Testosterone Therapy and Cardiovascular Risk - Advances and Controversies
Key Points
What is known
What this review adds
Summary
1. Bhasin, S., et al., Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab, 2010. 95(6): p. 2536-59.
2. Wang, C., et al., Investigation, treatment, and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA, and ASA recommendations. J Androl, 2009. 30(1): p. 1-9.
3. Bolona, E.R., et al., Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc, 2007. 82(1): p. 20-8.
4. Corona, G., et al., Testosterone supplementation and sexual function: a meta-analysis study. J Sex Med, 2014. 11(6): p. 1577-92.
5. Wang, C., et al., Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab, 2000. 85(8): p. 2839-53.
6. Hackett, G., et al., Testosterone replacement therapy with long-acting testosterone undecanoate improves sexual function and quality-of-life parameters vs. placebo in a population of men with type 2 diabetes. J Sex Med, 2013. 10(6): p. 1612-27.
7. Tong, S.F., et al., Effect of long-acting testosterone undecanoate treatment on quality of life in men with testosterone deficiency syndrome: a double blind randomized controlled trial. Asian J Androl, 2012. 14(4): p. 604-11.
8. Pexman-Fieth, C., et al., A 6-month observational study of energy, sexual desire, and body proportions in hypogonadal men treated with a testosterone 1% gel. Aging Male, 2014. 17(1): p. 1-11.
9. Yassin, D.J., et al., Long-term testosterone treatment in elderly men with hypogonadism and erectile dysfunction reduces obesity parameters and improves metabolic syndrome and health-related quality of life. J Sex Med, 2014. 11(6): p. 1567-76.
10. Srinivas-Shankar, U., et al., Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab, 2010. 95(2): p. 639-50.
11. Finkelstein, J.S., et al., Gonadal steroids and body composition, strength, and sexual function in men. N Engl J Med, 2013. 369(11): p. 1011-22.
12. Page, S.T., et al., Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab, 2005. 90(3): p. 1502-10.
13. Bhasin, S., et al., Effect of testosterone supplementation with and without a dual 5alpha-reductase inhibitor on fat-free mass in men with suppressed testosterone production: a randomized controlled trial. JAMA, 2012. 307(9): p. 931-9.
14. Haider, A., et al., Effects of long-term testosterone therapy on patients with "diabesity": results of observational studies of pooled analyses in obese hypogonadal men with type 2 diabetes. Int J Endocrinol, 2014. 2014: p. 683515.
15. Saad, F., et al., Long-term treatment of hypogonadal men with testosterone produces substantial and sustained weight loss. Obesity (Silver Spring), 2013. 21(10): p. 1975-81.
16. Traish, A.M., et al., Long-term testosterone therapy in hypogonadal men ameliorates elements of the metabolic syndrome: an observational, long-term registry study. Int J Clin Pract, 2014. 68(3): p. 314-29.
17. Yassin, A. and G. Doros, Testosterone therapy in hypogonadal men results in sustained and clinically meaningful weight loss. Clin Obes, 2013. 3(3-4): p. 73-83.
18. Hackett, G., et al., Testosterone replacement therapy improves metabolic parameters in hypogonadal men with type 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med, 2014. 11(3): p. 840-56.
19. Svartberg, J., et al., Testosterone treatment in elderly men with subnormal testosterone levels improves body composition and BMD in the hip. Int J Impot Res, 2008. 20(4): p. 378-87.
20. Aversa, A., et al., Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study. Aging Male, 2012. 15(2): p. 96-102.
21. Wang, C., et al., Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab, 2004. 89(5): p. 2085-98.
22. Wang, C., et al., Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin Endocrinol (Oxf), 2001. 54(6): p. 739-50.
23. Jones, T.H., et al., Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care, 2011. 34(4): p. 828-37.
24. Aversa, A., et al., Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med, 2010. 7(10): p. 3495-503.
25. Heufelder, A.E., et al., Fifty-two-week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl, 2009. 30(6): p. 726-33.
26. Haider, A., et al., Hypogonadal obese men with and without diabetes mellitus type 2 lose weight and show improvement in cardiovascular risk factors when treated with testosterone: An observational study. Obes Res Clin Pract, 2014. 8(4): p. e339-49.
27. Besen, J. and S.D. Gan, A critical evaluation of clinical research study designs. J Invest Dermatol, 2014. 134(3): p. e18.
28. Rohrig, B., et al., Types of study in medical research: part 3 of a series on evaluation of scientific publications. Dtsch Arztebl Int, 2009. 106(15): p. 262-8.
29. Vigen, R., et al., Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA, 2013. 310(17): p. 1829-36.
30. Morgentaler, A. and R. Kacker, Andrology: Testosterone and cardiovascular risk--deciphering the statistics. Nat Rev Urol, 2014. 11(3): p. 131-2.
31. Morgentaler, A. and B. Lunenfeld, Testosterone and cardiovascular risk: world's experts take unprecedented action to correct misinformation. Aging Male, 2014. 17(2): p. 63-5.
32. Finkle, W.D., et al., Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One, 2014. 9(1): p. e85805.
33. Morgentaler, A., Testosterone, cardiovascular risk, and hormonophobia. J Sex Med, 2014. 11(6): p. 1362-6.
34. Page, S.T., Testosterone, cardiovascular disease, and mortality in men: living in the dark. Lancet Diabetes Endocrinol, 2014.
35. Traish, A.M., A.T. Guay, and A. Morgentaler, Death by testosterone? We think not! J Sex Med, 2014. 11(3): p. 624-9.
36. FDA Citizen Petition Denial Response from FDA CDER to Public Citizen, avaliable at http://www.regulations.gov/#!documentDetail;D=FDA-2014-P-0258-0003, accessed Aug 31, 2014. 2014.
37. Baillargeon, J., et al., Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med, 2013. 173(15): p. 1465-6.
38. Gan, E.H., et al., A UK epidemic of testosterone prescribing, 2001-2010. Clin Endocrinol (Oxf), 2013. 79(4): p. 564-70.
39. Layton, J.B., et al., Testosterone lab testing and initiation in the United Kingdom and the United States, 2000 to 2011. J Clin Endocrinol Metab, 2014. 99(3): p. 835-42.
40. Handelsman, D.J., Pharmacoepidemiology of testosterone prescribing in Australia, 1992-2010. Med J Aust, 2012. 196(10): p. 642-5.
41. Handelsman, D.J., Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med J Aust, 2013. 199(8): p. 548-51.
42. Hall, S.A., et al., Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey. Arch Intern Med, 2008. 168(10): p. 1070-6.
43. Mulligan, T., et al., Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract, 2006. 60(7): p. 762-9.
44. Khera, M., et al., A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur Urol, 2014. 65(1): p. 115-23.
45. Moskovic, D.J., et al., The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. J Sex Med, 2013. 10(2): p. 562-9.
46. Haring, R., et al., Prospective association of low serum total testosterone levels with health care utilization and costs in a population-based cohort of men. Int J Androl, 2010. 33(6): p. 800-9.
47. Khaw, K.T., 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): p. 2694-701.
48. Laughlin, G.A., E. Barrett-Connor, and J. Bergstrom, Low serum testosterone and mortality in older men. J Clin Endocrinol Metab, 2008. 93(1): p. 68-75.
49. Corona, G., et al., Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol, 2011. 165(5): p. 687-701.
50. Haring, R., et al., Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20-79. Eur Heart J, 2010. 31(12): p. 1494-501.
51. Menke, A., et al., Sex steroid hormone concentrations and risk of death in US men. Am J Epidemiol, 2010. 171(5): p. 583-92.
52. Tivesten, A., et al., Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab, 2009. 94(7): p. 2482-8.
53. Yeap, B.B., 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(1): p. E9-18.
54. De Pergola, G., et al., Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes Relat Metab Disord, 2003. 27(7): p. 803-7.
55. Fu, L., Q.P. Gao, and J.X. Shen, Relationship between testosterone and indexes indicating endothelial function in male coronary heart disease patients. Asian J Androl, 2008. 10(2): p. 214-8.
56. Fukui, M., et al., Association between serum testosterone concentration and carotid atherosclerosis in men with type 2 diabetes. Diabetes Care, 2003. 26(6): p. 1869-73.
57. Makinen, J., et al., Increased carotid atherosclerosis in andropausal middle-aged men. J Am Coll Cardiol, 2005. 45(10): p. 1603-8.
58. Muller, M., et al., Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation, 2004. 109(17): p. 2074-9.
59. Soisson, V., et al., Low plasma testosterone and elevated carotid intima-media thickness: importance of low-grade inflammation in elderly men. Atherosclerosis, 2012. 223(1): p. 244-9.
60. Svartberg, J., et al., Low testosterone levels are associated with carotid atherosclerosis in men. J Intern Med, 2006. 259(6): p. 576-82.
61. Tsujimura, A., et al., Low serum free testosterone level is associated with carotid intima-media thickness in middle-aged Japanese men. Endocr J, 2012. 59(9): p. 809-15.
62. van den Beld, A.W., et al., Endogenous hormones and carotid atherosclerosis in elderly men. Am J Epidemiol, 2003. 157(1): p. 25-31.
63. Vikan, T., et al., Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromso study. Eur J Epidemiol, 2009. 24(6): p. 289-95.
64. Francomano, D., et al., Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study. J Endocrinol Invest, 2014. 37: p. 401-411.
65. Morgentaler, A., et al., Testosterone Therapy and Cardiovascular Risk: Advances and Controversies. Mayo Clinic Proceedings, 2015. 90(2): p. 224-251.