The FDA is proposing significant changes to testosterone replacement therapy (TRT) labeling that could make the hormone treatment more accessible to millions of men, but new cardiovascular risks have emerged that doctors say require careful monitoring. The agency is removing long-standing warnings about heart attack and stroke risk, while adding new cautions about atrial fibrillation, blood clots in the lungs, and acute kidney injury.

Testosterone is a hormone produced mainly in the testicles that plays crucial roles in men's health. It builds and preserves muscle mass, supports sexual function and mental resilience, and helps maintain energy and overall well-being. Testosterone naturally declines with age, dropping about 1% to 2% per year after men reach age 30.

When testosterone levels fall below normal and men experience symptoms like chronic fatigue or erectile dysfunction, they may be diagnosed with age-related hypogonadism. TRT, available as gels, skin patches, and injectables, can ease these symptoms, but the treatment has been controversial due to cardiovascular concerns.

What Changed in the FDA's Position on Testosterone Therapy?

In 2014, the FDA issued a warning linking TRT to higher risks of stroke, heart attack, and death. But new evidence is shifting that stance. The FDA's proposed labeling changes were prompted by results from the TRAVERSE clinical trial, an industry-sponsored study that found no elevated risk of cardiovascular events like stroke or heart attack in men taking TRT for age-related hypogonadism.

Based on these findings, the FDA recommended last year that manufacturers remove cautionary language from TRT labels warning of heart attack and stroke risk. This year, the agency proposed additional changes, including dropping language stating that TRT's safety and effectiveness are unproven in men with age-related hypogonadism.

However, the TRAVERSE study revealed a troubling trade-off. Compared with men given a placebo, TRT-treated men had higher risks for other serious side effects, including atrial fibrillation (an irregular heart rhythm), acute kidney injury, and blood clots in the lungs.

Which Men Should Be Most Cautious About TRT?

Experts emphasize that certain health conditions warrant extra caution before starting testosterone therapy. According to Dr. Marc B. Garnick, Gorman Brothers Professor of Medicine at Harvard Medical School and Editor in Chief of the Harvard Special Health Report Guide to Prostate Diseases, men with underlying clotting issues face particular risk.

Dr. Marc

"Many of the men who developed these problems may have had pre-existing abnormalities in platelet function or in coagulation factors that predispose them to blood clots. If I'm counseling a man who is contemplating TRT, I make sure he doesn't have underlying clotting issues," said Dr. Garnick.

Dr. Marc B. Garnick, Gorman Brothers Professor of Medicine at Harvard Medical School

Dr. Garnick also noted that testosterone therapy can increase red blood cell counts, measured as hemoglobin and hematocrit. These lab values need to be monitored regularly to avoid high levels that may give rise to circulatory problems.

Steps to Monitor Your Health While on Testosterone Therapy

• Regular Blood Work: Get routine checks of red blood cell counts (hemoglobin and hematocrit levels) to prevent dangerously high levels that could increase clot risk and other circulatory problems.
• Prostate-Specific Antigen (PSA) Testing: Undergo regular PSA checks to monitor for prostate cancer, since testosterone administration can cause small elevations in PSA levels that may lead to a cancer diagnosis.
• Baseline Clotting Assessment: Before starting TRT, discuss with your doctor whether you have any underlying clotting disorders or abnormalities in platelet function that could increase your risk of blood clots.
• Blood Pressure Monitoring: The FDA has proposed a new warning about potential treatment-related increases in blood pressure, so regular monitoring is essential.

The FDA continues to specify that men with metastatic prostate cancer should not use testosterone. For men with low-grade localized known or suspected prostate cancer, the FDA suggests a less strict warning, allowing them to discuss the pros and cons of TRT with their physician.

For men with benign prostate hyperplasia (BPH), an enlarged prostate that impedes urine flow, the FDA is recommending updated warnings. While the TRAVERSE clinical trial did not demonstrate worsening urinary symptoms in men with mild or moderate BPH symptoms, men with severe symptoms should avoid TRT.

What Does the FDA's Shift Mean for Access to Testosterone Therapy?

Dr. Garnick explained the broader implications of the FDA's proposed changes. "I think they're clearly easing the ability of men to access TRT and also easing the hesitancy of prescribers to make it available," he stated.

Dr. Garnick

Originally, TRT was approved for patients with little to no testosterone, such as those with Klinefelter's disease, a genetic condition that prevents the testicles from making enough hormone, or men who had both testicles removed. The FDA based its approval of these medicines on normalizing blood testosterone levels rather than on measures of effectiveness at relieving symptoms.

Age-related hypogonadism is defined as two separate morning testosterone values below 300 nanograms per deciliter, when blood levels are typically at their peak, along with symptoms such as decreased libido, fewer spontaneous erections, fatigue, low energy, or depressed mood. However, these symptoms vary from man to man and can result from other factors like insufficient sleep.

"If men with symptoms of hypogonadism are aware of the risks and have an informed discussion with their physician, I think it's perfectly appropriate to give TRT a try," said Dr. Garnick.

Dr. Marc B. Garnick, Gorman Brothers Professor of Medicine at Harvard Medical School

The bottom line: while the FDA is removing some barriers to testosterone therapy access, men considering TRT should have thorough conversations with their doctors about their individual cardiovascular and clotting risk factors, undergo baseline testing, and commit to regular monitoring of blood work and prostate health markers throughout treatment.