Generic placeholder image

Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Review Article

Growth Hormone, Atherosclerosis and Peripheral Arterial Disease: Exploring the Spectrum from Acromegaly to Growth Hormone Deficiency

Author(s): Herman R, Janez A, Mikhailidis DP, Poredos P, Blinc A, Sabovic M, Bajuk Studen K, Schernthaner GH, Anagnostis P, Antignani PL and Jensterle M*

Volume 22, Issue 1, 2024

Published on: 13 November, 2023

Page: [28 - 35] Pages: 8

DOI: 10.2174/0115701611269162231106042956

Price: $65

Open Access Journals Promotions 2
Abstract

Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are increasingly recognised for their role in cardiovascular (CV) physiology. The GH-IGF-1 axis plays an essential role in the development of the CV system as well as in the complex molecular network that regulates cardiac and endothelial structure and function. A considerable correlation between GH levels and CV mortality exists even among individuals in the general population without a notable deviation in the GHIGF- 1 axis functioning. In addition, over the last decades, evidence has demonstrated that pathologic conditions involving the GH-IGF-1 axis, as seen in GH excess to GH deficiency, are associated with an increased risk for CV morbidity and mortality. A significant part of that risk can be attributed to several accompanying comorbidities. In both conditions, disease control is associated with a consistent improvement of CV risk factors, reduction of CV mortality, and achievement of standardised mortality ratio similar to that of the general population. Data on the prevalence of peripheral arterial disease in patients with acromegaly or growth hormone deficiency and the effects of GH and IGF-1 levels on the disease progression is limited. In this review, we will consider the pivotal role of the GH-IGF-1 axis on CV system function, as well as the far-reaching consequences that arise when disorders within this axis occur, particularly in relation to the atherosclerosis process.

Keywords: Growth hormone, insulin-like growth factor 1, cardiovascular risk, atherosclerosis, peripheral arterial disease, acromegaly, growth hormone deficiency.

Graphical Abstract
[1]
Ayuk J, Sheppard MC. Growth hormone and its disorders. Postgrad Med J 2006; 82(963): 24-30.
[http://dx.doi.org/10.1136/pgmj.2005.036087] [PMID: 16397076]
[2]
Blum WF, Alherbish A, Alsagheir A, et al. The growth hormone–insulin-like growth factor-I axis in the diagnosis and treatment of growth disorders. Endocr Connect 2018; 7(6): R212-22.
[http://dx.doi.org/10.1530/EC-18-0099] [PMID: 29724795]
[3]
Feldt-Rasmussen U, Klose M. Adult growth hormone deficiency- clinical management. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, Eds. Endotext. MDText.com, Inc.: South Dartmouth (MA) 2000.
[4]
Bartke A. Growth hormone and aging: Updated review. World J Mens Health 2019; 37(1): 19-30.
[http://dx.doi.org/10.5534/wjmh.180018] [PMID: 29756419]
[5]
Scacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity. Int J Obes 1999; 23(3): 260-71.
[http://dx.doi.org/10.1038/sj.ijo.0800807] [PMID: 10193871]
[6]
Lavrentaki A, Paluzzi A, Wass JAH, Karavitaki N. Epidemiology of acromegaly: Review of population studies. Pituitary 2017; 20(1): 4-9.
[http://dx.doi.org/10.1007/s11102-016-0754-x] [PMID: 27743174]
[7]
Lombardi G, Di Somma C, Grasso LFS, Savanelli MC, Colao A, Pivonello R. The cardiovascular system in growth hormone excess and growth hormone deficiency. J Endocrinol Invest 2012; 35(11): 1021-9.
[PMID: 23143695]
[8]
Rizzo M, Rizvi A, Sudar E, et al. A review of the cardiovascular and anti-atherogenic effects of ghrelin. Curr Pharm Des 2013; 19(27): 4953-63.
[http://dx.doi.org/10.2174/1381612811319270018] [PMID: 23278489]
[9]
Caicedo D, Díaz O, Devesa P, Devesa J. Growth hormone (GH) and cardiovascular system. Int J Mol Sci 2018; 19(1): 290.
[http://dx.doi.org/10.3390/ijms19010290] [PMID: 29346331]
[10]
Ratku B, Sebestyén V, Erdei A, Nagy EV, Szabó Z, Somodi S. Effects of adult growth hormone deficiency and replacement therapy on the cardiometabolic risk profile. Pituitary 2022; 25(2): 211-28.
[http://dx.doi.org/10.1007/s11102-022-01207-1] [PMID: 35106704]
[11]
Wettersten N, Mital R, Cushman M, et al. Growth hormone concentration and risk of all-cause and cardiovascular mortality: The reasons for geographic and racial disparities in stroke (REGARDS) study. Atherosclerosis 2022; 359: 20-6.
[http://dx.doi.org/10.1016/j.atherosclerosis.2022.09.004] [PMID: 36155327]
[12]
Bartke A, Hascup E, Hascup K, Masternak MM. Growth hormone and aging: New findings. World J Mens Health 2021; 39(3): 454-65.
[http://dx.doi.org/10.5534/wjmh.200201] [PMID: 33663025]
[13]
Isgaard J, Arcopinto M, Karason K, Cittadini A. GH and the cardiovascular system: An update on a topic at heart. Endocrine 2015; 48(1): 25-35.
[http://dx.doi.org/10.1007/s12020-014-0327-6] [PMID: 24972804]
[14]
Maffei P, Dassie F, Wennberg A, Parolin M, Vettor R. The endothelium in acromegaly. Front Endocrinol 2019; 10: 437.
[http://dx.doi.org/10.3389/fendo.2019.00437] [PMID: 31396153]
[15]
Napoli R, Guardasole V, Angelini V, et al. Acute effects of growth hormone on vascular function in human subjects. J Clin Endocrinol Metab 2003; 88(6): 2817-20.
[http://dx.doi.org/10.1210/jc.2003-030144] [PMID: 12788893]
[16]
Gola M, Bonadonna S, Doga M, Giustina A. Clinical review: Growth hormone and cardiovascular risk factors. J Clin Endocrinol Metab 2005; 90(3): 1864-70.
[http://dx.doi.org/10.1210/jc.2004-0545] [PMID: 15585563]
[17]
Caicedo D, Devesa P, Arce VM, Requena J, Devesa J. Chronic limb-threatening ischemia could benefit from growth hormone therapy for wound healing and limb salvage. Ther Adv Cardiovasc Dis 2018; 12(2): 53-72.
[http://dx.doi.org/10.1177/1753944717745494] [PMID: 29271292]
[18]
Higashi Y, Gautam S, Delafontaine P, Sukhanov S. IGF-1 and cardiovascular disease. Growth Horm IGF Res 2019; 45: 6-16.
[http://dx.doi.org/10.1016/j.ghir.2019.01.002] [PMID: 30735831]
[19]
Wolters TLC, Netea MG, Riksen NP, Hermus ARMM, Netea-Maier RT. Acromegaly, inflammation and cardiovascular disease: A review. Rev Endocr Metab Disord 2020; 21(4): 547-68.
[http://dx.doi.org/10.1007/s11154-020-09560-x] [PMID: 32458292]
[20]
Higashi Y, Quevedo HC, Tiwari S, Sukhanov S, Shai SY, Anwar A, et al. The Interaction Between IGF-1, Atherosclerosis and Vascular Aging. Front Horm Res 2014; 43: 107-24.
[http://dx.doi.org/10.1159/000360571] [PMID: 24943302]
[21]
Wolters TLC, Netea MG, Hermus ARMM, Smit JWA, Netea-Maier RT. IGF1 potentiates the pro-inflammatory response in human peripheral blood mononuclear cells via MAPK. J Mol Endocrinol 2017; 59(2): 129-39.
[http://dx.doi.org/10.1530/JME-17-0062] [PMID: 28611056]
[22]
McCabe J, Ayuk J, Sherlock M. Treatment factors that influence mortality in acromegaly. Neuroendocrinology 2016; 103(1): 66-74.
[http://dx.doi.org/10.1159/000375163] [PMID: 25661647]
[23]
Ritvonen E, Löyttyniemi E, Jaatinen P, et al. Mortality in acromegaly: A 20-year follow-up study. Endocr Relat Cancer 2016; 23(6): 469-80.
[http://dx.doi.org/10.1530/ERC-16-0106] [PMID: 27185871]
[24]
Alhawyan FS. Mortality in acromegalic patients: Etiology, trends, and risk factors. Cureus 2021; 13(4): e14265.
[http://dx.doi.org/10.7759/cureus.14265] [PMID: 33959447]
[25]
Kasuki L, Rocha PS, Lamback EB, Gadelha MR. Determinants of morbidities and mortality in acromegaly. Arch Endocrinol Metab 2020; 63(6): 630-7.
[http://dx.doi.org/10.20945/2359-3997000000193] [PMID: 31939488]
[26]
Falch CM, Olarescu NC, Bollerslev J, Dekkers OM, Heck A. Trends in incidence and mortality risk for acromegaly in Norway: A cohort study. Endocrine 2022; 80(1): 152-9.
[http://dx.doi.org/10.1007/s12020-022-03275-6] [PMID: 36525222]
[27]
Maione L, Brue T, Beckers A, et al. Changes in the management and comorbidities of acromegaly over three decades: The french acromegaly registry. Eur J Endocrinol 2017; 176(5): 645-55.
[http://dx.doi.org/10.1530/EJE-16-1064] [PMID: 28246150]
[28]
Hong S, Kim KS, Han K, Park CY. Acromegaly and cardiovascular outcomes: A cohort study. Eur Heart J 2022; 43(15): 1491-9.
[http://dx.doi.org/10.1093/eurheartj/ehab822] [PMID: 34864952]
[29]
Rizzo M, Montalto G, Rizvi AA, Christ ER. The role of elevated growth hormone on the increased atherosclerosis in patients with acromegaly. Angiology 2012; 63(7): 492-4.
[http://dx.doi.org/10.1177/0003319712436578] [PMID: 22371625]
[30]
Ramos-Leví AM, Marazuela M. Bringing cardiovascular comorbidities in acromegaly to an update. how should we diagnose and manage them? Front Endocrinol 2019; 10: 120.
[http://dx.doi.org/10.3389/fendo.2019.00120] [PMID: 30930848]
[31]
Yen YS, Chen HS. Changes in cardiovascular risk factors in patients with acromegaly after trans-sphenoidal adenomectomy. Endocr J 2020; 67(12): 1169-77.
[http://dx.doi.org/10.1507/endocrj.EJ20-0159] [PMID: 32713864]
[32]
Parolin M, Dassie F, Martini C, et al. Preclinical markers of atherosclerosis in acromegaly: A systematic review and meta-analysis. Pituitary 2018; 21(6): 653-62.
[http://dx.doi.org/10.1007/s11102-018-0911-5] [PMID: 30225826]
[33]
Spille DC, Vorona E, Catalino MP, et al. Vascular anomalies in patients with growth hormone-secreting pituitary adenomas: illustrative case report and systematic review of the literature. Pituitary 2023; 26(1): 132-43.
[http://dx.doi.org/10.1007/s11102-022-01291-3] [PMID: 36508085]
[34]
de Almeida MCC, Freire CMV. Nunes M do CP, Soares BS, Barbosa MM, Giannetti AV. Subclinical atherosclerosis in acromegaly: Possible association with cardiovascular risk factors rather than disease activity. Growth Horm IGF Res 2022; 62: 101442.
[35]
Can M, Kocabas M, Karakose M, et al. Arterial stiffness, carotid intima-media thickness, endocan, and a disintegrin and metalloproteinase with thrombospondin type i motif 9 levels and their relationship with disease activity in patients with acromegaly with and without cardiovascular risk factors. Endocr Pract 2022; 28(3): 298-303.
[http://dx.doi.org/10.1016/j.eprac.2021.11.084] [PMID: 34843972]
[36]
Yaron M, Izkhakov E, Sack J, et al. Arterial properties in acromegaly: Relation to disease activity and associated cardiovascular risk factors. Pituitary 2016; 19(3): 322-31.
[http://dx.doi.org/10.1007/s11102-016-0710-9] [PMID: 26873588]
[37]
Siebert DM, Rao AL. The use and abuse of human growth hormone in sports. Sports Health 2018; 10(5): 419-26.
[http://dx.doi.org/10.1177/1941738118782688] [PMID: 29932857]
[38]
Brennan BP, Kanayama G, Hudson JI, Pope HG Jr. Human growth hormone abuse in male weightlifters. Am J Addict 2011; 20(1): 9-13.
[http://dx.doi.org/10.1111/j.1521-0391.2010.00093.x] [PMID: 21175915]
[39]
Hadžović A, Nakaš-Ićindić E, Kucukalić-Selimović E, Salaka AU. Growth hormone (GH) usage and abuse. Bosn J Basic Med Sci 2004; 4(4): 66-70.
[http://dx.doi.org/10.17305/bjbms.2004.3365] [PMID: 15629000]
[40]
Liu H, Bravata DM, Olkin I, et al. Systematic review: The effects of growth hormone on athletic performance. Ann Intern Med 2008; 148(10): 747-58.
[http://dx.doi.org/10.7326/0003-4819-148-10-200805200-00215] [PMID: 18347346]
[41]
Cittadini A, Berggren A, Longobardi S, et al. Supraphysiological doses of GH induce rapid changes in cardiac morphology and function. J Clin Endocrinol Metab 2002; 87(4): 1654-9.
[http://dx.doi.org/10.1210/jcem.87.4.8363] [PMID: 11932297]
[42]
Garcia JM, Merriam GR, Kargi AY. Growth hormone in aging. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, Eds. Endotext. South Dartmouth (MA): MDText.com Inc 2000.
[43]
Rudman D, Feller AG, Nagraj HS, et al. Effects of human growth hormone in men over 60 years old. N Engl J Med 1990; 323(1): 1-6.
[http://dx.doi.org/10.1056/NEJM199007053230101] [PMID: 2355952]
[44]
Fahy GM, Brooke RT, Watson JP, et al. Reversal of epigenetic aging and immunosenescent trends in humans. Aging Cell 2019; 18(6): e13028.
[http://dx.doi.org/10.1111/acel.13028] [PMID: 31496122]
[45]
McGrath S, Morris M, Bouloux PM. Growth hormone deficiency and atherosclerosis--is there a link. Growth Horm IGF Res 1999; (9): 9-13.
[46]
Rosén T, Bengtsson BÅ. Premature mortality due to cardiovascular disease in hypopituitarism. Lancet 1990; 336(8710): 285-8.
[http://dx.doi.org/10.1016/0140-6736(90)91812-O] [PMID: 1973979]
[47]
Stochholm K, Gravholt CH, Laursen T, et al. Mortality and GH deficiency: A nationwide study. Eur J Endocrinol 2007; 157(1): 9-18.
[http://dx.doi.org/10.1530/EJE-07-0013] [PMID: 17609396]
[48]
Melmed S. Pathogenesis and diagnosis of growth hormone deficiency in adults. N Engl J Med 2019; 380(26): 2551-62.
[http://dx.doi.org/10.1056/NEJMra1817346] [PMID: 31242363]
[49]
Yuen KCJ, Biller BMK, Radovick S, et al. American association of clinical endocrinologists and american college of endocrinology guidelines for management of growth hormone deficiency in adults and patients transitioning from pediatric to adult care. Endocr Pract 2019; 25(11): 1191-232.
[http://dx.doi.org/10.4158/GL-2019-0405] [PMID: 31760824]
[50]
Gola M, Giustina A. Growth hormone deficiency and cardiovascular risk: Do we need additional markers? Endocrine 2012; 42(2): 240-2.
[http://dx.doi.org/10.1007/s12020-012-9769-x] [PMID: 22907626]
[51]
Bioletto F, Prencipe N, Berton AM, et al. MRI assessment of cardiac function and morphology in adult patients with growth hormone deficiency: A systematic review and meta-analysis. Front Endocrinol 2022; 13910575.
[http://dx.doi.org/10.3389/fendo.2022.910575] [PMID: 35757407]
[52]
Ziagaki A, Blaschke D, Haverkamp W, Plöckinger U. Long-term growth hormone (GH) replacement of adult GH deficiency (GHD) benefits the heart. Eur J Endocrinol 2019; 181(1): 79-91.
[http://dx.doi.org/10.1530/EJE-19-0132] [PMID: 31100717]
[53]
Ramos-Leví AM, Marazuela M. Treatment of adult growth hormone deficiency with human recombinant growth hormone: an update on current evidence and critical review of advantages and pitfalls. Endocrine 2018; 60(2): 203-18.
[http://dx.doi.org/10.1007/s12020-017-1492-1] [PMID: 29417370]
[54]
Shimon I, Badiu C, Bossowski A, et al. Adult growth hormone deficiency in CEE region: Heterogeneity of the patient pathway. Growth Horm IGF Res 2019; 46-47: 44-9.
[http://dx.doi.org/10.1016/j.ghir.2019.06.001] [PMID: 31234055]
[55]
Borson-Chazot F, Serusclat A, Kalfallah Y, et al. Decrease in carotid intima-media thickness after one year growth hormone (GH) treatment in adults with GH deficiency. J Clin Endocrinol Metab 1999; 84(4): 1329-33.
[http://dx.doi.org/10.1210/jc.84.4.1329] [PMID: 10199774]
[56]
Capaldo B, Guardasole V, Pardo F, et al. Abnormal vascular reactivity in growth hormone deficiency. Circulation 2001; 103(4): 520-4.
[http://dx.doi.org/10.1161/01.CIR.103.4.520] [PMID: 11157716]
[57]
Pfeifer M, Verhovec R, Zizek B, Prezelj J, Poredos P, Clayton RN. Growth hormone (GH) treatment reverses early atherosclerotic changes in GH-deficient adults. J Clin Endocrinol Metab 1999; 84(2): 453-7.
[http://dx.doi.org/10.1210/jc.84.2.453] [PMID: 10022400]
[58]
Lanes R, Soros A, Flores K, Gunczler P, Carrillo E, Bandel J. Endothelial function, carotid artery intima-media thickness, epicardial adipose tissue, and left ventricular mass and function in growth hormone-deficient adolescents: Apparent effects of growth hormone treatment on these parameters. J Clin Endocrinol Metab 2005; 90(7): 3978-82.
[http://dx.doi.org/10.1210/jc.2005-0091] [PMID: 15870123]
[59]
Colao A, Di Somma C, Spiezia S, et al. Growth hormone treatment on atherosclerosis: results of a 5-year open, prospective, controlled study in male patients with severe growth hormone deficiency. J Clin Endocrinol Metab 2008; 93(9): 3416-24.
[http://dx.doi.org/10.1210/jc.2007-2810] [PMID: 18593773]
[60]
Suzuki K, Yanagi K, Shimizu M, et al. Effect of growth hormone replacement therapy on plasma diacron-reactive oxygen metabolites and endothelial function in Japanese patients: The great clinical study. Endocr J 2018; 65(1): 101-11.
[http://dx.doi.org/10.1507/endocrj.EJ17-0330] [PMID: 29070768]
[61]
Li G, del Rincon JP, Jahn LA, et al. Growth hormone exerts acute vascular effects independent of systemic or muscle insulin-like growth factor I. J Clin Endocrinol Metab 2008; 93(4): 1379-85.
[http://dx.doi.org/10.1210/jc.2007-2021] [PMID: 18182451]
[62]
Evans LM, Davies JS, Anderson RA, et al. The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency. Eur J Endocrinol 2000; 142(3): 254-62.
[http://dx.doi.org/10.1530/eje.0.1420254] [PMID: 10700719]
[63]
McCallum RW, Sainsbury CAR, Spiers A, et al. Growth hormone replacement reduces C-reactive protein and large-artery stiffness but does not alter endothelial function in patients with adult growth hormone deficiency. Clin Endocrinol 2005; 62(4): 473-9.
[http://dx.doi.org/10.1111/j.1365-2265.2005.02245.x] [PMID: 15807879]
[64]
Twickler TB, Wilmink HW, Schreuder PC, et al. Growth hormone (GH) treatment decreases postprandial remnant-like particle cholesterol concentration and improves endothelial function in adult-onset GH deficiency. J Clin Endocrinol Metab 2000; 85(12): 4683-9.
[http://dx.doi.org/10.1210/jc.85.12.4683] [PMID: 11134128]
[65]
Aa van der K, Am P, Tj R, Ep C, Aj Z, H P. Recombinant human GH replacement increases CD34+ cells and improves endothelial function in adults with GH deficiency. Eur J Endocrinol 2008; 159(2)
[66]
Colao A, Di Somma C, Filippella M, et al. Insulin-like growth factor-1 deficiency determines increased intima-media thickness at common carotid arteries in adult patients with growth hormone deficiency. Clin Endocrinol 2004; 61(3): 360-6.
[http://dx.doi.org/10.1111/j.1365-2265.2004.02105.x] [PMID: 15355453]
[67]
Colao A, Di Somma C, Rota F, et al. Common carotid intima-media thickness in growth hormone (GH)-deficient adolescents: a prospective study after GH withdrawal and restarting GH replacement. J Clin Endocrinol Metab 2005; 90(5): 2659-65.
[http://dx.doi.org/10.1210/jc.2004-1844] [PMID: 15713715]
[68]
Elhadd TA, Abdu TA, Oxtoby J, et al. Biochemical and biophysical markers of endothelial dysfunction in adults with hypopituitarism and severe GH deficiency. J Clin Endocrinol Metab 2001; 86(9): 4223-32.
[http://dx.doi.org/10.1210/jcem.86.9.7813] [PMID: 11549653]
[69]
Markussis V, Beshyah SA, Fisher C, Parker KH, Nicolaides AN, Johnston DG. Abnormal carotid arterial wall dynamics in symptom-free hypopituitary adults. Eur J Endocrinol 1997; 136(2): 157-64.
[http://dx.doi.org/10.1530/eje.0.1360157] [PMID: 9116910]
[70]
Oomen PHN, Beentjes JAM, Bosma E, Smit AJ, Reitsma WD, Dullaart RPF. Reduced capillary permeability and capillary density in the skin of GH-deficient adults: Improvement after 12 months GH replacement. Clin Endocrinol 2002; 56(4): 519-24.
[http://dx.doi.org/10.1046/j.1365-2265.2002.01517.x] [PMID: 11966745]
[71]
Tidblad A, Bottai M, Kieler H, Albertsson-Wikland K, Sävendahl L. Association of childhood growth hormone treatment with long-term cardiovascular morbidity. JAMA Pediatr 2021; 175(2): e205199.
[http://dx.doi.org/10.1001/jamapediatrics.2020.5199] [PMID: 33346824]
[72]
He X, Barkan AL. Growth hormone therapy in adults with growth hormone deficiency: A critical assessment of the literature. Pituitary 2020; 23(3): 294-306.
[http://dx.doi.org/10.1007/s11102-020-01031-5] [PMID: 32060708]
[73]
Chanson P. The heart in growth hormone (GH) deficiency and the cardiovascular effects of GH. Ann Endocrinol (Paris) 2021; 82(3-4): 210-3.
[http://dx.doi.org/10.1016/j.ando.2020.03.005] [PMID: 32473787]
[74]
Ricci Bitti S, Franco M, Albertelli M, et al. GH replacement in the elderly: Is it worth it? Front Endocrinol 2021; 12680579.
[http://dx.doi.org/10.3389/fendo.2021.680579] [PMID: 34211437]
[75]
Scarano E, Riccio E, Somma T, et al. Impact of long-term growth hormone replacement therapy on metabolic and cardiovascular parameters in adult growth hormone deficiency: comparison between adult and elderly patients. Front Endocrinol 2021; 12635983.
[http://dx.doi.org/10.3389/fendo.2021.635983] [PMID: 33716985]
[76]
Piskinpasa H, Okuturlar Y, Dogansen SC, et al. Visfatin levels may be an early marker of atherosclerosis in patients with acromegaly. Horm Metab Res 2019; 51(10): 649-54.
[http://dx.doi.org/10.1055/a-0998-4079] [PMID: 31487747]
[77]
Poredoš P, Schernthaner GH, Blinc A, et al. Endocrine disorders and peripheral arterial disease: A series of reviews. Curr Vasc Pharmacol 2023; 21(3): 147-8.
[http://dx.doi.org/10.2174/1570161121666230516141319] [PMID: 37194233]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy