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 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 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 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 Group, as provides answers to the following two questions:
- 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?
- Does testosterone therapy retard disease progression and ultimately enhance the clinical prognosis and survival?
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 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:
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