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Testosterone Therapy and Cardiovascular Risk - Advances and Controversies

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One of the most debated issues related to testosterone therapy is its effects on cardiovascular risk and clinical events, like for example heart attack.
January 27th, 2015 a comprehensive medical review paper was published, addressing the controversial topic of testosterone therapy and cardiovascular risk.[65] It was written by the Androgen Study Group academicians and published in Mayo Clinic Proceedings.
Here I summarizes key conclusions from this milestone medical review.

Key Points

• Low levels of total, bioavailable, and free testosterone are associated with increased risk of mortality from all causes and cardiovascular disease.
• Incident coronary artery disease is associated with lower levels of total, bioavailable, or free testosterone.
• Severity of coronary artery disease is inversely correlated with serum concentrations of total, bioavailable, or free testosterone.
• Carotid intima-media thickness and/or carotid plaque volume are inversely correlated with levels of total, bioavailable, or free testosterone.
• Testosterone therapy is associated with a significant reduction in obesity and fat mass.
• Testosterone therapy is associated with small decreases in levels of total cholesterol, HDL, and LDL. No clear effect on triglycerides has been documented.
• Testosterone therapy is associated with a decrease in serum glucose concentrations, HbA1c, and insulin resistance in diabetic and prediabetic men.
• Testosterone therapy is associated with an inconsistent reduction in serum concentrations of inflammatory markers.
• Testosterone therapy improves time to onset of symptomatic angina with exercise.
• Testosterone therapy improves exercise capacity and peak oxygen consumption in men with symptomatic congestive heart failure.
• Available evidence is insufficient to conclude whether there exists a relationship between ischemic stroke and blood androgen levels.

What is known

Hypogonadism, also known as testosterone deficiency, is a clinical syndrome characterized by a set of signs and symptoms in combination with low testosterone levels.[1, 2] Symptoms include decreased libido, erectile dysfunction, difficulty achieving orgasm, reduced intensity of orgasm, fatigue, decreased energy, depressed mood, irritability, and decreased sense of well-being. Objective signs include anemia, decreased bone density, reduced muscle strength and mass, increased body fat mass (both visceral and total), and weight gain.[1, 2]
The goal of treatment is to alleviate symptoms and signs by restoring testosterone concentrations to optimal levels within the physiological range. Established benefits of testosterone therapy in hypogonadal men include improved sexual desire and function [3-6], improved energy, mood and vitality [6-10], increased lean mass [5, 10-13], decreased waist circumference [14-18], reduced total body fat mass [10-13], and increased bone mineral density.[19-22] Promising new data reveals that testosterone therapy improves insulin sensitivity [23-25] and reduces blood glucose [14, 16, 26] and HbA1c [14, 16, 18, 26] levels in men with type 2 diabetes or obesity. 

What this review adds

The purpose of the Mayo Clinic Proceedings paper was to address the key scientific question - is testosterone therapy associated with increased cardiovascular risks? [65] 
An objective assessment of the medical research literature regarding testosterone and cardiovascular effects must include the large number of studies on testosterone deficiency and its consequences, as well as the effects of testosterone therapy on cardiovascular risk factors and clinical outcomes. The conclusions from this review are summarized in the key points above. 
As part of a comprehensive analysis it is also important to scrutinize studies with seemingly contradictory results.
Recent controversial studies
Against the background of well-documented health benefits of testosterone therapy in hypogonadal men, established in clinical trials, the Androgen Study Group finds it surprising that publication of two retrospective studies reporting increased risks of cardiovascular adverse events would cause such great concern. In medical research, the retrospective study design is one of the lowest quality evidence.[27, 28]
The first study, published in November 2013 by Vigen et al.[29], reported increased rates of heart attacks, strokes, and deaths in men who received testosterone prescriptions compared with untreated men, using unvalidated statistical methodology that reversed the raw data, which actually suggested that the percentage of adverse events in testosterone-treated men was lower, by half, compared with untreated men.[30] Large data errors revealed post-publication led to a call for retraction by 29 medical societies.[31] 
The second study, published in January 2014 by Finkle et al.[32], reported an increased rate of non-fatal myocardial infarctions in the period up to 90 days following receipt of a testosterone prescription compared with the prior 12 months. However, the observed myocardial infarction rate among men who received a testosterone prescription was only one-third the expected rate for the general population, and because of the absence of a control group of men who did not receive testosterone prescription one cannot determine whether these reported MI rates were higher, lower, or unchanged in association with a testosterone prescription.[33]
Although these 2 studies gained enormous media attention, neither provides credible evidence of increased risk, and they have undergone serious criticism in the scientific literature.[31, 33-35] The FDA itself commented on these studies, concluding that none provide compelling evidence of increased cardiovascular risk.[36] Indeed, it could be argued that the studies by Vigen et al.[29] and Finkle et al.[32] actually demonstrate protective effects of testosterone therapy on cardiovascular risk, as the percentage of events was lower by half in the former (before statistical manipulation), and overall myocardial infarct rates were only a fraction of expected rates in the latter.  
Testosterone prescriptions
Prescription rates for testosterone products have increased substantially worldwide over the last decade.[37-41] However, only 10% to 12% of hypogonadal patients are actually receiving testosterone treatment for their hypogonadism.[42, 43] The rise in testosterone prescriptions seems to have resulted from increased awareness of testosterone deficiency and the benefits of testosterone therapy among both physicians and patients, coupled with reduced concern regarding prostate cancer risk.[44] With the wealth of evidence outlined in the Mayo Clinic review, now doctors and patients can put their fears about cardiovascular risks to rest as well.  
Public health burden of hypogonadism
Notably, testosterone deficiency has been projected to be involved in the development of approximately 1.3 million new cases of cardiovascular disease, 1.1 million new cases of diabetes, and over 600,000 osteoporosis-related fractures over a 20-year period.[45] This in turn has been estimated to be directly responsible for approximately $190–$525 billion in inflation-adjusted U.S. health care expenditures.[45] In accordance with this, longitudinal models predict increased outpatient visits and costs from low baseline serum testosterone levels independent of socio-economic and lifestyle factors; even when controlling for age, men aged 20 - 79 years at baseline with low serum testosterone levels had 29% more outpatient visits and 38% higher outpatient costs after a 5-year follow up.[46]  
Numerous intervention studies have consistently demonstrated improvements in cardiovascular risk factors such as body fat mass and obesity [10-13], waist circumference [18, 24], and glycemic control.[18, 23, 24] These findings may explain the frequently observed outcome of increased mortality among men with low testosterone levels.[47-53] Importantly, testosterone deficiency in older men is associated with increased risk of death over the following 20 years, independent of multiple traditional risk factors and several preexisting health conditions.[48, 50] 
Notable key effects of testosterone therapy in regards to cardiovascular risk
As of this writing, ten studies have examined the association between endogenous testosterone levels and carotid intima-media thickness (CIMT), a surrogate measure of atherosclerosis. All 10 documented an inverse relationship of CIMT with total testosterone, free testosterone, or bioavailable testosterone, meaning that higher testosterone levels are associated with lower CIMT (i.e. less atherosclerosis).[54-63] It is notable that no study has reported a significant relationship between higher testosterone levels and increased carotid intima-media thickness. 
Further support comes from two small randomized placebo-controlled testosterone trials. The first of these showed a reduction in carotid intima media thickness among testosterone deficient men treated with testosterone, and found a positive correlation between the magnitude of the increase in testosterone levels with treatment and the magnitude of reduction in intima media thickness.[24]  
The second study compared 54 weeks of diet and exercise alone versus diet and exercise plus testosterone treatment with intramuscular injections of testosterone undecanoate in  severely obese hypogonadal men.[64] Testosterone treatment resulted in significant improvements in CIMT, cardiac ejection fraction, endothelial function, as well as epicardial fat, the latter being associated with coronary artery disease.[64] Notably, cessation of testosterone therapy resulted in return of CV factors to baseline 24 weeks later.[64] 
These results suggest a direct contribution of testosterone therapy to cardiovascular health in testosterone deficient men, and raise the possibility that restoring serum testosterone may actually reverse atherosclerosis in critical vascular beds. 


A wealth of modern data accumulated over the last two decades has demonstrated that a low testosterone level is associated with increased risk of development of cardiovascular risk factors, atherosclerosis and mortality, and that testosterone therapy has beneficial effects on multiple risk factors and risk biomarkers related to these clinical conditions.  
There are no large long-term, placebo-controlled randomized clinical trials of testosterone therapy to provide definitive conclusions about cardiovascular outcomes. However, looking at the totality of evidence from short to medium duration placebo-controlled randomized clinical trials showing beneficial effects on cardiovascular risk factors, one may question whether it would be ethical to withhold testosterone therapy in hypogonadal men allocated to a placebo group for a longer period of time.

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!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.

Last modified on Wednesday, 06 May 2015 21:24

Medical Writer & Nutritionist

MSc Nutrition

University of Stockholm & Karolinska Institute, Sweden 

   Baylor University, TX, USA

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