Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction
( Vol-4,Issue-7,July 2017 )

Graham M. R., Gu Y., Evans P. J., Cooper S. M., Davies B., Baker J. S.


APWV; BP; hsCRP; Homocysteine; PIIINP; RPP.


Objectives: In arterial hypertension, amino-terminal propeptide of type III procollagen (PIIINP) is elevated in arterial aneurysm tissue and associated with a poor prognosis following acute myocardial infarction (MI). Recombinant human growth hormone (rhGH) administration attenuates endothelial dysfunction but increases PIIINP. This study was conducted to establish if short-term rhGH administration affects PIIINP, endothelial function and selected cardiovascular disease (CVD) risk factors, in healthy males. Design: Method: Male subjects (n=48) were randomly assigned into two groups: (1): control group (C) n=24, mean ± SD, age 32 ± 11 years; height 1.8 ± 0.06 metres; (2): rhGH administration group (rhGH) n=24, mean ± SD, age 32 ± 9 years; height 1.8 ± 0.07 metres. Blood pressure (BP), heart rate (HR), arterial pulse wave velocity (APWV), and biochemical indices were investigated. Results: PIIINP (0.28±0.1 vs. 0.42±0.2, U/ml); Insulin like growth factor-I (159±54 vs. 323±93, ng.mL-1); resting HR (72±14 vs. 78±11, b.p.m.) and rate pressure product (RPP) (90±18 vs. 97±14, bpm x mm.Hg x 10-2) all significantly increased (P<0.05). Total cholesterol (4.7±0.9 vs. 4.4±0.7, mmol.L-1); high sensitivity C-reactive protein (1.77±2.1 vs. 1.29±1.6, mg.L-1); serum homocysteine (13.2±4.0 vs. 11.7±3.1, μmol.L-1) and APWV (9.97±1.38 vs. 9.18±1.6, m.s-1) all significantly decreased (P<0.05). Conclusion: Paradoxically, there was an improvement in CVD inflammatory markers and APWV; but PIIINP and resting RPP increased. Elevated PIIINP may have a confounding adverse effect on the endothelium, but may also provide clinical prognostic information in monitoring arterial hypertension, left ventricular function in the sub-acute phase following MI and endothelial function in aortic aneurysms.

ijaers doi crossref DOI:


Paper Statistics:
  • Total View : 63
  • Downloads : 13
  • Page No: 164-173
Cite this Article:
Graham M. R. et al ."Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction". International Journal of Advanced Engineering Research and Science(ISSN : 2349-6495(P) | 2456-1908(O)),vol 4, no. 7, 2017, pp.164-173 AI Publications, doi:10.22161/ijaers.4.7.26
Graham M. R., Gu Y., Evans P. J., Cooper S. M., Davies B., Baker J. S.(2017).Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction. International Journal of Advanced Engineering Research and Science(ISSN : 2349-6495(P) | 2456-1908(O)),4(7), 164-173.
Graham M. R., Gu Y., Evans P. J., Cooper S. M., Davies B., Baker J. S.. 2017,"Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction". International Journal of Advanced Engineering Research and Science(ISSN : 2349-6495(P) | 2456-1908(O)).4(7):164-173. Doi: 10.22161/ijaers.4.7.26
Graham M. R., Gu Y., Evans P. J., Cooper S. M., Davies B., Baker J. S.. 2017,Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction, International Journal of Advanced Engineering Research and Science(ISSN : 2349-6495(P) | 2456-1908(O)).4(7), pp:164-173
Graham M. R., Gu Y., Evans P. J., Cooper S. M., Davies B., Baker J. S.."Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction", International Journal of Advanced Engineering Research and Science(ISSN : 2349-6495(P) | 2456-1908(O)),vol.4,no. 7, pp.164-173,2017.
@article {grahamm.r.2017short-term,
title={Short-term rhGH increases PIIINP, a biomarker of endothelial dysfunction},
author={Graham M. R., Gu Y., Evans P. J., Cooper S. M., Davies B., Baker J. S.},
journal={International Journal of Advanced Engineering Research and Science},
year= {2017},

[1] Jensen LT, Hørslev-Petersen K, Toft P et al. Serum aminoterminal type III procollagen peptide reflects repair after acute myocardial infarction. Circulation 1990; 81:52–57.
[2] Høst NB, Jensen LT, Bendixen PM et al. The aminoterminal propeptide of type III procollagen provides new information on prognosis after acute myocardial infarction. Am J Cardiol 1995; 76: 869–873.
[3] Poulsen SH, Høst NB, Jensen SE et al. Relationship between serum amino-terminal propeptide of type III procollagen and changes of left ventricular function after acute myocardial infarction. Circulation 2000; 101: 1527–1532.
[4] Rossi A, Cicoira M, Golia G et al. Amino-terminal propeptide of type III procollagen is associated with restrictive mitral filling pattern in patients with dilated cardiomyopathy: a possible link between diastolic dysfunction and prognosis. Heart 2004; 90: 650–654.
[5] Safdar Z, Tamez E, Chan W et al. Circulating collagen biomarkers as indicators of disease severity in pulmonary arterial hypertension. JACC Heart Fail 2014; 2: 412-421.
[6] Lee CH, Lee WC, Chang SH et al. The N-Terminal Propeptide of Type III Procollagen in Patients with Acute Coronary Syndrome: A Link between Left Ventricular End-Diastolic Pressure and Cardiovascular Events. PLoS One 2015; 10(1): e114097, doi:10.1371/journal.pone.0114097.
[7] Ghorpade A, Baxter BT. Biochemistry and molecular regulation of matrix macromolecules in abdominal aortic aneurysms. Ann N Y Acad Sci 1996; 18: 138-150.
[8] Treska V, Topolcan O. “Plasma and tissue levels of collagen types I and III markers in patients with abdominal aortic aneurysms”. Int Angiol 2000; 19: 64-68.
[9] Ihara A, Kawamoto T, Matsumoto K et al. Relationship between hemostatic markers and circulating biochemical markers of collagen metabolism in patients with aortic aneurysm. Pathophysiol Haemost Thromb 2003; 33: 221-224.
[10] Verde GG, Santi I, Chiodini P et al. Serum type III procollagen propeptide levels in acromegalic patients. J Clin Endocrinol Metab 1986; 63: 1406-1410.
[11] Lombardi G, Galdiero M, Auriemma RS et al. Acromegaly and the cardiovascular system. Neuroendocrinology 2006; 83: 211-2177.
[12] Cittadini A, Cuocolo A, Merola B et al. Impaired cardiac performance in GH-deficient adults and its improvement after GH replacement. Am J Physiol 1994; 267: E219- E225.
[13] Pfeifer M, Verhovec R, Zizek B et al. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults, J Clin Endocrinol Metab 1999; 84: 453-457.
[14] Smith JC, Evans LM, Wilkinson I et al. Effects of GH replacement on endothelial function and large-artery stiffness in GH-deficient adults: a randomized, double-blind, placebo-controlled study, Clin Endocrinol 2002; 56: 493–501.
[15] Napoli R, Guardasole V, Matarazzo M et al. Growth hormone corrects vascular dysfunction in patients with chronic heart failure. J Am Coll Cardiol 2002; 39: 90-95.
[16] Holt RI, Erotokritou-Mulligan I, McHugh C et al. The GH-2004 project: the response of IGF1 and type III pro-collagen to the administration of exogenous GH in non-Caucasian amateur athletes, Eur J Endocrinol 2010; 163: 45-54.
[17] Velloso CP, Aperghis M, Godfrey R et al. The effects of two weeks of recombinant growth hormone administration on the response of IGF-I and N-terminal pro-peptide of collagen type III (P-III-NP) during a single bout of high resistance exercise in resistance trained young men. Growth Horm IGF Res 2013; 23: 76-80.
[18] Pronk NP. Short term effects of exercise on plasma lipids and lipoproteins in humans. Sports Med 1993; 16: 431–448.
[19] Ahokoski O, Virtanen A, Huupponen R et al. Biological day- to-day variation and daytime changes of testosterone, follitropin, lutropin and oestradiol-17b in healthy men. Clin Chem Lab Med 1998; 36: 485-491.
[20] Wu Z, Bidlingmaier M, Dall R et al. Detection of doping with human growth hormone. Lancet 1999; 13: 895.
[21] Goldman F, Buskirk ER. Body volume measurement by underwater weighing: description of a technique. in: Brozek, Henshel (eds.) 1961; 78–89.
[22] Wilmore JH. The use of actual, predicted and constant residual volumes in the assessment of body composition by underwater weighing”. Med Sci Sports Exerc 1969; 1: 87.
[23] Siri WE. Body composition from fluid spaces and density: analysis of methods, in: J. Brozek, A. Henschel (Eds.), Techniques for Measuring Body Composition. National Academy of Sciences/National Research Council, Washington, DC 1961; 223–224.
[24] Mattace-Raso F, Hofman A, Verwoert GC et al. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'establishing normal and reference values'. Eur Heart 2010; J 31: 2338-2350.
[25] Fletcher GF, Blair SN, Blumenthal J et al. Statement on exercise. Benefits and recommendations for physical activity programs for all Americans, a statement for health professionals by the committee on exercise and cardiac rehabilitation of the council on clinical cardiology, American heart association. Circulation 1992; 86: 340–344.
[26] Pickering TG, Hall JE, Appel LJ et al. Council on High Blood Pressure Research Professional and Public Education Subcommittee, American Heart Association. Recommendations for blood pressure measurement in humans: an AHA scientific statement from the Council on High Blood Pressure Research Professional and Public Education Subcommittee. J Clin Hypertens (Greenwich) 2005; 7: 102-109.
[27] Altman DG. How large a sample? In Statistics in Practice (eds. SM Gore and DG Altman), London, British Medical Association 1982; 6-8.
[28] Ghigo E, Aimaretti G, Maccario M et al. Dose-response study of GH effects on circulating IGF-I and IGFBP-3 levels in healthy young men and women. Am J Physiol Endocrinol Metab 1999; 276: 69-13.
[29] Fraser CG, Fogarty Y. Interpreting laboratory results. Br Med J 1989; 298: 1659-1660.
[30] Healy ML, Gibney J, Russell-Jones DL et al. High Dose Growth Hormone Exerts an Anabolic Effect at Rest and during Exercise in Endurance-Trained Athletes. J Clin Endocrinol Metab 2003; 11: 5221-5226.
[31] Melmed S. Medical progress: Acromegaly. N Engl J Med 2006; 14: 2558-2573.
[32] Ciulla MM, Epaminonda P, Paliotti R et al. Evaluation of cardiac structure by echoreflectivity analysis in acromegaly: effects of treatment. Eur J Endocrinol 2004; 151: 179-186.
[33] Cecelja M, Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension 2009; 54: 1328-1336.
[34] Ramsey MW, Goodfellow J, Jones CJ et al. Endothelial control of arterial distensibility is impaired in chronic heart failure. Circulation 1995; 92: 3212–3219.
[35] Anagnostis P, Efstathiadou ZA, Gougoura S et al. Oxidative stress and reduced antioxidative status, along with endothelial dysfunction in acromegaly. Horm Metab Res 2013; 45: 314-318.
[36] Wu D, Hu Q, Ma F et al. Vasorelaxant Effect of a New Hydrogen Sulfide-Nitric Oxide Conjugated Donor in Isolated Rat Aortic Rings through cGMP Pathway. Oxid Med Cell Longev 2016; 7075682. doi: 10.1155/2016/7075682.
[37] Materazzi S, Zagli G, Nassini R et al. Vasodilator activity of hydrogen sulfide (H2S) in human mesenteric arteries. Microvasc Res 2017; 109:38-44.
[38] Powrie JK, Bassett EE, Rosen T et al. GH-2000 Project Study Group. Detection of growth hormone abuse in sport. Growth Horm IGF Res 2007; 17: 220-226.
[39] Hoffman DM, Crampton L, Sernia C et al. Short term growth hormone (GH) treatment of GH deficient adults increases body sodium and extracellular water, but not blood pressure. J Clin Endocrinol Metab 1996; 81: 1123–1128.
[40] Møller J, Jørgensen JO, Møller N et al. Expansion of extracellular volume and suppression of atrial natriuretic peptide after growth hormone administration in normal man. Metabolic Effects of Growth Hormone in Humans. J Clin Endocrinol Metab 1991; 72: 768-772.
[41] Ronconi V, Giacchetti G, Mariniello B et al. Reduced nitric oxide levels in acromegaly: cardiovascular implications. Blood Pressure 2005; 14: 227–232.
[42] Nyström HC, Klintland N, Caidahl K et al. Short-term administration of growth hormone (GH) lowers blood pressure by activating eNOS/nitric oxide (NO)-pathway in male hypophysectomized (Hx) rats. BMC Physiol 2005; 5: 17.
[43] Graham MR, Baker JS, Evans P et al. Evidence for a decrease in cardiovascular risk factors following recombinant growth hormone administration in abstinent anabolic-androgenic steroid users. Growth Horm IGF Res 2007; 17: 201-209.
[44] Ndrepepa G, Braun S, Tada T et al. Comparative prognostic value of C-reactive protein & amp; fibrinogen in patients with coronary artery disease. Indian J Med Res 2014; 140: 392-400.
[45] Jae SY, Yoon ES, Jung SJ et al. Effect of cardiorespiratory fitness on acute inflammation induced increases in arterial stiffness in older adults. Eur J Appl Physiol 2013; 113: 2159-2166.
[46] Talikoti P, Bobby Z, Hamide A. Hyperhomocysteinemia, Insulin Resistance and High HS-CRP Levels in Prehypertension. J Clin Diagn Res 2014; 8: CC07- CC09.
[47] Lane HA, Grace F, Smith JC et al. Impaired vasoreactivity in bodybuilders using androgenic anabolic steroids. Eur J Clin Invest 2006; 36: 483-488.
[48] Graham MR, Grace FM, Boobier W et al. Homocysteine induced cardiovascular events: a consequence of long term anabolic-androgenic steroid (AAS) abuse. Br J Sports Med 2006; 40: 644–648.
[49] Graham MR, Baker JS, Davies B. Causes and Consequences of Obesity: Epigenetics and Hypokinesis? Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 2015; 8: 455-460.
[50] Zhou S, Zhang Z, Xu G. Notable epigenetic role of hyperhomocysteinemia in atherogenesis. Lipids Health Dis 2014; 13:134.
[51] Jin C, Guo J, Qiu X, Ma K et al. IGF-1 induces iNOS expression via the p38 MAPK signal pathway in the anti-apoptotic process in pulmonary artery smooth muscle cells during PAH. J Recept Signal Transduct Res 2014; 34: 325-31.
[52] Manhenke C, Ueland T, Jugdutt BI et al. The relationship between markers of extracellular cardiac matrix turnover: infarct healing and left ventricular remodelling following primary PCI in patients with first-time STEMI. Eur Heart 2014; 35: 395-402.