Subscribe to RSS
DOI: 10.1055/s-0030-1270075
Testosterone, Hemostasis, and Cardiovascular Diseases in Men
Publication History
Publication Date:
19 January 2011 (online)
ABSTRACT
Men have a higher incidence of cardiovascular disease (CVD) than women, and adverse thrombotic events increase with age. Recent experimental cross-sectional, and case-control studies have shown that testosterone may affect the hemostatic/fibrinolytic system in men in several ways. It has been hypothesized that physiological doses of testosterone would have a beneficial effect on tissue factor-induced thrombin generation and the development of CVD. The search for eternal youth has created a market for testosterone treatment in aging men during the last few years. However, whether testosterone supplementation could be useful in the treatment of testosterone-deficient elderly men is still controversial. The present review focuses on the coagulation system and CVD from the perspective of testosterone.
KEYWORDS
Testosterone - tissue factor-induced coagulation - coronary vascular disease - review
REFERENCES
- 1 Liu P Y, Death A K, Handelsman D J. Androgens and cardiovascular disease. Endocr Rev. 2003; 24 (3) 313-340
- 2 Svartberg J. Epidemiology: testosterone and the metabolic syndrome. Int J Impot Res. 2007; 19 (2) 124-128
- 3 Svartberg J, von Mühlen D, Mathiesen E, Joakimsen O, Bønaa K H, Stensland-Bugge E. Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med. 2006; 259 (6) 576-582
- 4 Khaw K T, Dowsett M, Folkerd E et al.. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation. 2007; 116 (23) 2694-2701
- 5 Laughlin G A, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab. 2008; 93 (1) 68-75
- 6 Vikan T, Schirmer H, Njølstad I, Svartberg J. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø Study. Eur J Endocrinol. 2009; 161 (3) 435-442
- 7 Wilkerson W R, Sane D C. Aging and thrombosis. Semin Thromb Hemost. 2002; 28 (6) 555-568
- 8 Svartberg J, Midtby M, Bønaa K H, Sundsfjord J, Joakimsen R M, Jorde R. The associations of age, lifestyle factors and chronic disease with testosterone in men: the Tromsø Study. Eur J Endocrinol. 2003; 149 (2) 145-152
- 9 Osterud B, Rapaport S I. Activation of factor IX by the reaction product of tissue factor and factor VII: additional pathway for initiating blood coagulation. Proc Natl Acad Sci U S A. 1977; 74 (12) 5260-5264
- 10 Broze Jr G J, Miletich J P. Characterization of the inhibition of tissue factor in serum. Blood. 1987; 69 (1) 150-155
- 11 Tilley R, Mackman N. Tissue factor in hemostasis and thrombosis. Semin Thromb Hemost. 2006; 32 (1) 5-10
- 12 Felmeden D C, Spencer C G, Chung N A et al.. Relation of thrombogenesis in systemic hypertension to angiogenesis and endothelial damage/dysfunction (a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial [ASCOT]). Am J Cardiol. 2003; 92 (4) 400-405
- 13 Sambola A, Osende J, Hathcock J et al.. Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity. Circulation. 2003; 107 (7) 973-977
- 14 Lim H S, Lip G Y, Beevers D G, Blann A D. Factors predicting the development of metabolic syndrome and type II diabetes against a background of hypertension. Eur J Clin Invest. 2005; 35 (5) 324-329
- 15 Masoud M, Sarig G, Brenner B, Jacob G. Orthostatic hypercoagulability: a novel physiological mechanism to activate the coagulation system. Hypertension. 2008; 51 (6) 1545-1551
- 16 Davies M J, Richardson P D, Woolf N, Katz D R, Mann J. Risk of thrombosis in human atherosclerotic plaques: role of extracellular lipid, macrophage, and smooth muscle cell content. Br Heart J. 1993; 69 (5) 377-381
- 17 Toschi V, Gallo R, Lettino M et al.. Tissue factor modulates the thrombogenicity of human atherosclerotic plaques. Circulation. 1997; 95 (3) 594-599
- 18 Moreno P R, Bernardi V H, López-Cuéllar J et al.. Macrophages, smooth muscle cells, and tissue factor in unstable angina. Implications for cell-mediated thrombogenicity in acute coronary syndromes. Circulation. 1996; 94 (12) 3090-3097
- 19 Agledahl I, Brodin E, Svartberg J, Hansen J B. Plasma free tissue factor pathway inhibitor (TFPI) levels and TF-induced thrombin generation ex vivo in men with low testosterone levels. Thromb Haemost. 2009; 101 (3) 471-477
- 20 Jin H, Lin J, Fu L et al.. Physiological testosterone stimulates tissue plasminogen activator and tissue factor pathway inhibitor and inhibits plasminogen activator inhibitor type 1 release in endothelial cells. Biochem Cell Biol. 2007; 85 (2) 246-251
- 21 Jin H, Qiu W B, Mei Y F, Wang D M, Li Y G, Tan X R. Testosterone alleviates tumor necrosis factor-alpha-mediated tissue factor pathway inhibitor downregulation via suppression of nuclear factor-kappa B in endothelial cells. Asian J Androl. 2009; 11 (2) 266-271
- 22 Agledahl I, Brodin E, Svartberg J, Hansen J B. Impact of long-term testosterone treatment on plasma levels of free TFPI and TF-induced thrombin generation ex vivo in elderly men with low testosterone levels. Thromb Haemost. 2009; 102 (5) 945-950
- 23 Rao L V, Pendurthi U R. Regulation of tissue factor-factor VIIa expression on cell surfaces: a role for tissue factor-factor VIIa endocytosis. Mol Cell Biochem. 2003; 253 ((1-2)) 131-140
- 24 Hanke H, Lenz C, Hess B, Spindler K D, Weidemann W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation. 2001; 103 (10) 1382-1385
- 25 Brodin E, Børvik T, Sandset P M, Bønaa K H, Nordøy A, Hansen J B. Coagulation activation in young survivors of myocardial infarction (MI)—a population-based case-control study. Thromb Haemost. 2004; 92 (1) 178-184
- 26 Danielsen R, Onundarson P T, Thors H, Vidarsson B, Morrissey J H. Activated and total coagulation factor VII, and fibrinogen in coronary artery disease. Scand Cardiovasc J. 1998; 32 (2) 87-95
- 27 Moor E, Silveira A, van't Hooft F et al.. Coagulation factor VII mass and activity in young men with myocardial infarction at a young age. Role of plasma lipoproteins and factor VII genotype. Arterioscler Thromb Vasc Biol. 1995; 15 (5) 655-664
- 28 Morrissey J H, Macik B G, Neuenschwander P F, Comp P C. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood. 1993; 81 (3) 734-744
- 29 Meade T W, Mellows S, Brozovic M et al.. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986; 2 (8506) 533-537
- 30 De Stavola B L, Meade T W. Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I). J Thromb Haemost. 2007; 5 (3) 461-471
- 31 Junker R, Heinrich J, Schulte H, van de Loo J, Assmann G. Coagulation factor VII and the risk of coronary heart disease in healthy men. Arterioscler Thromb Vasc Biol. 1997; 17 (8) 1539-1544
- 32 Bonithon-Kopp C, Scarabin P Y, Bara L, Castanier M, Jacqueson A, Roger M. Relationship between sex hormones and haemostatic factors in healthy middle-aged men. Atherosclerosis. 1988; 71 (1) 71-76
- 33 Phillips G B, Jing T Y, Resnick L M, Barbagallo M, Laragh J H, Sealey J E. Sex hormones and hemostatic risk factors for coronary heart disease in men with hypertension. J Hypertens. 1993; 11 (7) 699-702
- 34 De Pergola G, De Mitrio V, Sciaraffia M et al.. Lower androgenicity is associated with higher plasma levels of prothrombotic factors irrespective of age, obesity, body fat distribution, and related metabolic parameters in men. Metabolism. 1997; 46 (11) 1287-1293
- 35 Fearnley G R, Chakrabarti R. Increase of blood fibrinolytic activity by testosterone. Lancet. 1962; 2 (7247) 128-132
- 36 Phillips G B, Pinkernell B H, Jing T Y. The association of hyperestrogenemia with coronary thrombosis in men. Arterioscler Thromb Vasc Biol. 1996; 16 (11) 1383-1387
- 37 Yang X C, Jing T Y, Resnick L M, Phillips G B. Relation of hemostatic risk factors to other risk factors for coronary heart disease and to sex hormones in men. Arterioscler Thromb. 1993; 13 (4) 467-471
- 38 Glueck C J, Glueck H I, Stroop D, Speirs J, Hamer T, Tracy T. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidemic men. J Lab Clin Med. 1993; 122 (4) 412-420
- 39 Pugh P J, Channer K S, Parry H, Downes T, Jone T H. Bio-available testosterone levels fall acutely following myocardial infarction in men: association with fibrinolytic factors. Endocr Res. 2002; 28 (3) 161-173
- 40 Alexandersen P, Christiansen C. The aging male: testosterone deficiency and testosterone replacement. An up-date. Atherosclerosis. 2004; 173 (2) 157-169
- 41 Beer N A, Jakubowicz D J, Matt D W, Beer R M, Nestler J E. Dehydroepiandrosterone reduces plasma plasminogen activator inhibitor type 1 and tissue plasminogen activator antigen in men. Am J Med Sci. 1996; 311 (5) 205-210
- 42 Kluft C, Preston F E, Malia R G et al.. Stanozolol-induced changes in fibrinolysis and coagulation in healthy adults. Thromb Haemost. 1984; 51 (2) 157-164
- 43 Sue-Ling H M, Davies J A, Prentice C R, Verheijen J H, Kluft C. Effects of oral stanozolol used in the prevention of postoperative deep vein thrombosis on fibrinolytic activity. Thromb Haemost. 1985; 53 (1) 141-142
- 44 Anderson R A, Ludlam C A, Wu F C. Haemostatic effects of supraphysiological levels of testosterone in normal men. Thromb Haemost. 1995; 74 (2) 693-697
- 45 Smith A M, English K M, Malkin C J, Jones R D, Jones T H, Channer K S. Testosterone does not adversely affect fibrinogen or tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) levels in 46 men with chronic stable angina. Eur J Endocrinol. 2005; 152 (2) 285-291
- 46 Hackeng T M, Seré K M, Tans G, Rosing J. Protein S stimulates inhibition of the tissue factor pathway by tissue factor pathway inhibitor. Proc Natl Acad Sci U S A. 2006; 103 (9) 3106-3111
- 47 Toorians A W, Thomassen M C, Zweegman S et al.. Venous thrombosis and changes of hemostatic variables during cross-sex hormone treatment in transsexual people. J Clin Endocrinol Metab. 2003; 88 (12) 5723-5729
- 48 Hak A E, Witteman J C, de Jong F H, Geerlings M I, Hofman A, Pols H A. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab. 2002; 87 (8) 3632-3639
- 49 Muller M, van den Beld A W, Bots M L, Grobbee D E, Lamberts S W, van der Schouw Y T. Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation. 2004; 109 (17) 2074-2079
- 50 Jaffe M D. Effect of testosterone cypionate on postexercise ST segment depression. Br Heart J. 1977; 39 (11) 1217-1222
- 51 English K M, Steeds R P, Jones T H, Diver M J, Channer K S. Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study. Circulation. 2000; 102 (16) 1906-1911
- 52 Phillips G B, Yano K, Stemmermann G N. Serum sex hormone levels and myocardial infarction in the Honolulu Heart Program. Pitfalls in prospective studies on sex hormones. J Clin Epidemiol. 1988; 41 (12) 1151-1156
- 53 Yarnell J W, Beswick A D, Sweetnam P M, Riad-Fahmy D. Endogenous sex hormones and ischemic heart disease in men. The Caerphilly prospective study. Arterioscler Thromb. 1993; 13 (4) 517-520
- 54 Contoreggi C S, Blackman M R, Andres R et al.. Plasma levels of estradiol, testosterone, and DHEAS do not predict risk of coronary artery disease in men. J Androl. 1990; 11 (5) 460-470
- 55 Mikulec K H, Holloway L, Krasnow R E et al.. Relationship of endogenous sex hormones to coronary heart disease: a twin study. J Clin Endocrinol Metab. 2004; 89 (3) 1240-1245
- 56 Hautanen A, Mänttäri M, Manninen V et al.. Adrenal androgens and testosterone as coronary risk factors in the Helsinki Heart Study. Atherosclerosis. 1994; 105 (2) 191-200
- 57 Cauley J A, Gutai J P, Kuller L H, Dai W S. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Cardiol. 1987; 60 (10) 771-777
- 58 Freedman D S, O'Brien T R, Flanders W D, DeStefano F, Barboriak J J. Relation of serum testosterone levels to high density lipoprotein cholesterol and other characteristics in men. Arterioscler Thromb. 1991; 11 (2) 307-315
- 59 Agledahl I, Skjaerpe P A, Hansen J B, Svartberg J. Low serum testosterone in men is inversely associated with non-fasting serum triglycerides: the Tromsø study. Nutr Metab Cardiovasc Dis. 2008; 18 (4) 256-262
- 60 Svartberg J, von Mühlen D, Schirmer H, Barrett-Connor E, Sundfjord J, Jorde R. Association of endogenous testosterone with blood pressure and left ventricular mass in men. The Tromsø Study. Eur J Endocrinol. 2004; 150 (1) 65-71
- 61 Svartberg J, von Mühlen D, Sundsfjord J, Jorde R. Waist circumference and testosterone levels in community dwelling men. The Tromsø study. Eur J Epidemiol. 2004; 19 (7) 657-663
- 62 Svartberg J, Jenssen T, Sundsfjord J, Jorde R. The associations of endogenous testosterone and sex hormone-binding globulin with glycosylated hemoglobin levels, in community dwelling men. The Tromsø Study. Diabetes Metab. 2004; 30 (1) 29-34
- 63 McGrath K C, McRobb L S, Heather A K. Androgen therapy and atherosclerotic cardiovascular disease. Vasc Health Risk Manag. 2008; 4 (1) 11-21
- 64 Malkin C J, Pugh P J, Jones R D, Kapoor D, Channer K S, Jones T H. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab. 2004; 89 (7) 3313-3318
- 65 Yildiz O, Seyrek M. Vasodilating mechanisms of testosterone. Exp Clin Endocrinol Diabetes. 2007; 115 (1) 1-6
- 66 Haddad R M, Kennedy C C, Caples S M et al.. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. 2007; 82 (1) 29-39
- 67 Rosendaal F R, Helmerhorst F M, Vandenbroucke J P. Female hormones and thrombosis. Arterioscler Thromb Vasc Biol. 2002; 22 (2) 201-210
- 68 The Coronary Drug Project . The Coronary Drug Project. Initial findings leading to modifications of its research protocol. JAMA. 1970; 214 (7) 1303-1313
- 69 Svartberg J, Braekkan S K, Laughlin G A, Hansen J B. Endogenous sex hormone levels in men are not associated with risk of venous thromboembolism: the Tromso study. Eur J Endocrinol. 2009; 160 (5) 833-838
- 70 Ageno W, Becattini C, Brighton T, Selby R, Kamphuisen P W. Cardiovascular risk factors and venous thromboembolism: a meta-analysis. Circulation. 2008; 117 (1) 93-102
- 71 Abbott R D, Launer L J, Rodriguez B L et al.. Serum estradiol and risk of stroke in elderly men. Neurology. 2007; 68 (8) 563-568
- 72 Ferenchick G S, Hirokawa S, Mammen E F, Schwartz K A. Anabolic-androgenic steroid abuse in weight lifters: evidence for activation of the hemostatic system. Am J Hematol. 1995; 49 (4) 282-288
- 73 van Kesteren P J, Asscheman H, Megens J A, Gooren L J. Mortality and morbidity in transsexual subjects treated with cross-sex hormones. Clin Endocrinol (Oxf). 1997; 47 (3) 337-342
- 74 Li S, Li X, Li J, Deng X, Li Y, Cong Y. Experimental arterial thrombosis regulated by androgen and its receptor via modulation of platelet activation. Thromb Res. 2007; 121 (1) 127-134
Ellen BrodinM.D. Ph.D.
Hematological Research Group (HERG)
Department of Clinical Medicine, University of Tromsø, N-9037 Tromsø, Norway
Email: ellen.brodin@uit.no