Testosterone and cardiovascular risk in men
November 2014
Hypogonadism, also known as testosterone deficiency, is increasing in prevalence worldwide. While a rapidly expanding body of research is documenting the detrimental health consequences of hypogonadism, at the same time there is a prevailing concern and misunderstanding about the effects of testosterone therapy on cardiovascular risk. Here we present a summary of a recently published comprehensive review on the association of hypogonadism and cardiovascular risk factors, and the effect of testosterone therapy on those risk factors.1
KEY POINTS
- Testosterone deficiency is highly prevalent in men with cardiovascular disease and is associated with an increased mortality.
- Low testosterone also has an adverse effect on several cardiovascular risk factors, which include insulin resistance, diabetes, abnormal amount of cholesterol and/or fats in the blood, abdominal adiposity and blood vessel (endothelial) dysfunction.
- Animal studies and experiments on isolated cells indicate that many of the mechanisms that underlie the atherosclerotic process are beneficially modulated by testosterone.
- Testosterone replacement in men diagnosed with hypogonadism, in whom mid-normal range levels are achieved, have shown a beneficial effect on several cardiovascular risk factors, functional exercise capacity and also improved mortality.
- Studies where patients were either undertreated or given high-dose testosterone have been associated with an increased risk of cardiovascular-related events.
- The critical issue with testosterone therapy is to achieve an optimal testosterone level for every patient. As will most biological parameters, both too low and too high levels are deleterious.
What is known
A well documented observation is that the average life span of women is longer than that of men2 and life expectancy at birth for men is 5-13 years shorter than for women.3,4 Persistent sex differences in mortality remain ever after controlling for major risk factors; compared with women, men have 30% to 83% higher risks of death over a 13 year follow-up period.5
These sex differences are also present with regard to the onset and progression of cardiovascular disease.6 Men experience cardiovascular disease events up to 10 years earlier than women 7 and the age-standardized risk of death from cardiovascular disease has been shown to be 80% higher for men than for women.8 Even after controlling for major risk factors, compared with females, males are twice as likely to die from circulatory diseases and 2.4 times as likely to die of heart disease over a 13 year follow-up period.5
The most consistent sex differences in adult mortality are attributed to coronary heart disease, which is the most common vascular condition with consistently greater mortality rates and risks in men than women.9 Women in every country, whether heart disease rates are high or low, are at lower risk of fatal coronary heart disease compared with men, despite diverse lifestyles, diets, and workplace conditions.9 The remarkably similar male to female coronary heart disease mortality ratios (2.5–4.5) in adults in 52 countries 9 clearly indicate that there must be an intrinsic biological factor underlying the sex difference in total and coronary heart disease mortality.
Because testosterone levels are manifold higher in men than women, in the past, the higher cardiovascular risk in men was attributed to testosterone. The notion that testosterone is "bad for the heart" was supported by case reports of sudden cardiovascular death amongst male athletes abusing anabolic steroids (which are synthetic compounds similar to testosterone).10-14 However, today there is a large amount of evidence demonstrating that low levels of testosterone are associated with increased cardiovascular morbidity and mortality.15 In line with this, testosterone deficiency has emerged as an independent cardiovascular risk factor.16
What this paper adds
This review presents a number of cardio-protective actions of testosterone, and outlines beneficial effects of testosterone therapy on common cardiovascular risk factors like obesity, diabetes, blood cholesterol/lipid abnormalities, inflammation and coagulation.1
Atherosclerosis is a major underlying cause of cardiovascular disease. Animal studies demonstrate that hypogonadism increases atherosclerosis, and that testosterone therapy to achieve levels within the physiological range inhibits plaque formation and development of atherosclerosis. This supports the hypothesis that an age-related decline in testosterone contributes to the development and/or progression of the atherosclerotic process. Further support comes from the observation that as many as one in four men with heart disease have low testosterone levels.17
Testosterone also has beneficial effects on the vascular system, which is a direct target for androgen action.18 Many studies have demonstrated beneficial effects of testosterone on symptoms of angina, blood pressure and erectile dysfunction, likely due to the vasodilatory effect of testosterone and restoration of normal vascular function.
In the past, testosterone therapy was contraindicated in men with heart failure, as older formulations of testosterone led to supra-physiological levels which cause extracellular fluid retention. However, more recent placebo-controlled trials show significant functional and biochemical improvements in patients with heart failure when treated with testosterone therapy to levels within the mid-normal range.19 In addition, testosterone therapy improves exercise capacity in heart failure patients.19 It is notable that the magnitude of the improvement in exercise capacity is greater than that seen with other therapies commonly used for reducing morbidity and mortality in heart failure patients (such as ACE inhibitors and beta-blockers).
Despite all these beneficial effects of testosterone on the cardiovascular system, testosterone therapy is controversial and concerns have been raised in regard to the safety of testosterone therapy in men with cardiovascular disease. A few recent, highly flawed studies gave the false impression that testosterone therapy increases heart disease risk. However, several systematic reviews and meta-analyses of clinical studies of testosterone therapy have not demonstrated an increased risk of adverse cardiovascular events or mortality.20-23 We covered those misleading studies, and presented the latest study investigating the effect of testosterone therapy on heart attack, in a previous editorial Testosterone Treatment and Heart Attack Risk. As outlined there, to the contrary of recent media warnings, testosterone therapy may actually confer protection against myocardial infarction.24
Consequently, restoration of testosterone levels via testosterone therapy could offer cardiovascular, as well as many other health benefits in hypogonadal men.17 Clinical monitoring and titration of testosterone dose is of paramount importance and an obligatory prerequisite for testosterone therapy to confer improvements in health and wellbeing of hypogonadal men.1 Negative studies showing harm erroneously blamed testosterone, when in fact the blame is to be made on the study designs and treatment protocols.
References
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- A N. Male excess mortality between biology and culture. In: Pinnelli A, Racioppi F, Rettaroli R, eds. Genders in the Life Course. Vol 249281. New York: Springer; 2007 Return to content
- Drevenstedt GL, Crimmins EM, Vasunilashorn S, Finch CE. The rise and fall of excess male infant mortality. Proceedings of the National Academy of Sciences of the United States of America. Apr 1 2008;105(13):5016-5021. Return to content
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- Rogers RG, Everett BG, Onge JM, Krueger PM. Social, behavioral, and biological factors, and sex differences in mortality. Demography. Aug 2010;47(3):555-578. Return to content
- Wu FC, von Eckardstein A. Androgens and coronary artery disease. Endocrine reviews. Apr 2003;24(2):183-217. Return to content
- Hyvarinen M, Qiao Q, Tuomilehto J, Soderberg S, Eliasson M, Stehouwer CD. The difference between acute coronary heart disease and ischaemic stroke risk with regard to gender and age in Finnish and Swedish populations. International journal of stroke: official journal of the International Stroke Society. Jun 2010;5(3):152-156. Return to content
- Mikkola TS, Gissler M, Merikukka M, Tuomikoski P, Ylikorkala O. Sex differences in age-related cardiovascular mortality. PloS one. 2013;8(5):e63347. Return to content
- Kalin MF, Zumoff B. Sex hormones and coronary disease: a review of the clinical studies. Steroids. Aug 1990;55(8):330-352. Return to content
- Payne JR, Kotwinski PJ, Montgomery HE. Cardiac effects of anabolic steroids.Heart. May 2004;90(5):473-475. Return to content
- Nieminen MS, Ramo MP, Viitasalo M, et al. Serious cardiovascular side effects of large doses of anabolic steroids in weight lifters. European heart journal. Oct 1996;17(10):1576-1583. Return to content
- Baggish AL, Weiner RB, Kanayama G, et al. Long-term anabolic-androgenic steroid use is associated with left ventricular dysfunction. Circulation. Heart failure.Jul 2010;3(4):472-476. Return to content
- Kersey RD, Elliot DL, Goldberg L, et al. National Athletic Trainers' Association position statement: anabolic-androgenic steroids. Journal of athletic training. Sep-Oct 2012;47(5):567-588. Return to content
- Rothman RD, Weiner RB, Pope H, et al. Anabolic androgenic steroid induced myocardial toxicity: an evolving problem in an aging population. BMJ case reports.2011;2011. Return to content
- Mesbah Oskui P, French WJ, Herring MJ, Mayeda GS, Burstein S, Kloner RA. Testosterone and the cardiovascular system: a comprehensive review of the clinical literature. Journal of the American Heart Association. Dec 2013;2(6):e000272. Return to content
- Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease?Trends in endocrinology and metabolism: TEM. Aug 2010;21(8):496-503. Return to content
- Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS. Testosterone and atherosclerosis in aging men: purported association and clinical implications. American journal of cardiovascular drugs: drugs, devices, and other interventions.2005;5(3):141-154. Return to content
- Kelly DM, Jones TH. Testosterone: a vascular hormone in health and disease.The Journal of endocrinology. Jun 2013;217(3):R47-71 Return to content
- Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circulation. Heart failure. May 1 2012;5(3):315-321. Return to content
- Corona G, Rastrelli G, Monami M, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. European journal of endocrinology / European Federation of Endocrine Societies. Nov 2011;165(5):687-701. Return to content
- Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis.The Journal of clinical endocrinology and metabolism. Jun 2010;95(6):2560-2575. Return to content
- 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 Clinic proceedings. Mayo Clinic. Jan 2007;82(1):29-39. Return to content
- Carson CC, 3rd, Rosano G. Exogenous testosterone, cardiovascular events, and cardiovascular risk factors in elderly men: a review of trial data. The journal of sexual medicine. Jan 2012;9(1):54-67. Return to content
- Baillargeon J, Urban RJ, Kuo Y-F, et al. Risk of Myocardial Infarction in Older Men Receiving Testosterone Therapy. Ann Pharmacother 1060028014539918, first published on July 2, 2014 as doi:10.1177/1060028014539918. 2014. Return to content
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