The TRT Turnaround: How New Research Led the FDA to Reverse Testosterone Warnings

A Decade of Data: How the TRAVERSE Trial Reshaped the FDA's Testosterone Guidelines

 From Caution to Clarity: The FDA's Evolving Stance on Testosterone Warnings (2015 vs. 2025)

In the realm of public opinion, even that of healthcare professionals, there has been a great deal of misconceptions involving the safety and efficacy of testosterone when used as a medication in the past several decades.  This is mostly based on faulty research and clinical trials that were poorly designed and easily disproven. Medical guidance and governance of testosterone replacement therapy (TRT) has been significantly shaped by regulation from the U.S. Food and Drug Administration (FDA) which has finally taken a more educated approach and is now saying what many of us have known all along. In 2015, the FDA issued a stringent label warning for testosterone products, largely driven by concerns about heart health and potential cardiovascular risks. This warning was concerning to many patients and providers as it suggested a possible link between TRT and CV events. Well, let’s fast forward to February 2025, and the FDA has made a significant reversal, removing the most severe cardiovascular warnings while introducing new considerations to testosterone. This shift reflects a decade of evolving scientific understanding, particularly the findings of a pivotal clinical trial and no longer looks at antiquated trials to base their decisions.

The 2015 Warning: TRT and its Unwarranted Cardiovascular Concerns

Before 2015, anecdotal reports and some observational studies suggested a possible link between TRT and an increased risk of serious cardiovascular events, such as heart attack and stroke. Some of these studies drew their conclusions from elderly patients with preexisting heart conditions who started testosterone after having cardiovascular events. When there were additional cardiovascular events, they chalked it up to testosterone as the culprit despite a past history of heart problems. While these studies often had limitations in their design (e.g., retrospective analysis, small sample sizes, or not adequately accounting for confounding factors as discussed above), the FDA took a proactive, cautious stance.

So with poorly formulated data and concerns,  the FDA mandated a class-wide labeling change for all approved testosterone products in March of 2015. This included adding  a prominent "Boxed Warning", often referred to as a "black box warning" on all testosterone medications to highlight the “potential” for increased risk of heart attack and stroke in men taking prescription testosterone. This warning was broadly applied and put on all TRT formulations, such as patches, pellets, gels/creams or injectable testosterone, emphasizing the need for patient and provider caution and urging healthcare professionals to only prescribe testosterone for men with a confirmed medical condition associated with low testosterone, rather than for age-related decline alone. This action significantly impacted the prescribing practices for providers, making many doctors hesitant to initiate TRT due to the perceived elevated risk to the patients and the potential for litigation or malpractice for the clinician.

The FDA’s February 2025 Reversal: A Data-Driven Update

Fortunately the recent FDA update this past February of 2025 marks a substantial change in policy, primarily driven by the results of a study called the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) clinical trial (Yes, we know it’s long!). This was a large-scale, randomized, placebo-controlled study conducted that involved over 5,200 men who were diagnosed with hypogonadism and had a history or who were considered high risk of cardiovascular disease, and was designed specifically to evaluate the cardiovascular safety of testosterone therapy over a mean follow-up of close to three years (33 months to be exact).

Interestingly and to no surprise to those of us in the industry, the TRAVERSE trial’s key finding was that testosterone therapy was non-inferior to placebo regarding the incidence of major adverse cardiac events (MACE), meaning it did not significantly increase the risk of heart attack, stroke, or cardiovascular death in men on TRT. This solid evidence provided the scientific backing needed for the FDA to be forced to reconsider their earlier, more severe warnings and reevaluate their processes for determining when such warnings are justified and needed.

As a result, the FDA has now taken a few important steps in regard to testosterone and TRT.

1. Boxed Warning related to an increased risk of adverse cardiovascular outcomes have been removed!  These vague and unfounded warnings are no longer required and have been taken off of all testosterone product labels and packaging. This is the most impactful change, as it alleviates a significant concern for both prescribers and patients alike.
2. They also ADDED the results of the TRAVERSE trial to all testosterone product labels. This is useful in providing direct evidence of cardiovascular safety in a high-risk population especially for those whose beliefs were centered around previous warnings.
3. Retained the "Limitation of Use" language. For those patients interested in TRT for age-related hypogonadism, they are basically telling that while the cardiovascular risk warning is gone, testosterone is still approved only for men with low testosterone due to specific medical conditions, not solely for age related decline, though its difficult to determine the cause of Low T in many patients so its important that a licensed and experienced healthcare provider help make this diagnosis.
4. They added new warnings about increased blood pressure. While the TRAVERSE trial did not show increased MACE, they noted other post-market ambulatory blood pressure monitoring (ABPM) studies had consistently demonstrated that testosterone use, across various formulations, can possibly lead to increases in blood pressure in some men. The FDA is now requiring product-specific information on blood pressure changes and a new warning for products that previously lacked it. This makes it important for all patients to monitor their BP and discuss any changes with their doctor. Many studies suggest an opposite effect on blood pressure for men who are prescribed TRT, with it actually LOWERING BP in some men, so proper diagnosis and monitoring will be necessary.
5. Noted a higher incidence of pulmonary embolism and atrial fibrillation. In the testosterone group of the TRAVERSE trial, they saw a potential for a fib or pulmonary embolisms for some candidates, suggesting continued vigilance for these specific risks for patients in high risk groups.

Implications of the Shift on TRT and Testosterone for Patients and Providers

This dramatic change in just a decade, from 2015 to 2025 marks a win for science and a move towards more nuanced and evidence-based labeling system for testosterone products for the pharmacies that make them, providers that prescribe them and the patients who use them. By removing the broad cardiovascular black box warning on labels, it is expected to increase physician comfort in prescribing TRT for appropriately diagnosed hypogonadal men and allowing for meaningful treatment to be offered to patients where it was once not a consideration. However, there is always a potential risk as the new emphasis on blood pressure monitoring underscores the ongoing need for careful patient selection by physicians who offer HRT for men.  Thorough baseline assessments, reviewing past medical history and diligent follow-up for the men who being testosterone therapy, proper protocols and optimal patients’ safety and care can be prioritized. The FDA's evolving stance on testosterone reflects the dynamic nature of pharmaceutical and medical science, where new research and clinical studies constantly refine our understanding of drug safety and efficacy.

Dr. Timothy Wray Mackey, a distinguished physician at NovaGenix, brings extensive expertise in internal medicine and a specialized focus on hormone replacement therapy. A licensed DO with years of experience in both men and women's hormone replacement therapy, including a background in the U.S. Army, Dr. Mackey provides personalized care to patients seeking solutions for low testosterone, bioidentical hormone replacement, and various wellness needs. He is certified in anti-aging medicine and bio-identical hormone replacement therapy, ensuring a comprehensive and evidence-based approach to optimizing patient health and well-being.