title: Fifteen years of GH replacement increases bone mineral density in hypopituitary patients with adult-onset GH deficiency Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients Gender differences in the effects of long term growth hormone (GH) treatment on bone in adults with GH deficiency. Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. Does GH replacement therapy in adult GH-deficient patients result in recurrence or increase in size of pituitary tumours? Body composition and quality of life in adults with growth hormone deficiency; effects of low‐dose growth hormone replacement Adult mortality or morbidity is not increased in childhood-onset growth hormone deficient patients who received pediatric GH treatment: an analysis of the Hypopituitary Control and Complications Study (HypoCCS) Does a gender-related effect of growth hormone (GH) replacement exist on cardiovascular risk factors, cardiac morphology, and performance and atherosclerosis? Results of a two-year open, prospective study in young adult men and women with severe GH deficiency. Influence of GH substitution therapy in deficient adults on the recurrence rate of hormonally inactive pituitary adenomas: a case control study. The effect of low dose recombinant human growth hormone replacement on regional fat distribution, insulin sensitivity, and cardiovascular risk factors in hypopituitary adults. BENEFICIAL EFFECTS OF GROWTH HORMONE TREATMENT IN GH-DEFICIENT ADULTS Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. The optimal growth hormone replacement dose in adults, derived from bioimpedance analysis. Growth hormone treatment on atherosclerosis: results of a 5-year open, prospective, controlled study in male patients with severe growth hormone deficiency. Baseline characteristics and the effects of five years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset: a comparative, prospective study. Incidence of second neoplasm in childhood cancer survivors treated with GH: an analysis of GeNeSIS and HypoCCS.
abstract: Objective Few studies have determined the effects of more than 5–10 years of GH replacement  in adults on bone mineral content ( BMC ) and bone mineral density ( BMD ) . Design / patients In this prospect i ve , single-centre , open-label study , the effects of 15 years of GH replacement on BMC and BMD , measured using dual-energy X-ray absorptiometry , were determined in 126 hypopituitary adults ( 72 men ) with adult-onset GH deficiency ( GHD ) . Mean age was 49.4 ( range 22–74 ) years at the initiation of the study . Results The mean initial GH dose of 0.63 ( s.e.m . 0.03 ) mg/day was gradually lowered to 0.41 ( 0.01 ) mg/day after 15 years . The mean serum IGF1 SDS increased from −1.69 ( 0.11 ) at baseline to 0.63 ( 0.16 ) at the study end ( P<0.001 vs baseline ) . The 15 years of GH replacement induced a sustained increase in total body BMC ( + 5 % , P<0.001 ) and BMD ( + 2 % , P<0.001 ) . Lumbar ( L2–L4 ) spine BMC increased by 9 % ( P<0.001 ) and BMD by 5 % ( P<0.001 ) . In femur neck , a peak increase in BMC and BMD of 7 and 3 % , respectively , was observed after 7 years ( both P<0.001 ) . After 15 years , femur neck BMC was 5 % above the baseline value ( P<0.01 ) , whereas femur neck BMD had returned to the baseline level . In most variables , men had a more marked response to GH replacement than women . Conclusions Fifteen-year GH replacement in GHD adults induced a sustained increase in total body and lumbar ( L2–L4 ) spine BMC and BMD . In femur neck , BMC and BMD peaked at 7 years and then decreased towards baseline values Context : In clinical practice , the safety profile of GH replacement therapy for GH-deficient adults compared with no replacement therapy is unknown . Objective : The objective of this study was to compare adverse events ( AEs ) in GH-deficient adults who were GH-treated with those in GH-deficient adults who did not receive GH replacement .  Design and Setting : This was a prospect i ve observational study in the setting of US clinical practice s. Patients and Outcome Measures : AEs were compared between GH-treated ( n = 1988 ) and untreated ( n = 442 ) GH-deficient adults after adjusting for baseline group differences and controlling the false discovery rate . The st and ardized mortality ratio was calculated using US mortality rates . Results : After a mean follow-up of 2.3 years , there was no significant difference in rates of death , cancer , intracranial tumor growth or recurrence , diabetes , or cardiovascular events in GH-treated compared with untreated patients . The st and ardized mortality ratio was not increased in either group . Unexpected AEs ( GH-treated vs untreated , P ≤ .05 ) included insomnia ( 6.4 % vs 2.7 % ) , dyspnea ( 4.2 % vs 2.0 % ) , anxiety ( 3.4 % vs 0.9 % ) , sleep apnea ( 3.3 % vs 0.9 % ) , and decreased libido ( 2.1 % vs 0.2 % ) . Some of these AEs were related to baseline risk factors ( including obesity and cardiopulmonary disease ) , higher GH dose , or concomitant GH side effects . Conclusions : In GH-deficient adults , there was no evidence for a GH treatment effect on death , cancer , intracranial tumor recurrence , diabetes , or cardiovascular events , although the follow-up period was of insufficient duration to be conclusive for these long-term events . The identification of unexpected GH-related AEs reinforces the fact that patient selection and GH dose titration are important to ensure safety of adult GH replacement 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 BACKGROUND Four retrospective studies have reported premature mortality in patients with hypopituitarism with st and ard mortality ratios ( SMRs ) varying between 1.20 and 2.17 . Patients with hypopituitarism have complex endocrine deficiencies , and the mechanisms underpinning any excess mortality are unknown . Furthermore , the suggestion has emerged that endogenous growth-hormone deficiency might account for any excess mortality . We aim ed to clarify these issues by doing a large prospect i ve study of total and specific-cause mortality in patients with hypopituitarism . METHODS We followed up 1014 UK patients ( 514 men , 500 women ) with hypopituitarism from January , 1992 , to January , 2000 . 573 ( 57 % ) patients had non-functioning adenomas , 118 ( 12 % ) craniopharyngiomas , and 93 ( 9 % ) prolactinomas .  SMRs were calculated as the ratio of observed deaths to the number of deaths in an age-matched and sex-matched UK population . FINDINGS The number of observed deaths was 181 compared with the 96.7 expected ( SMR 1.87 [ 99 % CI 1.62 - 2.16 ] , p<0.0001 ) . Univariate analysis indicated that mortality was higher in women ( 2.29 [ 1.86 - 2.82 ] ) than men ( 1.57 [ 1.28 - 1.93 ] , p=0.002 ) , in younger patients , in patients with an underlying diagnosis of craniopharyngioma ( 9.28 [ 5.84 - 14.75 ] vs 1.61 [ 1.30 - 1.99 ] , p<0.0001 ) , and in the 353 patients treated with radiotherapy ( 2.32 [ 1.71 - 3.14 ] vs 1.66 [ 1.30 - 2.13 ] , p=0.004 ) . Excess mortality was attributed to cardiovascular ( 1.82 [ 1.30 - 2.54 ] , p<0.0001 ) , respiratory ( 2.66 [ 1.72 - 4.11 ] , p<0.0001 ) , and cerebrovascular ( 2.44 [ 1.58 - 4.18 ] , p<0.0001 ) causes . There was no effect of hormonal deficiency on mortality , except for gonadotropin deficiency , which , if untreated was associated with excess mortality ( untreated 2.97 [ 2.13 - 4.13 ] vs treated 1.42 [ 0.97 - 2.07 ] , p<0.0001 ) . Multiple regression analyses identified age at diagnosis , sex , a diagnosis of craniopharyngioma , and untreated gonadotropin deficiency as independent significant factors affecting mortality . INTERPRETATION Patients with hypopituitarism have excess mortality , predominantly from vascular and respiratory disease . Age at diagnosis , female sex , and above all , craniopharyngioma were significant independent risk factors . Specific endocrine-axis deficiency , with the exception of untreated gonadotropin deficiency , does not seem to have a role OBJECTIVE Hypopituitary GH-deficient patients have an increased cardiovascular mortality and GH replacement in this population has result ed in considerable therapeutic benefit . GH replacement involves administration of a potentially mitogenic substance to patients with a previous or residual pituitary tumour . Our objective was to evaluate whether GH replacement results in an increase in the size of pituitary tumours . METHODS This was a non-r and omised observational study on patients recruited from the endocrine clinic . All subjects had GH deficiency , proven on an insulin tolerance test and were divided into those who were or were not receiving long-term GH replacement .  Comparison of change in pituitary size was made with interval radiological imaging of the pituitary . RESULTS Seventy-five patients ( 40 men and 35 women ) were in the study , 47 were on long-term GH replacement and there were 28 controls . The average length of treatment for the treated group was 3.6 patient years . Thirty-nine patients in the treated group had at least 2 years of GH treatment between imaging studies of the pituitary . Two patients in the treated group had an increase in pituitary size ( non-functioning adenomas ) and two in the control group ( one functioning and one non-functioning adenoma adenoma ) . None of these four patients required further treatment . There was no statistically significant difference between the two groups . CONCLUSION Using a representative cohort of hypopituitary patients attending an endocrine clinic , GH replacement was not associated with an increased pituitary tumour recurrence rate . Although the results are not conclusive , in the period of observation GH had little adverse effect but longer studies are required to be certain OBJECTIVE Adult growth hormone deficiency ( AGHD ) is characterized by abnormalities in body composition and a poor perceived quality of life ( QoL ) . Weight‐based high‐dose growth hormone replacement ( GHR ) results in improvements in body composition and QoL in AGHD . However , a high patient percentage reported side‐effects on high‐dose GHR result ing in a high rate of patient withdrawal from growth hormone ( GH ) treatment . High‐dose GH therapy also leads to supraphysiological serum insulin‐like growth factor‐I ( IGF‐I ) concentrations that have been associated with breast and prostate cancer , raising major concerns over the use of such high‐dose GH regimen in AGHD . The aim of this study was to assess the effects of low‐dose growth hormone replacement ( GHR ) on body composition and QoL as early as 1 and 3 months Abstract Background The French Safety and Appropriateness of Growth Hormone treatments in Europe ( SAGhE ) cohort has raised concern of increased mortality risk during follow-up into adulthood in certain patients who had received growth hormone ( GH ) treatment during childhood . The Hypopituitary Control and Complications Study monitored mortality and morbidity of adult GH-deficient patients including those with childhood-onset GH deficiency ( COGHD ) who received GH treatment as children . Purpose Evaluate risk of mortality , cancer , myocardial infa rct ion ( MI ) and stroke in a prospect i ve observational study . Methods COGHD patients [ n = 1,204 , including 389 diagnosed with idiopathic COGHD ( ICOGHD ) ] had received pediatric GH treatment .  St and ardized mortality ratios ( SMRs ) , and cancer st and ardized incidence ratios ( SIRs ) in patients without a prior cancer were estimated relative to reference population s. Crude incidence rates were estimated for MI and stroke . Results No increased mortality or cancer incidence was observed , as compared with reference population s , during a follow-up of 3.7 ± 3.3 years ( mean ± SD ) . The overall SMR for COGHD was 1.14 [ 95 % confidence interval ( CI ) 0.55–2.10 ] , and for ICOGHD , 0.33 ( 0.01–1.84 ) . The overall cancer SIR for COGHD was 0.27 ( 0.01–1.50 ) , and for ICOGHD , 0.00 ( 0.00–2.45 ) . No incident case of MI was reported . The crude stroke incidence rate [ 181.3 per 100,000 person-years ] in COGHD patients was consistent with the rates reported in reference population s. No incident case of stroke was identified in ICOGHD patients who are presumed to have no increased stroke risk factors . Conclusions The results indicate no increased risk of mortality or incidence of cancer , stroke , or MI in adult GH-deficient patients who had previously received pediatric GH treatment CONTEXT GH secretion and response to GH replacement are gender-related . OBJECTIVE The objective of this study was to investigate the effects of GH deficiency ( GHD ) and replacement on the cardiovascular system according to gender . DESIGN The design was open and prospect i ve . SETTING The study was conducted at a university hospital . SUBJECTS Subjects included 36 severe adult-onset GHD patients ( 18 men , 20 women , aged < 45 yr ) ; 36 gender- , age- , and body mass index-matched healthy subjects served as controls . INTERVENTIONS Subjects received GH replacement at a median dose of 6.5 microg/kg.d in men and 7.7 microg/kg.d in women for 2 yr . MAIN OUTCOME MEASURES Homeostasis model assessment index , total to HDL cholesterol ratio , fibrinogen and C-reactive protein levels , left ventricular mass index , blood pressure , heart rate , diastolic filling , and systolic function at rest and at peak exercise and intima-media thickness ( IMT ) at common carotid arteries were measured . RESULTS Basal prevalence and /or degree of insulin resistance , lipid alterations , compromised cardiac function , and IMT were similar in women and men . Diastolic dysfunction was more prevalent in men ( 61 vs. 25 % , P = 0.036 ) . After GH replacement , IGF-I levels normalized in all patients . Lipid profile , fibrinogen , and C-reactive protein levels normalized in all cases . The total to HDL ratio ( P = 0.04 ) was higher in women than men . The homeostasis model assessment index persisted higher in GHD patients than controls and decreased only in GHD men ( P = 0.017 ) . Left ventricular mass index normalized during treatment in both women and men , abnormal diastolic function persisted in three women ( P = 0.031 ) , and abnormal systolic performance persisted in six women and one man ( P = 0.13 ) . IMT decreased similarly in women and men , persisting higher than in controls . Exercise performance normalized in all . CONCLUSIONS Two-year GH replacement has similar beneficial effects on cardiac and exercise performance and atherosclerosis in women and men with severe GHD OBJECTIVE Several studies documented metabolic and psychological benefits of GH substitution in deficient adults , most of them suffering from benign pituitary adenomas . Since GH substitution is considered to promote tumour regrowth , adequate treatment is performed with some reservation . Therefore , we aim ed to eluci date the effect of GH replacement therapy on tumour recurrence following surgery . METHODS In patients with hormonally inactive pituitary adenomas undergoing tumour surgery , a retrospective case-control study was performed . Pre- and postoperative magnetic resonance ( MR ) images of GH-treated and untreated patients were matched for best fit by two independent observers . The treated patients were retrieved from the surveillance programme of the German KIMS data base and the untreated from the data base of the Department of Neurosurgery , University of Erlangen . A total of 55 matched pairs were followed for at least 5 years . Tumour recurrence and progression rates were determined according to the postoperative MR . RESULTS There were 16 tumour progressions in the treatment group and 12 in the control group . Statistical analysis revealed no significant increase in either recurrence ( P = 0.317 ) or progression ( P = 0.617 ) within the follow-up period of 5 years when GH was adequately replaced . CONCLUSIONS This study provides further observational data of substitution therapy in GH-deficient adults with pituitary adenomas . Comparing long-term surgical results , we found no evidence that GH substitution should be withheld in deficient patients . Even residual tumour does not constitute a contraindication to GH replacement . However , since pituitary tumours are slow growing , an observational period of 5 years may not have been long enough to verify any absolute influence on recurrence potential GH deficiency is associated with increased cardiovascular morbidity , which may be determined by alterations in vascular risk factors . We report the effect of partially treated hypopituitarism and subsequent GH replacement ( mean dose , 0.2 IU/kg.week ) on putative cardiovascular risk factors in 22 nondiabetic hypopituitary subjects in a 6-month , double blind , controlled study ( active/placebo ratio , 11:11 ) . All patients were subsequently treated with GH for a further 6 months .  Total fat , percent body fat , and central fat were measured by dual energy x-ray absorptiometry .  The hypopituitary patients had increased percent fat ( P = 0.03 ) and central fat ( P < 0.01 ) compared with body mass index-matched controls . Before GH treatment , fasting ( total ) and specific insulin positively correlated with body mass index ( P = 0.02 and P < 0.001 , respectively ) , waist/hip ratio ( P = 0.05 and P = 0.01 ) , and central fat ( P = 0.03 and P = 0.003 ) . Specific insulin and insulin sensitivity ( IS ) , calculated by homeostatic model of assessment , were related to total fat ( P < 0.001 and P = 0.02 ) . GH treatment for 6 months led to a reduction in total fat ( P < 0.02 ) , percent fat ( P = 0.002 ) , central fat ( P = 0.012 ) , waist/hip ratio ( P < 0.05 ) , total cholesterol ( P = 0.03 ) , and apolipoprotein-B ( P = 00001 ) , as well as a decrease in the IS from 36.9 % ( range , 12 - 100 % ) to 25 % ( range , 2.5 - 55 % ; P = 0.0002 ) . This was paralleled by a rise in fasting ( total ) and specific insulin ( P = 0.016 and P = 0.002 ) . The degree of correlation among indices of IS , body composition , and fat distribution increased after GH treatment . Fasting plasma glucose rose significantly , but was within the reference range . During 12 months of GH therapy , a significant increase in serum lipoprotein-(a ) was observed ( P < 0.05 ) . Although GH has beneficial effects on central adiposity and lipid fractions , it is also associated with a decrease in IS ; these effects may vary between individuals 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 CONTEXT Patients with hypopituitarism have an increased st and ardized mortality rate . The basis for this has not been fully clarified . OBJECTIVE To investigate in detail the cause of death in a large cohort of patients with hypopituitarism subjected to long-term follow-up . DESIGN AND METHODS All-cause and cause-specific mortality in 1286 Swedish patients with hypopituitarism prospect ively monitored in KIMS ( Pfizer International Metabolic Data base ) 1995 - 2009 were compared to general population data in the Swedish National Cause of Death Registry . In addition , events reported in KIMS , medical records , and postmortem reports were review ed . MAIN OUTCOME MEASURES St and ardized mortality ratios ( SMR ) were calculated , with stratification for gender , attained age , and calendar year during follow-up . RESULTS An excess mortality was found , 120 deaths vs 84.3 expected , SMR 1.42 ( 95 % confidence interval : 1.18 - 1.70 ) . Infections , brain cancer , and sudden death were associated with significantly increased SMRs ( 6.32 , 9.40 , and 4.10 , respectively ) . Fifteen patients , all ACTH-deficient , died from infections . Eight of these patients were considered to be in a state of adrenal crisis in connection with death ( medical reports and post-mortem examinations ) . Another 8 patients died from de novo malignant brain tumors , 6 of which had had a benign pituitary lesion at baseline . Six of these 8 subjects had received prior radiation therapy . CONCLUSION Two important causes of excess mortality were identified : first , adrenal crisis in response to acute stress and intercurrent illness ; second , increased risk of a late appearance of de novo malignant brain tumors in patients who previously received radiotherapy . Both of these causes may be in part preventable by changes in the management of pituitary disease 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 The prevalence of clinical signs and symptoms related to fluid retention is high in most studies evaluating the efficacy of GH treatment in GH-deficient ( GHD ) adults . This may be a consequence of supraphysiological GH replacement . To examine whether fluid retention is a dose-related phenomenon , we evaluated the impact of various GH substitution doses on body fluid status in 46 GHD men participating in a 1-yr , double blind , and placebo-controlled study . The patients were r and omized to receive either placebo ( n = 13 ) or GH in a dose of 1 ( n = 11 ) , 2 ( n = 10 ) , or 3 ( n = 12 ) IU/m2.day , respectively . Treatment was started at one third of the predetermined dose and was subsequently increased by another third every month until the maintenance dose was reached . Tissue hydration was assessed by means of electrical impedance measurements . Normal values were obtained from 128 age- and sex-matched controls . In the untreated GHD state , whole body resistance was abnormally high ( observed , 642 + /- 82 omega ; predicted , 550 + /- 31 omega ; P < 0.001 ) . This was mainly caused by an increase in specific resistance of the lean body as a consequence of a reduction in extracellular water ( ECW ) . The first month of GH treatment was associated with a sharp decline in electrical resistance that was attributed to an increase in ECW . Whole body resistance reached its nadir after 3 months of treatment ( 517 + /- 72 omega , i.e. 19.6 + /- 6.5 % lower than before treatment ; P < 0.001 ) and did not change significantly thereafter . The GH-induced changes in body resistance were dose dependent . A significant decrease was observed with a dose as low as 0.33 IU/m2.day ( P < 0.005 ) . However , whole body resistance remained higher than normal in patients receiving less than 0.67 IU/m2.day ( P = 0.05 ) . Abnormally low resistance values , indicative of overhydration , were observed in patients receiving doses equal to or higher than 2 IU/m2.day ( P < 0.005 ) . Regression analysis of the pooled data showed that GH replacement in a dose of 1.10 IU/m2.day ( 95 % confidence interval , 0.85 - 1.45 IU/m2.day ) result ed in a normalization of whole body resistance . In conclusion , GH replacement therapy in adults rapidly corrects the preexisting deficit in ECW . This rehydration process is dose dependent and may result in a substantial weight gain . ( ABSTRACT TRUNCATED AT 400 WORDS BACKGROUND Severe GH deficiency ( GHD ) is associated with , increased cardiovascular risk and intima-media thickness ( IMT ) at major arteries . OBJECTIVE The objective of the study was to investigate the 5-yr effects of GH replacement on common carotid IMT and insulin resistance syndrome ( IRS ) ( at least two of the following : triglycerides levels > or = 1.7 mmol/liter , high-density lipoprotein-cholesterol levels < or = 1.0 mmol/liter , blood pressure above 130/85 mm Hg , fasting glucose 6.1 - 7 or 2 hr after glucose 7.7 - 11.1 mmol/liter ) . DESIGN This was an interventional , open , prospect i ve , controlled study . PATIENTS Patients included 35 men with severe GHD and 35 age-matched healthy men as controls . INTERVENTION All patients received st and ard replacement therapy ; GH replacement was added in 22 patients ( group A ) and refused by 13 others ( group B ) . MEASUREMENTS Five-year changes in IMT and IRS prevalence were measured . RESULTS At baseline , IMT was higher in the patients with ( P < 0.001 ) and without IRS ( P = 0.004 ) than in controls . Eighteen patients ( 51.4 % ) and two controls ( 5.7 % ; P < 0.0001 ) had IRS . At study end , use of lipid-lowering drugs ( 92.3 , vs. 13.6 and 34.3 % , P < 0.0001 ) , glucose-lowering drugs ( 69.2 vs. 31.4 and 22.7 % ; P = 0.016 ) , and antihypertensive drugs ( 61.5 vs. 20.0 and 4.5 % ; P < 0.0001 ) was higher in group B patients than controls and group A patients . IGF-I levels normalized in all group A patients and remained lower than -1 sd score in 77 % of group B patients . IMT significantly decreased only in group A and significantly increased in controls and nonsignificantly in group B patients . IRS prevalence significantly reduced only in group A patients . CONCLUSIONS Severely hypopituitary GHD men have more frequently increased IMT at common carotid arteries and IRS than controls . After 5 years , only in GH replaced patients , IMT and prevalence of IRS decreased The consequences of GH deficiency may differ if the disease is childhood onset or adulthood onset . In this single-center , prospect i ve study , 21 consecutive adults with childhood onset GH deficiency and 21 adults with adulthood onset GH deficiency , matched for age , gender , body mass index , and number of anterior pituitary hormonal deficiencies , were included . Baseline differences and differences in the responses in body composition , muscle strength , bone mass , and metabolic indices during 5-yr GH replacement were determined . The duration of GH deficiency was longer and serum IGF-I level and body height were lower in the childhood onset patients than in the adulthood onset patients . Body fat ( observed/predicted ratio ) was increased , and lean mass and muscle strength were decreased , in the childhood onset patients . Total body and lumbar ( L2-L4 ) bone mineral content and bone mineral density were lower in the childhood onset patients . Serum total cholesterol level was higher in the adulthood onset patients . The childhood onset and adulthood onset patients received a similar dose of GH . After adjustment for body weight , however , the dose of GH was higher in the childhood onset patients . The treatment responses were more marked in the childhood onset patients in lean mass , knee extensor strength , left-h and grip strength , and in total body and lumbar ( L2-L4 ) bone mineral content and bone mineral density . The reduction in serum total cholesterol concentration was more marked in the adulthood onset patients . At study end , no differences remained between the two study groups after the correction for body height in the statistical analysis . In conclusion , the baseline analysis suggests more decreased lean mass , muscle strength , and bone mass in the childhood onset patients whereas the lipid profile was more disturbed in the adulthood onset patients . The 5-yr GH replacement eliminated all the anthropodometric and metabolic differences between the two groups OBJECTIVE Childhood cancer survivors are commonly treated with GH for GH deficiency that develops either as a result of primary malignancy or its treatment . One study --the Childhood Cancer Survivor Study (CCSS)--demonstrated increased risk of second neoplasm ( SN ) in GH-treated childhood cancer survivors compared with non-GH treated , after adjusting for key risk factors . We assessed the incidence of SN in GH-treated childhood cancer survivors in outpatient observational studies of GH replacement . DESIGN Retrospective analysis of two prospect i ve cohort studies that collected data on safety of GH replacement as prescribed in clinical practice . METHODS Childhood cancer survivors enrolled in Eli Lilly and Company 's pediatric ( Genetics and Neuroendocrinology of Short Stature International Study ( GeNeSIS ) ) and adult ( Hypopituitary Control and Complications Study ( HypoCCS ) ) observational studies of GH treatment were assessed for incidence of SN . RESULTS The percentage of childhood cancer survivors treated with  GH  who developed a SN was 3.8 % in pediatric GeNeSIS participants and 6.0 % in adult HypoCCS participants . The estimated cumulative incidence of SN at 5 years of follow-up in these studies was 6.2 and 4.8 % respectively . CONCLUSIONS The incidence of SN in GeNeSIS and HypoCCS GH-treated participants is similar to the published literature and is thus consistent with increased risk of SN in childhood cancer survivors treated with GH . As follow-up times were relatively short ( <3 years ) , longer observation is recommended . Nevertheless , clinicians should be alerted to the possibility of increased risk of SN in childhood cancer survivors treated with GH  and continue chronic surveillance
target: 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 .
background: 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 .