Testosterone, Cardiovascular Risk, Mortality and Longevity

Testosterone, Cardiovascular Risk, Mortality and Longevity

Testosterone Therapy and Cardiovascular Risk: Advances and Controversies. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Mayo Clin. Proc. 2015;90(2):224-251.

Testosterone and mortality. Muraleedharan V, Jones TH. Clin. Endocrinol. (Oxf). 2014;81(4):477-487.

One of the most debated issues related to testosterone replacement therapy is its effects on cardiovascular risk and clinical events, like for example heart attack. A few flawed studies over the past years made it appear that testosterone replacement therapy increases cardiovascular risk and incidence of heart attacks. However, less known is the vast and rapidly accumulating body of evidence showing the contrary; that higher testosterone levels and testosterone replacement therapy actually may reduce mortality and increase longevity.

This editorial summarises key conclusions from a special medical review article on testosterone and cardiovascular risk, written by the Androgen Study Group1, as provides answers to the following two questions:2

  1. Is testosterone deficiency directly involved in the pathogenesis of these conditions or is it merely a biomarker of ill health and the severity of underlying disease processes?
  2. Does testosterone replacement therapy retard disease progression and ultimately enhance the clinical prognosis and survival?

KEY POINTS1,2

  • Low levels of testosterone are associated with increased risk of mortality from cardiovascular disease and all causes.
  • Development of damage or disease in the heart's major blood vessels (coronary artery disease), as well as its severity, is associated with lower testosterone levels.
  • Atherosclerosis (measured by ultrasound, also known as carotid intima-media thickness) is inversely correlated with testosterone levels, meaning that lower levels of testosterone are associated with more severe atherosclerotic deposits in arteries, especially the arteries that pass up the neck and supply the head.
  • Testosterone therapy is associated with a significant reduction in obesity and fat mass.
  • Testosterone therapy is associated with a decrease in blood sugar levels and insulin resistance, as well as improved glucose metabolism (measured by glycated hemoglobin, HbA1c) in pre-diabetic and diabetic men.
  • Testosterone therapy improves time to onset of symptomatic angina (a type of chest pain caused by reduced blood flow to the heart) with exercise.
  • Testosterone therapy improves exercise capacity and peak oxygen consumption in men with symptomatic congestive heart failure (a chronic condition in which the heart doesn't pump blood as well as it should).
  • Testosterone deficiency is an independent risk factor for future development of obesity, the metabolic syndrome and type 2 diabetes, which are all major risk factors for cardiovascular disease; the leading cause of death worldwide.
  • Testosterone deficiency is an indicator of general poor health and the severity of underlying disease processes.
  • Experimental data suggest that testosterone deficiency may be directly involved in the development of atherosclerosis and cardiovascular disease.
  • Men with testosterone deficiency have an up to 2-fold increased mortality risk primarily from cardiovascular disease.
  • Survival and longevity are the ultimate goals of interventions in medicine. Two notable studies show that testosterone therapy increases longevity in hypogonadal men by 2-fold.

What is known

It is well documented that low testosterone is an independent risk factor for future development of obesity, the metabolic syndrome and type 2 diabetes.3 These medical conditions are all major risk factors for cardiovascular disease, which is the leading cause of death worldwide.4 Cardiovascular disease alone claims more lives each year than any other major cause of death.4

Testosterone deficiency is associated with notable cardiovascular risk factors, including insulin resistance, abdominal obesity, dyslipidemia, endothelial dysfunction, hypertension, inflammation.3,5,6 We covered this in more detail in a previous editorial “Testosterone and Cardiovascular Risk in Men”.

Despite this, two studies alleged that testosterone therapy was harmful and made large media headlines.7,8 The first study, published in Nov 2013, compared the incidence of cardiovascular events (heart attack, stroke and mortality) between subjects who received testosterone therapy and those who did not.7 This was a heavily flawed study for many reasons. Notably, raw data showed less events of each endpoint in the testosterone-treated group, but questionable statistical analysis using greater than 50 variables then suggested the opposite result.7

The second study, which collected data from a health-care database following 55,593 prescriptions for testosterone, reported an increased risk of non-fatal heart attacks in the 3 months after the prescriptions were issued compared to the prior 12 months in these patients.8 There are several weaknesses in this study; no data on whether or not hypogonadism had been diagnosed or even if testosterone levels were measured, no evidence on compliance or monitoring of testosterone levels on treatment, hematocrit or PSA etc. Also, there were no data on fatal heart attacks; it could be argued that testosterone may have reduced the severity of events from fatal to non-fatal myocardial infarcts. Both of these studies have been heavily criticized by distinguished testosterone academicians and clinicians9-11 and a retraction has even been requested due to ethical misconduct and misleading information.12

What these new medical reviews add

A growing body of evidence shows that testosterone deficiency has adverse effects on several salient cardiovascular risk factors, and is associated with an increased severity of atherosclerosis; the root underlying cause of cardiovascular diseases like heart attack and stroke.

The observations that men with higher testosterone levels have reduced mortality and that low testosterone increases the risk of cardiovascular death, coupled with results showing a reduction in atherosclerosis with testosterone replacement therapy, suggest that testosterone deficiency over time has an adverse effect on the atherosclerotic process. This, together with the improvement of multiple established cardiovascular risk factors by testosterone therapy, suggest that testosterone therapy may help prevent the development and/or progression of atherosclerosis and cardiovascular disease.

The review by the Androgen Study Group in addition highlights two important, but relatively unknown, issues:

Testosterone prescriptions

Prescription rates for testosterone products have increased substantially worldwide over the last decade.13-17 However, despite this only 10% to 12% of testosterone deficient men are actually receiving testosterone treatment for their hypogonadism.18,19 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.20
We covered the topic of testosterone and prostate cancer in detail in a previous editorial “Testosterone and Prostate Cancer - a paradigm shift - "Bye-bye Androgen Hypothesis, Welcome Saturation Model".
With the wealth of evidence outlined in the Mayo Clinic review, now doctors and patients can be less concerned about cardiovascular risks.

Public health burden of hypogonadism

To the surprise of many, 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.21 This in turn has been estimated to be directly responsible for approximately $190–$525 billion in inflation-adjusted U.S. health care expenditures.21 Medical forecasts also predict increased outpatient visits and costs from low baseline testosterone levels, independent of socio-economic and lifestyle factors and age. Notably, men aged 20 - 79 years at baseline with low testosterone levels had 29% more outpatient visits and 38% higher outpatient costs after a 5-year follow up.22

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References

1. Morgentaler A, Miner MM, Caliber M, Guay AT, Khera M, Traish AM. Testosterone Therapy and Cardiovascular Risk: Advances and Controversies. Mayo Clin. Proc. 2015;90(2):224-251.
2. Muraleedharan V, Jones TH. Testosterone and mortality. Clin. Endocrinol. (Oxf). 2014;81(4):477-487.
3. Rao PM, Kelly DM, Jones TH. Testosterone and insulin resistance in the metabolic syndrome and T2DM in men. Nature reviews. Endocrinology. 2013;9(8):479-493.
4. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2015 Update: A Report From the American Heart Association. Circulation. 2014.
5. Kelly DM, Jones TH. Testosterone and cardiovascular risk in men. Front. Horm. Res. 2014;43:1-20.
6. Jones TH. Testosterone deficiency: a risk factor for cardiovascular disease? Trends in endocrinology and metabolism: TEM. 2010;21(8):496-503.
7. 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(17):1829-1836.
8. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS one. 2014;9(1):e85805.
9. Morgentaler A. Will I have a heart attack or stroke if I take testosterone therapy? The journal of sexual medicine. 2014;11(6):1601-1602.
10. Morgentaler A, Lunenfeld B. Testosterone and cardiovascular risk: world's experts take unprecedented action to correct misinformation. The aging male : the official journal of the International Society for the Study of the Aging Male. 2014;17(2):63-65.
11. Morgentaler A, Traish A, Kacker R. Deaths and cardiovascular events in men receiving testosterone. JAMA. 2014;311(9):961-962.
12. Morgentaler A. Letter to JAMA Asking for Retraction of Misleading Article on Testosterone Therapy. Availible at http://www.androgenstudygroup.org/initiatives/letter-to-jama-asking-for-retraction-of-misleading-article-on-testosterone-therapy, accessed July 2, 2014. 2014.
13. Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA internal medicine. 2013;173(15):1465-1466.
14. Gan EH, Pattman S, S HSP, Quinton R. A UK epidemic of testosterone prescribing, 2001-2010. Clin. Endocrinol. (Oxf). 2013;79(4):564-570.
15. Layton JB, Li D, Meier CR, 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):835-842.
16. Handelsman DJ. Pharmacoepidemiology of testosterone prescribing in Australia, 1992-2010. Med. J. Aust. 2012;196(10):642-645.
17. Handelsman DJ. Global trends in testosterone prescribing, 2000-2011: expanding the spectrum of prescription drug misuse. Med. J. Aust. 2013;199(8):548-551.
18. Hall SA, Araujo AB, Esche GR, et al. Treatment of symptomatic androgen deficiency: results from the Boston Area Community Health Survey. Arch. Intern. Med. 2008;168(10):1070-1076.
19. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int. J. Clin. Pract. 2006;60(7):762-769.
20. Khera M, Crawford D, Morales A, Salonia A, Morgentaler A. A new era of testosterone and prostate cancer: from physiology to clinical implications. Eur. Urol. 2014;65(1):115-123.
21. Moskovic DJ, Araujo AB, Lipshultz LI, Khera M. The 20-year public health impact and direct cost of testosterone deficiency in U.S. men. The journal of sexual medicine. 2013;10(2):562-569.
22. Haring R, Baumeister SE, Volzke H, 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):800-809.
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Last updated: 2017
G.GM.MH.04.2015.0334