Effects of growth hormone on body composition and bone metabolism

Physiologic effects of growth hormone (GH) extend beyond the stimulation of linear growth during childhood and adolescence. These effects include building and sustaining lean body mass, facilitating the utilization of fat mass for energy needs, and maintaining bone mineral density. These nongrowth effects of GH appear to be important throughout life. Children and adults with severe GHD demonstrate marked reductions in lean body mass, increases in percent body fat, and subnormal bone mineral density. Replacement of GH attenuates these abnormalities, though it remains unknown whether it does so completely. Children with body composition abnormalities resembling the GHD state (e.g., Prader-Willi syndrome) also appear to respond fovorably to administration of GH treatment, and demonstrate concomitant improvements in strength and agility. Long-term body composition benefits of GH supplementation in these and other non-GHD individuals remain unproven.     

The association between growth response to growth hormone and baseline body composition of children with growth hormone deficiency

ObjectiveWe wanted to examine the relationship between initial growth response to recombinant human Growth Hormone (rhGH) treatment and body composition in children with growth hormone deficiency (GHD).Design and methodsForty-two patients (21 boys and 21 girls) aged between 5.7–15.5 years (mean age: 10.8 ± 2.6 years) with isolated GHD. The auxological and laboratory data (GH and IGF-I levels) and results of bioelectrical impedance analyses were evaluated. Children with GHD were followed up for 12 months and categorized according to growth response to rhGH into good and poor responders (change in height of > 0.7 SDS or < 0.7 SDS over one year respectively). Mean doses of rhGH per kg of fat free mass (FFM) were calculated.ResultsForty-eight percent of patients showed a good growth response to rhGH therapy. At study entry, mean age, height SDS, weight SDS, serum IGF-1 SDS, IGFBP-3 SDS, growth velocity prior to rhGH therapy, GH after clonidine and l-dopa were similar in the two groups. At baseline, BMI SDS and waist–hip ratio were significantly higher in good responders (p = 0.02 and p = 0.006, respectively). Good responders had lower percentages of FFM (73.4 ± 8.9 vs. 83.1 ± 5.9) and total body water (TBW) (56.5 ± 5.3 vs. 63.1 ± 4.4), compared to poor responders (p < 0.05). There were significant correlations between changes in height SDS over one year and baseline body composition in children with GHD on rhGH treatment (r = ? 0.617 for percentage of FFM, r = ? 0.629 for percentage of TBW, p < 0.001). A correlation between BMI SDS, waist–hip ratio, mean rhGH dose per FFM and growth response was observed only in prepubertal subjects.ConclusionBaseline body composition data in children with GHD can be used to predict the growth response to rhGH treatment. A management strategy that involves titrating rhGH dose according to FFM as a means of optimizing the growth response to intervention requires further study.     

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

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

Adults with partial growth hormone deficiency have an adverse body composition

The current biochemical definition of severe GH deficiency (stimulated peak GH < 3 micro g/liter) provides good separation of GH-deficient (GHD) adults from normal subjects, although it may not account for all patients with impaired GH secretion. The vast majority of normal subjects display a peak GH level in excess of 7 micro g/liter in response to the insulin tolerance test. Using a peak GH response of 7 micro g/liter as an arbitrary upper limit, we investigated the effects of partial GH deficiency (GH insufficiency, GHI; peak GH response of 3-7 micro g/liter) on the body composition of hypopituitary adults. GHD adults (n = 30, peak GH < 3 micro g/liter) were of shorter stature than the controls. Body mass index was not significantly increased, but waist/hip ratio (0.885 vs. 0.818, P = 0.001) and skinfold thickness (78.2 vs. 59.6 mm, P = 0.003) were greater than control subjects. Bioimpedance analysis revealed these patients to have reduced lean body mass (LBM) (44.4 vs. 51.2 kg, P = 0.023) and increased fat mass (FM) (25.7 vs. 18.4 kg, P = 0.039). Dual-energy x-ray absorptiometry (DXA) analysis of body composition confirmed reduced LBM (43.6 vs. 50.6 kg, P = 0.010) and increased FM (26.0 vs. 19.2 kg, P = 0.015). The excess FM was observed to be primarily truncal in distribution. Similarly, GHI adults were of shorter stature but with increased waist/hip ratio (0.871 vs. 0.818, P = 0.006) and skinfold thickness (80.8 vs. 59.6 mm, P = 0.003), compared with controls. Bioimpedance analysis revealed a reduction in LBM (44.9 vs. 51.2 kg, P = 0.020). DXA studies confirmed the reduced LBM (45.0 vs. 50.6 kg, P = 0.041) and additionally noted an increase in percent FM (32.9 vs. 27.4%, P = 0.019). All measures of body composition in the GHI patients were intermediate between those of the controls and GHD patients. Serum leptin levels were significantly elevated in both the GHD (41.5 vs. 20.7 ng/ml, P = 0.009) and GHI (36.7 vs. 20.7 ng/ml, P = 0.022) adults, compared with healthy controls. The excess FM observed using DXA in the GHD and GHI adults equated to 6.5 kg (8%) and 3.5 kg (5.5%), respectively, relative to healthy controls. In summary, we have shown that adults with GHI have abnormalities of body composition characteristic of GHD. The degree of abnormality of body composition lies between that of healthy subjects and GHD adults and correlates with the IGF-I level. Any future trials of GH replacement in patients with GHI must await further studies to establish the exact impact of this relative deficiency on the broad spectrum of biological end points influenced by GH status.     

Effect of growth hormone and 17beta-oestradiol treatment on metabolism and body composition in girls with Turner syndrome

OBJECTIVE: Girls with Turner syndrome (TS) receive GH treatment during childhood, and in adolescence this treatment may be combined with oestradiol. We have studied the effects of this combined treatment on metabolism and body composition. MATERIAL AND METHODS: We performed a double-blind, placebo-controlled, randomized, crossover study. All girls with TS (n = 8, 16 +/- 2 years) were treated with placebo + placebo, GH + placebo or GH + 17beta-oestradiol for 2 months, and were studied at the end of each period. Controls (n = 10, 14 +/- 2 years) were studied once without treatment. Twenty-four-hour sampling of oestradiol, growth factors, insulin, glucose, lipolytic and gluconeogenic precursors was performed, followed by an oral glucose tolerance test (OGTT) and assessment of body composition and mineral content. RESULTS: GH induced insulin resistance, which was not aggravated further by concomitant oestradiol treatment. The 24-h integrated serum 17beta-oestradiol was reduced compared to controls (0.58 +/- 0.32 vs. 2.81 +/- 2.78 nmol/l/24 h, P = 0.032), but increased during GH + oestrogen (E2) treatment without reaching control levels, while GH + placebo caused a further reduction (anova, P = 0.008). Total fat mass was increased in girls with TS compared with controls (P = 0.009), while lean body mass (P = 0.02) and bone mineral content (P = 0.04) was decreased, with specific regional characteristics in body composition. CONCLUSION: GH treatment induces insulin resistance and changes in body composition in TS, which is not further compromised by concomitant oestradiol treatment. Body composition is changed in TS, with specific regional changes, in comparison with controls. Integrated 24-h oestradiol is low in TS, and is only partially restored during treatment with standard doses of 17beta-oestradiol.     

Body composition phenotypes in pathways to obesity and the metabolic syndrome

Dynamic changes in body weight have long been recognized as important indicators of risk for debilitating diseases. While weight loss or impaired growth can lead to muscle wastage, as well as to susceptibility to infections and organ dysfunctions, the development of excess fat predisposes to type 2 diabetes and cardiovascular diseases, with insulin resistance as a central feature of the disease entities of the metabolic syndrome. Although widely used as the phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI), that is, weight/height(2) (H(2)), which was developed as an operational definition for classifying both obesity and malnutrition, has considerable limitations in delineating fat mass (FM) from fat-free mass (FFM), in particular at the individual level. After an examination of these limitations within the constraints of the BMI-FM% relationship, this paper reviews recent advances in concepts about health risks related to body composition phenotypes, which center upon (i) the partitioning of BMI into an FM index (FM/H(2)) and an FFM index (FFM/H(2)), (ii) the partitioning of FFM into organ mass and skeletal muscle mass, (iii) the anatomical partitioning of FM into hazardous fat and protective fat and (iv) the interplay between adipose tissue expandability and ectopic fat deposition within or around organs/tissues that constitute the lean body mass. These concepts about body composition phenotypes and health risks are reviewed in the light of race/ethnic variability in metabolic susceptibility to obesity and the metabolic syndrome.     

Growth hormone deficiency in the transition period: body composition and gonad function

Recombinant GH therapy is normally administered to GH-deficient children in order to achieve a satisfactory height - the main target during childhood and adolescence. However, the role of GH does not end once final height has been reached, but continues during the so-called transition period. In this phase of life, the body undergoes several changes, both physical and psychological, that culminate in adulthood. During this period, GH has a part in numerous metabolic functions. These include the lipid profile, where it increases HDL and reduces LDL, with the global effect of cardiovascular protection. It also has important effects on body composition (improved muscle strength and lean body mass and reduced body fat), the achievement of proper peak bone density, and gonad maturation. Retesting during the transition period, involving measurement of IGF-I plus a provocative test (insulin tolerance test or GHRH + arginine test), is thus necessary to establish any persistent GH deficiency requiring additional replacement therapy. The close cooperation of the medical professionals involved in the patient's transition from a pediatric to an adult endocrinologist is essential. The aim of this review is to point out the main aspects of GH treatment on body composition, metabolic and gonad functions in the transition period.     

Total body composition in adult patients with growth hormone deficiency before and after its administration

Effect of growth hormone (GH) on the growth and development of children is generally known. Effects of GH in adults are favorable, though. The aim of the work was to verify effects of GH administration on body composition in adult patients with GH deficit (GHD). The authors examined 15 adult patients with GHD originated in 13 of them in adulthood and in two of them in childhood. Their mean age was 43.9 +/- 11.3 years, the mean body mass was 80.0 +/- 15.2 kg. The GH deficit was verified by the stimulation insulin tolerance test. For the period of 12 months, they were subcutaneously administered recombinant human GH in a substitution dose of 0.5 to 1.5 IU/m2 body surface/day. A stable substitution of the hormone was applied for the period of at least six months in all these patients provided any deficit of other hormones had not been demonstrated. The examination by whole-body dosimeter Lunar DPX-L was made in the patients before the GH treatment began and after 12 months of therapy. It enabled to determine the amount of lean body mass (LBM) and fatty mass. After 12 months of GH treatment the mean level of insulin-like growth factor (IGF-I) was increased (P = 0.002). A statistically significant increase of total LBM (48.6 +/- 9.8 vs. 50.8 +/- 9.9 kg, P = 0.004) developed, the fatty mass did not change. Nine of these 15 patients were further followed and the administration of GH proceeded for six months. The densitometric examination was repeated, but no change of LBM was observed. The administration of GH was halted and after the period of 12 months the whole-body densitometric examination was done. The increase of LBM lasted. The amount of fat mass did not change, a decrease of fatty mass was observed after the GH administration ended. After 12 months of GH treatment there was also an increase of maximal output reached on bicycle ergometer (157.3 +/- 34.2 vs. 197.5 +/- 68.1 W, P = 0.006). A positive correlation between LBM and maximal output reached on bicycle ergometer before GH administration (r = 0.58, P = 0.02) was observed. A favorable effect of the substitution dose of GS administered to adult patients with GHD on the increase of LBM and physical output was confirmed.     

Synergistic effects of testosterone and growth hormone on protein metabolism and body composition in prepubertal boys

During human puberty there is a substantial increase in growth hormone (GH) and sex steroidal hormone concentrations, as well as in GH production rates and insulin-like growth factor-I (IGF-I) These studies were designed to investigate some of the interactions of testosterone (T) and GH in the metabolic changes of puberty. Ten boys with severe GH deficiency (GHD) were studied (mean age, 12.5 +/- 0.5 years) using stable isotope infusions, indirect calorimetry, and body composition analysis. After the baseline study, they received 2 doses of T enanthate (50 to 75 mg, intramuscular [IM]), and they were studied again 4 weeks later. The boys were then begun on daily subcutaneous (SC) GH (0.3 mg/kg/wk), while T therapy was continued for another 4 weeks and the studies repeated a third time. The treatment order was randomized. Protein oxidation rates decreased after T alone (-28%, P <.01), decreasing further after combined T/GH treatment (-36% v baseline, P <.01). The nonoxidative leucine disposal (NOLD), a measure of whole body protein synthesis, increased significantly after combined T/GH regardless of treatment order. The combination of T/GH also resulted in greater changes in body composition than T alone, with comparable decreases in %FM and corresponding increases in fat free mass (FFM). Measures of carbohydrate (CHO) metabolism, including glucose production and oxidation rates, were unaffected by either T or T/GH combination. Plasma IGF-I concentrations increased after T treatment and even more after T/GH combination, regardless of the treatment order. In conclusion GH and T are synergistic on whole body protein anabolism and body composition in males, even at a young age, but the positive effects of T on protein anabolism and body composition appear to need a basal amount of GH for those effects to be observed. GH and T both potentiate the development of the full body composition and metabolic changes of puberty.     

Short-term effects of growth hormone on body composition as a predictor of growth

The objective of this study was to investigate whether short-term changes in metabolism, as a result of GH therapy, could be used to predict its growth effect after 1 yr. Twenty-eight children (8.7 +/- 2.8 yr) were selected, based on anthropometric criteria characterizing GH-deficient patients. In addition, 21 healthy, age- and sex-matched controls (8.9 +/- 3.1 yr) were included. Total body water (TBW) and height were measured before and at 6 wk and 1 yr after the start of treatment. After 1 yr of treatment, patients were divided into good and poor responders, based on a change in height of at least 0.7 SD. Because individuals of different heights were compared, changes in TBW after 6 wk were corrected for height(2), in accordance with the body mass index. Eighty percent of the children who showed a good response to GH therapy had a change in TBW divided by height(2) exceeding the 2 SD reference line of the controls. In contrast, poor responders did not differ from controls. Maximum GH concentrations found during endocrine tests were not significantly different between good and poor responders. Changes in body composition data, after 6 wk, proved valuable in identifying good responders to GH therapy.     

Pubertal alterations in growth and body composition: IX. Altered spontaneous secretion and metabolic clearance of growth hormone in overweight youth

Deconvolution analysis was used to determine 12-hour spontaneous nocturnal growth hormone (GH) secretion and GH half-life in lean (body mass index, <85th percentile; n = 39) and overweight (body mass index, > or =85th percentile; n = 18) youth. The integrated GH concentration, GH burst mass, and half-life were lower (P < .05) in overweight than in lean youth. For each unit increase in percentage of body fat, integrated serum GH concentrations, secretory burst mass, and half-life declined by 83.6 microg/L per minute (r = -0.39, P < .01), 0.22 microg/L (r = -0.28, P < .05), and 0.2 minute (r = -0.38, P < .01), respectively. The effect of overweight on GH secretion was independent of pubertal status. Hierarchical regression models tested the hypothesis that altered GH secretion in youth is more related to total adiposity than abdominal visceral fat. When age, sex, fat-free mass, testosterone, and estradiol were held constant, the sequential addition of abdominal visceral fat did not increase R2 for any GH secretion variable. Sequential addition of percentage of body fat increased R2 (P < .05) for integrated GH concentration, total secretory rate, secretory burst mass, and pulsatile production rate. We conclude that serum GH concentrations are reduced in overweight youth primarily because of reduced GH burst mass with no change in the number of secretory events and secondarily to reduced GH half-life. Based on the model that GH-releasing hormone predominantly increases GH pulse amplitude whereas somatostatin primarily controls GH pulse frequency, these results suggest that overweight in youth diminishes GH-releasing hormone stimulation resulting in truncated GH bursts but does not alter the number of somatostatin withdrawal intervals so that GH burst frequency is conserved.     

Energy expenditure and body composition in growth hormone deficient adults on exogenous growth hormone

OBJECTIVES We assessed whether the obesity observed in growth hormone deficient adults is maintained by a reduction in energy expenditure. We studied the effects of exogenous growth hormone on energy expenditure and body composition. DESIGN We performed an open study with growth hormone administered at 0 5 units per kilogram ideal body weight per week for 3 months. PATIENTS Seven growth hormone deficient adults were studied. Thirty-eight healthy volunteers had their resting metabolic rate measured, with seven of them proceeding to have their total energy expenditure assessed. MEASUREMENTS Total energy expenditure was measured by the doubly labelled water method (D₂0¹⁸), resting metabolic rate by ventilated hood indirect calorimetry, and fat free mass from the dilution volume of oxygen-18. Body composition and components of energy expenditure were assessed before, at 2 weeks and at the end of the 3-month treatment period on exogenous growth hormone. RESULTS Growth hormone deficient adults did not have a low total energy expenditure compared to healthy controls (13 12 vs 12 75 MJ/24 h) with only one patient expending less than 10 MJ/24 h. None had a resting metabolic rate lower than the 95% confidence limits of normality. The amount of energy expended on physical activity and thermogenesis was significant (6 54 MJ/24 h) and was similar to healthy controls (6 47 MJ/24 h). Resting metabolic rate increased by 15 9% after 14 days on exogenous growth hormone and was elevated 12-1% after 3 months treatment but the ratio to fat-free mass remained unaltered. Total energy expenditure increased by 13 4% after 14 days therapy. Fat-free mass increased significantly after 3 months treatment by (mean) 4 5 kg with no change in fat mass and no loss in body weight. CONCLUSIONS Obesity maintenance in growth hormone deficient adults is not a consequence of reduced total energy expenditure or a reduced exercise energy output. There was also no evidence for an energy sparing mechanism. Energy expenditure was increased by exogenous growth hormone but was not associated with a loss in fat mass or body weight suggesting the need for dietetic advice for those already obese at the outset of therapy.     

Development of the obese-hyperglycemic syndrome in mice with a growth hormone deficiency

By mating mice heterozygous for the recessive gene, obese (ob/+) (+/+), with mice homozygous for the recessive gene, dwarf (+/+) ($\text{dw}\text{dw}$, and subsequent mating of the offspring, mice homozygous for both the obese and dwarf gene were obtained. It was established that the genes for obese and dwarf mice belong to different linkage groups. The homozygous obese dwarf mice develop obesity and hyperinsulinemia. The degree of hyperglycemia developed by these homozygotes is not significantly different from that of nonobese dwarf mice. Because homozygous dwarf mice are deficient in growth hormone production, it was concluded that obesity and hyperin-sulinemia can develop under conditions of extreme growth hormone deficiency.