Testosterone therapy and cardiovascular risk - advances and controversies
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.
One of the most debated issues related to testosterone therapy is its effects on cardiovascular risk, such as heart attack and stroke. This editorial summarizes key conclusions from a special review article written by the Androgen Study Group and published in Mayo Clinic Proceedings.1
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.2,3 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.2,3 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.4,5
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 function6-9, improved energy, mood and vitality9-13, increased lean mass8,13-16, decreased waist circumference17-21, reduced total body fat mass13-16, and increased bone mineral density.22-25 Promising new data reveal that testosterone therapy improves insulin sensitivity26-28 and reduces blood glucose17,19,29 and HbA1c17,19,21,29 levels in men with type 2 diabetes or obesity.
Numerous studies have consistently demonstrated improvements in cardiovascular risk factors with testosterone therapy, such as body fat mass and obesity13-16, waist circumference21,27, and glycemic control.21,26,27 These findings may explain the frequently observed outcome of increased mortality among men with low testosterone levels.4,5,30-34
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?1
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.35,36
The first study, published in November 2013 by Vigen et al.37, reported increased rates of heart attacks, strokes, and deaths in men who received testosterone prescriptions compared with untreated men, using scrupulous 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.38 Large data errors revealed post-publication led to a call for retraction by 29 medical societies.39
The second study, published in January 2014 by Finkle et al.40, reported an increased rate of heart attacks in the period up to 90 days following receipt of a testosterone prescription compared with the prior 12 months. However, the observed number of heart attacks among men who received a testosterone prescription was only one-third of the expected rate in the general population, and because of the absence of a control group of men who did not receive testosterone prescription, one cannot determine whether the reported heart attack events were higher, lower, or unchanged in association with a testosterone prescription.41
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.39,41-43 The FDA itself commented on these studies, concluding that none provide compelling evidence of increased cardiovascular risk.44
Notable key effects of testosterone therapy in regards to cardiovascular risk
Supporting the conclusions from the review by the Androgen Study Group are two notable studies. The first of these showed a reduction in atherosclerosis (measured by carotid intima media thickness) among testosterone deficient men treated with testosterone.27 Interestingly, the greater the magnitude of the increase in testosterone levels with treatment, the greater the magnitude of atherosclerosis reduction.
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 obese hypogonadal men.45 Testosterone treatment resulted in significant reduction in atherosclerosis and improvement in heart function (measured by cardiac ejection fraction). Notably, cessation of testosterone therapy resulted in return of these health improvements to baseline 24 weeks later.45
These studies raise the possibility that restoring testosterone levels with testosterone therapy may actually reverse atherosclerosis in men who have testosterone deficiency.
Prescription rates for testosterone products have increased substantially worldwide over the last decade.46-50 However, only 10% to 12% of hypogonadal patients are actually receiving testosterone treatment for their hypogonadism.51,52 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.53 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.54 Over a 20-year period, T deficiency has been estimated to be directly responsible for approximately $190 to $525 billion in inflation-adjusted U.S. health care expenditures.54 In line 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.55
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.