Long‐term cardiovascular effects of growth hormone treatment in GH‐deficient adults Preliminary data in a small group of patients Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly OPPORTUNITY™: a large-scale randomized clinical trial of growth hormone in hemodialysis patients. Baseline characteristics and effects of growth hormone therapy over two years in younger and elderly adults with adult onset GH deficiency. Effects of Physiologic Growth Hormone Therapy on Bone Density and Body Composition in Patients with Adult-Onset Growth Hormone Deficiency Limited efficacy of growth hormone (GH) during transition of GH-deficient patients from adolescence to adulthood: a phase III multicenter, double-blind, randomized two-year trial. BENEFICIAL EFFECTS OF GROWTH HORMONE TREATMENT IN GH-DEFICIENT ADULTS Safety of Growth Hormone Treatment of Children with Idiopathic Short Stature: The US Experience Pilot study of growth hormone administration during the refeeding of malnourished anorexia nervosa patients. Effects of 7 years of growth hormone replacement therapy in hypopituitary adults. Growth hormone treatment in pediatric burns: a safe therapeutic approach. Gender differences in the effects of long term growth hormone (GH) treatment on bone in adults with GH deficiency. Effect of growth hormone treatment in patients with chronic fatigue syndrome: a preliminary study. The growth and cardiovascular effects of high dose growth hormone therapy in idiopathic short stature Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients. Continuation of growth hormone (GH) replacement in GH-deficient patients during transition from childhood to adulthood: a two-year placebo-controlled study. Recombinant human growth hormone treatment in children with thalassemia major.
OBJECTIVE The long‐term cardiovascular effects of GH administration in adults are of major clinical importance , given the increasing use of such treatment . We have evaluated long‐term cardiovascular effects of recombinant human GH ( rhGH ) substitution in GH deficient men 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 BACKGROUND Adult maintenance hemodialysis ( MHD ) patients experience high mortality and morbidity and poor quality of life ( QoL ) . Markers of protein-energy wasting are associated with these poor outcomes . The OPPORTUNITY ™ Trial examined whether recombinant human growth hormone ( hGH ) reduces mortality in hypoalbuminemic MHD patients . Secondary end points were effects on number of hospitalizations , cardiovascular events , lean body mass ( LBM ) , serum proteins , exercise capacity , QoL and adverse events . METHODS We performed a r and omized , double-blind , placebo-controlled , multicenter multinational trial stratified for diabetic status . Clinical ly , stable adult MHD patients with serum albumin < 4.0 g/dL were r and omized to subcutaneous injections of hGH , 20 μg/kg/day , or placebo . Planned treatment duration was 24 months for 2500 patients . The trial was terminated early due to slow recruitment . RESULTS Seven hundred and twelve patients were r and omized until trial termination ; 695 patients received at least one dose of trial medication . Mean treatment duration was 20 weeks ( no completers ) . There were no differences between groups in all-cause mortality , cardiovascular morbidity or mortality , serum albumin , LBM , physical exercise capacity or QoL.  The hGH group , compared to placebo , displayed a reduction in body weight , total body fat , serum high-sensitivity C-reactive protein and possibly homocysteine and an increase in serum high-density lipoprotein-cholesterol and transferrin levels . CONCLUSIONS Although the OPPORTUNITY ™ Trial was terminated early , treatment with hGH , compared to placebo , improved certain cardiovascular risk factors but did not reduce mortality , cardiovascular events or improve nutritional factors or QoL. The power for showing differences was substantially reduced due to the marked decrease in treatment duration and sample size 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 Adults with hypopituitarism receive therapy that replaces cortisol , thyroid hormone , and gonadal steroids , but growth hormone replacement has typically been reserved for children with growth hormone deficiency . However , several observations suggest that growth hormone may have an important role in maintaining bone density and body composition in adults .  Bone density is reduced in patients with growth hormone deficiency that develops during childhood or adulthood [ 1 - 3 ] . In vitro , growth hormone binds to growth hormone receptors on rat osteoblast-like cells and produces a mitogenic response mediated by local synthesis and action of insulin-like growth factor 1 ( IGF-1 ) [ 4 , 5 ] . Administration of growth hormone to adults with growth hormone deficiency increases serum and urine markers of bone turnover [ 6 - 10 ] . In adults with childhood-onset growth hormone deficiency ( in whom osteopenia probably results from a failure to reach peak bone mass ) , growth hormone therapy increases bone density [ 3 , 8 , 10 , 11 ] . However , the effects of growth hormone replacement on bone density in adult-onset growth hormone deficiency are largely unknown . In addition to having an increased risk for fracture , adults with growth hormone deficiency have an excess risk for cardiovascular-related death that may be attributed to increased central fat mass [ 12 - 17 ] . Growth hormone therapy reduces body fat and increases lean mass in adults with growth hormone deficiency , primarily those in whom the deficiency developed during childhood [ 6 - 9 , 18 - 20 ] . However , previous studies of growth hormone replacement in adults have several important limitations . First , most of these studies used pharmacologic rather than physiologic doses of growth hormone . Second , most have focused on childhood-onset growth hormone deficiency . Third , effects of growth hormone on bone density in patients with adult-onset growth hormone deficiency have not been examined in a controlled study . Because of these limitations , the critical question of whether long-term growth hormone therapy is beneficial in patients with adult-onset growth hormone deficiency has not been definitively answered . We sought to determine whether long-term growth hormone replacement therapy , given at a dose adjusted according to IGF-1 levels , improves bone density , bone turnover , body composition , and several variables associated with quality of life in patients with adult-onset growth hormone deficiency . Methods Patients Thirty-two men ( median age , 51 years ; range , 24 to 62 years ) with a history of pituitary disease were recruited from the Massachusetts General Hospital Neuroendocrine Clinical Center and from surrounding communities . Growth hormone secretion profiles in 23 of these patients have been reported elsewhere [ 21 ] . All patients met the following inclusion criteria : 1 ) normal growth and development , 2 ) benign sellar neoplasm , pituitary apoplexy , or idiopathic hypopituitarism diagnosed after age 18 years , and 3 ) peak serum growth hormone levels less than 5 mg/L after receipt of two pharmacologic stimuli on separate mornings . The 13 patients younger than 50 years of age received intravenous insulin , 0.1 U/kg of body weight , and oral clonidine , 0.15 mg . The 18 patients 50 years of age or older received oral clonidine , 0.15 mg , and intravenous arginine , 30 g ; these patients were given arginine rather than insulin to avoid potential cardiovascular complications of hypoglycemia . Patients were excluded if they had a history of acromegaly or diabetes mellitus ; were taking drugs ( such as phenytoin or etidronate ) known to affect bone density ; were not receiving st and ard thyroid or adrenal hormone replacement therapy  if the patient was deficient in those hormones ; or had begun receiving adrenal , gonadal , or thyroid hormone replacement therapy within 6 months before study enrollment . Growth hormone deficiency was caused by a clinical ly nonfunctioning pituitary adenoma in 12 patients , prolactinoma in 9 patients , craniopharyngioma in 9 patients , pituitary apoplexy in 4 patients , Cushing disease in 1 patient , and adult-onset idiopathic hypopituitarism in 1 patient . Twenty-one patients were deficient in adrenocorticotropin , thyroid-stimulating hormone , and gonadotropins .  Five patients had two of these deficiencies , 5 patients had one , and 1 patient had none . Twenty-five patients were treated surgically ( 16 of the 25 were also treated with radiation or bromocriptine , or both ) . Five patients received bromocriptine with or without radiation therapy , and 2 were treated with hormonal replacement only . The Subcommittee on Human Studies of the Massachusetts General Hospital approved the study , and all patients gave written informed consent . Protocol Patients were r and omly assigned to receive recombinant human growth hormone ( Nutropin , Genentech , Inc. , South San Francisco , California ) at a daily dose of 10 g/kg subcutaneously or a placebo . The computerized r and omization , done by statisticians at Genentech , Inc. , stratified patients to assure balance between the groups with respect to age . Staff at Genentech , Inc. , informed the primary investigator of treatment assignment by telephone ; the study physician kept the information in a private computer data base . Only the study physician was aware of the treatment assignment . Patients were admitted to the General Clinical Research Center for measurements of bone mineral density of the lumbar spine , femoral neck , and proximal radius . Body mass index , lean body mass , and percentage of body fat were also measured . Patients had echocardiography and were tested for strength and exercise capacity . Urine was collected for 24 hours for measurement of pyridinoline , deoxypyridinoline , calcium , and creatinine excretion . Fasting blood sample s were drawn at 0900 hours for measurement of IGF-1 , glucose , insulin , lipids , and hemoglobin A1c values . Patients returned at 1 week , 1 month , and 3 months for outpatient measurement of serum IGF-1 , glucose , insulin , lipid ( at 1 and 3 months ) , and hemoglobin A1c ( at 3 months only ) values . Patients were readmitted at 6 , 12 , and 18 months so that the baseline evaluation could be repeated . Echocardiography and tests of strength and exercise capacity were repeated only at the 18-month visit . The growth hormone dose was reduced by 25 % if the patient 's serum IGF-1 level was found to be elevated at the 6- or 12-month visit ; serum IGF-1 levels were remeasured approximately 1 month after the dose was decreased . The dose was further adjusted if necessary . To maintain patient blinding , each placebo recipient was asked to reduce his dose by 25 % during the first 6 months of the study . Bone Density Bone mineral density of the lumbar spine , femoral neck , radius , and total body was determined by dual-energy x-ray absorptiometry ( Hologic QDR-2000 , Waltham , Massachusetts ) . Density of the nondominant radius was measured at the junction of the proximal two thirds and the distal one third of the radial shaft ; the coefficient of variation for this measurement is 1.5 % [ 22 ] . The bone mineral density of the lumbar spine was assessed in the anteroposterior projection in all patients and in the lateral projection in the 22 patients whose body thickness did not exceed the manufacturer 's specified limit for the lateral measurement . Because lateral measurements of bone density in the spine eliminate the contribution of the posterior vertebral elements , they estimate trabecular bone mass better than do measurements made in the anteroposterior projection [ 23 ] . In 50 persons with paired measurements , the SDs for the anteroposterior and lateral measurements were 0.010 g/cm2 and 0.013 g/cm2 , respectively ; these values did not vary with bone density . The coefficient of variation for bone density at the femoral neck was 2.1 % in 51 persons with paired measurements [ 24 ] . All scans were review ed by one physician who did not know the patients ' treatment assignment . Follow-up scans were matched to baseline scans to ensure that identical bone regions were measured . Body Composition A research dietitian determined body mass index . Lean body mass and percentage of body fat were measured by dual-energy x-ray absorptiometry ( Hologic QDR-2000 ) . According to the manufacturer , the coefficient of variation is 1.0 % for lean mass and 1.5 % for percentage of body fat . This compares favorably with the coefficients of variation of other techniques for determining body composition , such as bioelectrical impedance ( 5 % ) , 40 K counting ( 3 % ) , and deuterium oxide dilation ( 3 % ) [ 25 ] . Biochemical Assays Serum IGF-1 levels were measured by radioimmunoassay after acid-alcohol extraction ( Nichols Institute , San Juan Capistrano , California ) . The ageadjusted normal ranges for this assay were 83.3 to 378.0 mg/L for men 20 to 40 years of age and 54.0 to 328.5 mg/L for men older than 40 years of age . Interassay coefficients of variation were 5.2 % at 121.5 mg/L and 15.2 % at 84.5 mg/L. Serum osteocalcin levels were measured by immunoradiometric assay ( SmithKline Beecham , Van Nuys , California ) . The intra-assay coefficients of variation were 11.5 % for low control serum pools ( 3 to 6 mg/L ) , 11.6 % for medium pools ( 6 to 10 mg/L ) , and 10.6 % for high pools ( 25 to 35 mg/L ) . Urinary excretion of total pyridinoline and deoxypyridinoline was measured using high-performance liquid chromatography ( SmithKline Beecham ) . The intra-assay coefficients of variation for measurement of pyridinoline levels were 9.5 % at 13.8 nmol/mmol of creatinine , 9.6 % at 37.0 nmol/mmol of creatinine , and 10.7 % at 47.5 nmol/mmol of creatinine . The intra-assay coefficients of variation for measurement of deoxypyridinoline excretion were 15.8 % at 3.2 nmol/mmol of creatinine , 13.5 % at 6.7 nmol/mmol of creatinine , and 9.8 % at 10.7 nmol/mmol of creatinine . Other assays were done at the Massachusetts General Hospital as described elsewhere [ 26 ] . Echocardiography Transthoracic two-dimensional echocardiography was done while patients were in the left lateral decubitus CONTEXT Treatment of GH-deficient adolescents in transition to adulthood remains challenging . OBJECTIVE The objective was to assess the safety and efficacy of GH in GH-deficient adolescents in transition . PATIENTS Fifty-eight GH-deficient adolescents ( mean age , 15.8 + /- 1.8 yr ; 33 males ) at near completion of their linear growth participated in the study . INTERVENTION Baseline studies were done while subjects were on GH . Subjects were retested ( insulin-induced hypoglycemia ) 4 wk after GH discontinuation and reclassified as persistently GH-deficient or controls ( n = 18 ) . GH-deficient subjects were r and omized to GH ( n = 25 , approximately 20 microg/kg.d ) or placebo ( n = 15 ) . SETTING The multicenter study was conducted over a 2-yr period . MAIN OUTCOMES Changes in body composition , bone mineral density ( BMD ) , quality of life ( QOL ) , cardiovascular and metabolic markers were measured . RESULTS All groups had normal measures of lipid and carbohydrate metabolism , body composition , BMD , cardiac function , muscle strength , and QOL at baseline and after 2 yr . IGF-I concentrations decreased in all , but less so in the GH-group ( P = 0.013 ) . There was a greater increase in lean body mass ( lesser adiposity ) in the GH group than placebo at 12 months , but not at 24 months . CONCLUSIONS 1 ) GH-deficient patients properly treated in childhood can have normal BMD , body composition , cardiac function , muscle strength , carbohydrate and lipid metabolism , and QOL when reaching adult height ; and 2 ) continuation of GH therapy for 2 yr did not change these measures as compared to placebo-treated or control subjects . GH-deficient adolescents in good metabolic status at the time of epiphyseal fusion may safely discontinue GH for at least 2 yr . Follow-up is needed to determine whether GH therapy is eventually warranted in subjects treated with GH during childhood A double-blind , placebo-controlled , crossover study on the effects of 4 months ' growth hormone ( GH ) treatment was carried out in 22 GH-deficient adults ( 8 women , 14 men ; mean [ SEM ] age 23.8 [ 1.2 ] years ) . 1 patient was withdrawn because of oedema . Mean total body weight of the other 21 did not change , whereas mean muscle volume of the thigh , estimated by computerised tomography ( CT ) , was significantly higher after GH than after placebo ( 70.0 [ 3.7 ] vs 66.3 [ 3.1 ] ml/0.8 cm cross-sectional slice ) . The mean adipose tissue volume of the thigh and subscapular skinfold thickness fell significantly during GH treatment . Growth hormone caused a small increase in the isometric strength of the quadriceps muscles and a significant rise in exercise capacity ( 60.8 [ 7.2 ] vs 54.2 [ 6.6 ] kJ ) . The heart rate both at rest and after maximum exercise was low during the placebo period and increased significantly during GH treatment . Blood pressure and echocardiographic wall mass of the left ventricle did not change during the study . Growth hormone increased both mean glomerular filtration rate and renal plasma flow from a subnormal level on placebo to a level comparable with that of an age-matched control group . The filtration fraction did not change . Urinary albumin excretion was in the low normal range and was not affected by GH treatment . Finally , GH treatment normalised mean circulating levels of insulin-like growth factor 1 ( IGF-1 ) , which were low after the placebo period ( 96 [ 9 ] micrograms/l placebo ; 224 [ 28 ] micrograms/l GH ) . These findings suggest that GH , in a conventional replacement dose , has several potentially beneficial effects in GH-deficient adults and therefore encourage future long-term trials Recombinant human growth hormone ( rhGH ) is approved in the United States for treatment of idiopathic short stature ( ISS ) . The occurrence of adverse events ( AEs ) and the long-term safety of rhGH treatment in this patient population are review ed . Data were analyzed from postmarketing surveillance studies that included ISS patients , prospect i ve ISS treatment trials and studies of specific AEs in smaller groups of rhGH-treated children . Frequency rates of targeted AEs ( i.e. , scoliosis , slipped capital femoral epiphysis , intracranial hypertension , pancreatitis ) in patients with ISS are similar to or lower than the rates observed in other rhGH-treated conditions . At dosages of 0.24–0.37 mg/kg/week , rhGH treatment in children with ISS does not adversely affect blood glucose levels . At dosages ≧0.3 mg/kg/week , a dose-dependent increase in mean fasting and stimulated insulin levels is observed . Current evidence derived from ‘ on-treatment ’ surveillance studies suggests that rhGH does not increase the risk for new malignancies in children with ISS.The  safety profile  of rhGH at doses ≤0.37 mg/kg/week for the treatment of children with ISS is similar to or better than the profile seen in other rhGH-treated conditions and is not associated with any predictable AEs . Due to a continuing trend toward dose escalation to achieve greater height-promoting effects and the possibility of delayed post-treatment effects of hyperinsulinemia and /or heightened GH and insulin-like growth factor I exposure on cancer risk , caution and ongoing scrutiny of risks versus benefits are warranted OBJECTIVE In anorexia nervosa ( AN ) , medical stabilization and nutritional repletion are pivotal steps toward physical and psychological recovery . Nutritional stabilization is often difficult in this patient group . Recombinant human growth hormone ( rhGH ) has been safely used as adjuvant therapy in other groups of malnourished patients . We hypothesize that rhGH treatment will hasten medical stabilization in AN patients . STUDY DESIGN Fifteen patients admitted for inpatient treatment for AN , ages 12 - 18 years , were enrolled in a 28-day r and omized , double-blind , placebo-controlled study . Patients received rhGH ( 0.05 mg/kg subcutaneously ) or an equivalent volume of placebo daily . Outcome measures included time to reach medical/cardiovascular stability , rate of weight gain , and duration of hospitalization . All patients received a st and ard refeeding protocol . RESULTS Mean admission body mass index was 14.5 kg/m2 . The rhGH and placebo groups did not differ significantly in admission weight , BMI or daily caloric intake . Patients treated with rhGH  reached medical/cardiovascular stability more rapidly than those treated with placebo ( median 17 vs. 37 days , p = 0.02 ) . Numerical but not statistically significant improvements were seen in weight gain and length of hospitalization in the rhGH group . CONCLUSION Patients treated with rhGH achieved medical/cardiovascular stability more rapidly than those treated with placebo , and this , in turn , decreased the length of stay Short-term studies of GH replacement in adult hypopituitarism have usually demonstrated beneficial effects on body composition and circulating lipids , with neutral or occasionally adverse effects on glucose tolerance . Fasting hyperinsulinemia has been reported . GH effects on cardiac function have been variable . The effects of long-term GH therapy , taking into account the consequences of increasing age , are not fully known . Thirty-three hypopituitary , initially middle-aged adults were studied over a 7-yr period ; 12 patients took GH therapy ( mean , 0.7 mg daily ) continuously ( group A ) ; 11 took GH for only 6 - 18 months , a minimum of 5 yr previously ( group B ) ; and 10 patients never received GH therapy  ( group C ) . Other pituitary replacement was maintained . Effects on anthropometry , body composition ( by bioimpedance analysis , total body potassium , and dual energy x-ray absorptiometry ) , circulating lipids , glucose and insulin concentrations , cardiac 2-dimensional and Doppler echocardiography , and exercise tolerance were assessed before and after the treatment period . Continuous GH therapy had no significant effect on body weight , but it prevented the increase in waist circumference and waist to hip ratio that occurred in the patients without GH substitution ( waist to hip ratio , group A , 0.87+/-0.08 at baseline , 0.85+/-0.09 at 7 yr ; group B , 0.89+/-0.11 at baseline , 0.94+/-0.11 at 7 yr ; P < 0.005 for GH effect ; group C , 0.87+/-0.10 at baseline , 0.92+/-0.10 at 7 yr ; P < 0.005 for GH effect ) . A GH-induced decrease in subscapular skinfold thickness was also observed . By bioimpedance analysis , GH therapy caused an increase in total body water and fat-free mass , and a decrease in the percent body fat . Although changes occurred with time in all groups , no significant additional GH therapy effects were observed on glucose tolerance , insulin concentrations , lipid levels , cardiac dimensions , echocardiographic diastolic function , or exercise tolerance . In conclusion , prolonged GH substitution in middle-aged hypopituitary adults causes a sustained improvement in body composition . Other benefits , e.g. on lipid levels and exercise tolerance , were not apparent at 7 yr when comparisons were made with GH-untreated hypopituitary controls . Potentially adverse effects on glucose tolerance and insulinemia did not develop with prolonged GH therapy OBJECTIVE To determine the safety and efficacy of recombinant human growth hormone ( rhGH ) in the treatment of children who are severely burned . SUMMARY BACKGROUND DATA During the last decade , we have used recombinant human growth hormone ( rhGH ; 0.2 mg/kg/day s.q . ) to successfully treat 130 children with more than 40 % total body surface area ( TBSA ) burns to enhance wound healing and decrease protein loss . A significant increase in the mortality of adult patients in the intensive care unit who were given rhGH  has recently been reported in two large European trials which questions the therapeutic safety of rhGH . METHODS The records of 263 children who were burned were review ed . Patients receiving either rhGH at 0.2 mg/kg/day subcutaneously as part of a r and omized clinical trial ( n = 48 ) or therapeutically ( n = 82 ) were compared with r and omized placebo-administered controls ( n = 54 ) , contiguous matched controls ( n = 48 ) , and matched patients admitted after August 1997 , after which no patients were treated with rhGH ( n = 31 ) . Morbidity and mortality , which might be altered by rhGH therapy , were considered with specific attention to organ function or failure , infection , hemodynamics , and calcium , phosphorous , and albumin balance . RESULTS A 2 % mortality was observed in both rhGH and saline placebo groups in the controlled studies , with no differences in septic complications , organ dysfunction , or heart rate pressure product identified . In addition , no difference in mortality could be shown for those given rhGH therapeutically versus their controls . No patient deaths were attributed to rhGH in autopsies review ed by observers blinded to treatment . Hyperglycemic episodes and exogenous insulin requirements were higher among rhGH recipients , whereas exogenous albumin requirements and the development of hypocalcemia was reduced . CONCLUSIONS Data indicate that rhGH used in the treatment of children who were severely burned is safe and efficacious We recently observed that among patients with GH deficiency due to adult-onset hypopituitarism , men responded with a greater increase in serum levels of insulin-like growth factor I ( IGF-I ) and biochemical markers of bone metabolism than women when the same dose of recombinant human GH ( rhGH ) per body surface area was administered for 9 months . In the present study , 33 of the 36 patients in the previous trial ( 20 men and 13 women ) continued therapy for up to 45 months . The dose of rhGH was adjusted according to side-effects and to maintain serum IGF-I within the physiological range . This result ed in a significant dose reduction in the men ; consequently , the women received twice as much rhGH as the men ( mean + /- SD , 1.9 + /- 1.1 vs. 1.0 + /- 0.6 U/day ; P < 0.01 ) . The increases in serum IGF-I levels and serum biochemical markers of bone metabolism were similar in men and women with these doses . The total bone mineral content ( BMC ) was increased after 33 and 45 months of treatment up to 5.1 % ( P = 0.004 and 0.0001 ) . Bone mineral density ( BMD ) , BMC , and the area of the femoral neck and the lumbar spine were also significantly increased after 33 and 45 months of treatment . When analyzed by gender , total body BMC , femoral neck BMD and BMC , and spinal BMC were significantly increased in males , but not in females ( P < 0.05 - 0.01 ) . In conclusion , rhGH treatment continued to have an effect on bone metabolism and bone mass for up to 45 months of therapy . The changes in bone mass were greater in the men , although they received lower doses of rhGH than the women . The results indicate that the sensitivity to GH in adult patients with GH deficiency is gender dependent The efficacy of growth hormone ( GH ) therapy was evaluated in patients with chronic fatigue syndrome ( CFS ) who had peak serum GH levels below 10 microg/l during stage-controlled sleep . Twenty patients ( 7 men , 13 women ; age range , 30 - 60 years ) with CFS were r and omized to receive placebo or GH therapy , 6.7 microg/kg/day ( 0.02 IU/kg/day ) , for 12 weeks . Following this double-blind treatment period , the 17 patients remaining in the study were given GH therapy at the above dose for an open period of 9 months . Mean ( + /- SD ) serum levels of insulin-like growth factor I ( IGF-I ) increased during GH treatment , from 173 + /- 46 microg/I to 296 + /- 89 microg/l ( P < 0.001 ) ; IGF-I SDS values increased from -0.45 + /- 1.14 to + 1.43 + /- 1.09 ( P < 0.001 ) . Fat-free mass and total body water were significantly increased after 12 months of treatment . Although quality of life , as assessed using two different question naires , did not improve significantly during GH treatment , four patients were able to resume work after a long period of sick leave OBJECTIVE It Is possible that high dose GH treatment may have beneficial effects on growth but important adverse effects on cardiac function . We have therefore Investigated the efficacy and cardiovascular effects of high dose biosynthetic human GH ( r‐hGH ) treatment in children with idiopathic short stature and a normal pretreatment height velocity Lean body mass ( LBM ) , fat mass ( FM ) , and total bone mineral content are significantly reduced in adult GHD subjects who had received pediatric GH .  To test the hypothesis that continued GH therapy after final height is necessary to attain adult body composition , we performed a prospect i ve , multinational , r and omized , controlled , 2-yr study in patients who completed pediatric GH treatment at final height . Patients were r and omized to GH at 25.0 microg/kg x d ( pediatric dose ; n = 58 ) or 12.5 microg/kg x d ( adult dose ; n = 59 ) or no GH treatment ( control ; n = 32 ) . LBM and FM were measured by dual energy x-ray absorptiometry and were central ly evaluated . IGF-I , IGF-binding protein-3 , and lipid concentrations were also measured central ly . During the 2 yr , GH-treated patients gained a significant amount of LBM compared with controls ( P < 0.001 ) , but the change with the higher pediatric dose ( 14.2 + /- 11.7 % ) was not different from that seen with the lower adult dose ( 12.7 + /- 9.4 % ; P = 0.970 ) . Similarly , the decrease in FM was significantly ( P = 0.029 ) influenced by treatment , but with no dose effect ( adult dose , -7.1 + /- 22.8 % ; pediatric dose , -6.0 + /- 26.6 % ; P = 0.950 ) . When the GH treatment effect was analyzed by gender , males gained 15.6 + /- 9.8 % and 14.3 + /- 11.7 % LBM ( P = 0.711 ) and lost 12.4 + /- 22.2 % and 11.0 + /- 27.1 % FM ( P = 0.921 ) with the low and high doses , respectively . Females gained 8.3 + /- 7.3 % and 12.5 + /- 12.8 % LBM with the two doses ( P = 0.630 ) , but increased their FM by 3.5 + /- 16.2 % with the lower dose and lost only 1.2 + /- 23.2 % FM with the higher dose ( P = 0.325 ) . A similar pattern was seen in IGF-I sd score ; the 2-yr GH dose response was significantly higher with the pediatric than with the adult dose in females ( P = 0.008 ) , but not males ( P = 0.790 ) . The divergent pattern of change in LBM and FM in males and females is consistent with normal developmental sexual dimorphism and indicates that GH-dependent progress to target body composition continues after the age at which GH treatment is usually terminated . Dose requirements may have to be adjusted by gender , with females requiring a higher dose than males Previous studies have demonstrated beneficial effects of GH replacement , in adults with GH deficiency ( GHD ) , on body composition , physical fitness , and quality of life . These studies , however , concern patients with adult-onset GHD or childhood-onset ( CO ) patients enrolled several years after withdrawal of initial therapy . So far , the effects of continuation of GH-administration in patients with CO-GHD have not been examined . We studied a group of nineteen young adults ( 13 males + 6 females ; 16 - 26 yr old ; mean age , 20.2 + /- 0.65 yr ) with CO-GHD , in a r and omized , parallel , double-blind ,  placebo-controlled trial for 1 yr , followed by an open phase with GH for 1 yr . All patients received GH therapy  at the start of study , and trial medication ( GH/placebo ) was given in a similar dose . Patients r and omized to continued GH treatment exhibited no significant changes in any parameters tested , but intra- and interindividual variations in insulin-like growth factor (IGF)-I levels could suggest compliance problems . Discontinuation of GH for 1 yr result ed in a decrease in serum IGF-I , from 422.0 + /- 56.8 to 147.8 + /- 33.4 microg/L , in the placebo group ( P = 0.003 ) . After discontinuation of GH for 1 yr , an increase in total body fat ( TBF , kg ) , measured by dual-energy x-ray absorptiometry scan , was seen [ placebo : 22.7 + /- 2.7 to 26.5 + /- 2.5 ( P = 0.01 ) ; GH : 16.2 + /- 2.1 to 17.2 + /- 2.1 ( not significant ) ] . Resumption of GH after placebo was followed by increments in serum IGF-I ( microg/L ) [ from 147.8 + /- 33.4 to 452 + /- 76 ( P = 0.001 ) ] and IGF-binding protein 3 , as well as in fasting glucose ( mmol/L ) [ 4.9 + /- 0.2 vs. 5.3 + /- 0.2 ( P = 0.03 ) ] . After resumption of GH lean body mass ( kg ) increased [ 52.4 + /- 4.9 vs. 60.7 + /- 5.6 ( P = 0.006 ) ] . Likewise , resumption of GH therapy increased thigh muscle volume and thigh muscle/fat ratio , as assessed by computed tomography [ muscle volume ( cm2/10 mm ) : 118.2 + /- 11.7 vs. 130.0 + /- 10.9 ( P = 0.002 ) ; muscle/fat ratio : 1.33 + /- 0.24 vs. 1.69 + /- 0.36 ( P = 0.02 ) ] . In conclusion , discontinuation of GH treatment in GHD patients , during the transition from childhood to adulthood , induces significant and potentially unfavorable changes in IGF-I and body composition , both of which are reversed after resumption of GH treatment . By contrast , continuation of GH therapy results in unaltered IGF-I and body composition . We recommend continuation of GH therapy in these patients , to be undertaken in collaboration between pediatricians and adult endocrinologists BACKGROUND To evaluate the growth hormone reserve and the growth hormone response to recombinant human growth hormone ( GH ) in prepubertal thalassemic children with growth retardation . METHODS Twenty thalassemic patients with short stature and delayed bone age were studied . Patients were r and omized into GH-treated ( n = 10 ) and non-GH treated ( control ; n = 10 ) groups . The GH-treated group received recombinant human (rh)-GH ( Genotropin ) at the dose of 0.7 IU/kg per week for 12 months . RESULTS There was a significant discordance between GH response to pharmacologic stimuli and physiological secretion of GH/GHRH testing . Following the administration of rhGH , growth velocity increased from 2.47 + /- 0.48 cm/year to 6.27 + /- 0.76 cm/year ( P = 0.005 ) , whereas there was not a similar change in the non-GH-treated group . The height velocities of the two groups during the 1 year follow-up period were significantly different ( 6.27 + /- 0.76 vs 3.99 + /- 0.34 cm/year ; P = 0.025 ) . There were significant differences between the height velocity improvements and height velocity st and ard deviation scores of the two groups as well . CONCLUSION The present study has demonstrated that rhGH is a safe and efficacious mode of treatment in thalassemic children
A positive effect of GH treatment on CVD and fracture risk could be concluded , but study design limitations have to be considered .
Stroke and secondary brain tumours remained more prevalent .
Regrowth and recurrences of (peri)pituitary tumours were not increased in patients with GH treatment compared to similar patients without GH treatment .
All fatal and nonfatal malignancies were not more prevalent in  GH-treated adults compared to the general population .
Due to the positive effects demonstrated in r and omized clinical trials on cardiovascular surrogate markers and bone metabolism , a positive effect of growth hormone ( GH ) treatment on clinical ly relevant end-points seems feasible .
In this review , we discuss the long-term efficacy and safety of GH treatment in adult patients with growth hormone deficiency ( GHD ) with emphasis on morbidity : fatal and nonfatal cardiovascular disease ( CVD ) and stroke , fractures , fatal and nonfatal malignancies and recurrences , and diabetes mellitus .