TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy. Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly Increased lipid peroxidation in adult GH-deficient patients: Effects of short-term GH administration Efficacy and safety of a new ready-to-use recombinant human growth hormone solution Long-acting PEGylated recombinant human growth hormone (Jintrolong) for children with growth hormone deficiency: phase II and phase III multicenter, randomized studies Baseline characteristics and effects of growth hormone therapy over two years in younger and elderly adults with adult onset GH deficiency. A randomized controlled trial of low-dose recombinant human growth hormone in the treatment of malnourished elderly medical patients. Long-term monitoring of insulin sensitivity in growth hormone-deficient adults on substitutive recombinant human growth hormone therapy. Effects of GH on cognitive function in elderly patients with adult-onset GH deficiency: a placebo-controlled 12-month study. Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function. Diagnostic strategy for growth hormone deficiency: relevance of IGF-1 determination as a screening test. Muscle strength in elderly adults with GH deficiency after 10 years of GH replacement.
OBJECTIVE Growth hormone ( GH ) has been suggested to modulate the release of some cytokines including TNF-alpha . To investigate TNF-alpha levels in children with GH deficiency ( GHD ) , to evaluate alteration in TNF-alpha levels during recombinant human GH ( rhGH ) treatment , and to analyze possible correlations between TNF-alpha and GH , IGF-1 and IGFBP-3 . DESIGN Twenty-four children , aged 12.60+/-2.27 years , with isolated GHD and given rhGH therapy , as subcutaneous ingestion of 0.03 - 0.04mg/kg once-daily dose , were evaluated . Eleven had complete and 13 had partial GHD . Thirty-three healthy children were studied as controls . Age and sex distribution , body mass indexes of two groups were similar . In children with GHD , blood sample s were drawn before ( TNF-alpha0 ) , and at 6 ( TNF-alpha6 ) and 12 ( TNF-alpha12 ) months of the treatment with rhGH .  TNF-alpha was determined using a human TNF-alpha ELISA assay ( Bio source International ) . RESULTS TNF-alpha0 levels were significantly higher in children with GHD than in controls ( 41.79+/-25.04 and 8.63+/-4.48pg/ml , respectively , p<0.001 ) and decreased significantly during rhGH treatment ( TNF-alpha0=41.79+/-25.04 , TNF-alpha6=13.67+/-9.95 , TNF-alpha12=10.86+/-6.61pg/ml , p<0.05 ) . There was no correlation between TNF-alpha levels and BMI , IGF-1/logIGF1 , IGFBP-3 levels and growth velocity of the patients with GHD . Although no correlation between TNF-alpha and peak GH levels after stimulation was present ; a moderate reverse correlation between TNF-alpha and basal serum concentrations of GH ( r=-0.512 , p=0.046 ) was demonstrated . CONCLUSIONS TNF-alpha levels are significantly higher in children with GHD than the controls , and long-term therapy with rhGH effectively reduces its level . Our data suggest that GH plays an inhibitory role on TNF-alpha release in humans . However , due to inconsistent results up to now , further prospect i ve , controlled and long term studies are needed to eluci date the issue The aim of this study was to assess the effects of replacement with recombinant human growth hormone ( rhGH ) in patients with GH deficiency ( GHD ) after treatment of acromegaly . Intervention study . Sixteen patients ( 8 men , age 56 years ) , treated for acromegaly by surgery and radiotherapy , with an insufficient GH response to insulin-induced hypoglycaemia , were treated with 1 year of rhGH replacement . Study parameters were assessed at baseline and after 1 year of rhGH replacement . Study parameters were cardiac function , body composition , bone mineral density ( BMD ) , fasting lipids , glucose , bone turnover markers , and Quality of Life ( QoL ) . During rhGH replacement  IGF-I concentrations increased from −0.4 ± 0.7 to 1.0 ± 1.5 SD ( P = 0.001 ) , with a mean daily dose of 0.2 ± 0.1 mg in men and 0.3 ± 0.2 mg in women . Nonetheless , rhGH replacement  did not alter cardiac function , lipid and glucose concentrations , body composition or QoL. Bone turnover markers ( PINP and β crosslaps ) levels increased ( P = 0.005 and P = 0.021 , respectively ) , paralleled by a small , but significant decrease in BMD of the hip . The beneficial effects of rhGH replacement in patients with GHD during cure from acromegaly are limited in this study Objective : Adult GH deficiency ( GHD ) syndrome is characterized by increased risk of atherosclerosis and hence of cardio- and cerebrovascular mortality . Oxidative stress appears to play an important role in early atherogenesis . Oxidized LDL represents an important predictor of cardiovascular risk and is mainly responsible for oxidative damage of the endothelium . Its concentrations are increased in GHD , but the association between this abnormality and oxidative stress is still unclear , due to the discordant results yielded by the few available studies . Design and methods : In 13 GHD patients , plasma lipid peroxide concentrations were measured before and after a 4-month treatment with recombinant human GH ( rhGH ) and compared with those of 13 age- and sex-matched controls . In the same subjects , the so-called “ lag-time ” , an index of anti-oxidant activity and thus of plasma oxidative balance , was also measured using a fluorescence kinetics method . Results : Before treatment , peroxide levels were significantly higher in patients than in controls ( 374.0±31.52 vs 268.0±8.51 U.C. , p<0.01 ) , whereas the lag-time was significantly lower ( 113.0±10.70 vs 168.0±7.80 min , p<0.01 ) . RhGH administration to patients result ed both in a significant decrease in lipid peroxide levels ( from 374.0±31.52 to 336.0±33.17 U.C. , p<0.01 ) and a significant prolongation of lag-time ( from 113.0±10.70 to 144.0±15.00 min , p<0.01 ) . After treatment , both parameters were no longer significantly different in patients and controls . Lagtime and peroxide levels at baseline did not show any correlation with IGF-I concentrations in GHD patients . After replacement therapy , however , lag-time was positively ( r2= 0.62 , p<0.01 ) , and peroxide levels negatively ( r2=0.41 , p<0.05 ) , correlated with IGF-I levels . Conclusions : These data support the view that adult GHD syndrome is characterized by an unbalance between pro- and anti-oxidant factors with marked preponderance of the former . This abnormality , likely contributing to the increased atherogenic risk of GHD patients , is corrected by short-term GH administration at a dose able to increase , although not to fully normalize , IGF-I levels We report 24-month interim results of two multicenter phase III studies in previously untreated children with growth failure secondary to GH deficiency ( GHD ) that were paramount to the development of a new recombinant human GH ( rhGH , somatropin ) , approved as the first ‘ biosimilar ’ in Europe . Study 1 consisted of 3 parts performed in 89 children . The objective was to compare efficacy and safety of the lyophilized formulation of the new somatropin [ Somatropin Powder ( S and oz ) ] with a licensed reference rhGH preparation and the liquid formulation of the new somatropin [ Somatropin Solution ( S and oz ) ] and to assess long-term efficacy and safety of this ready-to-use Somatropin Solution . Study 2 was performed in 51 children and design ed to demonstrate efficacy and safety of Somatropin Powder and to confirm its low immunogenic potential ; rhGH was given sc at a daily dose of 0.03 mg/kg . Primary [ body height , height SD score ( HSDS ) , height velocity , and height velocity ( HV ) SD score ( HVSDS ) ] and secondary [ IGF-I and IGF binding protein 3 ( IGFBP-3 ) ] efficacy end-points and safety parameters were assessed regularly . In study 1 , all treatments showed comparable increases in growth . The baseline-adjusted difference between Somatropin Powder and the reference rhGH product in mean HV was −0.20 cm/yr ( 95 % confidence interval ( CI ) [ −1.34;0.94 ] ) and in mean HVSDS was 0.76 ( 95 % CI [ −0.57;2.10 ] ) after 9 months . These very small differences demonstrate comparable therapeutic efficacy between the two treatments . The results of study 2 were consistent with those seen in study 1 . Equivalent therapeutic efficacy and clinical comparability in terms of safety and immunogenicity between Somatropin Powder and the reference rhGH product and between Somatropin Powder and Somatropin Solution was demonstrated . The safety and immunogenicity profiles were similar and as expected from experience with rhGH preparations Objective We assessed the efficacy and safety of a weekly pegylated human growth hormone ( PEG-rhGH ) ( Jintrolong ) vs daily rhGH for children with growth hormone deficiency ( GHD ) . Design Phase II and III , multicenter , open-label , r and omized controlled trials . Methods 108 and 343 children with treatment-naive GHD from 6 hospitals in China were enrolled in the phase II and III studies respectively . Patients in the phase II study were r and omized 1:1:1 to weekly Jintrolong ( 0.1 mg/kg/week PEG-rhGH complex ) , weekly Jintrolong ( 0.2 mg/kg/week PEG-rhGH complex ) or daily rhGH ( 0.25 mg/kg/week ) for 25 weeks . Patients in the phase III study were r and omized in a 2:1 ratio to weekly Jintrolong ( 0.2 mg/kg/week ) or daily rhGH ( 0.25 mg/kg/week ) for 25 weeks . The primary endpoint for both studies was height velocity ( HV ) increase at the end of treatment . Other growth-related parameters , safety and compliance were also monitored . Results The phase II study established the preliminary efficacy , safety and recommended dose of Jintrolong PEG-rhGH . In the phase III study , we demonstrated significantly greater HV increases in patients receiving Jintrolong treatment ( from 2.26 ± 0.87 cm/year to 13.41 ± 3.72 cm/year ) vs daily rhGH ( from 2.25 ± 0.82 cm/year to 12.55 ± 2.99 cm/year ) at the end of treatment ( P < 0.05 ) . Additionally , significantly greater improvement in the height st and ard deviation scores was associated with Jintrolong throughout the treatment ( P < 0.05 ) . Adverse event rates and treatment compliance were comparable between the two groups . Conclusion Jintrolong PEG-rhGH at a dose of 0.2 mg/kg/week for 25 weeks is effective and safe for GHD treatment and is non-inferior to daily rhGH CONTEXT The effects of GH replacement in elderly GH-deficient ( GHD ) adults are not well known . OBJECTIVE / DESIGN / PATIENTS In this prospect i ve , single-center , open-label study , baseline characteristics and the effects of 2-yr GH replacement were determined in 24 GHD adults above 65 yr of age and in 24 younger GHD patients ( mean age , 37 yr ; range , 27 - 46 yr ) . All patients had adult onset disease , and both groups were comparable in terms of the number of pituitary hormonal deficiencies , gender , body mass index , and waist/hip ratio . Duration of hypopituitarism was , however , longer in the elderly patients . RESULTS The mean maintenance dose of GH was 0.31 ( sem , 0.03 ) mg/d in the elderly GHD patients and 0.44 ( 0.04 ) mg/d in the younger patients . The less marked response in IGF-I sd score , total body fat , and extracellular water in the elderly patients lost significance when the dose of GH was accounted for in the statistical analyses . Despite the lower dose in the elderly GHD group , these patients had a more marked reduction in waist/hip ratio and serum low-density lipoprotein-cholesterol level , and these differences remained also after correction for duration of hypopituitarism . There was no difference at baseline or in responsiveness in lean mass , bone mineral density , and glucose homeostasis . CONCLUSIONS This study identifies elderly GHD adults as a GH-sensitive group in whom a low dose of GH can improve body composition and serum lipid profile without any significant impairment of glucose metabolism .  GH replacement should therefore be considered in elderly GHD adults High-dose recombinant human GH ( rhGH ) has been shown to improve the nutritional status of malnourished older adults . It is uncertain whether low-dose rhGH is effective and whether its effect on nutritional status will lead to any improvement in physical function . There is also no data on the outcome after a short course of rhGH treatment . The objectives of this study were to determine the efficacy of low-dose rhGH treatment for 4 weeks in malnourished elderly patients , its effect on physical functions , and the intermediate term outcome after a 4-week rhGH treatment . The study design was a r and omized , placebo-controlled , double-blind trial conducted in a university teaching hospital . The patients were 19 medically stable malnourished elderly subjects . Intervention in the rhGH group was as follows : rhGH ( Saizen , Serono , Switzerl and ) 0.09 IU/kg body weight ( BW ) 3 times weekly were given together with appropriate dietary intervention as prescribed by the dietitian . In the placebo group , equal volumes of normal saline per kilogram BW were given 3 times weekly together with the dietary intervention . The baseline demographic , anthropometric , nutritional , and hematological variables , measures of physical function , and insulin-like growth factor I levels in both groups were comparable . Compared with the placebo group , the GH-treated group showed a more rapid gain in BW ( after 3 weeks , + 1.27 + /- 0.36 vs. -0.28 + /- 0.37 kg ; P = 0.008 ) , total lean body mass ( change after 3 weeks by bio-impedance analysis , + 1.45 + /- 0.36 vs. -0.37 + /- 0.48 kg ; P = 0.009 ) and a faster improvement in 5-m walking time ( decrease after 4 weeks , 23.79 + /- 9.41 vs. 0.45 + /- 4.62 sec ; P = 0.047 ) . The hemoglobin level rose more in the rhGH than the placebo groups ( change at 8 weeks , + 0.84 + /- 0.34 vs. -0.42 + /- 0.29 g/dL ; P = 0.012 ) . Serum albumin level also showed a greater delayed increase in the rhGH group than in the placebo group ( change at 8 weeks , + 5.1 + /- 0.8 vs. 1.6 + /- 1.2 g/dL ; P = 0.023 ) . There was no statistically significant difference for other nutritional variables . There was a greater rise in the mean serum insulin-like growth factor I level at 4 weeks in the GH than in the placebo groups ( 197 + /- 58 vs. 54 + /- 26 U/L ; P = 0.034 ) . The improvement in the rhGH group gradually diminished on follow-up and became statistically insignificant 8 weeks after stopping rhGH treatment . There were no GH-related adverse effects . Low-dose rhGH was an effective and safe adjuvant to dietary augmentation for stable malnourished elderly subjects . It led to a faster gain in total lean body mass , which was associated with greater improvement in walking speed when compared with dietary intervention alone . There were no apparent side effects Since the effects of recombinant human growth hormone ( rhGH ) replacement therapy on glucose metabolism are still a matter of debate , the aim of the present study was to evaluate the impact of long-term rhGH treatment on insulin sensitivity . Simple indices of insulin resistance ( IR ) and insulin sensitivity ( IS ) , based on fasting glucose and insulin , such as the homeostasis model assessment of insulin resistance ( HOMA-IR ) and the quantitative insulin check index ( QUICKI ) , were used to estimate the degree of IR and IS in 20 normoglycemic patients ( 11 men and 9 women ; mean age , 44 + /- 14 years ) with severe adult-onset GH deficiency ( GHD ) . Measurements were determined at baseline and after 1 and 5 years of continuous rhGH therapy . Basal values were compared to those obtained in 20 healthy sex- and age-matched controls . Starting rhGH dose ranged from 3 to 8 microg/kg/d in keeping with sex and age , then doses were titrated according to insulin-like growth factor-I ( IGF-I ) levels . At baseline all patients had low IGF-I levels ( 10 + /- 5.4 nmol/L ) , high body mas index ( BMI ; 27.5 + /- 4 kg/m(2 ) ) , and elevated body fat percentage ( BF% ; 31.8 + /- 9.6 ) . Fasting glucose and insulin levels , as well as HOMA-IR and QUICKI , did not differ significantly from those recorded in the control group . After 1 year of rhGH replacement therapy , normalization in IGF-I levels and a significant reduction in BF% were observed ( P < .001 ) , and these effects were maintained after 5 years of treatment . Fasting glucose increased from 79 + /- 10 to 87 + /- 13 , and 87 + /- 12 mg/dL ( P < .05 ) after 1 and 5 years of therapy , respectively . Fasting insulin significantly increased after 1 year , without further modifications in the long-term follow-up . HOMA-IR significantly increased from 2.1 + /- 1.7 to 2.5 + /- 1.7 ( P < .05 ) after 1 year , then decreased to 2.3 + /- 1.5 ( P = not significant [ NS ] v basal ) after 5 years . A specular decrease in QUICKI from 0.37 + /- 0.05 to 0.34 + /- 0.03 ( P < .01 ) occurred after 1 year , with a trend to increase ( 0.35 + /- 0.04 ; P = NS v basal ) after 5 years . No patient developed impaired fasting glucose . In conclusion , rhGH therapy determined an increase in fasting glucose and insulin levels , causing in the short-term period a worsening of IS . The sustained reduction in BF% , without further deterioration of IS , suggests that long-term beneficial effects on body composition may overcome the negative influence of GH on glucose metabolism OBJECTIVE Young adults with childhood-onset GH deficiency ( GHD ) have reduced memory and attention , which can be improved by treatment with GH . Little information is available on cognitive function in elderly GHD patients . DESIGN Single center , double-blind , r and omized , placebo-controlled study of 52-week duration . METHODS Elderly GH therapy naïve GHD patients ( n=34 ; age range 60 - 77 years ) were enrolled and r and omized to receive placebo or GH therapy which was titrated to achieve a target IGF-I level of + 1 to + 2 s.d . of the normal mean for age . Cognitive function was assessed at baseline and after 24 and 52 weeks , using a computerized psychometric test package ( Neurobehavioral Examination System-2 ) . RESULTS The mean GH dose was 0.16+/-0.06 mg/day ; mean IGF-I increased from 135+/-59 ng/ml at baseline to 213+/-77 ng/ml during active treatment . The GH-treated group had better mean serial digit learning scores compared with placebo group ( P<0.05 ) . Assessment of effect sizes showed that improvements in memory occurred with GH after 24 weeks . The overall adverse event rates were similar in the GH and the placebo group . CONCLUSION This study indicates that GH replacement may be accompanied by improvement in certain measures of cognitive function in elderly patients with GHD CONTEXT Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient ( GHD ) adults are limited . OBJECTIVES The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults . DESIGN The study was a 6-month double-blind , placebo-controlled r and omized trial . SETTING The study was conducted at the General Clinical Research Center . PARTICIPANTS Thirty hypopituitary adults with GHD were studied . INTERVENTION Subjects were r and omized to recombinant human GH or placebo for 6 months , followed by open-label recombinant human GH for 12 months . MAIN OUTCOME MEASURES Primary endpoints were exercise duration , maximal oxygen consumption , and left ventricular ejection fraction . Secondary endpoints were echocardiographic indices of systolic and diastolic function , left ventricular mass , lipids , and body composition . RESULTS In the 6-month double-blind phase , mean GH dose was 0.64 mg/d . Mean IGF-I sd score increased from -4.5 to -1.0 . Exercise duration , maximal oxygen consumption , left ventricular ejection fraction , and other echocardiographic parameters were normal at baseline and did not change . GH decreased total and low-density lipoprotein cholesterol by 7.5 % ( P = 0.016 ) and 14.7 % ( P = 0.002 ) ( P = 0.04 vs. placebo ) . Mean lean body mass increased by 2.2 kg ( P = 0.004 ) , fat mass decreased by 1.7 kg ( P = 0.21 ) , and percent body fat decreased by 2.5 % ( P = 0.018 ) , although between-group changes were not significant . CONCLUSIONS Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol , increased IGF-I , and increased lean body mass . These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment BACKGROUND Adult growth hormone ( GH ) deficiency must be diagnosed before prescribing therapeutic recombinant human GH . We studied the clinical relevance of a diagnostic strategy for growth hormone deficiency ( GHD ) using IGF-1 determination as a first step . METHODS In 2000 and 2001 , we tested 142 adult patients with hypothalamo-pituitary disorders for somatotropic function using Insulin Tolerance Test ( ITT ) , the reference test for the diagnosis of GHD , with concomitant Insulin-like growth factor-1 ( IGF-1 ) determination , a marker of somatotropic function . Patients were classified as GHD ( peak GH concentration<3 ng/ml with the ITT ) or normal . SETTING Monocenter prospect i ve study in a tertiary referral center . RESULTS  GHD was diagnosed in 61 subjects . Using a ROC curve , a threshold IGF-1 concentration of 175 ng/ml yielded a negative predictive value of 89+/-5 % . A diagnostic strategy with IGF-1 determination as the first step followed by ITT for patients with an IGF-1 concentration below 175 ng/ml missed five of the 61 GHD patients , avoided 46/142 ITT and reduced the cost of diagnosis by 15 % . CONCLUSION We propose the use of a strategy consisting of IGF-1 determination followed , if below 175 ng/ml by confirmatory ITT to diagnose GHD in adults CONTEXT Only few studies have investigated the effects of GH replacement on muscle strength in elderly patients with GH deficiency ( GHD ) . OBJECTIVE , DESIGN , AND PATIENTS : In this prospect i ve open-labeled study , the effects of 10 years of GH replacement on muscle strength and neuromuscular function were followed in 24 elderly GHD adults ( mean age of 65.2 years ; range 61 - 74 years ) .  Muscle strength was compared with reference values obtained from the background population . RESULTS The mean initial GH dose of 0.72 mg/day was lowered to 0.37 mg/day . The mean IGF1 SDS increased from -1.10 at baseline to 1.17 at study end . GH replacement induced a sustained increase in lean body mass and a transient increase in isometric knee flexor strength . Isometric knee extensor strength was reduced after 10 years . However , after correction for age and gender , using observed/predicted value ratios , there was sustained and even progressive increase in most variables reflecting muscle strength . Measurements of neuromuscular function showed unchanged voluntary motor unit activation after 10 years . CONCLUSIONS Ten years of GH replacement therapy in elderly GHD adults result ed in a transient increase in isometric knee flexor strength , and provided protection from most of the normal age-related decline in muscle performance and neuromuscular function
RhGh did not consistently affect blood pressure or bone mineral density .
RhGH consistently improved quality of life ( QoL ) parameters reflected in AGHDA-scores .
Conclusion RhGH replacement in elderly subjects with GHD  decreases LDL cholesterol levels and improves QoL , but the effects on other parameters are not unequivocal .
There were no data on the efficacy and safety  of rhGH treatment in octogenarians with GHD
Context Recombinant human GH ( rhGH ) is prescribed for the treatment of adults with GH deficiency ( GHD ) .
However , conflicting data are available on the efficacy of rhGH treatment in elderly GHD patients .
Objective To assess the efficacy of rhGH treatment in elderly GHD subjects .