Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. Effect of growth hormone replacement therapy on the quality of life in women with growth hormone deficiency who have a history of acromegaly versus other disorders. MOD-4023, a long-acting carboxy-terminal peptide-modified human growth hormone: results of a Phase 2 study in growth hormone-deficient adults Effects of growth hormone treatment on arginine to asymmetric dimethylarginine ratio and endothelial function in patients with growth hormone deficiency. A longitudinal study of craniofacial growth in idiopathic short stature and growth hormone-deficient boys treated with growth hormone. Diagnostic strategy for growth hormone deficiency: relevance of IGF-1 determination as a screening test. Evaluation of coagulation and fibrinolytic parameters in adult onset GH deficiency and the effects of GH replacement therapy: a placebo controlled study. Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy. Effects of GH on lipid peroxidation and neutrophil superoxide anion‐generating capacity in hypopituitary adults with GH deficiency Baseline characteristics and effects of growth hormone therapy over two years in younger and elderly adults with adult onset GH deficiency. Long‐term cardiovascular effects of growth hormone treatment in GH‐deficient adults Preliminary data in a small group of patients TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy. 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. A Long-Acting Human Growth Hormone (Nutropin Depot®): Efficacy and Safety Following Two Years of Treatment in Children with Growth Hormone Deficiency The effects of five‐year growth hormone replacement therapy on muscle strength in elderly hypopituitary patients Limited effects of growth hormone replacement in patients with GH deficiency during long-term cure of acromegaly Gender differences in the effects of long term growth hormone (GH) treatment on bone in adults with GH deficiency.
A retrospective comparison was performed between 1411 hypopituitary adults without GH replacement [ mean age , 56.9 ( sd 18.6 ) yr ] and the normal population in terms of fatal and nonfatal morbidity . A similar prospect i ve comparison was then made in 289 hypopituitary patients on long-term GH replacement [ mean age , 47.6 ( sd 14.8 ) yr ; mean duration of GH treatment , 60 months ] . In the 1411 hypopituitary patients without GH replacement , overall mortality ( P < 0.001 ) , and the rates of myocardial infa rct ions ( P < 0.01 ) , cerebrovascular events ( P < 0.001 ) , and malignancies ( P < 0.001 ) were increased compared with the normal population . Colorectal cancer was the most common malignancy in this cohort ( P < 0.001 vs. the background population ) . In the 289 hypopituitary patients on GH replacement , overall mortality and the rate of malignancies were similar to the normal population . In the hypopituitary adults on GH therapy , the rate of myocardial infa rct ions was lower than that in the background population ( P < 0.05 ) , and there was a tendency toward an increased rate of cerebrovascular events . In conclusion , overall mortality and the rate of myocardial infa rct ions were increased in hypopituitary patients without GH replacement . An increased rate of malignancies was observed in the hypopituitary adults without GH therapy , with a predominance of colorectal cancer . GH replacement appeared to provide protection from myocardial infa rct ions . The rate of cerebrovascular events tended to be increased also in hypopituitary adults on GH therapy OBJECTIVE To compare the response in quality of life ( QoL ) to growth hormone ( GH ) replacement in women with GH deficiency ( GHD ) and a history of acromegaly with that in women with GHD of other causes . METHODS Fifty-five women with GHD were studied : 17 with prior acromegaly and 38 with other causes of GHD . We compared two 6-month , r and omized , placebo-controlled studies of GH therapy in women with hypopituitarism conducted with use of the same design -one in women with a history of acromegaly and one in women with no prior acromegaly .  QoL was assessed with the following question naires : the QoL- Assessment of Growth Hormone Deficiency in Adults ( AGHDA ) , the Symptom Question naire , and the 36-Item Short-Form Health Survey ( SF-36 ) . RESULTS The 2 groups had comparable mean pretreatment age , body mass index , and QoL scores and comparable mean GH dose at 6 months ( 0.61 ± 0.30 versus 0.67 ± 0.27 mg daily ) . After 6 months of GH replacement therapy , women with GHD and prior acromegaly demonstrated a greater improvement in AGHDA score , four SF-36 sub-scales ( Role Limitations due to Physical Health , Energy or Fatigue , Emotional Well-Being , and Social Functioning ) , and the Somatic Symptoms subscale of the Symptom Question naire than did women with GHD of other causes . Poorer pretreatment QoL was associated with a greater improvement in QoL after administration of GH . CONCLUSION In this study , GH replacement therapy  improved QoL in women with GHD and a history of acromegaly but not in women with GHD due to other hypothalamic and pituitary disorders . Further studies are needed to determine the long-term risks versus benefits of GH replacement in patients who develop GHD after definitive treatment for acromegaly Objective Growth hormone ( GH ) replacement therapy currently requires daily injections , which may cause distress and low compliance . C-terminal peptide (CTP)-modified growth hormone ( MOD-4023 ) is being developed as a once-weekly dosing regimen in patients with GH deficiency ( GHD ) . This study ’s objective is to evaluate the safety , pharmacokinetics ( PK ) , pharmacodynamics ( PD ) and efficacy of MOD-4023 administered once-weekly in GHD adults . Design 54 adults with GHD currently treated with daily GH were normalized and r and omized into 4 weekly dosing cohorts of MOD-4023 at 18.5 % , 37 % , 55.5 % or 123.4 % of individual cumulative weekly molar hGH dose . The study included 2 stages : Stage A assessed the effectiveness and PK/PD profiles of the 4 dosing regimens of MOD-4023 . Stage B was an extension period of once-weekly MOD-4023 administration ( 61.7 % molar hGH content ) to collect further safety data and confirm the results from Stage A. Results Dose-dependent response was observed for both PK and PD data of weekly MOD-4023 treatment . Insulin-like growth factor I ( IGF-I ) SDS levels were maintained within normal range . The 18.5 % cohort was discontinued due to low efficacy . MOD-4023 was well tolerated and exhibited favorable safety profile in all dose cohorts . The reported adverse events were consistent with known GH-related side effects . Conclusions Once-weekly MOD-4023 administration in GHD adults was found to be clinical ly effective while maintaining a favorable safety profile and may obviate the need for daily injections . Weekly GH injections may improve compliance and overall outcome . The promising results achieved in this Phase 2 study led to a pivotal Phase 3 trial , which is currently ongoing Patients with growth hormone deficiency ( GHD ) are known to have reduced life expectancy due to increased cardiovascular and cerebrovascular events . An increase in asymmetric dimethylarginine ( ADMA ) levels previously found in GHD patients could promote premature atherosclerosis . The aim of this study was to determine whether 6-month growth hormone ( GH ) replacement therapy was able to decrease ADMA levels and ameliorate endothelial dysfunction .  Thirty-one GHD patients were studied before and after 6 months of GH ( 4 microg/[kg d ] , daily ) replacement therapy . Reduced pretreatment levels of serum insulin-like growth factor ( IGF ) 1 were normalized during GH treatment ( 88.2 + /- 62.5 to 191.7 + /- 80.3 ng/mL , P < .0001 ) . After 6 months of GH replacement , plasma cyclic guanosine monophosphate levels significantly increased ( 2.14 + /- 0.52 to 3.54 + /- 1.2 ng/mL , P < .0001 ) , serum ADMA levels were significantly decreased ( 0.65 + /- 0.1 vs 0.59 + /- 0.11 mumol/L , P < .05 ) , and arganine ( Arg ) to ADMA ratio was significantly higher ( 155 + /- 53 vs 193 + /- 61 , P < .01 ) . No changes were observed for plasma nitric oxide end products ( nitrite and nitrate ) levels after GH treatment ( 21.9 + /- 14.9 vs 24.1 + /- 19.0 mumol/L , not significant ) . Basal forearm blood flow remained unchanged , whereas reactive hyperemia increased from 7.30 + /- 5.31 mL/100 mL forearm per minute before GH therapy to 13.18 + /- 7.30 mL/100 mL forearm per minute after 6 months of therapy ( P < .001 ) . There was a positive correlation between IGF-1 and cyclic guanosine monophosphate ( r = 0.73 , P < .0001 ) , IGF-1 and reactive hyperemia ( r = 0.63 , P < .0001 ) , and IGF-1 and Arg/ADMA ratio ( r = 0.44 , P < .01 ) . Conversely , a negative correlation was found between IGF-1 and ADMA levels ( r = -0.41 , P < .02 ) . At the end of the study period , fat-free mass , plasma glucose , and hemoglobin A(1c ) levels significantly increased , even if they were still in the reference range , suggesting moderate alteration of glucose metabolism . In conclusion , in GHD patients , GH replacement contributes to decreased , to some extent , cardiovascular risk , reducing ADMA levels and improving Arg/ADMA ratio and endothelial dysfunction The aim of this prospect i ve , longitudinal , controlled study is to describe the long-term safety and efficacy of growth hormone ( GH ) administration on craniofacial morphology in boys with short stature . Forty-six boys , who started GH treatment at the Department of Paediatrics Göteborg Paediatric Growth Research Centre , were consecutively included in the study . Twenty-five boys were classified as growth hormone-deficient ( GHD ) and 21 as idiopathic short stature ( ISS ) . The patients were injected with 33 ( n=31 ) or 67 ( n=15 ) microg GH/kg body weight/day . The mean age at the start of treatment was 11.8 years [ st and ard deviation ( SD ) 1.7 ] . To assess craniofacial growth , st and ard lateral cephalometric radiographs were obtained at the start of GH treatment , annually during 4 years , and at the end of GH treatment or when growth was less than 1 cm/year . The mean follow-up period was 6.4 years ( SD 1.4 ) . Growth changes were compared with boys from a semi-longitudinal reference group of 130 healthy subjects , 7 - 21 years of age . t-tests for independent and paired sample s and multiple regression analysis were applied . Age- and gender-specific st and ard deviation scores for the cephalometric variables were calculated . Repeated measures analysis of variance was used to identify significant covariates over time , such as low/high GH dose and GHD/ISS and orthodontic treatment . During the study period , eight ( out of 40 ) boys were treated with fixed orthodontic appliances , three with functional appliances ( activators ) , and three with other appliances ( plates and lingual arches ) . During GH treatment period , an overall enhancement in growth of the facial skeleton was observed in boys with short stature . The changes induced by GH yielded a more prognathic growth pattern , a more anterior position of the jaws in relation to the cranial base , and increased anterior rotation of the m and ible . The m and ibular corpus length and anterior face height of the GH-treated boys were greater at the end of the study compared with the boys in the reference group . No differences in growth response were noted either between the GHD and ISS boys or between those treated with either 33 ( low dose ) or 67 ( high dose ) microg GH/kg body weight/day . The only change that remained significantly correlated with orthodontic treatment was the alteration in m and ibular ramus height , showing a larger change in the boys who had not undergone orthodontic therapy . The findings of this study demonstrate that GH treatment has a favourable influence on the craniofacial growth pattern of boys with short stature without acromegalic features 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 OBJECTIVE Increased cardiovascular mortality/morbidity observed in patients with hypopituitarism is ascribed to growth hormone deficiency ( GHD ) because of its unfavorable cardiovascular risk profile . Abnormalities in the coagulation system may also contribute to increased cardiovascular morbidity/mortality . To get a better insight into the role of hemostasis in GHD we assessed several hemostatic markers at baseline and after 6 months of GH replacement therapy ( GHRT ) . DESIGN - PATIENTS : Nineteen patients with adult onset GHD were enrolled ( twelve patients into the treatment and seven patients into the placebo group )  into the study . Platelet count , collagen/epinephrine closure time , collagen/ADP closure time , fibrinogen , prothrombin time ( PT ) , activated partial thromboplastin time ( aPTT ) , antithrombin III ( AT III ) , protein C activity , protein S activity , lupus anticoagulant , antiphospholipid antibody immunoglobulin M , and antiphospholipid antibody immunoglobulin G were measured at baseline and 6 months after treatment . RESULTS The investigated parameters in the groups were similar at baseline except for low protein S ( PS ) activity . Protein S deficiency was observed in three of the patients in the GH treatment group at baseline , however the PS activity values normalized following GHRT .  AT III and protein C activities decreased when compared to baseline values in the treatment group but not in the placebo group . CONCLUSIONS We observed protein S deficiency more frequent than seen in the general population and normalization of protein S activity and decreases , in other natural anticoagulants following GHRT . Further studies are required to underst and the impact of these changes in cardiovascular morbidity and mortality in this patient population GH deficiency ( GHD ) is associated with increased prevalence of atherosclerosis and cardiovascular morbidity . Because monocytes play a crucial role in the development of atherosclerosis , we investigated in the present study the effect of GH deficiency and subsequent GH replacement on monocytic function in hypopituitary subjects . Twelve patients were r and omized to receive GH replacement therapy ( either 3 or 6 microg/kg x day , s.c . ) for 3 months . Plasma levels and monocyte production of cytokines and monocyte adhesion to endothelium were determined in controls and patients with GHD before and after GH treatment . Before GH therapy , patients with GHD had increased basal plasma tumor necrosis factor-alpha ( TNF alpha ; 220 % over control values ; P = 0.004 ) and interleukin-6 ( IL-6 ; 340 % over control values ; P 0.0009 ) levels . Basal monocyte production of both cytokines was also significantly higher in patients with GHD [ 484 % over control values for TNF alpha ( P = 0.0007 ) ; 1479 % over control values for IL-6 ( P = 0.035 ) ] . GH treatment for 3 months led to a reduction in plasma TNF alpha ( 135 % over control values ; P = 0.03 , pre- vs. post-GH therapy ) , monocyte TNF alpha production ( 204 % over control values ; P = 0.01 ) , plasma IL-6 ( 219 % over control values ; P = 0.07 ) , and monocyte IL-6 production ( 448 % over control values ; P = 0.01 ) . Plasma TNF alpha levels positively correlated with monocyte TNF alpha production in patients with GHD both before and after GH therapy ( P = 0.003 and P = 0.049 , respectively ) . A positive correlation ( P = 0.0003 ) was also observed between monocyte TNF alpha production and monocyte IL-6 production . There were no correlations between these plasma cytokine levels or monocyte cytokine production and parameters of body composition , lipid profile , or IGF-I and IGF-binding protein-3 levels . Before GH treatment , adhesiveness of monocytes to cultured aortic endothelial cells was also enhanced . This alteration was not reversed by GH administration . In conclusion , our results demonstrate that markers of monocyte activation are increased in patients with GHD and that GH replacement partly reduces these abnormalities . Reduction of cellular activation of monocytes by GH therapy could potentially contribute to reduce the risk of cardiovascular events in patients with GHD objectives  Untreated growth hormone deficiency ( GHD ) is implicated in the increased cardiovascular risk associated with adult hypopituitarism . Oxidative stress , predisposing to lipid peroxidation , may be an important mediator of endothelial dysfunction , a pro‐atherogenic state associated with adult GHD 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 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 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 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 BACKGROUND Nutropin Depots [ somatropin ( rDNA origin ) for injectable suspension ] is a long-acting form of human growth hormone ( GH ) to be administered by subcutaneous ( s.c . ) injection . The availability of this formulation offers the opportunity for greater convenience and compliance by decreasing the number of injections and frequency of administration required . OBJECTIVE To determine the efficacy and safety of a long-acting formulation of GH administered in children with GH deficiency ( GHD ) once or twice monthly for 2 years . PATIENTS Fifty-six previously untreated , prepubertal children with GHD received Nutropin Depot 1.5 mg/kg once monthly ( 1x/mo ) , or 0.75 mg/kg twice monthly ( 2x/mo ) for 24 months . The mean pretreatment growth rate was 5.0 + /- 2.4 cm/yr . RESULTS The 0 - 12 mo growth rate ( mean + /- SD ) was 8.3 + /- 1.5 cm/yr in the 1x/mo group and 8.2 + /- 2.0 cm/yr in the 2x/mo group . The 12 - 24 month growth rate was 7.2 + /- 1.5 cm/yr in the 1x/mo group and 6.9 + /- 1.5 cm/yr in the 2x/mo group . During the 24 months of treatment , height st and ard deviation score ( SDS ) increased by 1.0 + /- 0.5 SD in the two groups combined ( p < 0.0001 ) . The corresponding advancement in bone age was 2.2 + /- 0.7 yr , result ing in a gain in Bayley-Pinneau predicted adult height ( PAH ) SDS of 0.6 + /- 0.9 SD in the 1x/mo group and 0.6 + /- 1.0 SD in the 2x/mo group . No serious adverse events attributable to the study drug were reported . Injection site reactions were common , but resolved without intervention . Pre-dose fasting and postpr and ial glucose and insulin levels , as well as hemoglobin A1c levels , were unchanged from baseline values . CONCLUSIONS Treatment with Nutropin Depot is associated with catch-up growth and normal skeletal maturation and is a viable alternative to daily injections of GH in children with GHD Objective Little is known of the long‐term effects of GH replacement therapy on muscle strength in elderly adults with adult onset GH deficiency ( GHD ) . In this study , the effects of 5 years of GH replacement therapy on muscle function were determined in adults over 60 years of age with adult onset GHD 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 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
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 .