Nelson Vergel
Founder, ExcelMale.com
FDA Testosterone Regulation: The Complete Guide to Label Changes, Cardiovascular Safety, and the Future of TRT Access
Curated By Nelson Vergel | ExcelMale.com | Updated January 2026
Is testosterone replacement therapy finally being recognized for what it is—a legitimate medical treatment rather than a dangerous performance-enhancing drug? Curated By Nelson Vergel | ExcelMale.com | Updated January 2026
For over a decade, men with documented hypogonadism have faced significant barriers to accessing testosterone therapy due to regulatory warnings that many experts now consider outdated and overstated. In February 2025, the FDA made a landmark decision to remove the cardiovascular black box warning from all testosterone products—and in December 2025, an expert panel went even further, recommending that testosterone be removed from Schedule III controlled substance status entirely.
This comprehensive guide examines the regulatory history of testosterone, the pivotal TRAVERSE trial that changed everything, the ongoing debate about controlled substance classification, and what these changes mean for men seeking hormone optimization. Whether you're currently on TRT, considering treatment, or a healthcare provider navigating these evolving guidelines, understanding the current regulatory landscape is essential.
The Regulatory Journey: How We Got Here
The FDA's relationship with testosterone has been marked by increasing caution followed by a recent pivot toward evidence-based policy. Understanding this history provides crucial context for the current moment.2014-2015: The Era of Cardiovascular Warnings
In January 2014, the FDA issued a Drug Safety Communication warning of reported risks of stroke, heart attack, and death in men taking FDA-approved testosterone products. This was followed by increased reports of adverse cardiovascular outcomes that prompted the agency to convene a Joint Meeting of the Bone, Reproductive and Urologic Drugs and the Drug Safety and Risk Management Advisory Committee in September 2014.By March 2015, the FDA required all testosterone product labels to include a warning about possible increased cardiovascular risk and cautioned against using testosterone products for age-related testosterone decline—commonly called "late-onset hypogonadism." The agency mandated that testosterone be approved only for men with low testosterone due to specific medical conditions such as Klinefelter syndrome, pituitary injury, or damage from chemotherapy.
The TRAVERSE Trial: Resolving Decades of Uncertainty
The turning point came with the TRAVERSE trial (Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men), published in the New England Journal of Medicine in July 2023. This was the largest randomized controlled trial ever conducted to evaluate testosterone's cardiovascular safety.The study enrolled 5,246 men aged 45 to 80 years who had preexisting cardiovascular disease or were at high risk, along with documented hypogonadism (two fasting testosterone levels below 300 ng/dL) and symptoms of low testosterone. Participants were randomized to receive either daily transdermal 1.62% testosterone gel or placebo over a mean follow-up of 33 months.
Key Findings:
• Major adverse cardiovascular events (MACE) occurred in 7.0% of the testosterone group versus 7.3% in the placebo group (HR 0.96; 95% CI, 0.78-1.17; P<.001 for noninferiority)
• No increase in prostate cancer or prostate-related events
• A 22.5% reduction in new-onset diabetes in the testosterone group
• Improvements in sexual desire, sexual frequency, depression scores, and anemia
• Small increases in atrial fibrillation and acute kidney injury noted as secondary outcomes
As Dr. Steven Nissen, study chair and Chief Academic Officer of Cleveland Clinic's Heart, Vascular & Thoracic Institute, stated: "These findings provide reassurance about the cardiovascular safety of testosterone therapy over the typical duration of treatment in men in whom it is indicated."
February 2025: The FDA's Landmark Label Update
On February 28, 2025, the FDA informed sponsors of testosterone products about class-wide labeling changes based on the TRAVERSE trial results and required postmarket ambulatory blood pressure monitoring (ABPM) studies.What Changed
Changes Based on TRAVERSE Trial | Changes Based on ABPM Studies |
• Adding TRAVERSE trial results to all testosterone products • Removing language from the Boxed Warning related to increased risk of adverse cardiovascular outcomes • Retaining "Limitation of Use" language for age-related hypogonadism | • Adding product-specific information on increased blood pressure for products with completed ABPM studies • Adding new warning about increased blood pressure for products that currently lack such warnings |
December 2025: FDA Expert Panel Calls for Broader Reforms
On December 10, 2025, the FDA convened an expert panel composed primarily of urologists and federal health officials to discuss testosterone replacement therapy for men. The 13-person panel gave a resounding endorsement of TRT and made several far-reaching recommendations.Key Panel Recommendations
Recommendation | Objective |
Label Revision | Broaden indications to include all men with signs/symptoms of deficiency and low serum levels |
Declassification | Remove testosterone from Schedule III controlled substance status to reduce prescriber barriers |
Guideline Alignment | Harmonize FDA labels with American Urological Association and Endocrine Society standards |
Contraindication Removal | Eliminate prostate cancer contraindications not supported by contemporary evidence |
Enhanced Education | Improve provider and patient education regarding actual risks and benefits |
FDA Commissioner Martin Makary opened the discussion by acknowledging the parallel with the FDA's November 2025 decision to remove the black box warning from women's hormone replacement therapy. "According to the Journal of Clinical Endocrinology and Metabolism, 5.6% of men aged 30 to 79 have low testosterone and symptoms," he noted. "Why are we ignoring this topic?"
The Controlled Substance Controversy: Should Testosterone Be Descheduled?
One of the most significant recommendations from the December 2025 panel was the call to remove testosterone from Schedule III controlled substance status—a classification it has held since the Anabolic Steroid Control Act of 1990.Origins of Schedule III Classification
Testosterone was classified as a Schedule III controlled substance not because of medical evidence of dependence or abuse potential in therapeutic contexts, but as a response to athletic doping scandals in the 1980s. Notably, both the American Medical Association (AMA) and the Drug Enforcement Administration (DEA) originally opposed the classification, arguing that testosterone lacked the characteristics typically requiring such stringent regulation.As Dr. Landon Trost explained at the panel: "There is no evidence to suggest dependency at any physiologic levels with testosterone, in contrast to things like narcotics." Research from the University of Michigan demonstrated that while illicit steroid use initially declined following the 1990 legislation, usage rebounded and eventually surpassed pre-1990 levels within a decade—meaning the law failed its intended purpose while creating barriers for legitimate medical use.
How Schedule III Status Affects Patients
The controlled substance classification creates multiple barriers to care:• Prescription Limitations: Schedule III prescriptions cannot be filled or refilled more than five times or more than six months after the prescription date, requiring frequent office visits
• Provider Hesitancy: Many primary care physicians avoid prescribing testosterone due to DEA oversight requirements and stigma associated with controlled substances
• Telemedicine Restrictions: Controlled substance status limits telemedicine prescribing options, particularly affecting patients in rural areas
• Pharmacy Supply Issues: Some pharmacies limit Schedule III drug inventory, creating access problems
The comparison with estrogen is particularly striking: estrogen, the primary female hormone used in hormone replacement therapy, is not a controlled substance. There is no pharmacological justification for treating testosterone differently.
The Prostate Cancer Myth: What the Evidence Actually Shows
For decades, physicians operated under the assumption that testosterone "fuels" prostate cancer—a belief rooted in early 20th-century research by Charles Huggins, who won a Nobel Prize for demonstrating that castration caused prostate cancer regression. Modern evidence has thoroughly debunked this oversimplified view.Key findings:
• A 2008 analysis of 18 prospective studies involving nearly 4,000 men with prostate cancer found no relationship between baseline testosterone levels and cancer risk
• The TRAVERSE trial showed no increase in prostate cancer or prostate-related events in men receiving testosterone therapy
• A 2023 JAMA Network Open study confirmed that TRT does not increase prostate cancer risk in appropriately selected patients
• Studies following prostate cancer patients on TRT after definitive treatment show no increased risk of recurrence or progression
As Dr. Franck Mauvais-Jarvis of Tulane University stated at the December panel: "The bottom line is no, testosterone does not increase the risk of prostate cancer." The panel recommended removing the prostate cancer contraindications from testosterone labeling.
What TRT Patients Should Know: Realistic Risk Assessment
While the removal of cardiovascular warnings represents a major shift, testosterone therapy is not without considerations. The updated labeling and current evidence point to several areas requiring monitoring:Blood Pressure
The ABPM studies confirmed that testosterone use is associated with modest blood pressure increases class-wide. While the average increase in systolic blood pressure was only about 1.8 mmHg (clinically modest), the FDA now requires blood pressure warnings on all testosterone products. Regular monitoring is recommended, and testosterone is not recommended for men with uncontrolled hypertension.Venous Thromboembolism (VTE)
The TRAVERSE trial showed a higher incidence of venous thromboembolism events, including deep vein thrombosis and pulmonary embolism, in the testosterone group. Warnings about VTE have been on testosterone labels since 2014, and caution remains appropriate for men with a history of thromboembolic events.Erythrocytosis (Elevated Hematocrit)
Testosterone stimulates red blood cell production, which can lead to elevated hematocrit levels. Regular monitoring of complete blood count is standard practice, with dose adjustments or therapeutic phlebotomy if levels become excessive. Notably, the TRAVERSE trial found no association between hematocrit changes and cardiovascular event risk.Atrial Fibrillation
A small increase in non-fatal arrhythmias, including atrial fibrillation, was observed in TRAVERSE. This finding was noted as a secondary outcome and may warrant attention in patients with existing arrhythmia risk factors.Taking Action: How to Submit Comments to the FDA
The FDA has opened a public comment period related to testosterone replacement therapy. This is a significant opportunity for patients, healthcare providers, and advocates to influence policy.Deadline: February 9, 2026, at 11:59 PM Eastern Time
Where to Submit: Regulations.gov under docket number FDA-2025-N-6743
Comments may address the risks and benefits of testosterone therapy, the appropriateness of controlled substance classification, experiences with prescriber access barriers, and whether current labeling accurately reflects modern evidence.
Conclusion: A Turning Point for Men's Health
The regulatory landscape for testosterone therapy is undergoing its most significant transformation in decades. The removal of cardiovascular black box warnings based on the TRAVERSE trial, combined with the expert panel's call for descheduling and expanded indications, signals a potential new era for men's hormone health.For the millions of men with hypogonadism, these changes could mean easier access to a treatment that can dramatically improve quality of life, reduce disease risk, and potentially extend lifespan. As Dr. Mohit Khera of Baylor College of Medicine summarized: "Testosterone therapy is safe, effective, and preventive. Large randomized controlled trials and observational studies have demonstrated the safety and multiple clinical benefits of testosterone therapy."
The coming months will be critical as the FDA reviews public comments and considers implementing the panel's recommendations. Men who have struggled to access appropriate care may finally see policy catch up with science.
Related ExcelMale Forum Discussions
Explore these community discussions for additional insights:• FDA issues class-wide labeling changes for testosterone products — Comprehensive discussion of the February 2025 FDA announcement and expert reactions
• The FDA Was WRONG About Testosterone? Major Label Update Explained — Dr. Morgentaler and Dr. Brandon discuss the significance of the FDA reversal
• Tell The FDA Why Testosterone Should Not Be a Schedule III Controlled Substance — Guide to submitting public comments on testosterone descheduling
• The FDA is seeking your comments on black box warning for women's hormone therapy — Parallel developments in women's hormone therapy regulation
• What Really Happened at the FDA Menopause Panel — Context on FDA's evolving approach to hormone therapy regulation
Key References
1. Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. https://pubmed.ncbi.nlm.nih.gov/37326322/2. FDA issues class-wide labeling changes for testosterone products. FDA Drug Safety Communication. February 28, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-issues-class-wide-labeling-changes-testosterone-products
3. FDA Expert Panel on Testosterone Replacement Therapy for Men. December 10, 2025. https://www.fda.gov/patients/fda-expert-panels/fda-expert-panel-testosterone-replacement-therapy-men-12102025
4. Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744. https://academic.oup.com/jcem/article/103/5/1715/4939465
5. The Androgen Society Position Statement on Cardiovascular Safety of Testosterone Therapy. Mayo Clinic Proceedings. November 2024. https://www.androgensociety.org/announcements/press-release-march-2025
6. Anabolic Steroids Control Act of 1990. Pub. L. 101-647. https://www.dea.gov/drug-information/drug-scheduling
7. Hackett G. Cardiovascular safety of testosterone replacement therapy (TRAVERSE trial). Trends in Urology & Men's Health. 2024. https://onlinelibrary.wiley.com/doi/10.1002/tre.967
8. FDA panel calls to loosen restrictions on testosterone replacement therapy. NBC News. December 11, 2025. https://www.nbcnews.com/health/mens-health/fda-panel-testosterone-replacement-therapy-rcna248053
