One year of insulin-like growth factor I treatment does not affect bone density, body composition, or psychological measures in postmenopausal women

The activity of the hypothalamic-GH-insulin-like growth factor I (hypothalamic-GH-IGF-I) axis declines with age, and some of the catabolic changes of aging have been attributed to the somatopause. The purpose of this investigation was to determine the impact of 1 yr of IGF-I hormone replacement therapy on body composition, bone density, and psychological parameters in healthy, nonobese, postmenopausal women over 60 yr of age. Subjects (n = 16, 70.6 +/- 2.0 yr, 71.8 +/- 2.8 kg) were randomly assigned to either the self-injection IGF-I (15 microg/kg twice daily) or placebo group and were studied at baseline, at 6 months, and at 1 yr of treatment. There were no significant differences between the IGF-I and placebo groups in any of the measured variables at baseline. Fasting blood IGF-I levels were significantly elevated above baseline values (65.6 +/- 11.9 ng/mL) at 6 months (330.0 +/- 52.8) and 12 months (297.7 +/- 40.8) in the IGF-I treated group but did not change in the placebo subjects. Circulating levels of IGF-binding protein-1 and -3 were unaffected by the IGF-I treatment. Bone mineral density of the forearm, lumbar spine, hip, and whole body [as measured by dual-energy x-ray absorptiometry (DXA)] did not change in either group. Similarly, there was no difference in DXA-measured lean mass, fat mass, or percent body fat throughout the treatment intervention. Muscle strength values (grip, bench press, leg press), blood lipid parameters (cholesterol, high-density lipoprotein, low-density lipoprotein, triglycerides), and measures of postmeal glucose disposal were not altered by IGF-I treatment, although postmeal insulin levels were lower in the IGF-I subjects at 12 months. IGF-I did not affect bone turnover markers (osteocalcin and type I collagen N-teleopeptide), but subjects who were taking estrogen had significantly lower turnover markers than subjects who were not on estrogen at baseline, 6 months, and 12 months. Finally, the psychological measures of mood and memory were also not altered by the intervention. Despite the initial intent to recruit additional subjects, the study was discontinued after 16 subjects completed the protocol, because the preliminary analyses above indicated that no changes were occurring in any outcome variables, regardless of treatment regimen. Therefore, we conclude that 1 yr of IGF-I treatment, at a dose sufficient to elevate circulating IGF-I to young normal values, is not an effective means to alter body composition or blood parameters nor improve bone density, strength, mood, or memory in older women.     

Two years of treatment with recombinant human growth hormone increases bone mineral density in men with idiopathic osteoporosis

We have investigated the effects of GH treatment on bone turnover, bone size, bone mineral density (BMD), and bone mineral content (BMC) in 29 men, 27-62 yr old, with idiopathic osteoporosis. The patients were randomly assigned to treatment with GH, either as continuous treatment with daily injections of 0.4 mg GH/d (group A, n = 14) or as intermittent treatment with 0.8 mg GH/d for 14 d every 3 months (group B, n = 15). All patients were treated with GH for 24 months, with a follow-up period of 12 months, and also received 500 mg calcium and 400 U vitamin D3 daily during all 36 months. Fasting morning urine and serum samples were obtained for assay of IGF-I, bone markers, and routine laboratory tests at baseline, after 1, 12, 24, and 36 months. Body composition, BMD, and BMC were determined by dual-energy x-ray absorptiometry at baseline and every 6 months. After 2 yr, there was an increase in BMD in lumbar spine (by 4.1%) in group A, and in total body (by 2.6%) in group A and (by 2.7%) in group B. BMC of the total body and lean body mass increased, whereas fat mass decreased in both treatment groups. After 36 months, the BMD and BMC in lumbar spine and total body had increased further in both groups. We conclude that 2 yr of intermittent or continuous treatment with GH in men with idiopathic osteoporosis results in an increase in BMD and BMC that is sustained for at least 1 yr post treatment.     

Recombinant human growth hormone and recombinant human insulin-like growth factor I diminish the catabolic effects of hypogonadism in man: metabolic and molecular effects

Severe gonadal androgen deficiency can have profound catabolic effects in man. Hypogonadal men develop a loss of lean body mass, increased adiposity, and decreased muscle strength despite normal GH and insulin-like growth factor I (IGF-I) concentrations. We designed these studies to investigate whether GH or IGF-I administration to male subjects with profound hypogonadism can diminish or abolish the catabolic effects of testosterone deficiency. Moreover, we also examined the nature of the interactions among GH, IGF-I, and androgens in specific genes of the im system. A group of 13 healthy subjects (mean age, 22 +/- 1 yr) was studied at baseline (D1) and 10 weeks after being made hypogonadal using a GnRH analog (GnRHa; D2). At 6 weeks from baseline they were started on either recombinant human (rh) IGF-I (60 microg/kg, sc, twice daily) or rhGH (12.5 microg/kg, sc, daily) for 4 weeks. On each study day subjects had infusions of L-[(13)C]leucine; indirect calorimetry; isokinetic dynamometry of the knee extensors; determination of body composition (dual energy x-ray absortiometry) and hormone and growth factor concentrations, as well as percutaneous muscle biopsies. Their data were compared with those of previously studied male subjects who received only GNRHA: Administration of rhIGF-I and rhGH to the hypogonadal men had similar effects on whole body metabolism, with maintenance of protein synthesis rates, fat oxidation rates, and fat-free mass compared with the eugonadal state, preventing the decline observed with hypogonadism alone. This was further amplified by the molecular assessment of important genes in muscle function. During rhIGF-I treatment, im expression of IGF-I declined, and IGF-binding protein-4 increased, similar to the changes during GnRHa alone. However, rhGH administration was associated with a marked increase in IGF-I and androgen receptor messenger ribonucleic acid concentrations in skeletal muscle with a reciprocal decline in IGF-binding protein-4 expression in the hypogonadal men. The gene expression for myostatin did not change. These effects were accompanied by a much greater increase in plasma IGF-I concentrations after rhIGF-I (225 +/- 32 vs. 768 +/- 117 microg/L) compared with the concentrations achieved during rhGH (217 +/- 20 vs. 450 +/- 19 microg/L). We conclude that 1) rhGH and rhIGF-I both may be beneficial in preserving lean body mass and sustaining rates of protein synthesis during states of severe androgen deficiency in man; 2) GH may affect the im IGF system via an a paracrine, local production of IGF-I; 3) androgens may be necessary for the full anabolic effect of GH/IGF-I in man. These hormones, particularly GH, may play a role in the treatment of hypogonadal men rendered hypogonadal pharmacologically or those unable to take full testosterone replacement. The latter requires further study.     

Bone mineral content and bone metabolism during physiological GH treatment in GH-deficient adults--an 18-month randomised, placebo-controlled, double blinded trial

OBJECTIVE: To evaluate the effect of physiological adult growth hormone (GH) replacement on bones. DESIGN: Thirty-six prospective severely growth hormone-deficient (GHD) adults (22 females and 14 males) were randomised to either 18 months of GH (0.03 mU/kg/day) or placebo treatment. METHODS: Bone mineral density and content (BMD, BMC) and body composition were evaluated by dual energy X-ray absorptiometry at baseline and after 6, 12 and 18 months. Serum concentrations of insulin-like growth factor-I (IGF-I), IGF binding protein 3, osteocalcin, carboxyterminal propeptide of type I collagen, carboxyterminal crosslink telopeptide of type I collagen, amino-terminal propeptide of type III procollagen and urine pyridinolin and deoxypyridinolin were determined. RESULTS: IGF-I levels increased from 63.2 microg/l (+/-10.1) to 193.6 (+/- 25.8) microg/l (mean (+/-s.e.)) (P<0.001 compared with placebo). Markers of bone turnover increased significantly from 142% to 227% of baseline values (all P<0.001 compared with placebo). Body composition changes were an increase of lean body mass and a decrease of fat mass resulting in a reduction of percentage body fat of +/- 1.8 (+/- 3.8) in the GH-treated group vs an increase of 1.0 (+/-2.9)) in the placebo-treated group (P=0.002). CONCLUSIONS: No significant difference in BMD or BMC between the GH and placebo groups was found after 18 months. At several sites the variances of changes from baseline were significantly greater in the GH than in the placebo group, indicating an impact of the treatment. From baseline to 6 months an insignificant reduction of total BMD was seen while an increase of BMD was found from 6 to 18 months in the GH group compared with the placebo group.This placebo-controlled trial confirmed the longer term open studies on the effect on bones in patients with GHD, with an initial overrepresentation of bone resorption followed by an increase in BMD which at 18 months had reached baseline level.     

Reproducibility of fasting plasma leptin concentration in lean and obese humans

We determined the reproducibility of plasma leptin levels in 20 healthy subjects (10 men, 10 women; 10 lean, 10 obese) at stable body weight. Blood samples were obtained, after an overnight fast, between 0700 and 0800 on days 1, 2, 3, 4, 5, 12, 19, and 26. Body weights were recorded on the same days. Plasma leptin was measured using a specific radioimmunoassay. The mean +/- SE baseline body weights (kg) were 65.8 +/- 3.6 (lean) and 96.4 +/- 7.1 (obese). The body mass indices (BMI) were 22.9 +/- 2.8 kg/m2 (lean) and 32.7 +/- 2.2 kg/m2 (obese). The mean daily fasting plasma glucose level was 98.7 +/- 3.7 mg/dl. Baseline plasma leptin levels (ng/ml) were 5.3 +/- 0.75 in lean men, 14.9 +/- 4.6 in obese men, 11.2 +/- 2.8 in lean women, and 27.1 +/- 8.4 in obese women. Fasting leptin levels on days 2 to 26 were highly correlated with the baseline levels on day 1 (r2 = 0.9, P<0.0001). Body weights remained within 98%-102% of baseline, whereas intra-individual leptin levels fluctuated between 80% and 120% of baseline values, throughout the 26 days of study. We conclude that fasting plasma leptin levels are reproducible, with a maximum day-to-day variation of approximately 20%, in healthy, free-living, lean and obese persons who maintain a stable body weight.     

Effect of growth hormone on body composition and visceral adiposity in middle-aged men with visceral obesity

RATIONALE: GH replacement in GH-deficient adults results in an improvement in metabolic status. GH might also decrease visceral adiposity in obese adults that are not GH deficient. OBJECTIVE: Our objective was to determine the effects of supraphysiological GH therapy on the metabolic syndrome and visceral adiposity in men with low blood levels of IGF-I and the durability of these effects after stopping GH therapy. DESIGN: The study was a double-blind, placebo-controlled 6-month intervention trial followed by a blinded follow-up period of 6 months. SUBJECTS: Thirty nondiabetic middle-aged men with central adiposity (body mass index > 27 kg/m(2); waist circumference > 102 cm) participated. RESULTS: After 6 months of GH therapy, we observed an increase in weight and lean body mass (2.5 +/- 0.6 kg, P < 0.05 compared with baseline and placebo) and 8.8% reduction in visceral adiposity. GH increased resting energy expenditure by 172.5 +/- 41.6 kcal/24 h after 6 months of therapy. Fasting insulin, glucose, and the quantitative insulin sensitivity check index for insulin resistance increased during GH therapy. The effects of GH on fatness and visceral adiposity disappeared shortly after GH withdrawal, but weight remained increased over baseline and when compared with the placebo group (P < 0.05). CONCLUSION: These data suggest that GH therapy is associated with small but statistically significant decreases in visceral adiposity and an increase in lean mass and body weight. In viscerally obese subjects, supraphysiological GH administration is not an effective treatment; however, additional studies are needed to evaluate the effects of low-dose, physiological GH treatment.     

Muscle tissue in obesity with different distribution of adipose tissue. Effects of physical training

Obese men and women with the same body fat mass, as well as obese women in another study, were divided into groups with male or female type of body fat distribution, but again with similar body fat mass. The participants were examined with measurements of body composition, including muscle fiber distribution, as well as circulatory and metabolic variables before and after physical training under controlled conditions. Obese men had higher lean body mass, blood pressure, blood glucose and plasma insulin, C-peptide, cholesterol and triglyceride concentrations than age- and body fat-matched obese women. Obese women with male type of adipose tissue distribution showed the same differences (except cholesterol) in comparisons with women with female type of adipose tissue distribution. The women with male type obesity were also more insulin resistant in glucose clamp measurements, and had male type of muscle fiber distribution. Physical training in the group of obese men resulted in a decrease of body fat, a further increase of lean body mass, an increase of fast twitch, aerobic type, muscle fibres as well as lower plasma insulin, cholesterol and triglyceride concentrations and lower blood pressure. Obese women with male type distribution of adipose tissue responded to physical training essentially like men. The insulin sensitivity was improved to the same level as in obese women with female type of adipose tissue distribution. In contrast, the latter women showed an increase of body fat and no metabolic improvements after training. These results show that obese women with male type of body fat distribution also have male characteristics of muscle mass, morphology and function. It is suggested that the obesity complications associated with this condition are improved by physical training because of an adaptation to a negative energy balance, in combination with an improvement of insulin sensitivity of the muscle mass. In contrast, the failure of obese women with female type of adipose tissue distribution to adapt to a negative energy balance during physical training is probably explaining their failure to decrease body fat and to improve metabolism during physical training.     

Hyposomatomedinemia in the men of a Veterans Administration Nursing Home: prevalence and correlates

A previous study found hyposomatomedinemia to be common in the men of this VA Nursing Home. To gain information on the prevalence and correlates of this endocrine characteristic, we have measured plasma somatomedin C (SmC) in 69 Nursing Home men 55-95 years old (group I), and in 37 independent men 56-87 years old attending our geriatric medicine outpatient clinic (group II). In groups I and II, a clinical data base was compiled comprising: blood chemistries, measures of body composition - nutritional state and functional level, diagnoses, medications, and morbidity and mortality during the year after the SmC analysis. The mean +/- SD for SmC was significantly (p less than 0.05) lower in group I (0.35 +/- 0.21 units/ml) than in group II (0.45 +/- 0.13 units/ml). SmC less than 0.25 units/ml, a range consistent with severe growth hormone deficiency, was found almost exclusively in group I (31.8% of men in group I, 3.7% of men in group II). In either group I, or in groups I and II combined, SmC was significantly (p less than 0.05) correlated with body weight as percentage of ideal, midarm muscle circumference (MAMC) as percent of standard, diagnosis of cerebrovascular disease, and plasma testosterone level. Men with SmC values below 0.25 units/ml had significantly (p less than 0.05) lower values for body weight as percentage of ideal, and for MAMC as percentage of standard. Except for cerebrovascular disease, SmC did not correlate significantly (p greater than 0.05) with diagnosis, drugs, morbidity or mortality.     

Growth hormone induced lipolysis during short- and long-term administration in adult Prader–Willi patients

Prader-Willi syndrome (PWS) is a complex genetic disease, clinically characterised by short stature, abnormal body composition, with more body fat than lean body mass, hyperphagia and obesity. Partial growth hormone (GH) deficiency is common, and GH treatment to PWS children and adults has shown beneficial effects on body composition. In this study, we have evaluated indices of GH's lipolytic effect in 6 PWS adults analysing glycerol, lactate and glucose in dialysate from microdialysis in subcutaneous abdominal adipose tissue. The patients were four men and two women, 19-37 years old; all hypogonadal. BMI was 24.2-49.1, mean 35.9 kg/m(2). All had normal serum insulin levels. They received GH therapy (Genotropin Pfizer) during 12 months and doses were individually titrated to normal serum IGF-I for age. Immediately before treatment start and at 12 months, 30-36 h after the last GH injection, sampling of dialysate was carried out at night (11 p.m. to 7 a.m.), as well as after intravenously injection of a standardised GH dose (0.8 mg). At baseline individual mean night time glycerol and lactate were similar to levels in adults without PWS (160.7-278.1 micromol/L and 0.80-3.99 mmol/L, respectively), and did not change with 12 months GH treatment. Glucose levels were normal, except in a patient with diabetes, and did not change during the study. Compared to baseline the immediate effect of GH injection resulted in a significant increase in glycerol levels after 12 months. In conclusion, night time lipolytic response in this small group of PWS adults seemed normal and did not change after 12 months GH treatment. On the other hand short-term GH induced lipolysis increased, indicating normal lipolytic response in PWS.     

High-affinity growth hormone (GH)-binding protein (GHBP), body fat mass, and insulin-like growth factor-binding protein-3 predict the GHBP response to GH therapy in adult GH deficiency syndrome

The study objective was to investigate which baseline factors can accurately predict plasma high-affinity growth hormone (GH)-binding protein (GHBP) levels after GH replacement therapy in patients with GH deficiency (GHD). The study group consisted of 36 GHD patients (22 men and 14 women; mean age, 43.1 years; (range, 21 to 60) known to have adult-onset GHD for many years (range, 4 to 22). They were randomly divided into a GH-treated group (n = 19) and a placebo group (n = 17). Body composition (assessed by bioelectrical impendance analysis [BIA]), plasma GHBP (fast protein liquid chromatography [FPLC] size-exclusion gel chromatography), insulin-like growth factor-I (IGF-I), and IGF-binding protein-3 ([IGFBP-3] radioimmunoassays) were measured before and after 6 months. A stepwise multiple linear regression analysis with the plasma GHBP level after 6 months as the dependent variable was used to unravel significant explanatory (or predictor) variables. In contrast to placebo therapy, GH replacement therapy increased the mean plasma levels of IGF-I and IGFBP-3 to the normal range, whereas a small but statistically significant increase in plasma GHBP was observed. The combination of baseline plasma GHBP, body fat mass, and IGFBP-3 predicts posttreatment GHBP levels accurately (adjusted R2 = .97), indicating that baseline variables such as age, gender, fat-free mass, and IGF-I have no contribution. Furthermore, reliability analysis showed that the observed and predicted values for GHBP fit a strict parallel model. These findings indicate that the variations in body fat mass and IGFBP-3 among adult GHD subjects explain the reported variable response of GHBP to GH replacement therapy.     

Body composition in active acromegaly during treatment with octreotide: a double-blind, placebo-controlled cross-over study

OBJECTIVE In active acromegaly body composition is characteristically altered by an increase in lean body mass and a corresponding reduction in fat mass. These changes are induced by an excessive secretion of GH and insulin-like growth factor I (IGF-I). Growth hormone is an anabolic hormone and leads to stimulation of protein synthesis and an increased lipolysis in adipose tissue. Treatment with the somatostatin analogue, octreotide, has been shown to reduce GH levels causing reduced hormonal effects on target tissues. We have studied changes in body composition during short-term reduction in OH level by octreotide in active acromegaly. DESIGN Octreotide was compared to placebo in a double-blind, cross-over trial. Dual-energy X-ray absorptlometry scanning was employed to calculate body composition. Relations between body composition parameters and clinical signs of acromegaly (finger circumference and foot volume) were studied. PATIENTS Twelve patients with active acromegaly, confirmed by lack of GH suppression during oral glucose loading, were included. All had pituitary adenomas diagnosed by computed tomography. MEASUREMENTS Serum GH and IGF-I. Lean body mass, fat mass and total weight, foot volume and finger circumference. RESULTS Four weeks of octreotide treatment caused a 75% decrease in GH levels (n= 10), a reduction in IGF-I from 476 ± 51·9 (mean±SEM) to 233 μg/l ± 46·3 (P < 0·005) and a corresponding decrease In both body weight (2·51 kg ± 0·41) (P <0·005) and lean body mass (2·44 kg ± 0·48) (P < 0·005). No significant changes in fat mass were observed. These findings were paralleled by significant reductions in foot volume (44·50ml ± 17) (P < 0·05) and finger circumference (1·3 mm ± 0·3) (P < 0·05). CONCLUSIONS Short-term octreotide therapy reduces growth hormone levels leading to a significant reduction in lean body mass as assessed by dual-energy X-ray absorptiometry. Alterations in lean body mass were positively correlated with reductions in foot volume. Thus, simple clinical tests may be valuable in judging the effects of treatment in active acromegaly.     

Body weight, body composition, and bone turnover changes in patients with spondyloarthropathy receiving anti-tumour necrosis factor {alpha} treatment

OBJECTIVES: To determine the changes in body weight, body composition, and bone turnover in patients with spondyloarthropathy (SpA) treated with anti-tumour necrosis factor alpha (TNFalpha). PATIENTS AND METHODS: 19 patients with SpA (2 women, 17 men), aged 21-71 years, were studied in a 1 year prospective open study. 17 patients received infliximab: 3 or 5 mg/kg/infusion at weeks 0, 2, 6 and infusions in the case of a relapse (n = 14) or systematically (n = 3); 2 patients received etanercept (25 mg twice a week). Body weight, body composition (lean mass, fat mass), and bone mineral density (BMD; using dual energy x ray absorptiometry) were measured at baseline and at months 6 and 12. Serum insulin-like growth factor-I (IGF-I), bone markers (carboxy terminal telopeptide of collagen Iota (CTX) and procollagen type Iota N terminal propeptide (PINP)) were measured at baseline and months 3, 6, and 12. RESULTS: In 1 year there was a significant increase in body weight (mean (SD) 2.24 (3.1) kg, p = 0.0004), and in lean mass (1.4 (1.69) kg, p = 0.005), but no changes in fat mass. BMD increased at the spine (5.6%, p = 0.0005) and total femur (2.6%, p = 0.01). CTX decreased from the third month (-50%, p = 0.005) up to 1 year (-30%, p = 0.012), and a trend for an increase in PINP (10%, p = 0.06) and in IGF-I (15%, p = 0.04) was seen at month 3. CONCLUSION: These data confirm that treatment with anti-TNFalpha in SpA is associated with an increase of BMD, which results from a decrease of bone resorption. Increase in body weight and lean mass is observed in parallel with an increase in IGF-1.     

Plasma leptin concentrations and four-year weight gain among US men

OBJECTIVE: Leptin, a primarily adipose tissue-derived protein product of the obesity (ob) gene, is an important regulator of energy metabolism. The strong association between body fat mass and elevated circulating leptin levels in humans suggests that leptin resistance, rather than leptin production, may contribute to the development of obesity and associated disorders. The purpose of this study is to evaluate the relationship between circulating plasma leptin levels and regulation of body weight over time among US men. DESIGN: Four-year prospective study. SUBJECTS: A total of 247 men from the Health Professionals Follow-up Study, who at baseline (1994), were 47-64 y of age, were free of cardiovascular diseases, diabetes mellitus and malignant neoplasmas, and completed a detailed lifestyle questionnaire. In addition, all participants completed a follow-up questionnaire in 1998. MEASUREMENTS: Baseline plasma leptin levels and 4-y weight change. RESULTS: At the start of follow-up, men in the highest quintile for plasma leptin (mean=12.1 ng/ml) weighed more, were less physically active, and had higher circulating insulin levels than men in the lowest quintile (mean=2.7 ng/ml). After adjustments for baseline age, weight, height, smoking status, alcohol intake, and physical activity, each 10 ng/ml increase in plasma leptin concentration was associated with a 1.68 kg (95% CI 0.14-3.18 kg) weight gain over the 4-y follow-up period. The observed association between leptin level and weight gain was limited to men with a baseline body mass index (BMI) of > or =25 kg/m2, in whom a 10 ng/ml higher baseline leptin was associated with a 2.45 kg (95% CI 0.73-4.18-kg) weight gain. Further adjustments for baseline total energy intake, plasma insulin and soluble tumor necrosis factor receptors levels did not appreciably alter these results. Plasma insulin level was not independently associated with subsequent weight gain. CONCLUSION: These results suggest that elevated plasma leptin concentrations among overweight men may be a marker of leptin resistance and subsequent weight gain.     

Growth hormone and insulin-like growth factor I treatment increase testicular luteinizing hormone receptors and steroidogenic responsiveness of growth hormone deficient dwarf mice

To test the hypothesis that insulin-like growth factor (IGF-I) is required for the in vivo development of testicular Leydig cell function, either recombinant human GH [(hGH) (1.5 micrograms/g BW) or recombinant IGF-I (1 microgram/g BW) was injected three times daily into immature Snell dwarf mice (dw/dw) and into phenotypically normal control (Dw/-) for 7 days. In dw/dw mice hGH enhanced significantly body, liver, kidney, and testicular weight. In addition, hGH increased testicular LH receptors and the acute steroidogenic response to human CG, but there was no significant effect on basal plasma testosterone or plasma LH levels. The effects of IGF-I in body and kidney weight were less pronounced than those produced by hGH, but its effects on testicular weight and LH receptors, as well as on the acute steroidogenic response to human CG, were similar to that observed after hGH treatment. In Dw/- mice hGH had no effect on either body or organ weight or on testicular function, despite the fact that it induced a significant increase in plasma IGF-I levels. These results indicated that IGF-I is able to induce the maturation of Leydig cell function and that the effects of hGH on the testis are probably mediated by IGF-I. They also suggest that the delayed puberty associated with GH deficiency or resistance is most likely related to an IGF-I deficiency.     

Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial

Adult GH deficiency (AGHD) is characterized by an altered body composition, an atherogenic lipid profile, decreased exercise capacity, and diminished quality of life. We performed a randomized, double-blind, placebo-controlled, multicenter study in 166 subjects with AGHD to assess the effects of GH on these outcomes. GH was initiated at 0.0125 mg/kg.d, increased to 0.025 mg/kg.d as tolerated, or decreased to 0.00625 mg/kg.d for 12 months. Primary measures of efficacy included body composition, strength and endurance, and quality of life. Additional parameters included serum IGF-I concentrations, serum lipids, and bone mineral density. After 12 months, 79% of subjects remained on GH 0.0125 mg/kg.d, whereas 21% received 0.00625 mg/kg.d. GH-treated men and women demonstrated significant decreases in total body and trunk fat and increases in lean body mass over baseline. In GH-treated men, mean IGF-I SD scores exceeded age-adjusted normal ranges, whereas similar doses produced a smaller response in women. GH treatment was associated with significant improvements in total cholesterol and low-density lipoprotein (P < 0.05 for all). No significant treatment effects were observed in strength and endurance, quality of life, or bone mineral density. GH treatment was generally well tolerated. Subjects with AGHD should receive individualized GH therapy to maintain IGF-I between the mean value and +2 SD and improve body composition and cardiovascular risk factors.     

In-vitro response of erythroid progenitors from children with thalassaemia major to human growth hormone and insulin-like growth factor I

OBJECTIVE Most short-statured children with β-thalassaemia major have markedly reduced levels of circulating insulin-like growth factor I (IGF-I). Both human growth hormone (hGH) and IGF-I enhance the in-vitro growth of erythroid progenitors, with hGH exerting its effects via paracrine production of IGF-I. The aim of this study was to characterize further the hGH-IGF-l axis abnormalities in thalassaemia major by evaluating the erythroid potentiating effects of both peptides in cultures of thalassaemic and control erythroid progenitors. DESIGN Ten short-statured thalassaemic children and nine age-matched healthy donors were evaluated for the in-vitro response of their peripheral blood erythroid progenitors to stimulation with hGH and IGF-I. MEASUREMENTS The frequency of erythroid progenitors in serum-free cultures of thalassaemic and control peripheral blood mononuclear cells was enumerated following 14 days of incubation in the presence of hGH or IGF-I. RESULTS Biosynthetic hGH induced a similar dose-dependent magnitude of colony enhancement in cultures of erythroid progenitors from thalassaemic children, as compared to controls. Significant enhancement of colony growth was detected at 42 μ/I hGH, with a maximal effect detected at 83 μ/I of this hormone (173 ± 8 vs 153 ± 9% of baseline erythroid progenitors in patients versus controls, respectively). Enhancement of both thalassaemic and control erythroid precursors by hGH was completely abrogated by monoclonal antibodies (αIR-3) directed against the IGF-I membrane receptor, thereby confirming the normal capacity of thalassaemic accessory cells to produce IGF-I in response to hGH. Biosynthetic IGF-I also enhanced the growth of thalassaemic and control erythroid precursors to 172±17 and 159±10% of baseline at 100 and 10 U/I, respectively. CONCLUSIONS Our detection of a normal capacity of thalassaemic peripheral blood target cells to response to hGH and IGF-I suggests that these patients do not suffer from a specific defect in receptor and/or post-receptor mechanism(s) involving the response of these cells to both peptides. The normal responsiveness of thalassaemic target cells to hGH and IGF-I suggests that both peptides may be useful in the treatment of growth retardation in thalassaemia.     

Thyrotropin-releasing hormone (TRH)-induced growth hormone (hGH) responses in cirrhotic men.

The plasma growth hormone (hGH) responses to an intravenous challenge of 400 micrograms of thyrotropin-releasing hormone (TRH) were evaluated in 14 normal controls and in 29 chronic alcoholic men. The normal controls had either a minimal or no hGH response to TRH, having basal hGH levels of 0.9 +/- 0.2 ng per ml and peak hGH levels of 2.0 +/- 0.5 ng per ml. In contrast, the chronic alcoholic men had a basal hGH level of 2.8 +/- 0.4 ng per ml, 3 times the basal level of the normal controls (P less than 0.01). The peak hGH response of the alcoholic men was 7.4 +/- 1.5 ng per ml (P less than 0.01). The 29 alcoholic men could be divided into two groups based upon the presence or absence of cirrhosis as determined by liver biopsy. The 16 alcoholic men with cirrhosis had greater basal hGH levels (3.5 +/- 0.6 ng per ml) and peak hGH levels (9.5 +/- 2.3 ng per ml) than did the 13 alcoholic men without cirrhosis (basal hGH 2.1 +/- 0.6 ng per ml, peak hGH 4.9 +/- 1.5 ng/ml). Plasma estradiol levels were similar in the normal controls and in the alcoholic men. In contrast, plasma estrone was greater in the alcoholic men (32.2 +/- 3.5 pg per ml) than in the normal controls (18.9 +/- 1.8 pg per ml) (P less than 0.05). However, when the plasma estrone levels of alcoholic men with cirrhosis were compared to those of the alcoholic men without cirrhosis no difference existed. Thus it is difficult to ascribe the increased hGH responses of the cirrhotic alcoholic men when compared to those of the noncirrhotic alcoholic men as being a result of increased basal estrogen levels.     

GH administration and discontinuation in healthy elderly men: effects on body composition, GH-related serum markers, resting heart rate and resting oxygen uptake

BACKGROUND AND OBJECTIVES: GH administration results in increased lean body mass (LBM), decreased fat mass (FM) and increased energy expenditure (EE). GH therapy may therefore have potential benefits, especially in the elderly, who are known to have decreased function of the GH/IGF-I axis. Several studies have focused on effects of GH administration in the elderly in the last decade. However, very limited information is available regarding changes in body composition and EE upon GH discontinuation in the elderly. The present study therefore investigated the effects of 12 weeks of GH administration and subsequent discontinuation on body composition, resting oxygen uptake (VO2), resting heart rate (HR) and GH related serum markers in healthy elderly men. SUBJECTS AND METHODS: Sixteen healthy men [age 74 +/- 1 years (mean +/- SEM), height 174.2 +/- 1.6 cm, body weight 80.7 +/- 2.6 kg, body fat 27.5 +/- 1.1%] completed the study protocol. Recombinant human GH (1.80 +/- 0.24 IU/day) was administered for 12 weeks in a single-blinded, placebo-controlled design. Body composition (dual energy X-ray absorptiometry), resting VO2 (indirect calorimetry), resting HR (telemetry) and serum IGF-I, IGF-II, IGFBP-3 and acid labile subunit (ALS) were measured at baseline, after 12 weeks of GH administration and, additionally in the GH group, 1, 2, 3, 4, 5 and 9 days after GH discontinuation. RESULTS: Body weight was unchanged from baseline to 12 weeks in both groups. However, GH administration caused a decrease in FM (3.4 +/- 1.0 kg, P < 0.012), paralleled by a similar increase in LBM (3.2 +/- 0.4 kg, P < 0.0002). Resting VO2 and resting HR increased by 31 +/- 3.6% and 7.3 +/- 1.9 per minute, respectively, in the GH-group, where significant increases in serum IGF-I, IGFBP-3 and ALS also were noted. None of the above parameters changed in the placebo group. Within 2-3 days after GH discontinuation, the GH related serum markers and resting HR returned to baseline levels, whereas resting VO2 remained elevated even 9 days after GH discontinuation. In addition, GH discontinuation caused a significant decrease in body weight (1.86 +/- 0.35 kg), derived exclusively from a decrease in LBM (1.63 +/- 0.43 kg), while the decreased FM was maintained (12 weeks: 17.93 +/- 1.65 kg, +9 days: 17.74 +/- 1.62 kg). CONCLUSIONS: The increases in serum IGF-I, IGFBP-3, ALS and resting heart rate induced by 12 weeks of GH administration in elderly men returned to baseline levels within 2-3 days after GH discontinuation. However, resting VO2 remained elevated for a longer period. GH administration reduced fat mass but maintained body weight by increasing lean body mass. In contrast, 9 days of GH discontinuation reduced body weight exclusively by reducing lean body mass.     

Treatment of post-menopausal osteoporosis with a combination of growth hormone and pamidronate: a placebo controlled trial

OBJECTIVE It is known that growth hormone can Induce accelerated bone turnover in GH deficient people as well as healthy elderly people. In this study we examined the effect of recombinant human GH (rhGH) on bone mineral mass and bone turnover in the presence of the bone resorption inhibiting agent, pamidronate. Effects on body composition were also studied. METHODS Twenty-one post-menopausal osteoporotic women were treated with the bisphosphonate pamidronate during 12 months. During the Initial 6 months rhGH (0.0675 IU/kg, 3 times/week) was administered In a placebo controlled fashion (10 vs 11 patients). MEASUREMENTS Bone mineral Content (BMC) of the lumbar spine and femoral neck was measured with dual-energy X-ray absorptiometry and BMC of the distal and proximal forearm with single-photon absorptiometry. Body composition was measured with bioelectrical Impedance and total body dual-energy X-ray absorptiometry. Serum IGF-I and biochemical indices of bone turnover were also measured. RESULTS The group treated with rhGH showed a two to three-fold Increase In serum IGF-I levels. No effects on bone mineral mass were observed in the group treated with rhGH, either after the Initial 6 months of treatment with rhGH or after the total period of 12 months. In women treated with pamidronate, however, a consistent increase of about 5% at the lumbar spine and somewhat less in the distal forearm was reached from 6 months onwards. In neither group was any change observed in BMC at the femoral neck or forearm. Compared to baseline, the biochemical measurements of bone turnover showed a decrease of about 50% in the pamidronate treated group, but this effect was blunted in the group additionally treated with rhGH. The body composition measurements showed clear effects of rhGH administration: a decrease in fat mass of about 5% and an increase In lean body mass of about 3%. However, these effects disappeared after the treatment with rhGH was stopped and both fat mass and lean body mass returned to Initial values. CONCLUSIONS The present study suggests that treatment with rhGH blunted both the pamidronate induced accumulation of bone mineral mass and the reduction of biochemical markers of bone turnover. Furthermore, the positive effect of rhGH on body composition disappears completely after cessation of treatment with rhGH.     

Differential effects on kidney and liver growth of a non-viral hGH-expression vector in hypophysectomized mice

Non-viral gene transfer was investigated as a potential modality for the treatment of growth hormone deficiency (GHD) using hypophysectomized (Hx) mice as a model. Hx mice were injected with a control plasmid or a plasmid containing the human (h) GH gene driven by a ubiquitin promoter, or left untreated. Treatment with the hGH gene has previously been shown to normalize longitudinal growth and serum insulin-like growth factor I (IGF-I). The present study was conducted to examine the renal/hepatic changes and gene/peptide expression of the GH/IGF-I axis in animals chronically expressing hGH. Following a single hydrodynamic administration of a plasmid DNA containing the hGH gene, a sustained elevation of the circulating hGH level was observed throughout the entire observation period, with a concomitant normalization of circulating IGF-I and IGF-binding protein 3 (IGFBP-3). In addition, longitudinal growth was corrected by normalizing tibia length, tail length, and body weight gain. Interestingly, kidney weights were only partly normalized, whereas kidney glomerular volume and liver weights were fully normalized. Kidney and liver IGF-I protein content was reduced in the Hx mice, but was normalized by hGH treatment. Kidney and liver GH receptor (GHR) mRNA levels were unchanged in the Hx mice, whereas the liver IGF-I mRNA level was reduced in the Hx mice, but was normalized by hGH treatment.We conclude that non-viral hGH gene transfer in Hx mice, which normalizes longitudinal growth and serum IGF-I levels, has differential effects on renal growth and glomerular volume. The potential effects of such excess glomerular growth induced by this intervention require further investigation.