Testosterone Replacement Therapy & Cardiovascular Risk: Weighing the Evidence

Erik Gudmundson TRT Studies

When a man looks for ways to improve his health and quality of life it would not be wise to choose short-term benefits that lead to an eventual long-term loss. There has been some controversy in the past regarding testosterone replacement therapy (TRT) suggesting that men taking testosterone might have increased risk of illness down the line. One area of question regarding TRT is its effect on the rates of cardiovascular adverse events (CVAE). At Full Potential Men’s Clinic the published evidence leads us to believe that correcting a testosterone deficiency is healthier and safer than leaving that deficiency untreated. Let’s go over some of the information on TRT and cardiovascular health that leads us to believe that TRT is actually quite safe, as opposed to what some other sources would have you believe.

Testosterone has been studied quite a lot since it was isolated from animal tissue in 1935. It can be difficult to wade through everything that has been written on the hormone. In fact there is so much information we can sometimes see similar reports with the exact opposite conclusions. In cases like these it is important to weigh the quality of the data on each side of the question.

Studies Comparing Endogenous (Self-Made) Testosterone Levels

Malkin et al performed an interesting study which compared the blood testosterone levels in men who were about to undergo angiography (1). The testosterone levels were found to be similar between men with coronary heart disease (CHD) and those without. The more interesting part was the later finding that among men with CHD, those with higher testosterone levels at baseline had a much better cumulative survival time than those with lower levels. It appears at least where endogenously produced testosterone is concerned, that testosterone has a protective effect on the heart.

Alexandersen et al reviewed a number of articles on testosterone and CHD and composed a summary. They stated, “In conclusion, one intervention, eight cohort and several cross-sectional studies [29 out of 30 in the review] suggest either a neutral or a favourable effect of testosterone and DHEA-S on coronary heart disease in males. (2)” This review is helpful because sometimes we can get the wrong idea on a scientific question with limited data. As more studies are carried out with consistent results we can be more confident in our answer.

This isn’t even the tip of the iceberg of studies on testosterone levels and cardiovascular health. Still, it would appear that when men have healthy levels of testosterone they are at least no-more-likely to suffer or die from CHD and possibly are protected by these higher levels.

Studies Comparing Exogenous (Supplemented) Testosterone Levels

The next question a critical thinker might ask is, “Do we see the same neutral-to-protective effects on cardiovascular health in men taking TRT?” This question is not an easy one to answer. There is the temptation to either gloss-over huge swaths of information, or to become so inundated with data that we can’t process it all into a theme.

I was impressed though by an article by Borst et al (3) for the way it covered both sides of the issue with reasonable thoroughness without getting lost in details.

Articles Finding Increased Cardiovascular Risk With Testosterone Therapy & Critiques / Comments

This study (4) was halted when the incidence of cardiovascular adverse events (CVAE’s) was measured significantly higher than the placebo group. Randomized, controlled studies are typically thought of as high quality data, so one should not take this finding lightly. However in the light of other studies showing conflicting results we are left to question, “why in this specific experiment were there more AE’s?” Borst et al proposed an answer to this question which we will discuss.

This (5) so-called “study” is the “VA Study” that gets mentioned whenever CVD and TRT are discussed. While it certainly made headlines, the quality of the data it presents is quite poor. The Androgen Study Group wrote an open letter (6) calling for retraction of this study because its conclusions were the opposite of what its actual data showed, and because of the failure of the authors to make the necessary post-publication corrections.

This (7) study is a cohort study that analyzed the data in a health records database. They found that non-fatal heart attacks happened more frequently after starting TRT than during the year before. Cohort studies are limited in that they can only detect association between two events, but cannot prove causation. The article, itself, attempts to explain why TRT might lead to increased CVAE’s mentioning increased blood pressure, polycythemia, and estradiol.

In my experience more than half of physicians who prescribe testosterone are aware of the risk of polycythemia and do recommend that patients donate blood or have therapeutic phlebotomy performed regularly. It is true though that almost no physician who prescribes testosterone monitors or manages their patients for the increased risk caused by increased estradiol and other estrogens, among many other failures, and this increased risk is significant. We are very careful to monitor both polycythemia and estradiol, as well as blood pressure, and many other potential risk factors in general at Full Potential Men’s Clinic. One of the hallmarks of a high-quality TRT program is how well it manages estradiol and other estrogens. If these patients were monitored for these risk factors, they likely would have had decreased rather than potentially increased risk for CVAE’s

I wonder also what the results would have been if they had been able to include data on fatal heart attacks. Is it possible that fatal heart attacks happened more frequently during the next year for men who did not begin TRT?

One meta-analysis (8) (study of studies) found that there was increased risk of CVAE’s with testosterone therapy when the studies were not funded by the pharmaceutical industry, compared to no or decreased risk for CVAE’s when the studies were funded by the pharmaceutical industry. Very mysterious, because …

Articles Finding No or Decreased Cardiovascular Risk With Testosterone Therapy & Critiques / Comments

These two studies (9 and 10) are systematic reviews and meta-analyses (they are each a study of studies) of placebo-controlled randomized trials. The first meta-analysis study (9) included, reviewed, and studied more studies than (8) did (75 vs. 27 – a lot more data analyzed), and its result was quite to the contrary. Specifically, here is a quote from the second meta-analysis study (10): “The present systematic review and meta-analysis does not support a causal role between [testosterone supplementation (TS)] and adverse CV events. Our results are in agreement with a large body of literature from the last 20 years supporting TS of hypogonadal men as a valuable strategy in improving a patient’s metabolic profile, reducing body fat and increasing lean muscle mass, which would ultimately reduce the risk of heart disease.”

This study (11) is titled, “Low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina: a randomized, double-blind, placebo-controlled study.” This was a randomized controlled trial where men with chronic stable angina were given small amounts of testosterone to see if it improved their ability to exercise before their heart showed signs of angina on EKG. It was found that the men who were given testosterone were able to withstand exercise longer than the men in the placebo group without showing signs of angina on EKG.

This meta-analysis study (12) is titled, “Testosterone supplementation in heart failure: a meta-analysis.” This meta-analysis was a review of 6 randomized controlled trials again studying testosterone replacement in men with heart failure. The study found the men who received testosterone were able to walk farther in a set time and had more oxygen throughput than the placebo group. There were no significant CVAE’s in these studies.

This study (13) is titled, “Risk of myocardial infarction in older men receiving testosterone therapy.” This population-based cohort study used the Medicare records database to evaluate the risk of heart attack for men taking testosterone injections. Their results stated that when including all cardiovascular risk groups (low risk of heart attack to high risk) there was no increased rate of heart attack compared to men who did not take testosterone. In the specific case of men with high-risk the rates of heart attack were less than men who did not take testosterone.

Our Conclusions

Getting back to the question raised by the Basaria et al (4) (where the randomized controlled study was halted when the treatment group seemed to be having more CVAE’s), “why in this specific experiment were there more AE’s [when other studies seem to show different results]?” There was an attempt to answer this by Borst et al (3) by preparing their own systematic analysis. They wondered if the different testosterone medicines had different inherent risks. That analysis concluded, “Oral TRT produces significant CV risk. While no significant effects on CV risk were observed with either injected or transdermal TRT, the point estimates suggest that further research is needed to establish whether administration by these routes is protective or detrimental, respectively. Differences in the degree to which serum DHT is elevated may underlie the varying CV risk by TRT administration route, as elevated serum dihydrotestosterone has been shown to be associated with CV risk in observational studies.” So, taking into account multiple studies, we don’t continue to see the results of the Basaria (4) study. However, it appears that topical applications of testosterone are more likely to increase dihydrotestosterone, which is associated with increased CVAE’s.

What I take away from these two studies (3 & 4) is that TRT with injectable forms of testosterone is actually a low-risk avenue of treatment. Also, as with any medical treatment, proper monitoring by an experienced professional is highly important for these treatments to be health-promoting rather than risk-inducing.

To summarize, in this article we have presented a significant number of studies related to testosterone and cardiovascular health. While there are some studies that show a potential negative effect of TRT, the weight of the evidence favors TRT having a neutral effect on CVAE’s and for some men possibly reducing their risk. Certainly we ought to keep our minds open to advancing biomedical knowledge or new developments in how to address symptoms of hypogonadism or low testosterone. In the meantime it is reasonable to expect that men will still be heart-healthy as they get relief from their symptoms through appropriate, well-monitored TRT regimens.

Studies / Citations

  1. Malkin, Chris J., et al. “Low serum testosterone and increased mortality in men with coronary heart disease.” Heart 96.22 (2010): 1821-1825.
  2. Alexandersen, Peter, Jens Haarbo, and Claus Christiansen. “The relationship of natural androgens to coronary heart disease in males: a review.” Atherosclerosis 125.1 (1996): 1-13.
  3. Borst, Stephen E., et al. “Cardiovascular risks and elevation of serum DHT vary by route of testosterone administration: a systematic review and meta-analysis.” BMC medicine 12.1 (2014): 1.
  4. Basaria, Shehzad, et al. “Adverse events associated with testosterone administration.” New England Journal of Medicine 363.2 (2010): 109-122.
  5. Vigen, Rebecca, et al. “Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels.” Jama 310.17 (2013): 1829-1836.
  6. Morgentaler, Abraham, MD. “Letter to JAMA Asking for Retraction of Misleading Article on Testosterone Therapy.” The Androgen Study Group. N.p., 25 Mar. 2014. Web. 21 July 2016.
  7. Finkle, William D., et al. “Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men.” PloS one 9.1 (2014): e85805.
  8. Xu, Lin, et al. “Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials.” BMC medicine 11.1 (2013): 1.
  9. Shuster, Jonathan J., Jennifer D. Guo, and Jay S. Skyler. “Meta‐analysis of safety for low event‐rate binomial trials.” Research synthesis methods 3.1 (2012): 30-50.
  10. Corona, Giovanni, et al. “Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis.” Expert opinion on drug safety 13.10 (2014): 1327-1351.
  11. English, Katherine M., et al. “Low-Dose Transdermal Testosterone Therapy Improves Angina Threshold in Men With Chronic Stable Angina A Randomized, Double-Blind, Placebo-Controlled Study.” Circulation 102.16 (2000): 1906-1911.
  12. Toma, Mustafa, et al. “Testosterone supplementation in heart failure a meta-analysis.” Circulation: Heart Failure 5.3 (2012): 315-321.
  13. Baillargeon, Jacques, et al. “Risk of myocardial infarction in older men receiving testosterone therapy.” Annals of Pharmacotherapy (2014): 1060028014539918.