The influence of testosterone on cardiovascular disease in men

Czech version

Authors: J. Payer; A. Baňárová
Authors‘ workplace: V. interná klinika Lekárskej fakulty UK a FNsP Bratislava, Slovenská republika, prednosta prof. MUDr. Juraj Payer, CSc.
Published in: Vnitř Lék 2010; 56(7): 702-708
Category: 80th Birthday - Jaroslava Blahoše, MD, DrSc.

Overview

The influence of testosterone on cardiovascular disease is recently discussed question. Testosterone modulates vascular reactivity by genomic and nongenomic modes of action, it has an impact on endothelial function, production of proinflamatory cytokines and lipid profiles. The possible role of sex hormone binding globulin (SHBG) in androgen action by plasmatic membrane receptors breaks “the free hormone hypothesis”, especially when clinical trials reveal strong association between SHBG and risk factors of cardiovascular disease. The results of last clinical trials mention that androgen deficiency is associated with obesity, insulin resistance and dyslipidaemia. Large clinical trials demonstrated that androgen deficiency predict mortality in elderly men. Testosterone substitution restores vasoreactivity and endothelial function and could potentially reduce cardiovascular disease in men but to confirm this theory more large clinical trials are needed.

Key words:
testosterone – androgen deficiency – endotelial dysfunction – metabolic syndrome

Sources

1. Lerner DJ, Kannel WB. Patterns of coronary heart disease morbidity and mortality in the sexes: a 26‑year follow‑up of the Framingham population. Am Heart J 1986; 111: 383–390.

2. von Eckardstein A, Wu FC. Androgens and coronary artery disease. Endocr Rev 2003; 24: 183–217.

3. Blahoš J, Bleha O. Endokrinologie. 2. vyd. Praha: Avicenum 1988.

4. Kreze A, Langer P, Klimeš I et al. Všeobecná a klinická endokrinológia. Bratislava: Academic Electronic Press 2004: 423–429.

5. Horwitz KB, Horwitz LD. Canine vascular tissues are targets for androgens, estrogens, progestins and glucocorticoids. J Clin Invest 1982; 69: 750–758.

6. Hanke H, Lenz C, Hess B et al. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 2001; 103: 1382–1385.

7. Fujimoto R, Morimoto I, Morita E et al. Androgen receptors, 5 alfa‑reductase activity and androgen dependent proliferation of vascular smooth muscle cells. J Steroid Biochem Mol Biol 1994; 50: 169–174.

8. Cutolo M, Villaggio B, Barone A et al. Primary cultures of human synovial macrophages metabolize androgens. Ann N Y Acad Sci 1996; 784: 534–541.

9. Khetawat G, Faraday N, Nealen ML et al. Human megakaryocytes and platelets contain the estrogen receptor beta and androgen receptor (AR): testosterone regulates AR expression. Blood 2000; 95: 2289–2296.

10. Kahn SM, Hryb DJ, Nakhla AM et al. Sex hormone binding globulin is synthesized in target cells. J Endocrinol 2001; 175: 113–120.

11. Hammes A, Andreassen TK, Spoelgen R et al. Role of endocytosis in cellular uptake of sex steroids. Cell 2005; 122: 751–762.

12. Akishita M, Hashimoto M, Ohike Y et al. Low testosterone level is an independent determinant of endothelial dysfunction in men. Hypertens Res 2007; 30: 1029–1034.

13. Yue P, Chatterjee K, Beale C et al. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 1995; 91: 1154–1160.

14. Zitzmann M, Brune M, Kornmann B et al. The CAG repeat polymorphism in the AR gene affects high density lipoprotein cholesterol and arterial vasoreactivity. J Clin Endocrinol Metab 2001; 86: 4867–4873.

15. Foresta C, Zuccarello D, De Toni L at al. Androgens stimulate endothelial progenitor cells through an androgen-mediated pathway. Clin Endocrinol (Oxf) 2008; 68: 284–289.

16. Foresta C, Caretta N, Lana A et al. Reduced number of circulating endothelial progenitor cells in hypogonadal men. J Clin Endocrinol Metab 2006; 91: 4599–4602.

17. Fu L, Gao QP, Shen JX. Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian J Androl 2008; 10: 214–218.

18. Malkin CJ, Pugh PJ, Jones TH et al. Testosterone for secondary prevention in men with ischaemic heart disease? QJM 2003; 96: 521–529.

19. Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet tromboxane A2 receptor density and aggregation responses. Circulation 1995; 91: 2742–2747.

20. Kupelian V, Page ST, Araujo AB et al. Low sex hormone‑binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab 2006; 91: 843–850.

21. Araujo AB, Kupelian V, Page ST et al. Sex steroids and all cause and specific mortality in men. Arch Intern Med 2007; 167: 1252–1260.

22. Stellato RK, Feldman HA, Hamdy O et al. Testosterone, SHBG and the development of type 2 diabetes in middle-aged men: prospective results from the Massachusetts male aging study. Diabetes Care 2000; 23: 490–494.

23. Kupelian V, Hayes FJ, Link CL et al. Inverse association of testosterone and the metabolic syndrome in men is consistent across race and ethnic group. J Clin Endocrinol Metab 2008; 93: 3403–3410.

24. Muller M, Grobbee DE, den Tonkelaar I et al. Endogenous sex hormones and metabolic syndrome in aging men. J Clin Endocrinol Metab 2005; 90: 2618–2623.

25. Chubb SA, Hyde Z, Almeida OP et al. Lower sex hormone binding globulin is more strongly associated with metabolic syndrome than lower total testosterone in older men: the health in men study. Eur J Endocrinol 2008; 158: 785–792.

26. Laaksonen DE, Nikanen L, Punnonen K et al. Testosterone and SHBG predict the metabolic syndrome and diabetes in middle aged men. Diabetes Care 2004; 27: 1036–1041.

27. Haffner SM, Valdez RA, Mykkänen L et al. Decreased testosterone and dehydroepiandrosterone sulfate concentrations are associated with increased insulin and glucose concentrations in nondiabetic men. Metabolism 1994; 43: 599–603.

28. Laaksonen DE, Niskanen L, Punnonen K et al. Sex hormones, inflammation and the metabolic syndrome: a population‑based study. Eur J Endocrinol 2003; 149: 601–608.

29. Haffner SM, Mykkänen L, Valdez RA et al. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab 1993; 77: 1610–1615.

30. Keating NL, O‘Malley AJ, Freedland SJ. Diabetes and cardiovascular disease during androgen deprivation: observational study of veterans with prostate cancer. J Natl Cancer Inst 2010; 102: 39–46.

31. Barrett-Connor E. Lower endogenous androgen levels and dyslipidemia in men with non‑insulin‑dependent diabetes mellitus. Ann Intern Med 1992; 117: 807–811.

32. Andersson B, Mårin P, Lissner L et al. Testosterone concentration in women and men with NIDDM. Diabetes Care 1994; 17: 405–411.

33. Fukui M, Soh J, Tanaka M et al. Low serum testosterone concentration in middle-aged men with type 2 diabetes. Endocr J 2007; 54: 871–877.

34. Laughlin GA, Barrett-Connor E, Bergstrom J. Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008; 93: 68–75.

35. Vikan T, Schirmer H, Njølstad I et al. Endogenous sex hormones and the prospective association with cardiovascular disease and mortality in men: the Tromsø study. Eur J Endocrinol 2009; 161: 435–442.

36. Tivesten A, Vandenput L, Labrie F et al. Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009; 94: 2482–2488.

37. Smith GD, Ben-Shlomo Y, Beswick A et al. Cortisol, testosterone, and coronary heart disease: prospective evidence from the Cearphilly study. Circulation 2005; 112: 332–340.

38. Yeap BB, Hyde Z, Almeida OP et al. Lower testosterone levels predict incident stroke and transient ischemic attack in older men. J Clin Endocrinol Metab 2009; 94: 2353–2359.

39. Willnow TE, Hilpert J, Armstrong SA et al. Defective forebrain development in mice lacking gp330/megalin. Proc Natl Acad Sci USA 1996; 93: 8460–8464.

40. Rosner W, Hryb DJ, Kahn SM et al. Interactions of sex hormone‑binding globulin with target cells. Mol Cell Endocrinol 2010; 316: 79–85.

41. Swerdlow AJ, Higgins CD, Schoemaker MJ et al. Mortality in patients with Klinefelter syndrome in Britain: a cohort study. J Clin Endocrinol Metab 2005; 90: 6516–6522.

42. Bojesen A, Juul S, Birkebaek NH et al. Morbidity in Klinefelter syndrome, a Danish register study based on hospital discharge diagnoses. J Clin Endocrinol Metab 2006; 91: 1254–1260.

43. Bojesen A, Juul S, Birkebaek N et al. Increased mortality in Klinefelter syndrome. J Clin Endocrinol Metab 2004; 89: 3830–3834.

44. Kang SM, Jang Y, Kim JY et al. Effect of oral administration of testosterone on brachial arterial vasoreactivity in men with coronary artery disease. Am J Cardiol 2002; 89: 862–864.

45. Lu YL, Kuang L, Zhu H et al. Changes in aortic endothelium ultrastructure in male rats following castration, replacement with testosterone and administration of 5‑alpha-reductase inhibitor. Asian J Androl 2007; 9: 843–847.

46. English KM, Steeds RP, Jones TH et al. Low‑dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double‑blind, placebo-controlled study. Circulation 2000; 102: 1906–1911.

47. Pugh PJ, Jones TH, Channer KS. Acute haemodynamic effects of testosterone in men with chronic heart failure. Eur Heart J 2003; 24: 909–915.

48. Webb CM, Elkington AG, Kraidly MM et al. Effects of oral testosterone treatment on myocardial perfusion and vascular function in men with low plasma testosterone and coronary heart disease. Am J Cardiol 2008; 101: 618–624.

49. Kapoor D, Goodwin E, Channer KS et al. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154: 899–906.

50. Bhasin S. Effects of testosterone administration on fat distribution, insulin sensitivity and atherosclerosis progression. Clin Infect Dis 2003; 37 (Suppl 2): S142–S149.

51. Allan CA, Strauss BJ, Burger HG et al. Testosterone therapy prevents gain in adipose tissue and loss of skeletal muscle in nonobese aging men. J Clin Endocrinol Metab 2008; 93: 139–146.

52. Haffner SM, Karhapää P, Mykkänen L et al. Insulin resistance, body fat distribution and sex hormones in men. Diabetes 1994; 43: 212–219.

53. Dubey RK, Oparil S, Imthurn B et al. Sex hormones and hypertension. Cardiovasc Res 2002; 53: 688–708.

54. Haffner SM, Mykkänen L, Valdez RA et al. Relationship of sex hormones to lipids and lipoproteins in nondiabetic men. J Clin Endocrinol Metab 1993; 77: 1610–1615.