Effect of growth hormone treatment on adult height of children with idiopathic short stature. Genentech Collaborative Group.
BACKGROUND: Short-term administration of growth hormone to children with idiopathic short stature results in increases in growth rate and standard-deviation scores for height. However, the effect of long-term growth hormone therapy on adult height in these children is unknown. METHODS: We studied 121 children with idiopathic short stature, all of whom had an initial height below the third percentile, low growth rates, and maximal stimulated serum concentrations of growth hormone of at least 10 microg per liter. The children were treated with growth hormone (0.3 mg per kilogram of body weight per week) for 2 to 10 years. Eighty of these children have reached adult height, with a bone age of at least 16 years in the boys and at least 14 years in the girls, and pubertal stage 4 or 5. The difference between the predicted adult height before treatment and achieved adult height was compared with the corresponding difference in three untreated normal or short-statured control groups. RESULTS: In the 80 children who have reached adult height, growth hormone treatment increased the mean standard-deviation score for height (number of standard deviations from the mean height for chronologic age) from -2.7 to -1.4. The mean (+/-SD) difference between predicted adult height before treatment and achieved adult height was +5.0+/-5.1 cm for boys and +5.9+/-5.2 cm for girls. The difference between predicted and achieved adult height among treated boys was 9.2 cm greater than the corresponding difference among untreated boys with initial standard-deviation scores of less than -2, and the difference among treated girls was 5.7 cm greater than the difference among untreated girls. CONCLUSION: Long-term administration of growth hormone to children with idiopathic short stature can increase adult height to a level above the predicted adult height and above the adult height of untreated historical control children. (+info
Perioperative growth hormone treatment and functional outcome after major abdominal surgery: a randomized, double-blind, controlled study.
OBJECTIVE: To evaluate short- and long-term effects of perioperative human growth hormone (hGH) treatment on physical performance and fatigue in younger patients undergoing a major abdominal operation in a normal postoperative regimen with oral nutrition. SUMMARY BACKGROUND DATA: Muscle wasting and functional impairment follow major abdominal surgery. METHODS: Twenty-four patients with ulcerative colitis undergoing ileoanal J-pouch surgery were randomized to hGH (12 IU/day) or placebo treatment from 2 days before to 7 days after surgery. Measurements were performed 2 days before and 10, 30, and 90 days after surgery. RESULTS: The total muscle strength of four limb muscle groups was reduced by 7.6% in the hGH group and by 17.1% in the placebo group at postoperative day 10 compared with baseline values. There was also a significant difference between treatment groups in total muscle strength at day 30, and at the 90-day follow-up total muscle strength was equal to baseline values in the hGH group, but still significantly 5.9% below in the placebo group. The work capacity decreased by approximately 20% at day 10 after surgery, with no significant difference between treatment groups. Both groups were equally fatigued at day 10 after surgery, but at day 30 and 90 the hGH patients were less fatigued than the placebo patients. During the treatment period, patients receiving hGH had reduced loss of limb lean tissue mass, and 3 months after surgery the hGH patients had regained more lean tissue mass than placebo patients. CONCLUSIONS: Perioperative hGH treatment of younger patients undergoing major abdominal surgery preserved limb lean tissue mass, increased postoperative muscular strength, and reduced long-term postoperative fatigue. (+info
Long-term effects of growth hormone (GH) on body fluid distribution in GH deficient adults: a four months double blind placebo controlled trial.
OBJECTIVE: Short-term growth hormone (GH) treatment normalises body fluid distribution in adult GH deficient patients, but the impact of long-term treatment on body fluid homeostasis has hitherto not been thoroughly examined in placebo controlled trials. To investigate if the water retaining effect of GH persists for a longer time we examined the impact of 4 months GH treatment on extracellular volume (ECV) and plasma volume (PV) in GH deficient adults. DESIGN: Twenty-four (18 male, 6 female) adult GH deficient patients aged 25-64 years were included and received either GH (n=11) or placebo (n=13) in a double blind parallel design. METHODS: Before and at the end of each 4 month period ECV and PV were assessed directly using 82Br- and 125I-albumin respectively, and blood samples were obtained. RESULTS: During GH treatment ECV increased significantly (before: 20.48+/-0.99 l, 4 months: 23.77+/-1.38 l (P<0.01)), but remained unchanged during placebo administration (before: 16.92+/-1.01 l, 4 months: 17.60+/-1.24 l (P=0.37)). The difference between the groups was significant (P<0.05). GH treatment also increased PV (before: 3.39+/-0.27 l. 4 months: 3.71+/-0.261 (P=0.01)), although an insignificant increase in the placebo treated patients (before: 2.81+/-0.18 l, 4 months: 2.89+/-0.20 l (P=0.37)) resulted in an insignificant treatment effect (P=0.07). Serum insulin-like growth factor-I increased significantly during GH treatment and was not affected by placebo treatment. Plasma renin (mIU/l) increased during GH administration (before: 14.73+/-2.16, 4 months: 26.00+/-6.22 (P=0.03)) and remained unchanged following placebo (before: 20.77+/-5.13, 4 months: 20.69+/-6.67 (P=0.99)) leaving no significant treatment effect (P=0.08). CONCLUSION: The long-term impact of GH treatment on body fluid distribution in adult GH deficient patients involves expansion of ECV and probably also PV. These data substantiate the role of GH as a regulator of fluid homeostasis in adult GH deficiency. (+info
Long-term results of GH therapy in GH-deficient children treated before 1 year of age.
OBJECTIVES: To evaluate the long-term effects of GH therapy in early diagnosed GH-deficient patients treated before 1 year of age. STUDY DESIGN: We studied all 59 patients (33 males) recorded by Association France-Hypophyse and treated with GH (0.50+/-0.15 IU/kg (S.D.) per week) before 1 year of age. Clinical presentation and growth parameters under GH treatment were analyzed. RESULTS: Neonatal manifestations of hypopituitarism were frequent: hypoglycemia (n=50), jaundice (n=25) and micropenis (n=17/33). Although birth length was moderately reduced (-0.9+/-1.4), growth retardation at diagnosis (5.8+/-3.8 months) was severe (-3.5+/-1.9 standard deviation scores (SDS)). Fifty patients (85%) had thyrotropin and/or corticotropin deficiency. After a mean duration of GH therapy of 8.0+/-3.6 years, change in height SDS was +3.11+/-2.06 S.D., exceeding 4 SDS in 19 patients. Only 9 patients (15%) did not reach a height of -2 S.D. for chronological age and 20 patients (34%) exceeded their target height. Pretreatment height SDS was independently associated with total catch-up growth. CONCLUSION: Conventional doses of GH allow normalization of height in patients with early GH deficiency and treatment. (+info
Changes in body composition and leptin levels during growth hormone (GH) treatment in short children with various GH secretory capacities.
OBJECTIVE: The aim of this study was to follow changes in body composition, estimated by dual-energy X-ray absorptiometry (DXA), in relation to changes in leptin during the first year of GH therapy in order to test the hypothesis that leptin is a metabolic signal involved in the regulation of GH secretion in children. DESIGN AND METHODS: In total, 33 prepubertal children were investigated. Their mean (S.D.) chronological age at the start of GH treatment was 11.5 (1.6) years, and their mean height was -2.33 (0.38) S.D. scores (SDS). GH was administered subcutaneously at a daily dose of 0.1 (n=26) or 0.2 (n=7) IU/kg body weight. Ten children were in the Swedish National Registry for children with GH deficiency, and twenty-three children were involved in trials of GH treatment for idiopathic short stature. Spontaneous 24-h GH secretion was studied in 32 of the children. In the 24-h GH profiles, the maximum level of GH was determined and the secretion rate estimated by deconvolution analysis (GHt). Serum leptin levels were measured at the start of GH treatment and after 10 and 30 days and 3, 6 and 12 months of treatment. Body composition measurements, by DXA, were performed at baseline and 12 months after the onset of GH treatment. RESULTS: After 12 months of GH treatment, mean height increased from -2.33 to -1.73 SDS and total body fat decreased significantly by 3.0 (3.3)%. Serum leptin levels were decreased significantly at all time points studied compared with baseline. There was a significant correlation between the change in total body fat and the change in serum leptin levels during the 12 months of GH treatment, whereas the leptin concentration per unit fat mass did not change. In a multiple stepwise linear regression analysis with 12 month change in leptin levels as the dependent variable, the percentage change in fat over 12 months, the baseline fat mass (%) of body mass and GHt accounted for 24.0%, 11.5% and 12.2% of the variability respectively. CONCLUSIONS: There are significant correlations between changes in leptin and fat and endogenous GH secretion in short children with various GH secretory capacities. Leptin may be the messenger by which the adipose tissue affects hypothalamic regulation of GH secretion. (+info
GH-binding protein in obese men with varying glucose tolerance: relationship to body fat distribution, insulin secretion and the GH-IGF-I axis.
Bioelectrical impedance for measurement of total body fat and computed tomography for visceral and subcutaneous fat at umbilicus levels were performed in 34 obese and 10 lean men. Insulin secretion in response to an oral glucose tolerance test (OGTT) and a GH stimulation test by L-dopa, growth hormone-binding protein (GHBP) and IGF-I were measured. Obese subjects were divided into three groups according to the OGTT. The obese type II diabetes mellitus group had the highest GHBP levels and the most visceral fat. GHBP levels were most strongly correlated with the ratio of visceral fat area to body weight (VWR) above any other parameters (r = 0.725, P<0.001). The insulin and free fatty acid (FFA) areas under curves (AUC) during the OGTT, and the IGF-I level, were also positively correlated with GHBP levels (r = 0.474, P<0.005; r = 0.572, P<0.005; r = 0.453. P<0.005). GH-AUC to the L-dopa stimulation test was negatively correlated with GHBP levels (r = -0.432. P<0.005). Stepwise multiple linear regression analysis showed that VWR, FFA-AUC and insulin-AUC significantly contributed to the variability of GHBP (r2 = 0.58). In conclusion, we demonstrated that: (i) visceral fat amount mainly determined GHBP levels in obese men with varying glucose tolerance: (ii) hyperglycemia per se did not influence the GHBP level, whereas insulin and FFA could play a role in regulation of GHBP: and (iii) although GH was not the main regulator of GHBP, the unchanged IGF-I level despite GH hyposecretion suggests that increased GHBP levels reflect GH hypersensitivity in order to compensate for decreased GH secretion in obesity. (+info
Apo E phenotype and changes in serum lipids in adult patients during growth hormone replacement.
OBJECTIVE: To determine whether apo E phenotype influences changes in lipid profiles induced by growth hormone replacement in growth hormone (GH)-deficient adults. DESIGNS: Patients were treated for 6 months with recombinant human GH (hGH), given in a dose of 0.125 U/kg per week for 4 weeks followed by 0.25 U/kg per week thereafter. The effects on serum lipids and the influence of apo E phenotype were examined. METHODS: Thirty patients (aged 35.1+/-11.8 years: mean +/- S.D.) with adult growth hormone deficiency with included in the study. Fasting serum samples were analysed for apo E phenotype total cholesterol, high-density lipoprotein (HDL)-cholesterol, triglycerides, lipoprotein (a) (Lp(a)) and IGF-I. Low-density lipoprotein (LDL)-cholesterol was calculated using the Friedwald formula. RESULTS: Six months of replacement treatment with hGH resulted in a reduction in HDL-cholesterol from 0.90+/-0.10 to 0.68+/-0.08 mmol/l (P<0.01), and a small, non-significant reduction in total cholesterol from 6.14+/-0.40 to 5.99+/-0.35 mmol/l (P = 0.06). There was no significant change in the other lipid parameters. The decrease in HDL-cholesterol concentration was greater in patients carrying the apo E2 allele (0.40+/-0.07 mmol/l, P<0.05) than in patients homozygous for the apo E3 allele (0.23+/-0.04 mmol/l) and patients carrying the apo E4 allele (0.15+/-0.36 mmol/l). Patients with the apo E4 allele had lower baseline cholesterol concentrations than patients lacking the apo E4 allele, and this persisted after treatment with hGH (P<0.05). CONCLUSIONS: Apo E phenotype may be a determining factor in the response of HDL-cholesterol to hGH in GH-deficient adults. (+info
Decreased hexosamine biosynthesis in GH-deficient dwarf rat muscle. reversal with GH, but not IGF-I, therapy.
Enhanced glucose flux via the hexosamine biosynthesis pathway (HNSP) has been implicated in insulin resistance. We measured L-glutamine:D-fructose-6-phosphate amidotransferase activity (GFAT, a rate-limiting enzyme) and concentrations of UDP-N-acetyl hexosamines (UDP-HexNAc, major products of HNSP) in muscle and liver of growth hormone (GH)-deficient male dwarf (dw) rats. All parameters measured, except body weight, were similar in 5-wk-old control and dw rats. Muscle GFAT activity declined progressively with age in controls and dw rats but was consistently 30-60% lower in 8- to 14-wk-old dw rats vs. age-matched controls; UDP-HexNAc concentrations in muscle were concomitantly 30% lower in dw rats vs. controls (P < 0.01). Concentrations of UDP-hexoses, GDP-mannose, and UDP in muscle were similar in control and dw rats. Muscle HNSP activity was similarly diminished in fed and fasted dw rats. In liver, only a small difference in GFAT activity was evident between controls and dw rats, and no differences in UDP-HexNAc concentrations were observed. Treatment with recombinant human GH (rhGH) for 5 days restored UDP-HexNAc to control levels in dw muscles (P < 0.01) and partially restored GFAT activity. Insulin-like growth factor I treatment was ineffective. We conclude that GH participates in HNSP regulation in muscle. (+info