Testosterone and cardiovascular disease

Current Opinion in Endocrinology, Diabetes and Obesity

Volumn 21, Issue 3, 2014, Pages 202-208

  Schooling, C Mary ^a,b  

^a CITY UNIVERSITY OF NEW YORK   (United States)

^b UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

androgen; cardiovascular; Mendelian; risk factors; trial

Indexed keywords

HIGH DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN CHOLESTEROL; TESTOSTERONE; ANDROGEN;

ANDROGEN THERAPY; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; HEART INFARCTION; HUMAN; MENDELIAN RANDOMIZATION ANALYSIS; PHARMACOEPIDEMIOLOGY; PRESCRIPTION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; TESTOSTERONE BLOOD LEVEL; ADVERSE EFFECTS; BLOOD; CHEMICALLY INDUCED; DEFICIENCY; DRUG EFFECTS; HORMONE SUBSTITUTION; MALE; PATHOPHYSIOLOGY; PRACTICE GUIDELINE; RISK FACTOR;

ANDROGENS; CARDIOVASCULAR DISEASES; CHOLESTEROL, HDL; CHOLESTEROL, LDL; HORMONE REPLACEMENT THERAPY; HUMANS; MALE; MENDELIAN RANDOMIZATION ANALYSIS; MYOCARDIAL INFARCTION; PRACTICE GUIDELINES AS TOPIC; RANDOMIZED CONTROLLED TRIALS AS TOPIC; RISK FACTORS; TESTOSTERONE;

EID: 84899954927     PISSN: 1752296X     EISSN: 17522978     Source Type: Journal    
DOI: 10.1097/MED.0000000000000065     Document Type: Review

References (111)

1. Gan EH, Pattman S, Pearce S, Quinton R. Many men are receiving unnecessary testosterone prescriptions. BMJ 2012; 345:e5469.
2. Baillargeon J, Urban RJ, Ottenbacher KJ, et al. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013; 173:1465-1466.
3. Layton JB, Li D, Meier CR, et al. Testosterone Lab Testing and Initiation in the United Kingdom and the United States, 2000-2011. J Clin Endocrinol Metab 2014; jc20133570.
4. Handelsman DJ. Global trends in testosterone prescribing, 2010-2011: expanding the spectrum of prescription drug misuse. Med J Aust 2013; 199:548-551.
5. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:2536-2559.
6. Levine GN, D'Amico AV, Berger P, et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. CA Cancer J Clin 2010; 60:194-201.
7. Benson K, Hartz AJ. A comparison of observational studies and randomized, controlled trials. N Engl J Med 2000; 342:1878-1886.
8. Concato J, Shah N, Horwitz RI. Randomized, controlled trials, observational studies, and the hierarchy of research designs. N Engl J Med 2000; 342:1887-1892.
9. Prasad V, Jorgenson J, Ioannidis JP, Cifu A. Observational studies often make clinical practice recommendations: an empirical evaluation of authors' attitudes. J Clin Epidemiol 2013; 66:361-366.
10. Petitti D. Commentary: hormone replacement therapy and coronary heart disease: four lessons. Int J Epidemiol 2004; 33:461-463.
11. Manson JE, Chlebowski RT, Stefanick ML, et al. Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA 2013; 310:1353-1368.
12. Kalin MF, Zumoff B. Sex hormones and coronary disease: a review of the clinical studies. Steroids 1990; 55:330-352.
13. Tunstall-Pedoe H. Myth and paradox of coronary risk and the menopause. Lancet 1998; 351:1425-1427.
14. Barrett-Connor E. Sex differences in coronary heart disease. Why are women so superior? The 1995 Ancel Keys Lecture. Circulation 1997; 95:252-264.
15. The Coronary Drug Project. Findings leading to discontinuation of the 2.5-mg day estrogen group. The coronary Drug Project Research Group. JAMA 1973; 226:652-657.
16. Byar DP, Corle DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group studies. NCI Monogr 1988; 165-170.
17. 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.
18. Eyben FE, Graugaard C, Vaeth M. All-cause mortality and mortality of myocardial infarction for 989 legally castratedmen. Eur J Epidemiol 2005; 20:863-869.
19. Groth KA, Skakkebaek A, Host C, et al. Clinical review: Klinefelter syndrome - a clinical update. J Clin Endocrinol Metab 2013; 98:20-30.
20. Bhasin S, Pencina M, Jasuja GK, et al. Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 2011; 96:2430-2439.
21. Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease. J Endocrinol 2013; 217:R47-R71.
22. Yang Y. Trends in U.S. adult chronic disease mortality, 1960-1999: age, period, and cohort variations. Demography 2008; 45:387-416.
23. Araujo AB, Dixon JM, Suarez EA, et al. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96:3007-3019.
24. Ruige JB, Mahmoud AM, De BD, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 2011; 97:870-875.
25. Collier A, Ghosh S, McGlynn B, Hollins G. Prostate cancer, androgen deprivation therapy, obesity, the metabolic syndrome, type 2 diabetes, and cardiovascular disease: a review. Am J Clin Oncol 2012; 35:504-509.
26. Araujo AB, Kupelian V, Page ST, et al. Sex steroids and all-cause and causespecific mortality in men. Arch Intern Med 2007; 167:1252-1260.
27. Yeap BB, Alfonso H, Chubb SA, et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014; 99:E9-E18.
28. Soisson V, Brailly-Tabard S, Helmer C, et al. A J-shaped association between plasma testosterone and risk of ischemic arterial event in elderly men: the French 3C cohort study. Maturitas 2013; 75:282-288.
29. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004; 27:1036-1041.
30. Akishita M, Fukai S, Hashimoto M, et al. Association of low testosterone with metabolic syndrome and its components in middle-aged Japanese men. Hypertens Res 2010; 33:587-591.
31. Firtser S, Juonala M, Magnussen CG, et al. Relation of total and free testosterone and sex hormone-binding globulin with cardiovascular risk factors in men aged 24-45 years. The Cardiovascular Risk in Young Finns Study. Atherosclerosis 2012; 222:257-262.
32. Monroe AK, Dobs AS. The effect of androgens on lipids. Curr Opin Endocrinol Diabetes Obes 2013; 20:132-139.
33. Yeap BB, Knuiman MW, Divitini ML, et al. Differential associations of testosterone, dihydrotestosterone and estradiol with physical, metabolic and health-related factors in community-dwelling men aged 17-97 years from the Busselton Health Survey. Clin Endocrinol (Oxf) 2014; Jan 16. doi: 10.1111/cen.12407.
34. Miljkovic I, Cauley JA, Dressen AS, et al. Bioactive androgens and glucuronidated androgen metabolites are associated with subcutaneous and ectopic skeletal muscle adiposity among older black men. Metabolism 2011; 60:1178-1185.
35. Pospisilova H, Vankova M, Hill M, et al. The differences between aromatizable and nonaromatizable androgens in relation to body composition and metabolic syndrome risk factors in men. J Steroid Biochem Mol Biol 2012; 132:105-111.
36. Vandenput L, Mellstrom D, Lorentzon M, et al. Androgens and glucuronidated androgen metabolites are associated with metabolic risk factors in men. J Clin Endocrinol Metab 2007; 92:4130-4137.
37. Saylor PJ, Smith MR. Metabolic complications of androgen deprivation therapy for prostate cancer. J Urol 2013; 189:S34-S42.
38. Braga-Basaria M, Dobs AS, Muller DC, et al. Metabolic syndrome in men with prostate cancer undergoing long-term androgen-deprivation therapy. J Clin Oncol 2006; 24:3979-3983.
39. Smith MR, Lee H, McGovern F, et al. Metabolic changes during gonadotropin-releasing hormone agonist therapy for prostate cancer: differences from the classic metabolic syndrome. Cancer 2008; 112:2188-2194.
40. Hsing AW, Stanczyk FZ, Belanger A, et al. Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry. Cancer Epidemiol Biomarkers Prev 2007; 16:1004-1008.
41. Haring R, Baumeister SE, Nauck M, et al. Testosterone and cardiometabolic risk in the general population - the impact of measurement method on risk associations: a comparative study between immunoassay and mass spectrometry. Eur J Endocrinol 2013; 169:463-470.
42. Haring R, Ittermann T, Volzke H, et al. Prevalence, incidence and risk factors of testosterone deficiency in a population-based cohort of men: results from the study of health in Pomerania. Aging Male 2010; 13:247-257.
43. Sartorius G, Spasevska S, Idan A, et al. Serum testosterone, dihydrotestosterone and estradiol concentrations in older men self-reporting very good health: the healthy man study. Clin Endocrinol (Oxf) 2012; 77:755-763.
44. Shi Z, Araujo AB, Martin S, et al. Longitudinal changes in testosterone over five years in community-dwelling men. J Clin Endocrinol Metab 2013; 98:3289-3297.
45. Hsu B, Cumming RG, Blyth FM, et al. Longitudinal and cross-sectional relationships of circulating reproductive hormone levels to self-rated health and health-related quality of life in community-dwelling older men. J Clin Endocrinol Metab 2014; jc20133984.
46. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet 2000; 355:1491-1498.
47. Scher HI, Fizazi K, Saad F, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012; 367:1187-1197.
48. Fizazi K, Scher HI, Molina A, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2012; 13:983-992.
49. Auchus ML, Auchus RJ. Human steroid biosynthesis for the oncologist. J Investig Med 2012; 60:495-503.
50. Ferraldeschi R, de Bono J. Agents that target androgen synthesis in castration-resistant prostate cancer. Cancer J 2013; 19:34-42.
51. Labrie F. Intracrinology. Mol Cell Endocrinol 1991; 78:C113-C118.
52. Labrie F, Cusan L, Gomez JL, et al. Comparable amounts of sex steroids are made outside the gonads in men and women: strong lesson for hormone therapy of prostate and breast cancer. J Steroid Biochem Mol Biol 2009; 113:52-56.
53. Mauvais-Jarvis P, Bercovici JP, Crepy O, Gauthier F. Studies on testosterone metabolism in subjects with testicular feminization syndrome. J Clin Invest 1970; 49:31-40.
54. Moghissi E, Ablan F, Horton R. Origin of plasma androstanediol glucuronide in men. J Clin Endocrinol Metab 1984; 59:417-421.
55. Labrie F, Belanger A, Belanger P, et al. Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women. J Steroid Biochem Mol Biol 2006; 99:182-188.
56. Vandenput L, Labrie F, Mellstrom D, et al. Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men. J Bone Miner Res 2007; 22:220-227.
57. Schooling CM. Androgen activity, ischaemic heart disease and risk factors among men in NHANES III. Eur J Clin Invest 2013; 43:1273-1281.
58. Selvin E, Feinleib M, Zhang L, et al. Androgens and diabetes in men: results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Care 2007; 30:234-238.
59. Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310:1829-1836.
60. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of nonfatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9:e85805.
61. Lawlor DA, Harbord RM, Sterne JA, et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27:1133-1163.
62. Handelsman DJ. Mendelian randomization: loosening the Gordian knot of testosterone and male ageing. Asian J Androl 2013; 15:579-581.
63. Haring R, Teumer A, Volker U, et al. Mendelian randomization suggests noncausal associations of testosterone with cardiometabolic risk factors and mortality. Andrology 2013; 1:17-23.
64. Zhao J, Jiang C, Lam TH, et al. Genetically predicted testosterone and cardiovascular risk factors in men: a Mendelian randomization analysis in the Guangzhou Biobank Cohort Study. Int J Epidemiol 2014; 43:140-148.
65. Liverman CT, Blazer DG. Testosterone and Aging: Clinical Research Directions. Washington, DC, USA: The National Academy Press; 2004.
66. Schwartz LM, Woloshin S. Low "t" as in "template": how to sell disease. JAMA Intern Med 2013; 173:1460-1462.
67. Tsertsvadze A, Fink HA, Yazdi F, et al. Oral phosphodiesterase-5 inhibitors and hormonal treatments for erectile dysfunction: a systematic review and meta-analysis. Ann Intern Med 2009; 151:650-661.
68. Spitzer M, Basaria S, Travison TG, et al. Effect of testosterone replacement on response to sildenafil citrate in men with erectile dysfunction: a parallel, randomized trial. Ann Intern Med 2012; 157:681-691.
69. Ioannidis JP. Adverse events in randomized trials: neglected, restricted, distorted, and silenced. Arch Intern Med 2009; 169:1737-1739.
70. Calof OM, Singh AB, Lee ML, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60:1451-1457.
71. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007; 82:29-39.
72. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and metaanalysis. J Clin Endocrinol Metab 2010; 95:2560-2575.
73. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone and cardiovascular events among men: a systematic review and meta-analysis of placebocontrolled randomized trials. BMC Med 2013; 11:108.
74. Tugwell P, Judd MG, Fries JF, et al. Powering our way to the elusive side effect: a composite outcome 'basket' of predefined designated endpoints in each organ system should be included in all controlled trials. J Clin Epidemiol 2005; 58:785-790.
75. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med 2010; 363:109-122.
76. Testosterone treatment of men with alcoholic cirrhosis: a double-blind study. The Copenhagen Study Group for Liver Diseases. Hepatology 1986; 6:807-813.
77. Rockhold RW. Cardiovascular toxicity of anabolic steroids. Annu Rev Pharmacol Toxicol 1993; 33:497-520.
78. Ruige JB, Ouwens DM, Kaufman JM. Beneficial and adverse effects of testosterone on the cardiovascular system in men. J Clin Endocrinol Metab 2013; 98:4300-4310.
79. Nguyen PL, Je Y, Schutz FA, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a metaanalysis of randomized trials. JAMA 2011; 306:2359-2366.
80. Albertsen PC, Klotz L, Tombal B, et al. Cardiovascular morbidity associated with gonadotropin releasing hormone agonists and an antagonist. Eur Urol 2014; 65:565-573.
81. Bubley GJ. Is the flare phenomenon clinically significant? Urology 2001; 58:5-9.
82. LeLorier J, Gregoire G, Benhaddad A, et al. Discrepancies between metaanalyses and subsequent large randomized, controlled trials. N Engl J Med 1997; 337:536-542.
83. Inthout J, Ioannidis JP, Borm GF. Obtaining evidence by a single well powered trial or several modestly powered trials. Stat Methods Med Res 2012. [Epub ahead of print]
84. Hildreth KL, Barry DW, Moreau KL, et al. Effects of testosterone and progressive resistance exercise in healthy, highly functioning older men with low-normal testosterone levels. J Clin Endocrinol Metab 2013; 98:1891-1900.
85. Shaik S, Tsitouras PD, Bhasin S, et al. Testosterone effects on insulin sensitivity in old men in the TEAAM study as measured by the octreotide insulin suppression test. Poster SAT-567 ENDO2013 2013.
86. Jones TH, Arver S, Behre HM, et al. Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011; 34:828-837.
87. Cai X, Tian Y, Wu T, et al. Metabolic effects of testosterone replacement therapy on hypogonadal menwith type 2 diabetes mellitus:Asystematic review and meta-analysis of randomized controlled trials. Asian J Androl 2014; 16:146-152.
88. Somboonporn W, Davis S, Seif MW, Bell R. Testosterone for peri- and postmenopausal women. Cochrane Database Syst Rev 2005; CD004509.
89. Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail 2012; 5:315-321.
90. Shastri BR, Yaturu S. Metabolic complications and increased cardiovascular risks as a result of androgen deprivation therapy in men with prostate cancer. Prostate Cancer 2011; 2011:391576.
91. Van Poppel H, Tombal B. Cardiovascular risk during hormonal treatment in patients with prostate cancer. Cancer Manag Res 2011; 3:49-55.
92. Neuhauser HK, Thamm M, Ellert U, et al. Blood pressure percentiles by age and height from nonoverweight children and adolescents in Germany. Pediatrics 2011; 127:e978-e988.
93. Yip PM, Chan MK, Nelken J, et al. Pediatric reference intervals for lipids and apolipoproteins on the VITROS 5,1 FS Chemistry System. Clin Biochem 2006; 39:978-983.
94. Braun SR. Promoting "Low T": A Medical Writer's Perspective. JAMA Intern Med 2013; 173:1458-1460.
95. Furman RH. Are gonadal hormones (estrogens and androgens) of significance in the development of ischemic heart disease. Ann N Y Acad Sci 1968; 149:822-833.
96. Uzunova AD, Ramey ER, Ramwell PW. Arachidonate-induced thrombosis in mice: effects of gender or testosterone and estradiol administration. Prostaglandins 1977; 13:995-1002.
97. Pilo R, Aharony D, Raz A. Testosterone potentiation of ionophore and ADP induced platelet aggregation: relationship to arachidonic acid metabolism. Thromb Haemost 1981; 46:538-542.
98. Ajayi AA, Mathur R, Halushka PV. Testosterone increases human platelet thromboxane A2 receptor density and aggregation responses. Circulation 1995; 91:2742-2747.
99. Ajayi AA, Halushka PV. Castration reduces platelet thromboxane A2 receptor density and aggregability. QJM 2005; 98:349-356.
100. Torres IP, El HM, Zamora-Gonzalez J, et al. Modulation of aortic vascular reactivity by sex hormones in a male rat model of metabolic syndrome. Life Sci 2007; 80:2170-2180.
101. Malkin CJ, Jones RD, Jones TH, Channer KS. Effect of testosterone on ex vivo vascular reactivity in man. Clin Sci (Lond) 2006; 111:265-274.
102. Gosavi S, Mukherjee D. Review of newer anticoagulants and anti platelet agents in acute coronary syndrome and cardiovascular diseases. Cardiovasc Hematol Agents Med Chem 2013; 11:194-202.
103. Danesh J, Collins R, Peto R, Lowe GD. Haematocrit, viscosity, erythrocyte sedimentation rate: meta-analyses of prospective studies of coronary heart disease. Eur Heart J 2000; 21:515-520.
104. Boffetta P, Islami F, Vedanthan R, et al. A U-shaped relationship between haematocrit and mortality in a large prospective cohort study. Int J Epidemiol 2013; 42:601-615.
105. Toss F, Nordstrom A, Nordstrom P. Association between hematocrit in late adolescence and subsequent myocardial infarction in Swedish men. Int J Cardiol 2013; 168:3588-3593.
106. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 2013; 368:22-33.
107. Le TY, Ashton AW, Mardini M, et al. Role of androgens in sex differences in cardiac damage during myocardial infarction. Endocrinology 2014; 155:568-575.
108. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med 2013; 369:1011-1022.
109. Smith AG, Muscat GE. Skeletal muscle and nuclear hormone receptors: implications for cardiovascular and metabolic disease. Int J Biochem Cell Biol 2005; 37:2047-2063.
110. Doshi P, Dickersin K, Healy D, et al. Restoring invisible and abandoned trials: a call for people to publish the findings. BMJ 2013; 346:f2865.
111. Loder E, Godlee F, Barbour V, Winker M. Restoring the integrity of the clinical trial evidence base. BMJ 2013; 346:f3601.