Testosterone Black Box Warning History: How It Was Added and Why It Was Removed

Written by Keen Meds  ·  Reviewed by Licensed Clinical Providers  ·  March 1, 2026

Key Insight: The FDA cardiovascular black box warning added to testosterone in 2015 was based primarily on two observational studies — neither of which was a randomized controlled trial. TRAVERSE (NEJM 2023) provided the definitive RCT evidence that led to its removal in March 2025.

If you looked up testosterone therapy in the past decade, you likely encountered warnings about cardiovascular risk. For most of that period, every FDA-approved testosterone product in the United States carried a black box warning, the most serious warning category the FDA applies, about the potential for heart attacks and strokes. That warning was added in 2015. It was removed in March 2025.

Understanding why the warning was added, what evidence it was based on, and why it was ultimately removed is essential context for any patient or clinician evaluating testosterone therapy. The history involves two contested observational studies, a decade of scientific debate, and ultimately the largest randomized controlled trial ever conducted for testosterone therapy.

The 2013 Studies That Triggered the Warning

The chain of events that led to the black box warning began with two publications in 2013 and 2014.

In November 2013, Vigen et al. published an observational study in JAMA examining medical records from approximately 8,700 men who had undergone coronary angiography at VA facilities. Among those with low testosterone who had received TRT, the study reported a higher rate of adverse events including death, heart attack, and stroke compared to men who did not receive TRT.

The Vigen study attracted immediate and intense criticism from endocrinologists, cardiologists, and statisticians. Reviewers identified a significant data error: the study's outcome data appeared to include a substantial number of women in the testosterone-treated cohort, an obvious methodological impossibility that raised fundamental questions about data integrity. Critics also noted that the study was retrospective, non-randomized, and did not adequately control for the underlying cardiovascular risk of the treated population, who may have been sicker at baseline than the comparison group.

In January 2014, Finkle et al. published a study in PLoS ONE using insurance claims data from approximately 55,000 men. This analysis suggested that men who had filled a testosterone prescription had a higher rate of nonfatal myocardial infarction in the 90 days following the prescription fill compared to the 12 months prior. The comparison was to the patients' own pre-prescription period, a design that does not account for the possibility that men seek out TRT when they are already experiencing declining health.

Both studies generated extensive media coverage framing testosterone therapy as a cardiac risk. The coverage was widespread and alarming in tone, and it reached patients as well as clinicians.

The FDA's 2014 Review and 2015 Action

In September 2014, the FDA announced that it was reviewing the potential cardiovascular risks of approved testosterone products. The review was prompted by the Vigen and Finkle publications as well as a separate meta-analysis by Xu et al. (2013) that had found increased cardiovascular events in testosterone-treated groups across multiple small trials.

At a January 2015 advisory committee meeting, the FDA's joint Bone, Reproductive, and Urologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted to recommend labeling changes. The FDA acted on these recommendations in March 2015, requiring two new black box warnings on all FDA-approved testosterone products: one regarding cardiovascular risk and one regarding the potential for abuse and dependence.

The cardiovascular black box warning stated that testosterone products had "been associated with serious adverse events, including serious cardiovascular events." It did not state that a causal relationship had been established, but the black box format conveyed to clinicians and patients that the FDA considered the risk serious and documented.

Major endocrinology and urology organizations, including the Endocrine Society and the American Urological Association, expressed concern about the FDA's decision. Their position was that the evidence base for the warning was insufficient, derived from non-randomized observational studies with significant methodological limitations, and that the regulatory action risked deterring appropriate treatment of men with clinically confirmed hypogonadism.

The Period of Scientific Debate (2015-2022)

Following the 2015 labeling action, the scientific literature on testosterone and cardiovascular outcomes continued to expand. Multiple large observational datasets and meta-analyses were published over the subsequent seven years, and the results were inconsistent.

Some studies found associations between testosterone therapy and adverse cardiovascular outcomes. Others found neutral or even potentially protective associations, particularly in men whose testosterone was normalized to physiological ranges. The lack of consistent signal across diverse datasets reinforced the argument that the observational data were confounded by factors that made the treated and untreated populations non-comparable at baseline.

The fundamental limitation of all these observational analyses was that they could not establish causation. Men who received testosterone prescriptions differed in systematic ways from men who did not, and it was not possible to fully account for those differences statistically. What the field needed was a large, well-powered, properly randomized controlled trial.

The FDA had required, as part of its 2014 action, that testosterone manufacturers conduct a clinical trial to evaluate cardiovascular safety. That requirement became the direct origin of the TRAVERSE trial.

TRAVERSE (2023): The Definitive Answer

The TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men) enrolled 5,246 men between 45 and 80 years of age with confirmed hypogonadism and either pre-existing cardiovascular disease or an elevated cardiovascular risk profile. Participants were randomly assigned to receive oral testosterone undecanoate or placebo, with a median follow-up of approximately 3.2 years.

The primary outcome was major adverse cardiovascular events (MACE), defined as a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The trial was designed as a non-inferiority study -- it was not testing whether testosterone was beneficial for cardiovascular outcomes, but whether it was non-inferior to placebo in a high-risk population.

The main result, published by Lincoff et al. in the New England Journal of Medicine in 2023, was a hazard ratio of 0.96 (95% confidence interval 0.83 to 1.12) for MACE in the testosterone group compared to placebo. This satisfied the pre-specified non-inferiority margin and definitively established that testosterone therapy, in men with hypogonadism and elevated cardiovascular risk, did not increase the risk of major cardiovascular events.

The trial also identified two secondary findings that warranted monitoring attention: atrial fibrillation was slightly more common in the testosterone group (3.5% vs. 2.4%), as was pulmonary embolism (0.9% vs. 0.5%). These findings were noted in the TRAVERSE publication and have been incorporated into updated clinical guidance, though they were not primary endpoints and did not alter the overall non-inferiority conclusion.

March 2025: The FDA Removes the Black Box Warning

In March 2025, the FDA announced the removal of the cardiovascular black box warning from all approved testosterone products. The agency cited the TRAVERSE trial as the primary evidence basis for the action. The FDA's determination was that the TRAVERSE data, as a large, well-powered randomized controlled trial in a high-risk population, provided a level of evidence that the prior observational studies could not match.

The removal of the black box warning does not mean testosterone therapy carries no cardiovascular considerations. Clinicians evaluating patients for TRT still assess individual cardiovascular risk, and the monitoring signals identified in TRAVERSE -- particularly atrial fibrillation and pulmonary embolism -- remain relevant to clinical decision-making. The abuse and dependence black box warning added in 2015 remains in place.

What the March 2025 action establishes is that the evidentiary basis for characterizing testosterone therapy as carrying a serious, documented cardiovascular risk did not hold up against the highest standard of clinical evidence: a properly randomized, adequately powered, long-term controlled trial.

Understanding Your Testosterone Today

The removal of the testosterone cardiovascular black box warning in March 2025 reflects how medical evidence is meant to work: observational signals prompt investigation, randomized trials provide answers, and regulatory decisions follow the evidence. For patients with clinically low testosterone, the primary question is not whether the treatment carries a theoretical cardiovascular concern -- TRAVERSE answered that -- but whether their symptoms and lab values indicate a clinical need for treatment.

Keen Meds connects you with licensed clinical providers for a telehealth evaluation and lab review. If your testosterone is clinically low, you may qualify for a prescription for Testosterone Spray Rx -- a needle-free transdermal testosterone program.