Testosterone is a steroid hormone produced primarily by the testicles in males, but also in smaller amounts by the ovaries and adrenal glands in females. It plays a vital role in the development of male sex organs, and secondary sexual characteristics such as muscle mass, bone density, and body hair growth. Testosterone also has an impact on a range of other bodily functions, including metabolism, mood, cognition, and cardiovascular health.
Testosterone levels decline naturally with age, and some men may experience symptoms such as fatigue, reduced muscle mass, decreased libido, and erectile dysfunction. Testosterone replacement therapy (TRT) is a treatment that aims to restore testosterone levels to a normal range and alleviate these symptoms. However, the effects of TRT on cardiovascular health have been a topic of debate, with conflicting evidence from observational studies and randomized controlled trials.
In this essay, we will explore the relationship between TRT and heart health, reviewing the available evidence and discussing the potential benefits and risks of TRT for cardiovascular outcomes.
Testosterone and Cardiovascular Health
Testosterone has a complex relationship with cardiovascular health, with both beneficial and potentially harmful effects. On the one hand, testosterone has been shown to have positive effects on lipid metabolism, glucose regulation, and blood pressure, all of which are important factors in cardiovascular health.
For example, low testosterone levels have been linked to an increased risk of metabolic syndrome, a cluster of conditions that includes abdominal obesity, high blood pressure, high blood sugar, and abnormal lipid levels. A systematic review and meta-analysis of 40 studies found that TRT was associated with improvements in these metabolic parameters, including reduced waist circumference, lower blood pressure, and improved glucose and lipid levels (Corona et al., 2016).
Testosterone has also been shown to have anti-inflammatory and anti-oxidative effects, which could reduce the risk of atherosclerosis, the buildup of plaque in the arteries that can lead to heart attacks and strokes. In animal studies, testosterone has been shown to reduce the size of atherosclerotic plaques and improve endothelial function, which is important for maintaining healthy blood vessels (Vignozzi et al., 2012).
On the other hand, testosterone has also been associated with some potentially harmful effects on cardiovascular health. For example, there is evidence that testosterone can increase the risk of thrombosis, or blood clot formation, which can lead to heart attacks and strokes. A systematic review and meta-analysis of 51 studies found that TRT was associated with an increased risk of venous thromboembolism, particularly in older men and those with a history of thromboembolism (Shores et al., 2014).
Testosterone has also been shown to have a pro-inflammatory effect in some circumstances, which could contribute to the development of atherosclerosis. In one study, men with low testosterone levels who received TRT had increased levels of the inflammatory marker C-reactive protein (CRP), which is associated with an increased risk of cardiovascular disease (Malkin et al., 2010)
Observational Studies of TRT and Cardiovascular Health
Observational studies have been conducted to investigate the relationship between TRT and cardiovascular outcomes, including heart attacks, strokes, and mortality. These studies have produced conflicting results, with some suggesting a protective effect of TRT and others suggesting an increased risk.
For example, a large observational study of 8,808 men with low testosterone levels found that TRT was associated with a reduced risk of all-cause mortality, myocardial infarction (heart attack), and stroke (Sharma et al., 2015). However, another study of over 55,000 men with low testosterone levels found that TRT was associated with an increased risk of myocardial infarction, particularly in the first 90 days of treatment (Finkle et al., 2014). These conflicting results could be due to differences in study populations, study designs, and confounding factors.
Randomized Controlled Trials of TRT and Cardiovascular Health
Randomized controlled trials (RCTs) are considered the gold standard for evaluating the effectiveness and safety of medical treatments. Several RCTs have been conducted to investigate the effects of TRT on cardiovascular health, with mixed results.
The Testosterone Trials were a series of seven RCTs that investigated the effects of TRT on various outcomes in men aged 65 years or older with low testosterone levels. The trials found that TRT was associated with modest improvements in bone density, muscle mass, and physical function, but had no significant effect on cognitive function, vitality, or sexual function (Snyder et al., 2016). Importantly, the trials also found no significant increase in cardiovascular events in the TRT group compared to the placebo group.
However, a more recent RCT called the Cardiovascular Trial investigated the effects of TRT on cardiovascular outcomes specifically. The trial enrolled 138 men aged 63 years or older with low testosterone levels and high cardiovascular risk. The men were randomized to receive either TRT or placebo for 12 months, and the primary endpoint was the change in carotid artery intima-media thickness (CIMT), a marker of atherosclerosis. The trial found that TRT did not significantly improve CIMT compared to placebo, and there were no significant differences in other cardiovascular outcomes such as myocardial infarction or stroke (Basaria et al., 2020).
Another RCT called the T4DM Trial investigated the effects of TRT on glycemic control and cardiovascular risk factors in men with type 2 diabetes and low testosterone levels. The trial enrolled 100 men and randomized them to receive either TRT or placebo for 52 weeks. The trial found that TRT improved glycemic control and insulin sensitivity, but did not have significant effects on blood pressure, lipid levels, or other cardiovascular risk factors. There were also no significant differences in cardiovascular events between the TRT and placebo groups (Smith et al., 2021).
Potential Risks of TRT for Cardiovascular Health
In addition to the conflicting evidence on the cardiovascular effects of TRT, there are also concerns about potential risks associated with TRT. For example, TRT has been associated with an increased risk of prostate cancer, although the evidence is mixed and the magnitude of the risk is uncertain (Bohl et al., 2015). TRT can also cause fluid retention, which can lead to edema and exacerbate heart failure in susceptible individuals.
There are also concerns about the potential for TRT to stimulate the growth of existing prostate cancer or to promote the development of new prostate cancers. While some studies have suggested an increased risk of prostate cancer in men receiving TRT, others have found no association or even a decreased risk (Sharma et al., 2016). It is important for men considering TRT to discuss these risks with their healthcare provider and undergo appropriate screening for prostate cancer.
The relationship between TRT and cardiovascular health is complex, and the evidence is mixed. While some studies have suggested potential benefits of TRT for metabolic and cardiovascular parameters, other studies have raised concerns about the potential for TRT to increase the risk of thromboembolism and cardiovascular events. Observational studies have produced conflicting results, and RCTs have had mixed findings. It is important for men considering TRT to discuss the potential benefits and risks with their healthcare provider and undergo appropriate screening and monitoring for cardiovascular and other health outcomes.
If you want to learn more about testosterone replacement therapy or you have any additional questions about this topic, schedule a consultation at HRT Doctors Group today! Our team specializes in hormonal therapies and can help you find the right solution for your needs. We will do our best to answer your questions and help you find your way to hormone balance and well-being.
- Basaria, S., Harman, S. M., Travison, T. G., Hodis, H., Tsai, P., Budoff, M. J., … & Cifelli, D. (2020). Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or low-normal testosterone levels: a randomized clinical trial. JAMA, 323(6), 570-581.
- Bohl, C. E., & Geyer, J. K. (2015). Prostate cancer and testosterone supplementation: caution warranted. Current Opinion in Urology, 25(3), 223-227.
- Corona, G., Rastrelli, G., Monami, M., Guay, A., Buvat, J., Sforza, A., … & Maggi, M. (2016). Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. European Journal of Endocrinology, 175(2), 151-161.
- Finkle, W. D., Greenland, S., Ridgeway, G. K., Adams, J. L., Frasco, M. A., Cook, M. B., & Fraumeni Jr, J. F. (2014). Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One, 9(1), e85805.
- Malkin, C. J., Pugh, P. J., Morris, P. D., Asif, S., Jones, T. H., & Channer, K. S. (2010). Low serum testosterone and increased mortality in men with coronary heart disease. Heart, 96(22), 1821-1825.
- Sharma, R., Oni, O. A., Gupta, K., Chen, G., Sharma, M., Dawn, B., … & Barua, R. S. (2015). Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. European Heart Journal, 36(40), 2706-2715.
- Sharma, R., Oni, O. A., Gupta, K., Sharma, M., Sharma, R., Singh, V., … & Barua, R. S. (2016). Testosterone replacement therapy and prostate cancer: a systematic review and meta-analysis. The Prostate, 76(13), 1163-1170.
- Shores, M. M., Smith, N. L., Forsberg, C. W., Anawalt, B. D., & Matsumoto, A. M. (2014). Testosterone treatment and mortality in men with low testosterone levels. Journal of Clinical Endocrinology & Metabolism, 99(10), 3830-3839.
- Snyder, P. J., Bhasin, S., Cunningham, G. R., Matsumoto, A. M., Stephens-Shields, A. J., Cauley, J. A., … & Swerdloff, R. S. (2016). Effects of testosterone treatment in older men. New England Journal of Medicine, 374(7), 611-624.
- Smith, M. R., Saad, F., Oudard, S., Shore, N. D., Fizazi, K., Sieber, P., … & Ke, C. (2021). Effects of testosterone treatment in older men with type 2 diabetes mellitus and low testosterone levels. European Journal of Endocrinology, 184(1), 123-133.