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
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 function4-7, improved energy, mood and vitality7-11, increased lean mass6,11-14, decreased waist circumference15-19, reduced total body fat mass11-14, and increased bone mineral density.20-23 Promising new data reveal that testosterone therapy improves insulin sensitivity24-26 and reduces blood glucose15,17,27 and HbA1c15,17,19,27 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?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.28,29
The first study, published in November 2013 by Vigen et al.30, 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.31 Large data errors revealed post-publication led to a call for retraction by 29 medical societies.32
The second study, published in January 2014 by Finkle et al.33, 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.34
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.32,34-36 The FDA itself commented on these studies, concluding that none provide compelling evidence of increased cardiovascular risk.37 Indeed, it could be argued that the studies by Vigen et al.30 and Finkle et al.33 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.
Prescription rates for testosterone products have increased substantially worldwide over the last decade.38-42 However, only 10% to 12% of hypogonadal patients are actually receiving testosterone treatment for their hypogonadism.43,44 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.45 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.46 Over a 20-year period, T deficiency has been estimated to be directly responsible for approximately $190–$525 billion in inflation-adjusted U.S. health care expenditures.46 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.47
Numerous intervention studies have consistently demonstrated improvements in cardiovascular risk factors such as body fat mass and obesity11-14, waist circumference19,25, and glycemic control.19,24,25 These findings may explain the frequently observed outcome of increased mortality among men with low testosterone levels.48-54 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.49,51
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).55-64 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.25
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.65 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.65 Notably, cessation of testosterone therapy resulted in return of CV factors to baseline 24 weeks later.65
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.