title: Effects of Ghrelin Administration on Left Ventricular Function, Exercise Capacity, and Muscle Wasting in Patients With Chronic Heart Failure Anamorelin in patients with non-small-cell lung cancer and cachexia (ROMANA 1 and ROMANA 2): results from two randomised, double-blind, phase 3 trials. Polymorphisms of genes coding for ghrelin and its receptor in relation to anthropometry, circulating levels of IGF-I and IGFBP-3, and breast cancer risk: a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials. Prospective Safety Surveillance of GH-Deficient Adults: Comparison of GH-Treated vs Untreated Patients Physiologic concentrations of exogenously infused ghrelin reduces insulin secretion without affecting insulin sensitivity in healthy humans. Circulating Insulin-Like Growth Factor-I and Binding Protein-3 and Risk of Prostate Cancer Serum Ghrelin Levels and Risk of Subsequent Adenocarcinoma of the Esophagus Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study Changes in plasma ghrelin concentration immediately after gastrectomy in patients with early gastric cancer. Ghrelin strongly stimulates growth hormone release in humans. Ghrelin as an acute-phase reactant during postoperative stress response. Circulating gastrin and ghrelin levels in patients with colorectal cancer: correlation with tumour stage, Helicobacter pylori infection and BMI. Appetite-regulating hormone changes in patients with craniopharyngioma. Effects of ghrelin administration during chemotherapy with advanced esophageal cancer patients Circulating ghrelin levels are decreased in human obesity. Pharmacodynamic hormonal effects of anamorelin, a novel oral ghrelin mimetic and growth hormone secretagogue in healthy volunteers.
abstract: Background —Ghrelin is a novel growth hormone – releasing peptide that also induces vasodilation , inhibits sympathetic nerve activity , and stimulates feeding through growth hormone – independent mechanisms . We investigated the effects of ghrelin on left ventricular ( LV ) function , exercise capacity , and muscle wasting in patients with chronic heart failure ( CHF ) . Methods and Results —Human synthetic ghrelin ( 2 & mgr;g/kg twice a day ) was intravenously administered to 10 patients with CHF for 3 weeks . Echocardiography , cardiopulmonary exercise testing , dual x-ray absorptiometry , and blood sampling were performed before and after ghrelin therapy . A single administration of ghrelin elicited a marked increase in serum GH ( 25-fold ) . Three-week administration of ghrelin result ed in a significant decrease in plasma norepinephrine ( 1132±188 to 655±134 pg/mL ; P<0.001 ) . Ghrelin  increased LV ejection fraction ( 27±2 % to 31±2 % ; P<0.05 ) in association with an increase in LV mass and a decrease in LV end-systolic volume . Treatment with ghrelin  increased peak workload and peak oxygen consumption during exercise  . Ghrelin  improved muscle wasting , as indicated by increases in muscle strength and lean body mass . These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy . Conclusions —These preliminary results suggest that repeated administration of ghrelin improves LV function , exercise capacity , and muscle wasting in patients with CHF BACKGROUND Patients with advanced cancer frequently experience anorexia and cachexia , which are associated with reduced food intake , altered body composition , and decreased functionality . We assessed anamorelin , a novel ghrelin-receptor agonist , on cachexia in patients with advanced non-small-cell lung cancer and cachexia . METHODS ROMANA 1 and ROMANA 2 were r and omised , double-blind , placebo-controlled phase 3 trials done at 93 sites in 19 countries . Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia ( defined as ≥5 % weight loss within 6 months or body-mass index < 20 kg/m(2 ) ) were r and omly assigned 2:1 to anamorelin 100 mg orally once daily or placebo , with a computer-generated r and omisation algorithm stratified by geographical region , cancer treatment status , and weight loss over the previous 6 months . Co- primary efficacy endpoints were the median change in lean body mass and h and grip strength over 12 weeks and were measured in all study participants ( intention-to-treat population ) . Both trials are now completed and are registered with Clinical Trials.gov , numbers NCT01387269 and NCT01387282 . FINDINGS From July 8 , 2011 , to Jan 28 , 2014 , 484 patients were enrolled in ROMANA 1 ( 323 to anamorelin , 161 to placebo ) , and from July 14 , 2011 , to Oct 31 , 2013 , 495 patients were enrolled in ROMANA 2 ( 330 to anamorelin , 165 to placebo ) . Over 12 weeks , lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 ( median increase 0·99 kg [ 95 % CI 0·61 to 1·36 ] vs -0·47 kg [ -1·00 to 0·21 ] , p<0·0001 ) and ROMANA 2 ( 0·65 kg [ 0·38 to 0·91 ] vs -0·98 kg [ -1·49 to -0·41 ] , p<0·0001 ) . We noted no difference in h and grip strength in ROMANA 1 ( -1·10 kg [ -1·69 to -0·40 ] vs -1·58 kg [ -2·99 to -1·14 ] , p=0·15 ) or ROMANA 2 ( -1·49 kg [ -2·06 to -0·58 ] vs -0·95 kg [ -1·56 to 0·04 ] , p=0·65 ) . There were no differences in grade 3 - 4 treatment-related adverse events between study groups ; the most common grade 3 - 4 adverse event was hyperglycaemia , occurring in one ( < 1 % ) of 320 patients given anamorelin in ROMANA 1 and in four ( 1 % ) of 330 patients given anamorelin in ROMANA 2 . INTERPRETATION Anamorelin significantly increased lean body mass , but not h and grip , strength in patients with advanced non-small-cell lung cancer . Considering the unmet medical need for safe and effective treatments for cachexia , anamorelin might be a treatment option for patients with cancer anorexia and cachexia . FUNDING Helsinn Therapeutics Ghrelin , an endogenous lig and for the growth hormone secretagogue receptor , has two major functions : the stimulation of the growth hormone production and the stimulation of food intake . Accumulating evidence also suggests a role of ghrelin in cancer development . We conducted a case-control study on 1359 breast cancer cases and 2389 matched controls , nested within the European Prospect i ve Investigation into Cancer and Nutrition , to examine the association of common genetic variants in the genes coding for ghrelin ( GHRL ) and its receptor ( GHSR ) with anthropometric measures , circulating insulin growth factor I ( IGF-I ) and insulin-like growth factor-binding protein 3 and breast cancer risk .  Pair-wise tagging was used to select the 15 polymorphisms that represent the majority of common genetic variants across the GHRL and GHSR genes . A significant increase in breast cancer risk was observed in carriers of the GHRL rs171407-G allele ( odds ratio : 1.2 ; 95 % confidence interval : 1.0 - 1.4 ; P = 0.02 ) . The GHRL single-nucleotide polymorphism rs375577 was associated with a 5 % increase in IGF-I levels ( P = 0.01 ) . A number of GHRL and GHSR polymorphisms were associated with body mass index ( BMI ) and height ( P between < 0.01 and 0.04 ) . The false-positive report probability ( FPRP ) approach suggests that these results are noteworthy ( FPRP < 0.20 ) . The results presented here add to a growing body of evidence that GHRL variations are associated with BMI . Furthermore , we have observed evidence for association of GHRL polymorphisms with circulating IGF-I levels and with breast cancer risk . These associations , however , might also be due to chance findings and further large studies are needed to confirm our results BACKGROUND Cancer anorexia-cachexia syndrome is associated with increased morbidity and mortality . Anamorelin is an oral ghrelin-receptor agonist with appetite-enhancing and anabolic activity . We assessed the effects of anamorelin on body composition , strength , quality of life , biochemical markers , and safety in patients with cancer anorexia-cachexia . METHODS Data were pooled , a priori , from two completed phase 2 , multicentre , placebo-controlled , double-blind trials in patients with advanced or incurable cancer and weight loss of 5 % or more . Patients were stratified by weight loss severity ( 5 - 15 % , > 15 % ) and r and omly allocated ( 1:1 ) with a computer-generated r and omisation schedule to anamorelin hydrochloride 50 mg or placebo once-daily for 12 weeks . Primary outcome was lean body mass by dual-energy x-ray absorptiometry over the 12 week treatment period in eligible patients who had at least one dose of study drug and post-treatment efficacy assessment .  We assessed safety in all patients who received at least one dose of study drug . The trials are registered with Clinical Trials.gov , numbers NCT00219817 and NCT00267358 . FINDINGS Between June 29 , 2005 , and Oct 26 , 2006 , we enrolled 44 patients in the anamorelin group and 38 patients in the placebo group . 74 patients were eligible for the efficacy analyses . Over 12 weeks , lean body mass increased in 38 patients in the anamorelin group by a least-squares mean of 1.89 kg ( 95 % CI 0.84 to 2.95 ) compared with a decrease of a least-squares mean of -0.20 kg ( -1.23 to 0.83 ) for 36 patients in the placebo group ( difference 2.09 kg [ 0.94 - 3.25 ] ; p=0.0006 ) . 42 ( 95 % ) of 44 patients treated with anamorelin and 33 ( 87 % ) of 38 patients treated with placebo had adverse events . The most common grade 3 - 4 adverse events ( treatment-related or not ) in the anamorelin group were fatigue , asthenia , atrial fibrillation , and dyspnoea ( two [ 5 % ] each ) ; in the placebo group , such events were pneumonia ( three [ 8 % ] ) and anaemia , thrombocytopenia , abdominal pain , anxiety , and dyspnoea ( two [ 5 % ] each ) . INTERPRETATION Anamorelin treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome . These findings support further investigation in this setting . FUNDING Helsinn Therapeutics ( US ) , Helsinn Healthcare SA 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 BACKGROUND Infusion of ghrelin to supraphysiologic levels inhibits glucose-stimulated insulin secretion , reduces insulin sensitivity , and worsens glucose tolerance in humans . OBJECTIVE The purpose of this study was to determine the effects of lower doses of ghrelin on insulin secretion and insulin sensitivity in healthy men and women . METHODS Acyl ghrelin ( 0.2 and 0.6 nmol kg(-1 ) h(-1 ) ) or saline was infused for 225 minutes in 16 healthy subjects on 3 separate occasions in r and omized order . An i.v . glucose tolerance test was performed , and the insulin sensitivity index ( SI ) was derived from the minimal model . Insulin secretion was measured as the acute insulin response to glucose ( AIRg ) and the disposition index was computed as AIRg × SI . RESULTS Ghrelin infusions at 0.2 and 0.6 nmol kg(-1 ) h(-1 ) raised steady-state plasma total ghrelin levels 2.2- and 6.1-fold above fasting concentrations . Neither dose of ghrelin altered fasting plasma insulin , glucose , or SI , but both doses reduced insulin secretion compared with the saline control , computed either as AIRg ( 384 ± 75 and 354 ± 65 vs 520 ± 110 pM · min [ mean ± SEM ] , respectively ; P < .01 for both low- and high-dose vs saline ) or disposition index ( 2238 ± 421 and 2067 ± 396 vs 3339 ± 705 , respectively ; P < .02 for both comparisons ) . The high-dose ghrelin infusion also decreased glucose tolerance . CONCLUSIONS Ghrelin infused to levels occurring in physiologic states such as starvation decreases insulin secretion without affecting insulin sensitivity . These findings are consistent with a role for endogenous ghrelin in the regulation of insulin secretion and suggest that ghrelin antagonism could improve β-cell function Some recent epidemiologic studies have failed to confirm positive associations between insulin-like growth factor-I ( IGF-I ) and the risk of prostate cancer observed in earlier studies but have reported suggestive evidence for a positive association between IGF-binding protein-3 ( IGFBP-3 ) and prostate cancer risk , a result contradicting the earlier assumption that high levels of IGFBP-3 would be protective against prostate cancer . We tested the association between IGF-I and IGFBP-3 and prostate cancer risk by measuring the two peptides in plasma sample s collected at baseline in a prospect i ve cohort study of 17,049 men . We used a case-cohort design , including 524 cases diagnosed during a mean of 8.7 years follow-up and a r and omly sample d subcohort of 1,826 men . The association between each peptide level and prostate cancer risk was tested using Cox models adjusted for country of birth and alcohol consumption . The risk of prostate cancer was not associated with baseline levels of IGF-I or the molar ratio IGF-I/IGFBP-3 ( all odds ratios are between 0.82 and 1.08 ; Ptrend ≥ 0.2 ) , whereas the risk increased with baseline levels of IGFBP-3 ( Ptrend = 0.008 ) , the hazard ratio ( HR ) associated with a doubling of the concentration of IGFBP-3 being 1.70 ( 95 % confidence interval , 1.15 - 2.52 ) . The HR for quartile 4 relative to quartile 1 of IGFBP-3 was 1.49 ( 95 % confidence interval , 1.11 - 2.00 ) . The HRs did not differ by tumor aggressiveness or age at onset ( all Ps ≥ 0.4 ) . In our study , high levels of IGFBP-3 but not IGF-I were associated with an increased risk of prostate cancer . ( Cancer Epidemiol Biomarkers Prev 2006;15(6):1137–41 OBJECTIVE : Several large studies have shown a negative association between Helicobacter pylori ( H. pylori ) infection and esophageal adenocarcinoma .  Diminution of gastric ghrelin secretion by H. pylori could protect against esophageal malignancy by decreasing appetite , food intake , and acid production , thereby decreasing weight and gastroesophageal reflux . METHODS : We evaluated the association of ghrelin with esophageal adenocarcinoma using a population from a previous nested case-control study . Among 128,992 enrolled in a multiphasic health checkup ( MHC ) between 1964 and 1969 , 52 patients developed esophageal adenocarcinoma by the year 2000 . Three r and om controls from the MHC cohort were matched to each case by age , sex , race , and the date and site of their MHC . Serum sample s collected at the MHC had been previously tested for IgG antibodies against H. pylori and the CagA protein . Serum ghrelin concentrations were determined by a commercial EIA on 52 % of the initial subjects ( 31 cases and 79 controls ) . RESULTS : A concentration of ghrelin greater than 3,200 pg/mL at MHC ( fourth quartile ) was associated with a lower risk of esophageal cancer ( H. pylori and body mass index [ BMI ] adjusted OR = 0.18 [ CI 0.04–0.78 ] ) . This inverse association was seen only in overweight subjects ( BMI ≥ 25 , P value for interaction = 0.09 ) . The effects of H. pylori and ghrelin were independent . CONCLUSION : Contrary to the original hypothesis , high rather than low serum ghrelin was associated with protection against esophageal adenocarcinoma but only among overweight subjects Twenty-one adult patients were r and omised to receive ghrelin on days 1 and 8 and placebo on days 4 and 11 or vice versa , given intravenously over a 60-min period before lunch : 10 received 2 μg kg−1 ( lower-dose ) ghrelin ; 11 received 8 μg kg−1 ( upper-dose ) ghrelin . Active and total ghrelin , growth hormone ( GH ) , and insulin-like growth factor 1 levels were monitored at baseline ( 4–5 days before day 1 ) , during treatment days , and at end of study ( day 17/18 ) . Drug-related adverse events ( assessed by NCI-CTC-toxicity criteria and cardiac examination ) did not differ between ghrelin and placebo . No grade 3/4 toxicity or stimulation of tumour growth was observed . The peak increase of GH , a biological marker of ghrelin action , was 25 ng ml−1 with lower-dose and 42 ng ml−1 with upper-dose ghrelin . Morning fasting total ghrelin levels were higher ( P<0.05 ) for upper-dose patients at end of study ( 3580 pg ml−1 ) than at baseline ( 990 pg ml−1 ) . Insulin-like growth factor 1 levels did not change . At day 8 , 81 % of patients preferred ghrelin to placebo as against 63 % at the end of study . Nutritional intake and eating-related symptoms , measured to explore preliminary efficacy , did not differ between ghrelin and placebo . Ghrelin is well tolerated and safe in patients with advanced cancer .  For safety , tolerance , and patients ' preference for treatment , no difference was observed between the lower- and upper-dose group Although the majority of circulating ghrelin originates from the stomach , no prospect i ve study of the proportion of ghrelin derived from the stomach has been reported . Patients with early gastric cancer who underwent gastric resection were divided into three groups according to the extent and site of gastric resection :  subtotal gastrectomy group ( n = 24 ) ,  proximal gastrectomy group ( n = 4 ) , and  total gastrectomy group ( n = 12 ) . Patients with advanced gastric cancer who underwent gastrojejunostomy without gastrectomy served as the bypass group ( n = 5 ) .  Blood sample s were collected from all patients preoperatively , at 1 h after gastric resection or gastrojejunostomy , and on postoperative d 1 , 3 , and 7 . The plasma ghrelin level was determined in all sample s and expressed as a percentage of the preoperative level . In the bypass group , no significant drop in the ghrelin level was observed at 1 h after gastrojejunostomy , and the ghrelin level remained stable through postoperative d 7 . In the subtotal gastrectomy group , the ghrelin concentration reached a nadir of 38.8 + /- 12.9 % of preoperative levels at 1 h after gastric resection and then gradually increased to 88.1 + /- 13.2 % by postoperative d 7 . In the proximal gastrectomy group , the nadir ghrelin level was 24.5 + /- 15.4 % at 1 h after gastric resection and was followed by a gradual recovery . However , the recovery rate was slower than that in the subtotal gastrectomy group , with the ghrelin level reaching only 47.6 + /- 18.8 % by postoperative d 7 ( P < 0.05 ) . In the total gastrectomy group , the nadir ghrelin level was 28.6 + /- 11.1 % at 1 h after gastric resection and remained at 30.0 + /- 13.2 % until postoperative d 7 . These results suggest that compensatory ghrelin production can occur in the remnant stomach after the surgical removal of part of the stomach and that the proximal fundus is more important than the distal antrum and body in terms of the capacity for ghrelin production . The principal site of ghrelin production is clearly the stomach , which contributes 70 % of the circulating ghrelin concentration Ghrelin is a recently identified endogenous lig and for the GH secretagogue receptor and is involved in a novel system for regulating GH release . However , little is known about its GH-releasing activity and other endocrine effects in humans . To address this issue , we studied the GH , ACTH , cortisol , PRL , LH , FSH , and TSH responses to synthetic human ghrelin . In four normal male adults ( 28 - 37 yr ) , iv ghrelin administration released GH in a dose-dependent manner and 0.2 , 1.0 , and 5.0 microg/kg ghrelin produced 43.3 + /- 6.0 , 81.5 + /- 12.7 , and 107.0 + /- 10.7 ng/mL of the GH peak values at 30 min , respectively . ACTH , cortisol , and PRL levels were also elevated after ghrelin injection , while the lowest dose ( 0.2 microg/kg ) result ed in only minimum peak values of these hormones ( 22.8 + /- 3.0 pg/mL , 9.4 + /- 1.9 microg/dL , and 4.6 + /- 0.6 ng/mL , respectively ) . There were no significant changes in LH , FSH , or TSH levels . This is the first study showing evidence that ghrelin strongly stimulates GH release in humans Ghrelin is a growth hormone-releasing peptide , discovered in 1999 by Kojima et al. Its potential role in inflammation and stress response is not yet clear . The purpose of this study was to characterize perioperative levels of circulating ghrelin in relation to different surgical procedures . The authors compared plasma ghrelin changes with cortisol , cytokines , and acute-phase proteins . The prospect i ve study was performed on 22 patients with resection for colon cancer ( group 1 ) . Group 2 , functioning as a comparative group , consisted of 22 patients with elective laparotomic cholecystectomy .  Plasma concentrations of ghrelin , cortisol , tumor necrosis factor-alpha ( TNF-alpha ) , interleukin-1beta , IL-6 , IL-8 , soluble IL-2 receptor , C reactive protein , and alpha1-antitrypsin were estimated repeatedly during a 72-hour postoperative period . Data revealed significant elevation of plasma ghrelin 24 hours after resection of coli ( median 508.0 ng/l , interquartile range 398.2 - 633.7 ng/l ) in relation to both preoperative levels ( 317.6 ng/l , 253.4 - 355.1 ng/l , p<0.01 ) and group 2 maximal postoperative levels ( 386.2 ng/l , 324 - 432 ng/l , p<0.05 ) . Ghrelin levels returned to initial status 36 - 48 hours after surgery with subsequent decline to subnormal levels . The regression coefficient was the highest for ghrelin and TNF-alpha 24 hours after laparotomy ( r=0.64 , p<0.05 ) and for ghrelin and IL-6 24 hours after surgery ( r=0.56 , p<0.05 ) . Maximal postoperative levels of all tested parameters except for cortisol and IL-1beta differed significantly between both patient groups at p<0.05 . After large abdominal surgery , ghrelin shows itself as an acute-phase reactant . The significant correlation between ghrelin and inflammatory cytokines supposes their regulatory role in this period . Our comparison of more- and less-invasive surgical procedures with similar nutritional restrictions argues for a dominant role of inflammatory factors in postoperative ghrelin elevation Many studies have pointed out a possible role of gut peptides , including gastrin and ghrelin , in the pathogenesis and natural history of gastrointestinal malignancies , one of the most common death cause in the Western world . The objective of this work is to check gastrin and ghrelin serum levels in patients with colorectal cancer according to tumour 's location , stage , Helicobacter pylori infection and BMI , in order to underst and the two peptides ' behaviour through the tumour 's natural history and evaluate their assay 's use in research and clinical practice . Twenty-nine subjects affected by colorectal cancer and 50 healthy controls were studied .  Circulating gastrin and ghrelin levels and H. pylori serum antibodies were assessed by radioimmunologic assay and ELISA method .  Gastrin and ghrelin serum levels were respectively slightly higher and significantly lower in colon cancer patients than in controls . Gastrin levels were higher in patients carrying left colon cancer and H. pylori infection while ghrelin levels were lower in both these groups . Both hormones ' serum levels decreased from tumour earlier to later stages . Significant differences persisted in the correlation between BMI and ghrelin levels in controls but not in patients . Additional studies are necessary to ascertain the significance of gastrin and ghrelin opposite behaviour in colon cancer probably linked with interferences in endocrine pathways involving other gut peptides in this compromised condition Patients with craniopharyngioma ( CP ) , an embryological tumor located in the hypothalamic and /or pituitary region , often suffer from uncontrolled eating and severe obesity . We aim ed to compare peripherally secreted hormones involved in controlling food intake in normal weight and obese children and adolescents with CP vs. controls .  Plasma insulin , glucose , total ghrelin , and peptide-YY ( PYY ) levels were assessed under fasting conditions as well as 60 min after liquid mixed meal in four groups : Normal weight ( n = 12 ) and obese ( n = 15 ) CP patients , and 12 normal weight and 15 obese otherwise healthy BMI - , gender- and age-matched controls .  Homeostasis model assessment of insulin resistance ( HOMA(IR ) ) , as well as quantitative insulin sensitivity check index ( QUICKI ) were calculated . Obese CP subjects had significantly higher HOMA(IR ) , higher baseline and postmeal insulin but lower ghrelin levels , weaker postmeal changes for PYY , and lower QUICKI compared to obese controls . QUICKI data from all CP patients correlated positively with ghrelin and PYY % postmeal changes ( ghrelin : r = 0.38 , P = 0.023 ; PYY r = 0.40 , P = 0.017 ) and negatively with st and ard deviation score- BMI ( SDS- BMI : r = -0.49 , P = 0.002 ) . Tumor growth of 87 % obese and 58 % of normal weight CP patients affected the hypothalamic area which was associated with higher SDS- BMI and weaker % postmeal ghrelin changes ( P = 0.014 ) compared to CP patients without hypothalamic tumor involvement . Blunted postmeal ghrelin and PYY responses in obese CP subjects are likely due to their higher degree of insulin resistance and lower insulin sensitivity compared to matched obese controls . Thus , insulin resistance in CP patients seems to affect eating behavior by affecting meal responses of gut peptides Cisplatin reduces plasma ghrelin levels through the 5‐hydroxytryptamine ( 5‐HT ) receptor . This may cause cisplatin‐induced gastrointestinal disorders and hinders the continuation of chemotherapy . The authors of this report conducted a prospect i ve , r and omized phase 2 trial to evaluate the effects of exogenous ghrelin during cisplatin‐based chemotherapy Ghrelin is a novel endogenous natural lig and for the growth hormone ( GH ) secretagogue receptor that has recently been isolated from the rat stomach . Ghrelin administration stimulates GH secretion but also causes weight gain by increasing food intake and reducing fat utilization in rodents . To investigate the possible involvement of ghrelin in the pathogenesis of human obesity , we measured body composition ( by dual X-ray absorption ) as well as fasting plasma ghrelin concentrations ( radioimmunoassay ) in 15 Caucasians ( 8 men and 7 women , 31+/-9 years of age , 92+/-24 kg body wt , and 29+/-10 % body fat , mean + /- SD ) and 15 Pima Indians ( 8 men and 7 women , 33+/-5 years of age , 97+/-29 kg body wt , and 30+/-8 % body fat ) .  Fasting plasma ghrelin was negatively correlated with percent body fat ( r = -0.45 ; P = 0.01 ) , fasting insulin ( r = -0.45 ; P = 0.01 ) and leptin ( r = -0.38 ; P = 0.03 ) concentrations . Plasma ghrelin concentration was decreased in obese Caucasians as compared with lean Caucasians ( P < 0.01 ) . Also , fasting plasma ghrelin was lower in Pima Indians , a population with a very high prevalence of obesity , compared with Caucasians ( 87+/-28 vs. 129+/-34 fmol/ml ; P < 0.01 ) . This result did not change after adjustment for fasting plasma insulin concentration . There was no correlation between fasting plasma ghrelin and height . Prospect i ve clinical studies are now needed to establish the role of ghrelin in the pathogenesis of human obesity OBJECTIVE Activation of ghrelin receptors stimulates GH secretion and appetite , increasing lean body mass and body weight . However , clinical use of ghrelin is limited because it has a short half-life and must be administered parenterally . Anamorelin is a novel , orally active , non-peptidic ghrelin mimetic and growth hormone secretagogue . Our objective was to evaluate its hormonal effects in healthy subjects . DESIGN A double-blind , r and omized , placebo-controlled study evaluated the short-term effects of anamorelin on GH , insulin-like growth factor-1 ( IGF-1 ) , insulin-like growth factor binding protein 3 ( IGFBP-3 ) , prolactin , ACTH , LH , FSH , TSH , cortisol , insulin and glucose .  Normal healthy volunteers ( n=32 ) recruited from the general population were administered escalating doses of anamorelin ( 25 , 50 , and 75 mg daily ) vs. placebo . RESULTS Anamorelin significantly increased GH levels at all doses ( p < or=0.01 ) . Effects on the somatotropic axis were maintained , as evidence d by sustained increases in IGF-1 and IGFBP-3 compared to placebo following 5 - 6 days of treatment . Negligible effects on other anterior pituitary hormone profiles and on fasting glucose were noted and all mean hormone levels remained within normal range . Some degree of insulin resistance as assessed by HOMA-IR was evident after treatment with 75 mg dose but not with the 25 or the 50 mg doses . Significant dose-related increases in body weight were recorded . Changes in body weight directly correlated with changes in IGF-1 levels .  Anamorelin was well tolerated . CONCLUSIONS Anamorelin increases GH , IGF-1 , IGFBP-3 and body weight with good tolerability and selectivity , without affecting other anterior pituitary axes or fasting glucose levels
target: The majority of in vivo studies showed a null or inverse association of ghrelin with risk and progression of most cancers , suggesting that ghrelin/ghrelin-receptor agonist treatment may have a favorable safety profile to use for cancer cachexia .
background: Ghrelin is a hormone with multiple physiologic functions , including promotion of growth hormone release , stimulation of appetite and regulation of energy homeostasis .
  Treatment with ghrelin/ghrelin-receptor agonists is a prospect i ve therapy for disease-related cachexia and malnutrition .
  In vitro studies have shown high expression of ghrelin in cancer tissue , although its role including its impact in cancer risk and progression has not been established .