Testosterone is the primary male sex hormone and has essential bodily roles, such as maintaining and developing sex organs and genitalia, muscle mass, red blood cell levels, bone density, sense of well-being, and sexual and reproductive function.
After reaching a peak in your 30's, testosterone concentrations decrease about 1% yearly. In addition, 10-15% of middle-aged and older men have testosterone levels below the lower limit of the normal range for healthy young men. Patients with low testosterone who are symptomatic should be treated with testosterone replacement therapy (TRT).
Symptoms of testosterone deficiency include:
- Sexual symptoms (decreased libido, poor erections).
- Loss of skeletal muscle.
- Impaired physical performance.
- Low bone mineral density.
- Increased incidence of osteoporosis.
- Increased body fat.
- Increased risk of diabetes and metabolic syndrome.
- Increased incidence of depression.
No clear evidence exists that testosterone treatment increases the risk of major cardiovascular (CV) events. Previous studies have reported conflicting data on the possible risk between CV events and TRT. In addition, until now, there has not been a study long enough or large enough to clarify the CV risk associated with testosterone treatment.
Findings from what researchers call "the largest testosterone replacement therapy (TRT) trial ever" suggest TRT is not associated with an increase in major adverse cardiovascular events. The study pertains to middle-aged and older hypogonadal men with a pre-existing or high cardiovascular disease (CVD) risk.
Results from the recently published TRAVERSE trial found that major cardiac issues were not more common among men using testosterone gel than those using a placebo.
The TRAVERSE trial, conducted at the Cleveland Clinic, is a randomized, double-blind study in which 5,246 men between the ages of 45-80 were randomly assigned to receive either daily transdermal 1.62% testosterone gel or placebo gel over 22 months. Results showed no significant difference in the rate of heart attacks, strokes, or death from any CV problem between patients who used testosterone gel and those using a placebo.
Major cardiac events occurred in 182 patients in the testosterone group and 190 patients in the placebo group. However, patients in the testosterone group did have a higher incidence of irregular heartbeat, acute kidney injury, and pulmonary embolism: current guidelines advise caution in using TRT in men with a history of blood clots.
According to Dr. Joshua Halpern, a urologist at Northwestern Medicine in Chicago, "This [study] has provided the closest thing we have to a definitive answer about cardiovascular risk and testosterone therapy."
While this study addressed short and medium-duration TRT treatment, it did not address the risk of long-term risks. In addition, the study only evaluated testosterone in gel form, so findings may not apply to other modes of testosterone delivery, such as injections and pills. However, the results of the TRAVERSE trial should help alleviate concerns patients and physicians have related to TRT and CV disease risks.
This large study helps fill in a void of understanding how testosterone treatment affects CVD outcomes for men with testosterone deficiency. It is well established that testosterone levels decline with age while CV mortality increases. The TRAVERSE study clarifies that TRT does not increase the risk of CV events.
A 2022 study also uncovered evidence that helps dispel the myth that TRT contributes to CV events. The study found no evidence that testosterone increases short-term to medium-term CV risks in hypogonadal men. The study compared mortality and cardiovascular and cerebrovascular events during follow-up. More than 3,000 participants were randomized to either the testosterone or placebo groups. However, little data evaluated testosterone's CV safety longer than a 12-month treatment.
History of Testosterone/CV Disease Studies
The TRAVERSE trial was born out of necessity. In 2010, a small study was terminated due to an increased incidence of CV events among patients who received testosterone. In response to this and concerns over conflicting data regarding the CV safety of TRT, the Food and Drug Administration (FDA) conducted a review that revealed that many men were being treated with testosterone therapy without their serum testosterone levels ever being checked.
In response to small studies showing a risk of adverse CV events associated with testosterone therapy, in 2014 the FDA mandated that safety warning labels, also known as Black Box Warnings, be placed on all testosterone products indicating their use potentially increased risk of stroke and heart attack.
In 2015, the FDA required the makers of testosterone products to "conduct a well-designed clinical trial to more clearly address the question of whether an increased risk of heart attack or stroke exists" for men who take testosterone. As a result, the TRAVERSE trial was initiated to address the required FDA mandate.
Whether the FDA will remove or alter testosterone products' mandated CV safety warning is unclear.
The TRAVERSE study provides the most definitive answer to questions related to the risk of CV events due to TRT.
- Testosterone therapy appears to be generally safe from an overall CV standpoint.
- The incidence of irregular heartbeat, acute kidney injury, and pulmonary embolism was higher in the testosterone patient group.
- Avoiding TRT in men with a history of thromboembolic events, atrial fibrillation, or kidney insufficiency (disease) may be prudent.
- The latest research results apply to patients with symptomatic hypogonadism and do not address the safety of testosterone in people with normal testosterone levels who take testosterone solely to build muscle.
- Drug manufacturers created the TRAVERSE trial in response to the FDA's requirement in 2015 that manufacturers of TRT conduct a study addressing testosterone and CVD.