title: Cardiovascular effects of growth hormone treatment in growth-hormone-deficient adults: stimulation of the renin-aldosterone system. Pregnancy-associated plasma protein-A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. Moderate doses of hGH (0.64 mg/d) improve lipids but not cardiovascular function in GH-deficient adults with normal baseline cardiac function. Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. Adult Growth Hormone Deficiency Study Group. Growth hormone (GH) replacement decreases serum total and LDL-cholesterol in hypopituitary patients on maintenance HMG CoA reductase inhibitor (statin) therapy Fifteen years of GH replacement improves body composition and cardiovascular risk factors Cardiac function in growth hormone deficient patients before and after 1 year with replacement therapy: a magnetic resonance imaging study Association between premature mortality and hypopituitarism. West Midlands Prospective Hypopituitary Study Group. The influence of growth hormone replacement on peripheral inflammatory and cardiovascular risk markers in adults with severe growth hormone deficiency. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Hemostatic risk factors in patients with coronary artery disease and type 2 diabetes - a two year follow-up of 243 patients Growth hormone (GH) replacement reduces total body fat and normalizes insulin sensitivity in GH-deficient adults: a report of one-year clinical experience. Effects of 7 years of growth hormone replacement therapy in hypopituitary adults. Long-term monitoring of insulin sensitivity in growth hormone-deficient adults on substitutive recombinant human growth hormone therapy. Effects of growth hormone administration on inflammatory and other cardiovascular risk markers in men with growth hormone deficiency. A randomized, controlled clinical trial. Diagnosis and treatment of acromegaly complications TNF-alpha levels in children with growth hormone deficiency and the effect of long-term growth hormone replacement therapy. Effects of GH treatment in GH-deficient adults on adiponectin, leptin and pregnancy-associated plasma protein-A. 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. Growth hormone replacement reduces C‐reactive protein and large‐artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency Effects of growth hormone treatment on arginine to asymmetric dimethylarginine ratio and endothelial function in patients with growth hormone deficiency. Adiponectin as predictor for diabetes among pre-diabetic groups Increased lipid peroxidation in adult GH-deficient patients: Effects of short-term GH administration Effects of GH on lipid peroxidation and neutrophil superoxide anion‐generating capacity in hypopituitary adults with GH deficiency Evaluation of coagulation and fibrinolytic parameters in adult onset GH deficiency and the effects of GH replacement therapy: a placebo controlled study. Adolescents with partial growth hormone (GH) deficiency develop alterations of body composition after GH discontinuation and require follow-up. Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. Continuation of growth hormone (GH) replacement in GH-deficient patients during transition from childhood to adulthood: a two-year placebo-controlled study. Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. Malignant disease and cardiovascular morbidity in hypopituitary adults with or without growth hormone replacement therapy. Low‐dose growth hormone replacement lowers plasma leptin and fat stores without affecting body mass index in adults with growth hormone deficiency Atherogenic lipoprotein phenotype and low-density lipoprotein size and subclasses in patients with growth hormone deficiency before and after short-term replacement therapy. C-reactive protein and the risk of developing hypertension. Growth hormone treatment on atherosclerosis: results of a 5-year open, prospective, controlled study in male patients with severe growth hormone deficiency. Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year. Long‐term cardiovascular effects of growth hormone treatment in GH‐deficient adults Preliminary data in a small group of patients One year of GH replacement therapy with a fixed low-dose regimen improves body composition, bone mineral density and lipid profile of GH-deficient adults. Alterations of monocyte function in patients with growth hormone (GH) deficiency: effect of substitutive GH therapy. Continued growth hormone (GH) treatment after final height is necessary to complete somatic development in childhood-onset GH-deficient patients.
abstract: 1 . In adult humans with growth hormone deficiency , treatment with growth hormone has recently been shown to have major anabolic effects and to improve exercise performance . The cardiovascular effects of growth hormone in adults with growth hormone deficiency were examined in 24 patients treated with recombinant human growth hormone ( 0.07 units/kg at night ) in a double-blind , placebo-controlled trial lasting 6 months . 2 . Compared with placebo , resting M-mode echocardiography showed increases in left ventricular end-diastolic dimension and stroke volume in the group treated with recombinant human growth hormone . No differences were noted between the groups with respect to left ventricular end-systolic dimension , fractional shortening , wall thicknesses or mean arterial blood pressure . Left ventricular myocardial mass increased in the group given recombinant human growth hormone . 3 . The supine plasma renin activity was increased and remained elevated over the 6 months , whereas the plasma aldosterone concentration was unchanged , after treatment with recombinant human growth hormone . Clinical signs of sodium retention were evident during the first 3 months of treatment with recombinant human growth hormone . 4 . We conclude that treatment with recombinant human growth hormone in adults with growth hormone deficiency result ed in small increases in left ventricular pre-load , due to the sodium-retaining action of growth hormone . Activation of the renin-aldosterone system was involved in such changes . Myocardial hypertrophy was observed without changes in mean arterial pressure , reflecting the anabolic action of growth hormone OBJECTIVES The goal of this study was to determine the predictive value of pregnancy-associated plasma protein-A ( PAPP-A ) in patients with acute coronary syndromes ( ACS ) . BACKGROUND Pregnancy-associated plasma protein-A is a zinc-binding matrix metalloproteinase abundantly expressed in eroded and ruptured plaques and may serve as a marker of plaque destabilization . METHODS In 547 patients with angiographically vali date d ACS and in a heterogeneous emergency room population of 644 patients with acute chest pain , respectively , PAPP-A as well as markers of myocardial necrosis ( troponin T [ TnT ] ) , ischemia ( vascular endothelial growth factor [ VEGF ] ) , inflammation ( high-sensitivity C-reactive protein [ hsCRP ] ) , anti-inflammatory activity ( interleukin [IL]-10 ) , and platelet activation ( soluble CD40 lig and [ sCD40L ] ) were determined . Patients were followed for the occurrence of death or myocardial infa rct ion . RESULTS In patients with ACS , elevated PAPP-A levels ( > 12.6 mIU/l ) indicated an increased risk ( odds ratio 2.44 [ 95 % confidence interval ( CI ) 1.43 to 4.15 ] ; p = 0.001 ) . When the analysis was restricted to TnT-negative patients , PAPP-A still identified a subgroup of high-risk patients ( odds ratio [ OR ] 2.72 [ 95 % confidence interval ( CI ) 1.25 to 5.89 ] ; p = 0.009 ) . In a multivariable model , PAPP-A ( OR 2.01 ; p = 0.015 ) , sCD40L ( OR 2.37 ; p = 0.003 ) , IL-10 ( OR 0.43 ; p = 0.003 ) , and VEGF ( OR 2.19 ; p = 0.018 ) were independent predictors . Prospect i ve validation in patients with chest pain confirmed that  PAPP-A levels reliably identify high-risk patients ( adjusted OR 2.32 [ 95 % CI 1.32 to 4.26 ] ; p = 0.008 ) . Patients negative for all three markers ( TnT , sCD40L , and PAPP-A ) were at very low cardiac risk ( 30 days : 3.0 % event rate ; no death ) . CONCLUSIONS The PAPP-A level as a marker of plaque instability is a strong independent predictor of cardiovascular events in patients with ACS . Simultaneous determination of biomarkers with distinct pathophysiological profiles appears to remarkably improve risk stratification in patients with ACS CONTEXT Data regarding effects of lower-dose GH on cardiopulmonary function in GH-deficient ( GHD ) adults are limited . OBJECTIVES The objective was to assess effects of lower-dose GH on exercise capacity and echocardiographic parameters in GHD adults . DESIGN The study was a 6-month double-blind , placebo-controlled r and omized trial . SETTING The study was conducted at the General Clinical Research Center . PARTICIPANTS Thirty hypopituitary adults with GHD were studied . INTERVENTION Subjects were r and omized to recombinant human GH or placebo for 6 months , followed by open-label recombinant human GH for 12 months . MAIN OUTCOME MEASURES Primary endpoints were exercise duration , maximal oxygen consumption , and left ventricular ejection fraction . Secondary endpoints were echocardiographic indices of systolic and diastolic function , left ventricular mass , lipids , and body composition . RESULTS In the 6-month double-blind phase , mean GH dose was 0.64 mg/d . Mean IGF-I sd score increased from -4.5 to -1.0 . Exercise duration , maximal oxygen consumption , left ventricular ejection fraction , and other echocardiographic parameters were normal at baseline and did not change . GH decreased total and low-density lipoprotein cholesterol by 7.5 % ( P = 0.016 ) and 14.7 % ( P = 0.002 ) ( P = 0.04 vs. placebo ) . Mean lean body mass increased by 2.2 kg ( P = 0.004 ) , fat mass decreased by 1.7 kg ( P = 0.21 ) , and percent body fat decreased by 2.5 % ( P = 0.018 ) , although between-group changes were not significant . CONCLUSIONS Human GH did not improve exercise performance or echocardiographic parameters or decrease fat mass but significantly decreased total and low-density lipoprotein cholesterol , increased IGF-I , and increased lean body mass . These results indicate that responses to human GH are variable and should be assessed at baseline and during treatment The onset of adult GH deficiency may be during either adulthood ( AO ) or childhood ( CO ) , but potential differences have not previously been examined . In this study the baseline and GH therapy ( 12.5 micrograms/kg per day ) data from CO ( n = 74 ; mean age 29 yr ) and AO ( n = 99 ; mean age 44 yr ) GH-deficient adult patients have been compared . The first 6 months comprised r and omized , double-blind treatment with GH or placebo , then all patients were GH-treated for a further 12 months . At baseline the height , body weight , body mass index , lean body mass , and waist/hip ratio of AO patients were significantly ( P < 0.001 ) greater than in CO patients . Serum insulin-like growth factor-I ( IGF-I ) levels were below normal but were lower in CO than AO patients ( P < 0.001 ) , and the correlation with IGF binding protein-3 was stronger in CO than in AO patients . Osteocalcin concentration in CO patients was above the normal range and significantly greater than in AO patients . Both groups had significant psychosocial distress , but the deviation from normality was greater in AO patients . Throughout GH therapy there was a significant increase in lean body mass and significant decrease in percent body fat and sum of skinfolds in each group . Wais/hip ratio was decreased by long-term therapy in AO but not CO patients . Total and low density lipoprotein cholesterol levels were decreased from baseline at 6 months in AO but not CO patients and high density lipoprotein cholesterol was increased in both groups throughout therapy . IGF-I and IGF binding protein-3 were increased into the normal range by GH therapy in both groups . Mean osteocalcin level in AO patients was increased at 6 months with no further change with GH therapy , whereas in CO patients there was a steep increase up to 12 months but then a sharp decrease . Nottingham Health Profile scores showed significant improvements in physical mobility and energy at 18 months of therapy in AO patients but no consistent effects in CO patients . GH-induced side effects were mainly reported by AO patients ; very few CO patients reported treatment-emergent adverse events . These results demonstrate significant differences in clinical and biochemical presentation and responses to therapy of the adult GH deficiency syndrome . This is consistent with the existence of two entities , developmental ( CO ) and metabolic ( AO ) , and the different functions of GH at different periods of life Objective Adult onset GH deficiency ( GHD ) is characterized by abnormalities of serum lipoprotein profiles and GH replacement results in favourable alterations in serum total and low density lipoprotein (LDL)‐cholesterol . Preliminary evidence has indicated that the effect of GH replacement in this respect may be additive to that of HMG CoA reductase inhibitor ( statin ) therapy . We have examined this possibility during prospect i ve follow‐up of adult onset hypopituitary patients enrolled in KIMS ( Pfizer International Metabolic Data base ) , a pharmacoepidemiological study of GH replacement in adult hypopituitary patients Objective Few studies have determined the effects of more than 5–10 years of GH replacement  in adults on  body composition and cardiovascular risk factors . Design / patients In this prospect i ve , single-center , open-label study , the effects of 15 years of GH replacement on body composition and cardiovascular risk factors were determined in 156 hypopituitary adults ( 93 men ) with adult-onset GH deficiency ( GHD ) . Mean age was 50.5 ( range 22–74 ) years at study start .  Body composition was measured using dual-energy X-ray absorptiometry . Results The mean initial GH dose of 0.55 ( s.e.m . 0.03 ) mg/day was gradually lowered to 0.40 ( 0.01 ) mg/day after 15 years . The mean serum IGF1 SDS increased from −1.53 ( 0.10 ) at baseline to 0.74 ( 0.13 ) at study end ( P<0.001 vs baseline ) . Lean soft tissue ( LST ) increased to 3 % above the baseline level at study end ( P<0.001 ) . After a 9 % decrease during the first year of treatment ( P<0.001 vs baseline ) , body fat ( BF ) started to increase and had returned to the baseline level after 15 years . Serum levels of total cholesterol and LDL-cholesterol decreased and serum HDL-cholesterol level increased . Fasting plasma glucose increased from 4.4 ( 0.1 ) at baseline to 4.8 ( 0.1 ) mmol/l at study end ( P<0.001 ) . However , blood HbA1c decreased from 5.0 ( 0.1 ) to 4.6 ( 0.1 ) % ( P<0.001 ) . Conclusions Fifteen-year GH replacement in GHD adults induced a transient decrease in BF and sustained improvements of LST and serum lipid profile . Fasting plasma glucose increased whereas blood HbA1c was reduced Assessed by conventional echocardiography the influence of growth hormone deficiency ( GHD ) and effects of replacement therapy on left ventricle ( LV ) function and mass ( LVM ) have shown inconsistent results . We aim ed to evaluate cardiac function before and during replacement therapy employing the gold st and ard method cardiac magnetic resonance imaging ( CMRI ) and measurements of circulating levels of B-type natriuretic peptides .  Sixteen patients ( 8 males and 8 females , mean age 49 years ( range 18–75 ) ) with severe GHD and 16 matched control subjects were included . CMRI was performed at baseline and after 1 year of GH replacement therapy .  IGF-I , B-type natriuretic peptide ( BNP ) and N-terminal pro-BNP ( NT-proBNP ) were measured after 0 , 1 , 2 , 3 , 6 and 12 months of treatment . IGF-I Z-score increased from ( median ( IQR ) ) −2.3 ( −3.8 to −1.4 ) to 0.5 ( −0.3 to 1.7 ) . LVM index ( LVMI ) , ejection fraction ( range 63–80 % ) , cardiac output index and levels of BNP and NT-proBNP were similar at baseline in patients compared to controls ( P-values from 0.09 to 0.37 ) . The patients had significantly smaller LV end-diastolic volume index ( P = 0.032 ) and end-systolic volume index ( P = 0.038 ) . No significant change in LV systolic function or LVM occurred during 1 year of GH treatment . BNP levels were unchanged ( P = 0.88 ) , whereas NT-proBNP tended to decrease ( P = 0.052 ) . Assessed by the highly sensitive and precise CMRI method , untreated GHD was not associated with impaired systolic function or reduced LVMI and 1 year of GH replacement using physiological doses did not influence cardiac mass or function 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 BACKGROUND Adult GHD syndrome is associated with clustering of adverse cardiovascular ( CV ) risk factors such as abnormal body composition , dyslipidemia , insulin resistance and abnormal haemostatic factors . There is a wealth of evidence linking CV events with elevated levels of inflammatory markers ( hs-CRP and IL-6 ) in the general population ; however data on their abnormalities in GHD and specially the effects of GH replacement ( GHR ) on these inflammatory markers are limited . OBJECTIVE To study the effects of GHR on inflammatory markers , glucose homeostasis and body composition in a cohort of adults with recently diagnosed severe GHD due to hypothalamic pituitary disease . DESIGN Fifteen hypopituitary adults ( 11 males , mean age 48.5 years ) with recently diagnosed , severe GHD were recruited . Patients received GHR ( in addition to other pituitary hormone replacements ) titrated to clinical response and to normalize age and gender adjusted IGF-1 levels . Weight , waist hip ratio ( WHR ) , body composition , fasting plasma glucose and insulin , insulin resistance index ( HOMA-IR ) , fasting serum lipid levels , hs-CRP , IL-6 and TNF-alpha were measured at baseline and following a minimum 6 months of stable maintenance GHR . RESULTS GHR result ed in a physiological increase in IGF-1 SDS [ median -0.6 to + 0.39 , P<0.0001 ] , improved quality of life ( mean pre-treatment AGHDA score 16 vs. post-treatment score 7 , P<0.0001 ) and reduction in WHR ( 0.94 vs. 0.92 , P=0.01 ) . There were no significant changes in body weight and composition . Levels of hs-CRP ( log transformed , mean ( SD ) ) were significantly reduced following GHR ( pre 1.21 ( 0.9 ) vs. post 0.27 ( 0.9 ) , P<0.0001 ) but TNF-alpha and IL-6 levels remained unchanged . Fasting glucose ( mmol/L ) [ 4.6 ( 0.1 ) vs. 5.1 ( 0.1 ) , P=0.003 ] , fasting insulin ( muU/mL ) [ 9.4 ( 8.1 ) vs. 12.1 ( 9.2 ) , P=0.03 ] and HOMA-IR [ 1.2 ( 1.0 ) vs. 1.5 ( 1.1 ) P=0.02 ] ( all pre-GHR vs. post-GHR and mean ( SD ) ) significantly increased following GHR indicating increased insulin resistance . Significant improvements were noted in fasting LDL-cholesterol ( LDL-C ) and HDL-cholesterol ( HDL-C ) levels following GHR [ 3.4 ( 0.9 ) vs. 2.9 ( 0.7 ) , P=0.03 and 1.2 ( 0.2 ) vs. 1.3 ( 0.2 ) , P=0.02 , respectively ] ( all pre-GHR vs. post-GHR and mean ( SD ) ) . Levels of total cholesterol and triglycerides did not change following GHR . CONCLUSIONS Physiological GHR for at least 6 months in hypopituitary adults with recently diagnosed severe GHD result ed in favourable changes in hs-CRP , WHR , fasting LDL-C and HDL-C levels all of which are recognised CV risk markers . However , there remains a high prevalence of obesity in this population and given the worsening of insulin sensitivity in the short term with GHR , monitoring and aggressive treatment of established CV risk factors is essential to reduce premature atherosclerotic CVD in this patient population CONTEXT Inflammation is hypothesized to play a role in development of type 2 diabetes mellitus ( DM ) ; however , clinical data addressing this issue are limited . OBJECTIVE To determine whether elevated levels of the inflammatory markers interleukin 6 ( IL-6 ) and  C-reactive protein ( CRP ) are associated with development of  type 2 DM in healthy middle-aged women . DESIGN Prospect i ve , nested case-control study . SETTING The Women 's Health Study , an ongoing US primary prevention , r and omized clinical trial initiated in 1992 . PARTICIPANTS From a nationwide cohort of 27 628 women free of diagnosed DM , cardiovascular disease , and cancer at baseline , 188 women who developed diagnosed DM over a 4-year follow-up period were defined as cases and matched by age and fasting status with 362 disease-free controls . MAIN OUTCOME MEASURES Incidence of confirmed clinical ly diagnosed type 2 DM by baseline levels of IL-6 and CRP . RESULTS Baseline levels of IL-6 ( P<.001 ) and CRP ( P<.001 ) were significantly higher among cases than among controls . The relative risks of future DM for women in the highest vs lowest quartile of these inflammatory markers were 7.5 for IL-6 ( 95 % confidence interval [ CI ] , 3.7 - 15.4 ) and 15.7 for CRP ( 95 % CI , 6.5 - 37.9 ) . Positive associations persisted after adjustment for body mass index , family history of diabetes , smoking , exercise , use of alcohol , and hormone replacement therapy ; multivariate relative risks for the highest vs lowest quartiles were 2.3 for IL-6 ( 95 % CI , 0.9 - 5.6 ; P for trend = .07 ) and 4.2 for CRP ( 95 % CI , 1.5 - 12.0 ; P for trend = .001 ) . Similar results were observed in analyses limited to women with a baseline hemoglobin A(1c ) of 6.0 % or less and after adjustment for fasting insulin level . CONCLUSIONS Elevated levels of CRP and IL-6 predict the development of type 2 DM . These data support a possible role for inflammation in diabetogenesis BackgoundThrombosis is regarded to be a key factor in the development of acute coronary syndromes in patients with coronary artery disease ( CAD ) . We hypothesize , that hemostatic and rheological risk factors may be of major relevance for the incidence and the risk stratification of these patients . Methods In 243 patients with coronary artery disease and stable angina pectoris parameters of metabolism , hemostasis , blood rheology and endogenous fibrinolysis were assessed . Patients were prospect ively followed for 2 years in respect to elective revascularizations and acute coronary syndromes . Results During follow-up 88 patients presented with cardiac events , 22 of those were admitted to the hospital because of acute events , 5 Patients were excluded due to non- cardiac death . Patients with clinical events were found to be more frequently diabetic and presented with a more progressed coronary atherosclerosis . Even though patients with diabetes mellitus demonstrated a comparable level of multivessel disease ( 71 % vs. 70 % ) the rate of elective revascularization  was higher ( 41 % vs. 28 % , p < 0.05 ) . The results were also unfavorable for the incidence of acute cardiovascular events ( 18 % vs. 8 % , p < 0.01 ) . In comparison to non-diabetic patients diabetics demonstrated significantly elevated levels of fibrinogen ( 352 ± 76 vs. 312 ± 64 mg/dl , p < 0.01 ) , plasma viscosity ( 1.38 ± 0.23 vs. 1.31 ± 0.16 mPas , p < 0.01 ) , red blood cell aggregation ( 13.2 ± 2.5 vs. 12.1 ± 3.1 E , p < 0.05 ) and plasmin-activator-inhibitor ( 6.11 ± 3.4 vs. 4.7 ± 2.7 U/l , p < 0.05 ) . Conclusion Pathological alterations of fibrinogen , blood rheology and plasminogen-activator-inhibtor as indicators of a procoagulant state are of major relevance for the short-term incidence of cardiac events , especially in patients with diabetes mellitus type 2 , and may be used to stratify patients to specific therapies The effects of GH replacement on body fat composition and insulin sensitivity were assessed in GH-deficient adults . The patients were r and omized into a double-blind , placebo-controlled study of human recombinant GH replacement therapy for 6 months ( period 1 ) , followed by an open phase of GH for another 6 months ( period 2 ) . Anthropometric variables , body fat composition ( fat % ) , and biochemical parameters were measured during the trial . Measurements of in vivo insulin sensitivity were carried out at the commencement of the study and on completion of the trial by modified insulin suppression test . The modified insulin suppression test was performed both in the morning ( AM ) and in the afternoon ( PM ) to further evaluate the PM-AM steady-state plasma glucose ( SSPG ) pattern . We found that the GH-deficient adults had more body fat and were insulin resistant . Significant reduction in fat % and total body fat mass was found in the active arm of period 1 without alteration of body weight . Besides , we demonstrated , for the first time , the GH replacement for 6 months did not alter the insulin sensitivity , but replacement for a longer period ( 12 months ) normalized not only the AM SSPG level but also the PM-AM SSPG pattern . We also found a positive correlation between SSPG ( regardless of AM vs. PM ) and fat % and total body fat mass . In conclusion , normalization of insulin sensitivity in GH-deficient adults after replacement of GH may be related to the reduction of total body fat 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 Since the effects of recombinant human growth hormone ( rhGH ) replacement therapy on glucose metabolism are still a matter of debate , the aim of the present study was to evaluate the impact of long-term rhGH treatment on insulin sensitivity . Simple indices of insulin resistance ( IR ) and insulin sensitivity ( IS ) , based on fasting glucose and insulin , such as the homeostasis model assessment of insulin resistance ( HOMA-IR ) and the quantitative insulin check index ( QUICKI ) , were used to estimate the degree of IR and IS in 20 normoglycemic patients ( 11 men and 9 women ; mean age , 44 + /- 14 years ) with severe adult-onset GH deficiency ( GHD ) . Measurements were determined at baseline and after 1 and 5 years of continuous rhGH therapy . Basal values were compared to those obtained in 20 healthy sex- and age-matched controls . Starting rhGH dose ranged from 3 to 8 microg/kg/d in keeping with sex and age , then doses were titrated according to insulin-like growth factor-I ( IGF-I ) levels . At baseline all patients had low IGF-I levels ( 10 + /- 5.4 nmol/L ) , high body mas index ( BMI ; 27.5 + /- 4 kg/m(2 ) ) , and elevated body fat percentage ( BF% ; 31.8 + /- 9.6 ) . Fasting glucose and insulin levels , as well as HOMA-IR and QUICKI , did not differ significantly from those recorded in the control group . After 1 year of rhGH replacement therapy , normalization in IGF-I levels and a significant reduction in BF% were observed ( P < .001 ) , and these effects were maintained after 5 years of treatment . Fasting glucose increased from 79 + /- 10 to 87 + /- 13 , and 87 + /- 12 mg/dL ( P < .05 ) after 1 and 5 years of therapy , respectively . Fasting insulin significantly increased after 1 year , without further modifications in the long-term follow-up . HOMA-IR significantly increased from 2.1 + /- 1.7 to 2.5 + /- 1.7 ( P < .05 ) after 1 year , then decreased to 2.3 + /- 1.5 ( P = not significant [ NS ] v basal ) after 5 years . A specular decrease in QUICKI from 0.37 + /- 0.05 to 0.34 + /- 0.03 ( P < .01 ) occurred after 1 year , with a trend to increase ( 0.35 + /- 0.04 ; P = NS v basal ) after 5 years . No patient developed impaired fasting glucose . In conclusion , rhGH therapy determined an increase in fasting glucose and insulin levels , causing in the short-term period a worsening of IS . The sustained reduction in BF% , without further deterioration of IS , suggests that long-term beneficial effects on body composition may overcome the negative influence of GH on glucose metabolism BACKGROUND Growth hormone-deficient adults have increased cardiovascular mortality . Growth hormone replacement may affect cardiovascular risk . Inflammation plays an important role in atherosclerosis , and inflammatory markers are predictive of cardiovascular events . OBJECTIVE To investigate the effect of growth hormone replacement on inflammatory and other cardiovascular risk factors . DESIGN R and omized , single-blind , placebo-controlled trial . PATIENTS 40 men with adult-onset growth hormone deficiency . INTERVENTION Growth hormone or placebo given for 18 months at a dose adjusted for normal serum insulin-like growth factor I level . MEASUREMENTS Anthropometric , hemoglobin A1c , and central fat values were assessed every 6 months . Levels of glucose , insulin , insulin-like growth factor I , and lipids were measured at 1 , 3 , 6 , 12 , and 18 months . C-reactive protein , serum amyloid polypeptide A , inteleukin-6 , and lipoprotein(a ) levels were determined at baseline and 6 and 18 months . RESULTS C-reactive protein and inteleukin-6 levels decreased in growth hormone recipients compared with placebo recipients ( differences between groups , -1.9 + /- 0.6 mg/L [ P = 0.0027 ] and -1.3 + /- 0.5 ng/L [ P = 0.013 ] , respectively ) . Changes in serum amyloid polypeptide A levels between groups did not reach statistical significance ( difference between groups , -2.4 + /- 1.2 mg/L ; P = 0.056 ) . Serum cholesterol levels , low-density lipoprotein cholesterol levels , and ratios of total cholesterol to high-density lipoprotein cholesterol decreased in growth hormone recipients in the first 3 months compared with placebo recipients ( differences between groups , -0.86 + /- 0.17 mmol/L [ -33.2 + /- 6.6 mg/dL ] [ P < 0.001 ] , -0.63 + /- 0.20 mmol/L [ -24.5 + /- 5.9 mg/dL ] [ P < 0.001 ] , and -0.56 + /- 0.26 [ P = 0.040 ] , respectively ) , but the decrease was not maintained from month 6 to month 18 . Lipoprotein(a ) levels increased ( difference between groups , 22.0 + /- 8.0 mg/L ; P = 0.0096 ) . Short-term increases occurred in glucose levels , insulin levels , and insulin-to-glucose ratios ( differences between groups , 0.54 + /- 0.16 mmol/L [ 9.6 + /- 2.8 mg/dL ] [ P = 0.0018 ] , 37.9 + /- 9.6 pmol/L [ P < 0.001 ] , and 6.0 + /- 1.8 [ P = 0.0025 ] , respectively ) , but only the increase in glucose level was maintained over the long term ( difference between groups , 0.56 + /- 0.17 mmol/L [ 10.0 + /- 3.1 mg/dL ] ; P = 0.0026 ) . Hemoglobin A1c values did not change . Truncal fat-to-total fat ratios decreased ( difference between groups , -0.018 + /- 0.007 ; P = 0.0087 ) . CONCLUSIONS Long-term growth hormone replacement in men reduces levels of inflammatory cardiovascular risk markers , decreases central fat , and increases lipoprotein(a ) and glucose levels without affecting lipid levels The Pituitary Society in conjunction with the European Neuroendocrine Association held a consensus workshop to develop guidelines for diagnosis and treatment of the co-morbid complications of acromegaly . Fifty nine pituitary specialists ( endocrinologists , neurosurgeons and cardiologists ) assessed the current published literature on acromegaly complications in light of recent advances in maintaining tight therapeutic control of GH hypersecretion . The impact of elevated GH levels on cardiovascular disease , hypertension , diabetes , sleep apnea , colon polyps , bone disease , reproductive disorders , and neuropsychologic complications were considered . Guidelines are proposed for effective management of these complications in the context of overall acromegaly control . When appropriate , requirements for prospect i ve evidence -based studies and surveillance data base development are enunciated . Effective management of co-morbid acromegaly complications will lead to improved morbidity and mortality in acromegaly 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 OBJECTIVE  GH deficiency ( GHD ) in adults is associated with adverse effects on metabolism and increased cardiovascular risk . Pregnancy-associated plasma protein-A ( PAPP-A ) is a protease that promotes IGF-I availability in vascular tissues . PAPP-A levels appear to correlate with carotid intima-media thickness and have been proposed as an early predictor of cardiac events . The aim of our study was to evaluate PAPP-A levels in GHD adults at baseline and after GH replacement and correlate them with changes in body composition , lipid profile , glucose homeostasis , inflammatory markers and in leptin and adiponectin . PATIENTS AND METHODS Fourteen GHD adults were evaluated at baseline and after 1 year of GH therapy .  All patients were compared at baseline with 28 age- , sex- and body mass index ( BMI ) -matched control subjects . RESULTS At baseline , GHD adults showed higher PAPP-A levels ( P=0.03 ) and higher leptin ( P=0.04 ) , fibrinogen ( P=0.002 ) and highly sensitive C-reactive protein ( P=0.01 ) values than controls . Therapy with GH  reduced PAPP-A ( P=0.03 ) and fibrinogen levels ( P=0.002 ) while increased BMI ( P=0.01 ) and reduced waist-hip ratio ( WHR ; P=0.05 ) were observed . Insulin and homeostasis model assessment of insulin resistance index increased after treatment ( P<0.004/P=0.007 ) , without changes in leptin or adiponectin levels . PAPP-A values correlated positively with BMI and WHR and negatively with adiponectin before and after treatment , with no correlation with glucose homeostasis parameters , lipid profile or leptin . CONCLUSIONS Our study suggests that PAPP-A expression is increased in GHD adults , and that 1 year of GH replacement therapy is able to reduce PAPP-A levels in this population . However , further studies are required to determine whether this decrease correlates with an improvement in atherosclerosis 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 Hypopituitary patients have an increased risk of vascular mortality that may relate to growth hormone deficiency ( GHD ) . We investigated the effects of 6 months of GH therapy on large‐ and small‐artery function and high‐sensitivity C‐reactive protein ( hsCRP ) in a cohort of GH‐deficient patients . Sixteen hypopituitary patients were r and omized to 6 months of GH therapy or no treatment , then vice versa . hsCRP , 24‐h blood pressure ( BP ) and pulse wave velocity ( PWV ) were measured and resistance arteries were used to construct concentration – response curves to endothelium‐dependent and ‐independent agents . GH therapy increased IGF‐1 from 60 ± 7·2 to 167 ± 16·2 µg/l [ confidence interval ( CI ) 94·9 , 138·8 , P < 0·001 ] . hsCRP declined after 6 months of GH from 3·8 ± 0·88 to 2·0 ± 0·49 mg/l ( CI 0·73 , 3·57 , P = 0·006 ) . Mean arterial BP fell from 91·7 ± 1·5 to 89·3 ± 1·2 mmHg ( CI 0·81 , 4·07 , P = 0·005 ) , as did PWV ( 8·1 ± 0·4 to 6.7 ± 0·5 m/s ) . The decline in PWV correlated with the decline in hsCRP ( r = 0·68 , P = 0·01 ) . Resistance artery function was unchanged after GH therapy . GH replacement may lead to differentially altered production of vasorelaxant agents from the endothelium of large and small arteries . Reduction in vascular inflammation may be associated with reduced vascular risk 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 Adiponectin is found to associate with diabetes in studies apart from cohort studies . This prospect i ve cohort study is to evaluate the predictive role of adiponectin in diabetes among participants with impaired fasting glucose ( IFG ) . A total of 42,845 participants who visited 7 health examination centers located in Seoul and Kyunggi province , South Korea , during 2004–2008 were first included . Of the 42,845 participants , 5,085 participants had IFG . IFG was categorized as stage 1 ( fasting glucose 100–109 mg/dL ) or stage 2 ( 110–125 mg/dL ) . The incidence rates of diabetes were followed up to December , 2011 . Hazard ratios ( HRs ) and 95 % confidence intervals ( CI ) were performed by Cox proportional hazard model . Of the 5,085 participants , 652 participants developed  diabetes during a mean follow-up of 4.4 years . Low adiponectin was associated with diabetes among men with stage 2 IFG ( HR , 1.78 ; 95 % CI , 1.33–2.38 ) while it was associated with diabetes among women with stage 1 IFG ( HR , 2.64 ; 95 % CI , 1.38–5.03 ) and stage 2 IFG ( HR , 2.17 ; 95 % CI , 1.07–4.42 ) . When combined men and women , the association between adiponectin and diabetes was statistically significant in stage 2 IFG with an increase of about 82 % ( HR , 1.82 ; 95 % CI , 1.40–2.39 ) after adjusting for age , sex , body mass index , waist circumference , and fasting serum glucose . There was an interaction by sex and stage 1 IFG in the association between adiponectin and risk of diabetes ( P < 0.001 ) . Adiponectin was independently associated with diabetes among participants with IFG . This association was apparent in stage 2 IFG . Adiponectin may be used as a predictor of diabetes in patients having IFG Objective : Adult GH deficiency ( GHD ) syndrome is characterized by increased risk of atherosclerosis and hence of cardio- and cerebrovascular mortality . Oxidative stress appears to play an important role in early atherogenesis . Oxidized LDL represents an important predictor of cardiovascular risk and is mainly responsible for oxidative damage of the endothelium . Its concentrations are increased in GHD , but the association between this abnormality and oxidative stress is still unclear , due to the discordant results yielded by the few available studies . Design and methods : In 13 GHD patients , plasma lipid peroxide concentrations were measured before and after a 4-month treatment with recombinant human GH ( rhGH ) and compared with those of 13 age- and sex-matched controls . In the same subjects , the so-called “ lag-time ” , an index of anti-oxidant activity and thus of plasma oxidative balance , was also measured using a fluorescence kinetics method . Results : Before treatment , peroxide levels were significantly higher in patients than in controls ( 374.0±31.52 vs 268.0±8.51 U.C. , p<0.01 ) , whereas the lag-time was significantly lower ( 113.0±10.70 vs 168.0±7.80 min , p<0.01 ) . RhGH administration to patients result ed both in a significant decrease in lipid peroxide levels ( from 374.0±31.52 to 336.0±33.17 U.C. , p<0.01 ) and a significant prolongation of lag-time ( from 113.0±10.70 to 144.0±15.00 min , p<0.01 ) . After treatment , both parameters were no longer significantly different in patients and controls . Lagtime and peroxide levels at baseline did not show any correlation with IGF-I concentrations in GHD patients . After replacement therapy , however , lag-time was positively ( r2= 0.62 , p<0.01 ) , and peroxide levels negatively ( r2=0.41 , p<0.05 ) , correlated with IGF-I levels . Conclusions : These data support the view that adult GHD syndrome is characterized by an unbalance between pro- and anti-oxidant factors with marked preponderance of the former . This abnormality , likely contributing to the increased atherogenic risk of GHD patients , is corrected by short-term GH administration at a dose able to increase , although not to fully normalize , IGF-I levels 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 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 It is now a consensus to resume GH treatment in adolescents with severe GH deficiency ( GHD ) at retesting to prevent the occurrence of adult GHD syndrome . However , we do not have any data on the follow-up of adolescents with nonsevere GHD at completion of treatment . This report presents preliminary data from a 1-yr prospect i ve study that includes the first 91 patients retested .  Anthropometric data , IGF-I and IGF binding protein-3 levels , glycemia and insulinemia , lipid profile , and body composition using dual x-ray absorptiometry and abdominal computed tomography scan were recorded at completion of GH treatment and 1 yr later . Body composition was significantly different at both evaluations , with increased total body fat and decreased lean body mass in the partial GHD group vs. the normal group . Moreover , these alterations worsened after 1 yr without GH in the partial GHD group , whereas there were no modifications in the normal group . We did not find any metabolic alterations such as elevated triglyceride , total cholesterol , or insulin levels .  Adolescents with reconfirmed partial GHD exhibit alterations in body composition after 1 yr without GH , whereas those retested normal do not . These changes are similar to those described in severe GHD , although less marked , and justify a precise follow-up 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 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 The effects of GH replacement therapy on energy metabolism are still uncertain , and long-term benefits of increased muscle mass are thought to outweigh short-term negative metabolic effects . This study was design ed to address this issue by examining both short-term ( 1 wk ) and long-term ( 6 months ) effects of a low-dose ( 9.6 micro g/kg body weight.d ) GH replacement therapy or placebo on whole-body glucose and lipid metabolism ( oral glucose tolerance test and euglycemic hyperinsulinemic clamp combined with indirect calorimetry and infusion of 3-[(3)H]glucose ) and on muscle composition and muscle enzymes/metabolites , as determined from biopsies obtained at the end of the clamp in 19 GH-deficient adult subjects . GH therapy result ed in impaired insulin-stimulated glucose uptake at 1 wk ( -52 % ; P = 0.008 ) and 6 months ( -39 % ; P = 0.008 ) , which correlated with deterioration of glucose tolerance ( r = -0.481 ; P = 0.003 ) . The decrease in glucose uptake was associated with an increase in lipid oxidation at 1 wk ( 60 % ; P = 0.008 ) and 6 months ( 60 % ; P = 0.008 ) and a concomitant decrease in glucose oxidation . The deterioration of glucose metabolism during GH therapy also correlated with the enhanced rate of lipid oxidation ( r = -0.508 ; P = 0.0002 ) . In addition , there was a shift toward more glycolytic type II fibers during GH therapy . In conclusion , replacement therapy with a low-dose GH in GH-deficient adult subjects is associated with a sustained deterioration of glucose metabolism as a consequence of the lipolytic effect of GH , result ing in enhanced oxidation of lipid substrates . Also , a shift toward more insulin-resistant type II X fibers is seen in muscle . Glucose metabolism should be carefully monitored during long-term GH replacement therapy 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 The ob gene product , leptin , is considered to be a marker of adipose tissue mass and a possible homeostatic regulator of body mass . Our objective was to examine the effect of GH replacement on adipose tissue stores and leptin in adult hypopituitarism OBJECTIVE Patients with growth hormone deficiency ( GHD ) have increased cardiovascular risk and may show elevated triglyceride and reduced high density lipoprotein ( HDL ) cholesterol concentrations , two lipid abnormalities usually accompanied by increased small dense LDL in the ' atherogenic lipoprotein phenotype ' ( ALP ) . In the present study , we directly investigated ( 1 ) whether hypopituitary patients with GHD have increased small dense LDL ; ( 2 ) whether growth hormone replacement therapy ( GHRT ) beneficially impact on such particles ; ( 3 ) the prevalence of ALP in GHD and GHRT patients . DESIGN AND METHODS In 14 hypopituitary patients with GHD ( 44 + /- 13 years , body mass index ( BMI ) 27 + /- 3 ) before and after 4 months of GHRT , and in 11 healthy age- and BMI -matched controls we measured plasma lipids and LDL size and subclasses by gradient gel electrophoresis . RESULTS Compared with controls , GHD showed increased triglycerides ( P = 0.0024 ) , similar total and LDL cholesterol levels and a tendency towards reduced HDL cholesterol concentrations ( P = 0.0894 ) . GHRT reduced total and LDL cholesterol levels ( P = 0.0303 and 0.0120 respectively ) , but no effect was found on triglycerides and HDL cholesterol levels . LDL size was unchanged in GHD versus controls ( 269 + /- 9 vs 274 + /- 6 A , P = ns ) , but LDL subclass analysis revealed a shift towards more dense particles ( P = 0.0046 ) . GHRT had no significant impact on LDL size and subclasses . The prevalence of ALP was 14 % in GHD and 7 % in GHRT . CONCLUSIONS In GHD patients , individual features of ALP ( including increased small dense LDL ) may be common , but complete ALP is relatively uncommon . Short-term replacement therapy seems to be ineffective on such lipid alterations , but the effect of a longer GHRT remains to be assessed CONTEXT Although it has been hypothesized that hypertension is in part an inflammatory disorder , clinical data linking inflammation with incident hypertension are scarce . OBJECTIVE To examine whether C-reactive protein levels , a marker of systemic inflammation , are associated with incident hypertension . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve cohort study that began in 1992 of 20 525 female US health professionals aged 45 years or older who provided baseline blood sample s with initially normal levels of blood pressure ( BP ) ( systolic BP < 140 mm Hg and diastolic BP < 90 mm Hg , and no history of hypertension or antihypertensive medications ) and then followed up for a median of 7.8 years for the development of incident hypertension .  Plasma C-reactive protein levels were measured and baseline coronary risk factors were collected . MAIN OUTCOME MEASURE Incident hypertension , defined as either a new physician diagnosis , the initiation of antihypertensive treatment , or self-reported systolic BP of at least 140 mm Hg or a diastolic BP of at least 90 mm Hg . RESULTS During follow-up , 5365 women developed incident hypertension .  In crude models , the relative risks ( RRs ) and 95 % confidence intervals ( CIs ) of developing hypertension from the lowest ( referent ) to the highest levels of baseline C-reactive protein were 1.00 , 1.25 ( 95 % CI , 1.14 - 1.40 ) , 1.51 ( 95 % CI , 1.35 - 1.68 ) , 1.90 ( 95 % CI , 1.72 - 2.11 ) , and 2.50 ( 95 % CI , 2.27 - 2.75 ) ( linear trend P<.001 ) . In fully adjusted models for coronary risk factors , the RRs and 95 % CIs were 1.00 , 1.07 ( 95 % CI , 0.95 - 1.20 ) , 1.17 ( 95 % CI , 1.04 - 1.31 ) , 1.30 ( 95 % CI , 1.17 - 1.45 ) , and 1.52 ( 95 % CI , 1.36 - 1.69 ) ( linear trend P<.001 ) . C-reactive protein was significantly associated with an increased risk of developing hypertension in all prespecified subgroups evaluated , including those with very low levels of baseline BP , as well as those with no traditional coronary risk factors . Similar results were found when treating C-reactive protein as a continuous variable and controlling for baseline BP . CONCLUSION C-reactive protein levels are associated with future development of hypertension , which suggests that hypertension is in part an inflammatory disorder 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 gene product from the ob gene , leptin , has recently been characterized in humans . The circulating level of leptin is related to body mass index ( BMI ) and more closely to estimates of total body fat , whereas visceral fat has been reported to be of minor importance . However , it is unknown if leptin is directly regulated by hormones that influence substrate metabolism and body composition . We studied leptin in adult growth hormone (GH)-deficient ( GHD ) patients substituted with GH treatment for 12 months in a parallel double-blind , placebo-controlled study . Twenty-seven GHD adults aged 44.9 + /- 1.9 years underwent  anthropometric measurements  for determination of regional and total body fat ( BMI , waist to hip ratio [ WHR ] , computed tomographic [ CT ] scan , dual-energy x-ray absorptiometry [ DEXA ] scan , and bioimpedance analysis [ BIA ] ) before and after 12 months of placebo-controlled GH substitution ( 2 IU/m2 ) in a parallel design . The same measurements were performed in 42 healthy adults aged 39.1 + /- 1.7 years . The logarithm of serum leptin levels correlated positively with abdominal subcutaneous fat and total body fat ( BIA and DEXA ) in untreated GHD patients and healthy subjects . Fasting insulin did not correlate with leptin levels in either of the groups . After 12 months of GH administration , the body composition of GHD patients was significantly changed with respect to a marked decrease in body fat . The relations of leptin to the estimates of body fat were maintained , and leptin was furthermore related to BMI and fasting insulin . In multiple linear regression analyses , additional estimates of visceral adiposity ( intraabdominal fat and maximal anterior-posterior diameter determined by CT scan ) were significant determinants of leptin in the healthy subjects . The increase in fasting insulin levels during GH substitution correlated negatively with the reduction in leptin levels ( r = -.823 , P = .003 ) . At baseline , leptin levels were increased in the patients compared with controls in both sexes ( women , 21.8 + /- 3.3 v 11.3 + /- 1.4 ng/mL , P = .002 ; men , 8.1 + /- 1.2 v 4.7 + /- 0.7 ng/mL , P = .008 ) . Leptin levels were similar in GHD patients treated for 12 months compared with healthy controls for both women and men ( women , 15.9 + /- 2.3 and 11.3 + /- 1.4 ng/mL , P = .163 ; men , 7.1 + /- 2.8 and 4.7 + /- 0.7 ng/mL , P = .759 ) . In healthy adults and in GHD patients , leptin levels were significantly higher in women than in men ( 11.3 + /- 1.4 v 4.7 + /- 0.7 ng/mL , P < .001 ; 21.8 + /- 3.3 v 8.1 + /- 1.2 ng/mL , P < .001 ) . Gender remained a significant determinant of leptin levels in several models of multiple linear regression analysis also including age , estradiol levels , insulin , and estimates of body fat . We conclude that leptin is increased but not differently regulated in GHD patients compared with normal subjects , and that leptin levels are closely related to estimates of body fat . This relationship is maintained during a decrease in body fat due to GH substitution 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 We have studied the effects on body composition and metabolism of a fixed low dose of growth hormone ( GH ) , 0.6 IU ( 0.2 mg)/day , administered for 12 months to GH-deficient ( GHD ) adults . DESIGN AND METHODS Prospect i ve open-label study , using 18 GHD patients ( 11 women , 7 men ; aged 21 - 58 years ) . All investigations were performed at baseline and after 12 months . Body composition was determined by dual energy X-ray absorptiometry . RESULTS Total body fat decreased ( -1.74+/-2.87 % ) and lean body mass ( LBM ) increased ( 1.27+/-2.08 kg ) after therapy ( P < 0.05 ) . Changes in truncal fat did not reach statistical significance , but a decrease varying from 0.72 to 2.78 kg ( 1 to 8.7 % ) was observed in 13 ( 72 % ) patients . Bone mineral density ( BMD ) increased at lumbar spine , total femur and femoral neck ( P < 0.05 ) . Levels of total and low-density lipoprotein (LDL)-cholesterol were lower after therapy ( P < 0.05 ) , and their changes were directly associated with values at baseline . Insulin levels increased and the insulin resistance index worsened at 12 months ( P < 0.05 ) . Median IGF-I s.d . score was -4.30 ( range , -11.03 to -0.11 ) at baseline and -1.73 ( range , -9.80 to 2.26 ) at 12 months . Normal age-adjusted IGF-I levels were obtained with therapy in 5 of 11 patients who had low IGF-I levels at baseline . Changes in IGF-I levels were not correlated with any biological end point , except changes in LBM ( r = 0.53 , P = 0.02 ) . Side effects were mild and disappeared spontaneously . CONCLUSIONS One-year of a fixed low-dose GH regimen in GHD adults result ed in a significant reduction in body fat , total cholesterol and LDL-cholesterol , and a significant increase in LBM and BMD at lumbar spine and femur , regardless of normalization of IGF-I levels . This regimen led to an elevation of insulin levels and a worsening of the insulin resistance index 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 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
target: Emerging cardiovascular risk factors/markers such as proinflammatory cytokines , C-reactive protein , and adipokines are also increased in GHD patients .
  Increased cardiovascular morbidity and mortality have also been reported in GHD .
  GH treatment has been shown to improve both traditional and emerging cardiovascular risk factors and markers .
  The GHD population may be considered at high cardiovascular risk , and GH substitution may be expected to bring an added value to patients with hypopituitarism in terms of cardiovascular protection .
background: CONTEXT GH deficiency ( GHD ) of the adult is a clinical condition characterized by the presence of several traditional and emerging cardiovascular risk factors that can significantly increase cardiovascular morbidity and mortality .
  It is still an open issue whether GH replacement is able not only to improve cardiovascular risk factors but also to decrease cardiovascular morbidity and mortality .
  EVIDENCE SYNTHESIS In untreated GHD , cardiovascular risk is increased due to abnormal lipid profile ( increased total and low-density lipoprotein cholesterol , increased triglycerides , and reduced high-density lipoprotein cholesterol ) and impaired glucose metabolism .