender and anthropometric and metabolic variables. SUBJECTS: Twenty-one GH deficient adult hypopituitary patients (15 women, six men) and 21 (14 women, seven men) age, sex and body mass index (BMI) matched healthy controls. MEASUREMENTS: After an overnight fast, anthropometric parameters were measured and body composition was determined by a bioelectrical impedance analyser. Venous blood samples were obtained for the measurements of glucose, total cholesterol, high density lipoprotein (HDL) cholesterol, triglyceride, intact insulin, insulin-like growth factor 1 (IGF-1) and leptin concentrations. Serum leptin and hormones were analysed by radioimmunoassay. RESULTS: Hypopituitary patients with GH deficiency showed significantly higher triglyceride, total and low density lipoprotein (LDL) cholesterol and lower HDL cholesterol concentrations on conventional replacement therapy. The unfavourable lipid profile was particularly evident in women. Significantly higher leptin concentrations were found in patients compared with healthy controls with similar body fat content (23. 5+/-11.8 ng/ml vs 11.7+/-6.9 ng/ml, P=0.01). This difference remained significant even when leptin values were expressed in relation to fat mass percentage (0.79+/-0.40 vs. 0.42+/-0.17 ng/ml%, P<0.05) and fat mass kg (1.32+/-0.81 vs 0.66+/-0.30 ng/ml kg, P<0. 05). Significant positive correlations were observed between leptin concentrations and body fat percentage and age in the control group. In patients the sole significant relation between leptin and study parameters was the positive correlation observed between leptin and total cholesterol concentrations. Serum leptin concentrations were significantly higher in women than men in the control group, but not in the patients. No significant gender difference was observed when leptin concentrations were expressed in relation to fat mass (percentage and kg). CONCLUSION: Growth hormone deficient hypopituitary patients (particularly women) on conventional replacement therapy have a more atherogenic lipid profile. Leptin concentrations are increased in GH deficient adults even after adjustment for percentage body fat and body fat mass (kg). Although the nature of our data does not allow us to draw any conclusions on the mechanism(s) of increased leptin concentrations in GH deficiency, decreased central sensitivity to leptin and increased leptin production from per unit fat mass, or alterations in leptin clearance, might be operative.     

Leptin in postmenopausal women: influence of hormone therapy, insulin, and fat distribution

Whether use of hormone-replacement therapy (HRT) influences menopause-related changes in body weight is unclear. HRT may affect energy balance by influencing synthesis of the adipocyte-derived hormone leptin. The objectives of this study were to: 1) identify factors influencing circulating leptin in postmenopausal women; 2) determine whether HRT influences serum leptin after adjusting for confounding factors; and, 3) identify potential independent effects of HRT or leptin on resting energy expenditure (REE). Subjects were 54 postmenopausal women, 45-55 yr old, 35 of whom used HRT (estrogen plus progestin). Total and regional body composition and fat distribution were determined by dual-energy x-ray absorptiometry and computed tomography; fasting serum leptin and insulin, by RIA; and REE, by indirect calorimetry. Stepwise multiple linear regression analysis indicated that serum leptin could best be predicted from total fat mass, fasting serum insulin, and total lean mass [log leptin = 1.08 x log fat mass) + (0.46 x log insulin) + (-1.25 x log lean mass) + 1.88; model R2 = 0.78, P < 0.001]. Multiple linear regression analysis indicated that visceral fat was independently related to leptin (parameter estimate = 0.23, P < 0.05), after adjusting for s.c. abdominal fat and leg fat, as well as lean mass and insulin. After adjusting for total fat mass, total lean mass, and fasting insulin, serum leptin did not differ between users and nonusers of HRT (21.7 +/- 1.0 vs. 20.2 +/- 1.3 ng/mL, P = 0.369, adjusted mean +/- SE, respectively). Serum estradiol was inversely correlated with (adjusted) leptin in non-HRT users (r = -0.50), suggesting that ovarian senescence may lead to an increase in leptin. Multiple linear regression analysis indicated that REE (adjusted for fat mass, fat-free mass, and ethnicity) was not associated with leptin (P = 0.298) or hormone use status (P = 0.999; 1323 +/- 31 vs. 1316 +/- 42 kcal/day, adjusted mean +/- SE for users and nonusers, respectively). These results indicate that, in postmenopausal women: 1) total fat mass, lean mass, and fasting insulin, but not HRT, are significant determinants of serum leptin; 2) visceral and s.c. fat contribute to serum leptin; and, 3) neither HRT nor leptin is independently related to REE.     

Withdrawal of long-term physiological growth hormone (GH) administration: differential effects on bone density and body composition in men with adult-onset GH deficiency

Adults with acquired GH deficiency (GHD) have been shown to have osteopenia associated with a 3-fold increase in fracture risk and exhibit increased body fat and decreased lean mass. Replacement of GH results in decreased fat mass, increased lean mass, and increased bone mineral density (BMD). The possible differential effect of withdrawal of GH replacement on body composition compartments and regional bone mass is not known. We performed a randomized, single blind, placebo-controlled 36-month cross-over study of GH vs. placebo (PL) in adults with GHD and now report the effect of withdrawal of GH on percent body fat, lean mass, and bone density, as measured by dual energy x-ray absorptiometry. Forty men (median age, 51 yr; range, 24-64 yr) with pituitary disease and peak serum GH levels under 5 microg/L in response to two pharmacological stimuli were randomized to GH therapy (starting dose, 10 microg/kg x day, final dose 4 microg/kg x day) vs. PL for 18 months. Replacement was provided in a physiological range by adjusting GH doses according to serum insulin-like growth factor I levels. After discontinuation of GH, body fat increased significantly (mean +/- SEM, 3.18 +/- 0.44%; P = 0.0001) and returned to baseline. Lean mass decreased significantly (mean loss, 2133 +/- 539 g; P = 0.0016), but remained slightly higher (1276 +/- 502 g above baseline; P = 0.0258) than at study initiation. In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 +/- 0.00042, g/cm2 x month; P = 0.005) between months 18-36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.     

Body composition and resting energy expenditure in humans: role of fat, fat-free mass and extracellular fluid

OBJECTIVE: The objective of this study was to determine whether there are independent effects of extracellular fluid volume (ECF) and fat mass (FM) on resting energy expenditure (REE) relative to fat-free mass (FFM) in adult men and women. METHODS: Multiple linear regression analysis was used to relate REE, as determined by indirect calorimetry, to FFM and FM (measured using dual energy X-ray absorptiometry) and ECF (measured using bromide space and/or the radiosulfate washout space) in 153 women and 100 men with varying amounts of body fat. RESULTS: REE correlated significantly with FFM and FM in women (r=0.65 and r=0.63, both P<0.001) and men (r=0.62 and r=0.48, both P<0.001, FFM and FM, respectively). In a multiple linear regression analysis FFM, FM and age significantly contributed to the ability to predict REE in both genders. The models that were derived were not significantly different between women and men. In women the contribution to REE from FM was easier to detect when FM was greater. Adjustment of FFM for ECF did not improve the relationship between FFM and REE. CONCLUSIONS: FFM, FM and age are significant, independent predictors of REE in both men and women. Adjustment of FFM for ECF does not improve the ability of FFM to predict REE, which suggests that ECF is a highly integrated component of FFM in healthy adults. Expressing REE relative to FFM alone will introduce errors when lean and obese populations are compared.     

Effects of exercise training and hormone replacement therapy on lean and fat mass in postmenopausal women

BACKGROUND: Menopause is associated with decreases in lean mass and increases in fat mass. Serum hormone levels and hormone replacement therapy (HRT) may modify the effects of exercise training on body composition in postmenopausal women. METHODS: We assessed the changes in total body and regional lean soft tissue and fat mass (using dual-energy x-ray absorptiometry) in 94 sedentary postmenopausal women, aged 40-65 years, after 12 months of resistance and weight-bearing aerobic exercise training. Women currently on oral HRT (n = 39) and not on HRT (n = 55) were randomized within groups to exercise and no exercise, resulting in four groups: exercise + HRT (n = 20), HRT (n = 22), exercise (n = 24), and control (n = 28). Fasting blood samples were measured for resting serum total levels of estrone, estradiol, cortisol, androstenedione, growth hormone, and insulin-like growth factor 1 at baseline and 12 months. RESULTS: We found significant effects of exercise on increases in total body, arm, and leg lean soft tissue mass, and decreases in leg fat mass and percentage of body fat. There were no interaction effects of exercise and HRT on the changes in muscle strength and body composition. No significant changes in total hormone levels were found after 12 months. CONCLUSIONS: Exercise training resulted in significant beneficial changes in lean soft tissue and fat mass in early postmenopausal women. These changes in body composition were neither influenced by prolonged HRT use nor accompanied by changes in total levels of the hormones determined in this study.     

Interleukin-6, tumour necrosis factor-alpha and insulin relationships to body composition, metabolism and resting energy expenditure in a migrant Asian Indian population

OBJECTIVE: Systemic inflammation and insulin resistance may play important roles in the pathogenesis of obesity-related diseases for which migrant Asian Indians are at particularly high risk. We examined relationships between markers of insulin resistance and inflammation, resting energy expenditure (REE), and body composition. DESIGN AND METHODS: Measurements were made of total and regional body composition, including regional fat mass (FM) and appendicular skeletal muscle mass (ASMM) by dual-energy X-ray absorptiometry (DXA), REE by indirect calorimetry and fasting interleukin (IL)-6, tumour necrosis factor (TNF)-alpha, glucose and insulin, in 79 healthy Asian Indians (38F, 41M; age 30-49 years) from urban Auckland, New Zealand. Beta-cell function (HOMA B%) and insulin sensitivity (HOMA S%) were derived using homeostatic model assessment. RESULTS: Men had a more central distribution of body fat than women. REE was strongly correlated with IL-6 concentrations in men but not in women. In both sexes, IL-6 was associated positively with percentage body fat and HOMA B% and inversely with ASMM and HOMA S%. Insulin increased and HOMA S% decreased with increasing waist-to-hip ratio and abdominal-to-thigh fat ratio in men but not in women. TNF-alpha was not significantly associated with any of the variables examined. CONCLUSION: Relationships between body fat distribution and HOMA S% were strongly sex dependent and may indicate a greater propensity for development of the metabolic syndrome among male Asian Indians than females in the age group examined.     

Efficacy and safety of individualized growth hormone treatment in adult Japanese patients with growth hormone deficiency

OBJECTIVE: The aim of the study was to evaluate the efficacy and safety of growth hormone (GH) treatment in Japanese adult patients with GH-deficiency. In the extension of the efficacy study, the effect of individualized-dosing (ID), based on insulin-like growth factor-I (IGF-I) levels, and fixed-dose (FD) GH regimens on body composition, were compared in Japanese GH-deficient adults. DESIGN: Randomized, double-blind (DB), placebo-controlled, 24-week treatment period followed by 48-week, open-label study in 43 endocrinology clinics in Japan. Patients received DB treatment with GH (0.012 mg/kg/day; n=57) or placebo (n=60) followed by open-label GH in an ID (n=75) or FD (0.012 mg/kg/day; n=38) regimen. SUBJECTS: Adult Japanese GH-deficient patients (peak GH<3 ng/mL). MEASUREMENTS: Trunk and total body fat (BF), lean body mass (LBM), and adverse events were determined. RESULTS: Percentage trunk fat was reduced significantly more in GH- than in placebo-treated patients at 24 weeks (-16.2 vs. 1.7%, p<0.0001). Open-label treatment with an ID or FD GH regimen provided similar reductions in percentage trunk fat (-8.12 vs. -9.35%), and total BF (-0.92 vs. -0.70 kg) and a comparable increase in LBM (1.032 vs. 0.97 kg). Mean+/-SD GH doses (mg/kg/day) at 48 weeks were significantly lower with the ID GH regimen (ID, 0.0082+/-0.0050; FD, 0.0095+/-0.0033; p<0.05). The safety profile was comparable between ID and FD groups. CONCLUSIONS: Treatment with GH was associated with a significant reduction in trunk fat and improvement in serum lipid profile in Japanese adult GH-deficient patients. The improvement in body composition and tolerability were comparable between ID and FD GH regimens despite a significantly lower daily GH dose with the ID regimen.     

Growth hormone decreases visceral fat and improves cardiovascular risk markers in women with hypopituitarism: a randomized, placebo-controlled study

CONTEXT: Data regarding gender-specific efficacy of GH on critical endpoints are lacking. There are no randomized, placebo-controlled studies of physiological GH therapy solely in women. OBJECTIVE: Our objective was to determine the effects of physiological GH replacement on cardiovascular risk markers and body composition in women with GH deficiency (GHD). DESIGN: This was a 6-month, randomized, placebo-controlled, double-blind study. SETTING: The study was conducted at the General Clinical Research Center. STUDY PARTICIPANTS: 43 women with GHD due to hypopituitarism were included in the study. INTERVENTION: Study participants were randomized to receive GH (goal mid-normal serum IGF-1) or placebo. MAIN OUTCOME MEASURES: Cardiovascular risk markers, including high-sensitivity C-reactive protein, tissue plasminogen activator, and body composition, including visceral adipose tissue by cross-sectional computed tomography, were measured. RESULTS: Mean daily GH dose was 0.67 mg. The mean IGF-1 sd score increased from -2.5 +/- 0.3 to -1.4 +/- 0.9 (GH) (P < 0.0001 vs. placebo). High-sensitivity C-reactive protein decreased by 38.2 +/- 9.6% (GH) vs.18.2 +/- 6.0% (placebo) (P = 0.03). Tissue plasminogen activator and total cholesterol decreased, and high-density lipoprotein increased. Homeostasis model assessment-insulin resistance and other markers were unchanged. Body fat decreased [-5.1 +/- 2.0 (GH) vs. 1.9 +/- 1.0% (placebo); P = 0.002] as did visceral adipose tissue [-9.0 +/- 5.9 (GH) vs. 4.3 +/- 2.7% (placebo); P = 0.03]. Change in IGF-1 level was inversely associated with percent change in visceral adipose tissue (r = -0.61; P = 0.002), total body fat (r = -0.69; P < 0.0001), and high-sensitivity C-reactive protein (r = -0.51; P = 0.003). CONCLUSIONS: Low-dose GH replacement in women with GHD decreased total and visceral adipose tissue and improved cardiovascular markers, with a relatively modest increase in IGF-1 levels and without worsening insulin resistance.