Brief Reports
Copyright ©The Author(s) 2005. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2005; 11(25): 3925-3930
Published online Jul 7, 2005. doi: 10.3748/wjg.v11.i25.3925
Clinical evidence of growth hormone for patients undergoing abdominal surgery: Meta-analysis of randomized controlled trials
Yong Zhou, Xiao-Ting Wu, Gang Yang, Wen Zhuang, Mao-Ling Wei
Yong Zhou, Xiao-Ting Wu, Gang Yang, Wen Zhuang, Department of General Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Mao-Ling Wei, Chinese Evidence-Based Medicine/Cochrane Center, Chengdu 610041, Sichuan Province, China
Author contributions: All authors contributed equally to the work.
Supported by the China Medical Board of New York No. 98-680
Correspondence to: Professor Xiao-Ting Wu, Department of General Surgery, West China Hospital, Sichuan University, 37 Guo Xue Road, Chengdu 610041, Sichuan Province, China. nutritioner@163.com
Telephone: +86-28-85422480 Fax: +86-28-85422411
Received: May 27, 2004
Revised: June 12, 2004
Accepted: June 17, 2004
Published online: July 7, 2005

Abstract

AIM: To assess the effectiveness and safety of perioperative growth hormone (GH) in patients undergoing abdominal surgery.

METHODS: We searched the following electronic databases: MEDLINE, EMBASE, the Cochrane Controlled Trials Register, Chinese Bio-medicine Database. The search was undertaken in February 2003. No language restrictions were applied. Randomized controlled trials (RCT) comparing GH with placebo in patients undergoing abdominal surgery were extracted and evaluated. Methodological quality was evaluated using the Jadad scale.

RESULTS: Eighteen trials involving 646 patients were included. The combined results showed that GH had a positive effect on improving postoperative nitrogen balance (standardized mean difference [SMD] = 3.37, 95%CI [2.46, 4.27], P < 0.00001), and decreasing the length of hospital stay (weighted mean difference [WMD] = -2.07, 95%CI [-3.03, -1.11], P = 0.00002), and reducing the duration of postoperative fatigue syndrome (SMD = -1.83, 95%CI [-2.37, -1.30], P < 0.00001), but it could increase blood glucose levels (WMD = 0.91, 95%CI [0.56, 1.25], P < 0.00001).

CONCLUSION: GH for patients undergoing abdominal surgery is effective and safe, if blood glucose can be controlled well. Further trials are required with a sufficient size to account for clinical heterogeneity and to measure other important outcomes such as infection, morbidity, mortality, fluid retention, immunomodulatory effects, and tumor recurrence.

Key Words: Perioperative growth hormone, Abdominal surgery



INTRODUCTION

Catabolism and negative nitrogen balance is a part of the metabolic reaction to major abdominal surgical trauma. It is a concern to surgeons because the catabolic response is correlated with the overall surgical morbidity rate, causing prolonged convalescence. Growth hormone (GH) has been shown to have anabolic effects and to reduce or even prevent nitrogen catabolism in patients undergoing abdominal surgery. The effect of GH has recently been studied by many researchers. In 1974 Wilmore et al[1] suggested that adequate nutritional intake was necessary for GH to have nitrogen-saving effects. In 1986 the study by Phillips[2] demonstrated that GH stimulated hepatic production of somatomedin (insulin-like growth factor-I, IGF-I) whose action could promote diverse anabolic processes, such as synthesis of RNA, DNA, proteins or proteoglycans. However, the effects of GH on nonmetabolic clinical outcome remain unclear.

Meta-analysis has been gradually used in medicine to improve the statistical efficiency, to evaluate the disadvantages of formulated researches and hypothesis, and to reach reliable conclusions from the mixed assortment of potentially relevant studies to determine the most promising directions for future researches. We performed a meta-analysis of available studies to assess the effectiveness and safety, in order to improve our understanding of the clinical effects of perioperative GH treatment of patients undergoing abdominal surgery; clinical outcomes including nitrogen balance, length of hospital stay, blood glucose, and postoperative fatigue syndrome were measured. Other important outcomes, such as infection, morbidity, mortality, fluid retention, immunomodulatory effects and tumor recurrence, were also measured.

MATERIALS AND METHODS
Identification of trials

Our aim was to identify all relevant randomized controlled trials (RCT) that compared GH with placebo in patients undergoing abdominal surgery. A RCT was defined as a trial in which patients were assigned prospectively to one of two interventions by random allocation. We used a multimethod to identify relevant studies for the present review. A computerized literature search of MEDLINE from 1966 to October 2002 was conducted using the following search terms: operation OR surgery OR postoperative OR perioperative AND GH AND RCT (publication type) or controlled clinical trials or clinical trials, randomized. In addition, we searched Embase (1980-2002), Cochrane Controlled Trials Register (Issue 1, 2003), and Chinese Bio-medicine Database (1979-2002), reviewed our personal files, and contacted experts in the field. Bibliographies of all selected articles and review articles that included information on GH were reviewed for other relevant articles. This search strategy was done iteratively, until no new potential, randomized, controlled trial citations were found on review of the reference lists of retrieved articles.

Study selection and data extraction

The following selection criteria were used to identify published studies for inclusion in this analysis: study design - randomized clinical trial, population - hospitalized adult patients undergoing abdominal surgery, intervention - GH vs placebo initiated at the same time and with the same nutrition support, and outcome variables - at least one of the following primary outcome variables: nitrogen balance, length of hospital stay, blood glucose, postoperative fatigue syndrome, incidence of infection, morbidity, mortality, fluid retention, immunomodulatory effects, and tumor recurrence. Study selection and data abstraction were conducted independently by the two investigators.

Data analysis

The incidences of infection, tumor recurrence, fluid retention, morbidity, and mortality were treated as binary variables. Nitrogen balance, length of hospital stay, blood glucose, postoperative fatigue syndrome, and immunomodulatory effects were treated as continuous variables. Data analysis was performed using the random effect model with meta- analysis software (RevMan 4.2; Cochrane Collaboration, Oxford, UK). The continuous data outcomes were presented with 95% confidence intervals (CIs). When authors reported standard deviations, we used them directly. When standard deviations were not available, we computed them from the observed mean differences (either differences in changes or absolute readings) and the test statistics. When the test statistics were not available, given a P value, we computed the corresponding test statistics from tables for the normal distribution. We tested heterogeneity between trials with χ2 tests, with P < 0.05 indicating significant heterogeneity[3]. Methodological quality was evaluated using the Jadad scale[4].

RESULTS

From 460 articles screened, 38 were identified as RCT comparing GH with placebo and included for data extraction. Twenty studies were excluded, and the remaining 18 trials were included in the present meta-analysis[5-22]. Only one study[19] was in Chinese. Articles were excluded for the following reasons, namely the outcomes of interest were not recorded[23-37] and some articles repeated[38-42]. A total of 646 patients were enrolled in the included studies. The characteristics of studies included in meta-analysis comparing GH with placebo are presented in Table 1. Not all of the studies reported the outcome of interest, postoperative nitrogen balance was reported in 11 studies[5-15], length of hospital stay in 3 studies[17-19], postoperative fatigue syndrome in 3 studies[20-22], blood glucose in 6 studies[12-17].

Table 1 Characteristics of studies included in meta-analysis comparing GH with placebo.
StudyYearJadad scoreReferenceOperationGH
Lehner199236Gastrectomy or colectomy0.15 IU/kg/d for 7 d
López199317Gastrointestinal surgery24 IU/d for 5 d
Wong199528Laparoscopic cholecystectomy12 IU/d for 5 d
Tacke199419Cholecystectomy8 IU/d for 7 d
Saito1992310Abdominal aortic aneurysm repair0.3 IU/kg/d for 6 d
Kolstad2001511Abdominal surgery0.3 IU/kg/d for 5 d
Jensen1998512Abdominal aortic aneurysm repair0.3 IU/kg/d for 6 d
Ponting1988213Ileoanal J-pouch surgery12 IU/d for 6 d
Hammarqvist1992114Cholecystectomy8 IU/d for 7 d
Jiang1989415Gastrectomy or colectomy0.15 IU/kg/d for 7 d
Mjaaland1991316Gastrointestinal surgery24 IU/d for 5 d
Barle2001117Laparoscopic cholecystectomy12 IU/d for 5 d
Vara-Thorbeck 11993318Cholecystectomy8 IU/d for 7 d
Barry 21998419Abdominal aortic aneurysm repair0.3 IU/kg/d for 6 d
Liu2001520Abdominal surgery0.3 IU/kg/d for 5 d
Barry 11999321Abdominal aortic aneurysm repair0.3 IU/kg/d for 6 d
Kissmeyer-Nielsen1999522Ileoanal J-pouch surgery12 IU/d for 6 d
Vara-Thorbeck 21996323Cholecystectomy8 IU/d for 7 d

The combined results showed that GH had a positive effect on improving the postoperative nitrogen balance (standardized mean difference [SMD] = 3.37, 95%CI [2.46, 4.27], P < 0.00001) (Table 2), and decreasing the length of hospital stay (weighted mean difference [WMD]=-2.07, 95%CI [-3.03, -1.11], P = 0.00002) (Table 3), and reducing the duration of postoperative fatigue syndrome (SMD = -1.83, 95%CI [-2.37, -1.30], P < 0.00001) (Table 4), but it could increase blood glucose levels (WMD = 0.91, 95%CI [0.56, 1.25], P < 0.00001) (Table 5).

Table 2 Random effect model of standardized mean difference (95%CI) in improving postoperative nitrogen balance (A) and in reducing the duration of postoperative fatigue syndrome (C) and weighted mean difference (95%CI) in decreasing the length of hospital stay (B) and in increasing blood glucose levels (D) with GH as compared with placebo.
StudyTreatmentTreatmentControlControlWeightSMD (random)
nMean (SD)nMean (SD)%95%CI
Ponting61.8 (0.40)5-0.90 (0.70)6.234.46 [1.85, 7.07]
Jiang9-7.10 (3.12)9-32.60 (4.20)6.276.56 [3.97, 9.16]
Mjaaland94.1 (1.10)10-3.10 (1.80)8.364.55 [2.69, 6.41]
Hammarqvist8-2.32 (1.66)9-7.09 (0.71)8.913.63 [1.94, 5.32]
Lehner19-4.30 (9.60)21-14.80 (3.30)11.941.46 [0.76, 2.17]
Saito18-18.00 (3.30)18-185.00 (58.00)10.63.98 [2.80, 5.15]
López9-7.30 (2.80)9-20.70 (4.10)9.093.64 [2.00, 5.27]
Tacke9-10.00 (2.61)10-20.47 (3.86)9.853 [1.60, 4.40]
Wong83 (0.90)7-1.30 (0.75)7.154.85 [2.59, 7.11]
Jenson9-47 (20.00)10-73.00 (20.00)11.121.24 [0.24, 2.25]
Kolstad11-3.90 (0.40)10-5.70 (0.90)10.492.53 [1.32, 3.73]
Total (95%CI)1151181003.37 [2.46, 4.27]
Table 3 Random effect model of standardized mean difference (95%CI) in improving postoperative nitrogen balance (A) and in reducing the duration of postoperative fatigue syndrome (C) and weighted mean difference (95%CI) in decreasing the length of hospital stay (B) and in increasing blood glucose levels (D) with GH as compared with placebo.
StudyTreatmentTreatmentControlControlWeightWMD (fixed)
nMean (SD)nMean (SD)%95%CI
Barry 2813 (2.00)1017.00 (3.00)17.05-4 [-6.32, -1.68]
Liu109.7 (1.80)1010.50 (1.30)48.41-0.8 [-2.18, 0.58]
Vara-Thorbeck 1879.6 (3.60)9312.50 (7.10)34.54-2.9 [-4.53, -1.27]
Total (95%CI)105113100-2.07 [-3.03, -1.11]
Table 4 Random effect model of standardized mean difference (95%CI) in improving postoperative nitrogen balance (A) and in reducing the duration of postoperative fatigue syndrome (C) and weighted mean difference (95%CI) in decreasing the length of hospital stay (B) and in increasing blood glucose levels (D) with GH as compared with placebo.
StudyTreatmentTreatmentControlControlWeightSMD (fixed)
nMean (SD)nMean (SD)%95%CI
Barry 171.6 (1.20)104.90 (2.20)21.23-1.68 [-2.84, -0.52]
Kissmeyer-Nielsen91.37 (0.55)102.73 (2.00)31.57-0.86 [-1.82, 0.09]
Vara-Thorbeck 2221.52 (0.43)263.14 (0.75)47.2-2.55 [-3.33, -1.77]
Total (95%CI)3846100-1.83 [-2.37, -1.30]
Table 5 Random effect model of standardized mean difference (95%CI) in improving postoperative nitrogen balance (A) and in reducing the duration of postoperative fatigue syndrome (C) and weighted mean difference (95%CI) in decreasing the length of hospital stay (B) and in increasing blood glucose levels (D) with GH as compared with placebo.
StudyTreatmentTreatmentControlControlWeightWMD (random)
nMean (SD)nMean (SD)%95%CI
Barle106.4 (1.00)105.40 (0.50)11.981 [0.31, 1.69]
Hammarqvist85.6 (0.30)94.80 (0.20)20.690.8 [0.55, 1.05]
Jiang96.17 (0.51)96.06 (0.50)16.260.11 [-0.36, 0.58]
Mjaaland95.75 (0.43)104.90 (0.30)18.940.85 [0.51, 1.19]
Ponting69.4 (0.70)57.20 (0.50)11.682.2 [1.49, 2.91]
Vara-Thorbeck 1876.56 (1.02)935.66 (0.71)20.460.9 [0.64, 1.16]
Total (95%CI)1291361000.91 [0.56, 1.25]
DISCUSSION

The results must be interpreted with the difference in patients, dose or length of treatment, and unexplained heterogeneity. Clinical heterogeneity in the form of age, etiology and operation of patients points to the possibility of bias.

This meta-analysis did not show that GH had a positive effect on improving postoperative nitrogen balance. Eleven studies involving 233 patients were included. Although there was a heterogeneity (test for heterogeneity χ2 = 44.48, df = 10, P < 0.00001), the result was sure. Because all the 11 studies showed that GH had a positive effect on improving postoperative nitrogen balance with a statistical significance (minimum of SMD = 1.24, 95%CI [0.24, 2.25]). However, it seems that different doses had different effects, subgroup was not used. What attention should be paid to is that some studies only reported the cumulated nitrogen balance or the daily nitrogen balance. Further research should be done to assess the possible best dose.

To date, only three studies involving 218 patients, have examined whether treatment with GH could influence the length of hospital stay. The combined results showed that administration of GH could decrease the length of hospital stay. The results must be interpreted with caution due to the small size. Two of three trials[17,18] showed statistically and clinically significant differences in the length of hospital stay. So, further trials are required with a sufficient size to account for clinical heterogeneity and length of hospital stay. This meta-analysis showed that administration of GH could reduce the duration of postoperative fatigue syndrome after 1 mo. Three studies involving 84 patients were included. The evidence was not strong due to the small size and unexplained heterogeneity. It is also important to recognize that two[20,21] of the RCTs included in this review were not designed specifically to reduce postoperative fatigue and provided few or no theoretical rationales as to why the intervention under study might be expected to attenuate it. Attempts to assess fatigue objectively by measuring, for example, physical activity, time taken to return to normal routine, or involuntary or voluntary muscle force were problematic because they could be confounded by numerous factors including pain and anxiety. Much effort has therefore been devoted to developing short and easy-to-use questionnaires that could provide some quantification of a patient’s subjective feeling of fatigue. Future research should ensure that an adequate measure of subjective fatigue is employed, possibly in tandem with important objective measures, such as time taken to return to work.

This meta-analysis did not show that GH might increase blood glucose levels. Six studies involving 265 patients were included. Of the six, only the study of Jiang et al[14] did not reach a statistical significance (SMD = 0.11, 95%CI [-0.36, 0.58]). Low-dose GH and hypocaloric nutrition may be the reason. Confirmation of the diabetogenic properties of GH was made after it was administered in excess to experimental animals and men. Transgenic animals, which over-expressed GH, developed insulin resistance, marked hyperinsulinemia, hyperglycemia, and hypertriglyceridemia in association with a number of molecular abnormalities[43,44]. Patients with acromegaly developed insulin resistance and hyperinsulinemia, while up to 40% became diabetic[45,46]. There is evidence that insulin resistance caused by GH plays an important role in the rise of blood glucose. In addition, GH could stimulate lipolysis with the release of glycerol and non-esterified fatty acids (NEFA). This provides a further mechanism for the diabetogenic properties of GH through the effect of NEFA to increase hepatic glucose output and decrease peripheral glucose oxidation according to the glucose-fatty acid cycle[47,48]. In fact, in the study of Berman et al[23] the GH group had significantly elevated urine glucose levels throughout the study period, consistent with the demonstrated hyperglycemia and only moderately elevated insulin levels. Treatment with GH did result in hyperglycemia, and two patients were removed from the study. Hyperglycemia associated with GH administration could be treated easily by insulin, especially in long-term GH administration.

Only one RCT[36] conducted an analysis of a multicenter study with 104 patients undergoing major gastrointestinal surgery to assess the risk of long-term tumor recurrence after short-term (5 d) postoperative GH treatment. The study was a follow-up of a previous randomized study investigating the effect of three different doses of GH (0.075, 0.15, and 0.30 IU/kg/d) on the postoperative cumulative nitrogen balance in patients undergoing major surgery. Tumors recurred in 20 (35%) patients who were evaluated for and treated with GH (n = 57). This accounted for 4 of 17 (23%) patients given 0.075 IU/kg/d of GH, 9 of 20 (45%) given 0.15 IU/kg/d of GH, and 7 of 20 (35%) given 0.30 IU/kg/d. By comparison, tumors recurred in 8 of 18 (44%) of patients given placebo. The result of this study demonstrated that short-term treatment with GH for 5 d after major gastrointestinal surgery for adenocarcinoma did not increase the risk of tumor recurrence. But the group size was too small to further stratify the patients according to tumor type and tumor stage, so that no information was gained about the influence of GH dose in certain tumor stages.

Fluid retention is one of known side effects of GH administration. The sodium and fluid retaining impact of GH was demonstrated in humans almost 50 years ago by Ikkos et al[49]. Underlying mechanisms of GH-induced fluid retention are as follows. GH could increase glomerular filtration rate mediated by insulin-like growth factor (IGF-I)[50-52], stimulate the renin-angiotensin-aldosterone system (RAAS)[53-57], reduce atrial natriuretic factors[58-61], and prostaglandins could play a role in GH-induced fluid retention[62]. In the study of Berman et al[23], two GH patients were removed from the study for fluid retention. These patients were in the immediate postoperative period. However, whether the fluid retention was a result of surgery or GH administration could not be determined.

GH should not be given in acute inflammatory disease states. Findings by Takala et al[63], pointed to the immunomodulatory effects of GH. These authors described higher hospital mortality in a Finish and an European study on critically ill non-cancer patients. It was proposed that the higher mortality was due to the application of GH at a later stage during the inflammatory disease process, leading to uncontrolled systemic inflammation. However, infection was not measured in these trials except one[17]. Only one RCT[18] reported the morbidity and mortality, so we could not draw a conclusion due to the small size. But there are still four studies[64-67] awaiting assessment in other languages or we cannot find the full text.

In conclusion, perioperative GH treatment of patients undergoing abdominal surgery can improve the postoperative nitrogen balance, and decrease the length of hospital stay, and reduce the duration of postoperative fatigue syndrome. But it might increase blood glucose levels. However, the evidence is not strong due to the difference in patients, dose or length of treatment, and unexplained heterogeneity. In order to examine the effectiveness and safety of perioperative GH treatment of patients undergoing abdominal surgery, further trials are required with a sufficient size to account for the clinical heterogeneity and to measure other important outcomes such as infection, morbidity, mortality, fluid retention, immunomodulatory effects, and tumor recurrence.

ACKNOWLEDGEMENTS

We are sincerely grateful to the principal investigators of all the trials who provided additional unpublished information. We also thank Susanne Ebrahim and Karla Bergerhoff for diligent working in Cochrane Metabolic and Endocrine Disorders Group and Ming Liu, He-Ming Huang, Bin Lv, Eewen, Jian-Kun Hu, Hua Jiang and Shu-Ai Xiao for providing additional references.

Footnotes

Science Editor Wang XL and Li WZ Language Editor Elsevier HK

References
1.  Wilmore DW, Moylan JA, Bristow BF, Mason AD, Pruitt BA. Anabolic effects of human growth hormone and high caloric feedings following thermal injury. Surg Gynecol Obstet. 1974;138:875-884.  [PubMed]  [DOI]
2.  Phillips LS. Nutrition, somatomedins, and the brain. Metabolism. 1986;35:78-87.  [PubMed]  [DOI]
3.  Oxman AD, Cook DJ, Guyatt GH. Users' guides to the medical literature. VI. How to use an overview. Evidence-Based Medicine Working Group. JAMA. 1994;272:1367-1371.  [PubMed]  [DOI]
4.  Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.  [PubMed]  [DOI]
5.  Lehner JH, Jauch KW, Berger G. A multicentre study of the dose response effect of human recombinant growth hormone (rhGH) on cumulative nitrogen balance (CNB) in patients after major abdominal surgery [abstract]. Clin Nutr. 1992;11:75-76.  [PubMed]  [DOI]
6.  López J, Fernóndez C, Carriedo D. Metabolic effects of re-combinant growth hormone following major surgery of the digestive tract [abstract]. Medicina Intensiva. 1993;17:82.  [PubMed]  [DOI]
7.  Wong WK, Soo KC, Nambiar R, Tan YS, Yo SL, Tan IK. The effect of recombinant growth hormone on nitrogen balance in malnourished patients after major abdominal surgery. Aust N Z J Surg. 1995;65:109-113.  [PubMed]  [DOI]
8.  Tacke J, Bolder U, Löhlein D. Improved cumulated nitrogen balance after administration of recombinant human growth hormone in patients undergoing gastrointestinal surgery. Infusionsther Transfusionsmed. 1994;21:24-29.  [PubMed]  [DOI]
9.  Saito H, Taniwaka K, Muto T. Effects of growth hormone dose after major abdominal operation: a randomized, prospective, multicenter trial [abstract]. Clin Nutr. 1992;11:9.  [PubMed]  [DOI]
10.  Kolstad O, Jenssen TG, Ingebretsen OC, Vinnars E, Revhaug A. Combination of recombinant human growth hormone and glutamine-enriched total parenteral nutrition to surgical patients: effects on circulating amino acids. Clin Nutr. 2001;20:503-510.  [PubMed]  [DOI]
11.  Jensen MB, Kissmeyer-Nielsen P, Laurberg S. Perioperative growth hormone treatment increases nitrogen and fluid balance and results in short-term and long-term conservation of lean tissue mass. Am J Clin Nutr. 1998;68:840-846.  [PubMed]  [DOI]
12.  Ponting GA, Halliday D, Teale JD, Sim AJ. Postoperative positive nitrogen balance with intravenous hyponutrition and growth hormone. Lancet. 1988;1:438-440.  [PubMed]  [DOI]
13.  Hammarqvist F, Strömberg C, von der Decken A, Vinnars E, Wernerman J. Biosynthetic human growth hormone preserves both muscle protein synthesis and the decrease in muscle-free glutamine, and improves whole-body nitrogen economy after operation. Ann Surg. 1992;216:184-191.  [PubMed]  [DOI]
14.  Jiang ZM, He GZ, Zhang SY, Wang XR, Yang NF, Zhu Y, Wilmore DW. Low-dose growth hormone and hypocaloric nutrition attenuate the protein-catabolic response after major operation. Ann Surg. 1989;210:513-524; discussion 524-525.  [PubMed]  [DOI]
15.  Mjaaland M, Unneberg K, Hotvedt R, Revhaug A. Nitrogen retention caused by growth hormone in patients undergoing gastrointestinal surgery with epidural analgesia and parenteral nutrition. Eur J Surg. 1991;157:21-27.  [PubMed]  [DOI]
16.  Barle H, Råhlén L, Essén P, McNurlan MA, Garlick PJ, Holgersson J, Wernerman J. Stimulation of human albumin synthesis and gene expression by growth hormone treatment. Clin Nutr. 2001;20:59-67.  [PubMed]  [DOI]
17.  Vara-Thorbeck R, Guerrero JA, Rosell J, Ruiz-Requena E, Capitán JM. Exogenous growth hormone: effects on the catabolic response to surgically produced acute stress and on postoperative immune function. World J Surg. 1993;17:530-537; discussion 530-537;.  [PubMed]  [DOI]
18.  Barry MC, Mealy K, Sheehan SJ, Burke PE, Cunningham AJ, Leahy A, Bouchier Hayes D. The effects of recombinant human growth hormone on cardiopulmonary function in elective abdominal aortic aneurysm repair. Eur J Vasc Endovasc Surg. 1998;16:311-319.  [PubMed]  [DOI]
19.  Liu W. The impact of pretreatment with recombinant human growth hormone on intestinal barrier function and cell im-mune function. Zhongguo Linchuang Yingyang Zazhi. 2001;4:77-80.  [PubMed]  [DOI]
20.  Barry MC, Mealy K, O'Neill S, Hughes A, McGee H, Sheehan SJ, Burke PE, Bouchier-Hayes D. Nutritional, respiratory, and psychological effects of recombinant human growth hormone in patients undergoing abdominal aortic aneurysm repair. JPEN J Parenter Enteral Nutr. 1999;23:128-135.  [PubMed]  [DOI]
21.  Kissmeyer-Nielsen P, Jensen MB, Laurberg S. Perioperative growth hormone treatment and functional outcome after major abdominal surgery: a randomized, double-blind, controlled study. Ann Surg. 1999;229:298-302.  [PubMed]  [DOI]
22.  Vara-Thorbeck R, Guerrero JA, Ruiz-Requena E, García-Carriazo M. Can the use of growth hormone reduce the postoperative fatigue syndrome? World J Surg. 1996;20:81-6; discussion 86-87.  [PubMed]  [DOI]
23.  Berman RS, Harrison LE, Pearlstone DB, Burt M, Brennan MF. Growth hormone, alone and in combination with insulin, increases whole body and skeletal muscle protein kinetics in cancer patients after surgery. Ann Surg. 1999;229:1-10.  [PubMed]  [DOI]
24.  Carli F, Webster JD, Halliday D. A nitrogen-free hypocaloric diet and recombinant human growth hormone stimulate post-operative protein synthesis: fasted and fed leucine kinetics in the surgical patient. Metabolism. 1997;46:796-800.  [PubMed]  [DOI]
25.  Carli F, Webster JD, Halliday D. Growth hormone modulates amino acid oxidation in the surgical patient: leucine kinetics during the fasted and fed state using moderate nitrogenous and caloric diet and recombinant human growth hormone. Metabolism. 1997;46:23-28.  [PubMed]  [DOI]
26.  Hammarqvist F, Sandgren A, Andersson K, Essén P, McNurlan MA, Garlick PJ, Wernerman J. Growth hormone together with glutamine-containing total parenteral nutrition maintains muscle glutamine levels and results in a less negative nitrogen balance after surgical trauma. Surgery. 2001;129:576-586.  [PubMed]  [DOI]
27.  Inoue Y, Copeland EM, Souba WW. Growth hormone enhances amino acid uptake by the human small intestine. Ann Surg. 1994;219:715-722; discussion 722-724.  [PubMed]  [DOI]
28.  Kissmeyer P, Moller J, Bach Jensen M, Laurberg S. Effect of growth hormone on the atabolic response to elective J-pouch surgery [abstract]. Int J Colorectal Dis. 1997;12:189.  [PubMed]  [DOI]
29.  Mjaaland M. Growth hormone after gastrointestinal surgery: effect on skeletal muscle metabolism [abstract]. Clin Nutr. 1990;9:13.  [PubMed]  [DOI]
30.  Mjaaland M. The effect of growth hormone on postoperative nitrogen balance [abstract]. Ann Chir Gynaecol. 1989;78:14.  [PubMed]  [DOI]
31.  Mjaaland M, Unneberg K, Larsson J, Nilsson L, Revhaug A. Growth hormone after abdominal surgery attenuated forearm glutamine, alanine, 3-methylhistidine, and total amino acid efflux in patients receiving total parenteral nutrition. Ann Surg. 1993;217:413-422.  [PubMed]  [DOI]
32.  Mjaaland M, Unneberg K, Bjøro T, Revhaug A. Growth hormone treatment after abdominal surgery decreased carbohydrate oxidation and increased fat oxidation in patients with total parenteral nutrition. Metabolism. 1993;42:185-190.  [PubMed]  [DOI]
33.  Møller J, Jensen MB, Frandsen E, Møller N, Kissmeyer P, Laurberg S. Growth hormone treatment improves body fluid distribution in patients undergoing elective abdominal surgery. Clin Endocrinol (Oxf). 1998;49:597-602.  [PubMed]  [DOI]
34.  Plank LD, Hill GL. Use of bioimpedance spectroscopy to assess effects of perioperative treatment with growth hormone on fluid changes in patients undergoing major surgery. Ann N Y Acad Sci. 2000;904:190-192.  [PubMed]  [DOI]
35.  Saito H, Taniwaka K, Fukushima R, Sawada T, Muto T, Morioka Y. Growth hormone treatment stimulates immune responsiveness after abdominal surgery [abstract]. Clin Nutr. 1990;9:16.  [PubMed]  [DOI]
36.  Tacke J, Bolder U, Herrmann A, Berger G, Jauch KW. Long-term risk of gastrointestinal tumor recurrence after postoperative treatment with recombinant human growth hormone. JPEN J Parenter Enteral Nutr. 2000;24:140-144.  [PubMed]  [DOI]
37.  Vara-Thorbeck R, Guerrero JA, Ruiz-Requena ME, Capitán J, Rodriguez M, Rosell J, Mekinassi K, Maldonado M, Martin R. Effects of growth hormone in patients receiving total parenteral nutrition following major gastrointestinal surgery. Hepatogastroenterology. 1992;39:270-272.  [PubMed]  [DOI]
38.  Barle H, Essén P, Nyberg B, Olivecrona H, Tally M, McNurlan MA, Wernerman J, Garlick PJ. Depression of liver protein synthesis during surgery is prevented by growth hormone. Am J Physiol. 1999;276:E620-E627.  [PubMed]  [DOI]
39.  He G, Jiang Z, Yang N, Shu H, Wilmore DW. Effect of recombinant growth hormone on amino acids metabolism in blood and urine after major operation. Zhongguo Yixue Kexueyuan XueBao. 1997;19:192-196.  [PubMed]  [DOI]
40.  Jiang Z, He G, Wang X, Yang N, Wilmore DW. [The effect of nutrition support and recombinant growth hormone on body composition and muscle function in postoperative patients]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 1994;16:443-447.  [PubMed]  [DOI]
41.  Mealy K, Barry M, O'Mahony L, Sheehan S, Burke P, McCormack C, Whitehead AS, Bouchier-Hayes D. Effects of human recombinant growth hormone (rhGH) on inflammatory responses in patients undergoing abdominal aortic aneurysm repair. Intensive Care Med. 1998;24:128-131.  [PubMed]  [DOI]
42.  Vara-Thorbeck R, Ruiz-Requena E, Guerrero-Fernández JA. Effects of human growth hormone on the catabolic state after surgical trauma. Horm Res. 1996;45:55-60.  [PubMed]  [DOI]
43.  Valera A, Rodriguez-Gil JE, Yun JS, McGrane MM, Hanson RW, Bosch F. Glucose metabolism in transgenic mice containing a chimeric P-enolpyruvate carboxykinase/bovine growth hormone gene. FASEB J. 1993;7:791-800.  [PubMed]  [DOI]
44.  Ikeda A, Chang KT, Matsumoto Y, Furuhata Y, Nishihara M, Sasaki F, Takahashi M. Obesity and insulin resistance in human growth hormone transgenic rats. Endocrinology. 1998;139:3057-3063.  [PubMed]  [DOI]
45.  Ezzat S, Forster MJ, Berchtold P, Redelmeier DA, Boerlin V, Harris AG. Acromegaly. Clinical and biochemical features in 500 patients. Medicine (Baltimore). 1994;73:233-240.  [PubMed]  [DOI]
46.  Colao A, Baldelli R, Marzullo P, Ferretti E, Ferone D, Gargiulo P, Petretta M, Tamburrano G, Lombardi G, Liuzzi A. Systemic hypertension and impaired glucose tolerance are independently correlated to the severity of the acromegalic cardiomyopathy. J Clin Endocrinol Metab. 2000;85:193-199.  [PubMed]  [DOI]
47.  Gerich JE, Lorenzi M, Bier DM, Tsalikian E, Schneider V, Karam JH, Forsham PH. Effects of physiologic levels of glucagon and growth hormone on human carbohydrate and lipid metabolism. Studies involving administration of exogenous hormone during suppression of endogenous hormone secretion with somatostatin. J Clin Invest. 1976;57:875-884.  [PubMed]  [DOI]
48.  Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest. 1983;72:1737-1747.  [PubMed]  [DOI]
49.  Ikkos D, Luft R, Sjogren B. Body water and sodium in patients with acromegaly. J Clin Invest. 1954;33:989-994.  [PubMed]  [DOI]
50.  Guler HP, Schmid C, Zapf J, Froesch ER. Effects of recombinant insulin-like growth factor I on insulin secretion and renal function in normal human subjects. Proc Natl Acad Sci U S A. 1989;86:2868-2872.  [PubMed]  [DOI]
51.  Hirschberg R, Kopple JD. Evidence that insulin-like growth factor I increases renal plasma flow and glomerular filtration rate in fasted rats. J Clin Invest. 1989;83:326-330.  [PubMed]  [DOI]
52.  Hirschberg R, Brunori G, Kopple JD, Guler HP. Effects of insulin-like growth factor I on renal function in normal men. Kidney Int. 1993;43:387-397.  [PubMed]  [DOI]
53.  Venning EH, Lucis OJ. Effect of growth hormone on the biosynthesis of aldosterone in the rat. Endocrinology. 1962;70:486-491.  [PubMed]  [DOI]
54.  Ho KY, Weissberger AJ. The antinatriuretic action of biosynthetic human growth hormone in man involves activation of the renin-angiotensin system. Metabolism. 1990;39:133-137.  [PubMed]  [DOI]
55.  Cuneo RC, Salomon F, Wilmshurst P, Byrne C, Wiles CM, Hesp R, Sönksen PH. Cardiovascular effects of growth hormone treatment in growth-hormone-deficient adults: stimulation of the renin-aldosterone system. Clin Sci (Lond). 1991;81:587-592.  [PubMed]  [DOI]
56.  Herlitz H, Jonsson O, Bengtsson BA. Effect of recombinant human growth hormone on cellular sodium metabolism. Clin Sci (Lond). 1994;86:233-237.  [PubMed]  [DOI]
57.  Ross EJ, Vant Hoff W, Crabbe J, Thorn GW. Aldosterone excretion in hypopituitarism and after hypophysectomy in man. Am J Med. 1960;28:229-238.  [PubMed]  [DOI]
58.  Donath MY, Zierhut W, Gosteli-Peter MA, Hauri C, Froesch ER, Zapf J. Effects of IGF-I on cardiac growth and expression of mRNAs coding for cardiac proteins after induction of heart hypertrophy in the rat. Eur J Endocrinol. 1998;139:109-117.  [PubMed]  [DOI]
59.  Donath MY, Gosteli-Peter MA, Hauri C, Froesch ER, Zapf J. Insulin-like growth factor-I stimulates myofibrillar genes and modulates atrial natriuretic factor mRNA in rat heart. Eur J Endocrinol. 1997;137:309-315.  [PubMed]  [DOI]
60.  Tanaka N, Ryoke T, Hongo M, Mao L, Rockman HA, Clark RG, Ross J. Effects of growth hormone and IGF-I on cardiac hypertrophy and gene expression in mice. Am J Physiol. 1998;275:H393-H399.  [PubMed]  [DOI]
61.  Harder BA, Schaub MC, Eppenberger HM, Eppenberger-Eberhardt M. Influence of fibroblast growth factor (bFGF) and insulin-like growth factor (IGF-I) on cytoskeletal and contractile structures and on atrial natriuretic factor (ANF) expression in adult rat ventricular cardiomyocytes in culture. J Mol Cell Cardiol. 1996;28:19-31.  [PubMed]  [DOI]
62.  Tönshoff B, Nowack R, Kurilenko S, Blum WF, Seyberth HW, Mehls O, Ritz E. Growth hormone-induced glomerular hyperfiltration is dependent on vasodilating prostanoids. Am J Kidney Dis. 1993;21:145-151.  [PubMed]  [DOI]
63.  Takala J, Ruokonen E, Webster NR, Nielsen MS, Zandstra DF, Vundelinckx G, Hinds CJ. Increased mortality associated with growth hormone treatment in critically ill adults. N Engl J Med. 1999;341:785-792.  [PubMed]  [DOI]
64.  Gottardis M, Gruber E, Benzer A, Murr C, Schmoigl C, Hackl JM, Balogh D. [Effects of short-term application of recombinant human growth hormone on urea production rate in patients in the early postoperative phase]. Infusionsther Transfusionsmed. 1993;20:142-147.  [PubMed]  [DOI]
65.  Guerrero JA, Capitán JM, Rosell J, Ruiz ME, García E, García-Carriazo M, Maldonado MJ, Vara Thorbeck R. Effect of growth hormone and parenteral nutrition on the catabolic phase following major digestive surgery. Rev Esp Enferm Dig. 1992;81:379-382.  [PubMed]  [DOI]
66.  Martín R, Cano MD, Guerrero JA, Segovia E, Vara Thorbeck R. Growth hormone and its effects on cholesterol and lipoprotein metabolism following surgical intervention (hGH and cholesterol metabolism during surgery). Nutr Hosp. 1998;13:181-185.  [PubMed]  [DOI]
67.  Wennstrom I, Wernerman J, Hammarqvist F. Postoperative effects of growth hormone and insulin-like growth factor-I on the nitrogen balance and muscle amino acid pattern [abstract]. Clin Nutr. 1999;18:14.  [PubMed]  [DOI]