Testosterone Replacement Therapy After the TRAVERSE Trial

Neutral safety finding for topical gel--green light for broader therapy?

By Peter A. McCullough, MD, MPH

Serum testosterone concentration drops as a function of age in the norman human male. Low testosterone (hypogonadism) becomes increasingly common with age. Estimates vary depending on the definition used, but studies suggest that approximately 20% of men older than age 45 have low testosterone levels, with prevalence rising steadily in older age groups. Some reviews have estimated testosterone deficiency affects roughly 30% of men between ages 40 and 79, particularly among those with obesity, diabetes, metabolic syndrome, and other chronic health conditions. Testosterone levels also naturally decline by about 1% per year beginning in a man’s 30s. [amjmed.com], [nature.com]

Summary of the JAMA Medical News

A July 2026 JAMA Medical News article reviews whether recent evidence—particularly the TRAVERSE trial—supports broader prescribing of testosterone replacement therapy (TRT).

Background

Testosterone therapy experienced a dramatic rise in popularity during the “low T” boom of the early 2000s. Direct-to-consumer advertising and specialized clinics promoted TRT for symptoms such as fatigue, decreased libido, and reduced vitality. Concerns subsequently emerged that testosterone was being overprescribed, often without appropriate diagnostic confirmation, while questions arose regarding cardiovascular safety.

In 2015, the FDA required manufacturers to add warnings regarding possible cardiovascular risks and mandated a large clinical trial to better assess safety.

The TRAVERSE Trial

The TRAVERSE study enrolled more than 5,200 men aged 45 to 80 years with symptoms of hypogonadism and either known cardiovascular disease or elevated cardiovascular risk.

The primary finding was reassuring: testosterone gel (not injections) therapy did not increase major adverse cardiovascular events such as heart attack, stroke, or cardiovascular death compared with placebo.

These findings have become a major reason HHS is now recommending updates to testosterone product labeling.

Proposed Label Changes

HHS has proposed three major revisions:

1. Removal of language stating that safety and effectiveness have not been established for age-related hypogonadism.

2. Narrowing prostate cancer contraindications primarily to men with metastatic prostate cancer.

3. Updating warnings regarding benign prostatic hyperplasia (BPH) to reflect evidence that TRT generally does not worsen urinary symptoms in most men when appropriately monitored.

Supporters argue these changes better reflect current evidence and may improve access for appropriately selected patients.

Ongoing Concerns

Despite the reassuring cardiovascular results, several experts remain cautious.

Key concerns include:

• Increased rates of atrial fibrillation seen in the testosterone group.

• Higher rates of pulmonary embolism (blood clots).

• More acute kidney injury events.

• An unexpected increase in fractures reported in secondary analyses.

• Limited long-term follow-up (average approximately 33 months).

• Exclusion of men at elevated prostate cancer risk.

• Evaluation of only one testosterone formulation (AndroGel), making generalization to injections and other preparations uncertain.

Some investigators worry that the study could unintentionally encourage broader testosterone prescribing beyond the population actually studied.

Who Should Receive Topical Testosterone?

The article emphasizes a broad consensus among experts:

• TRT should not be prescribed based on symptoms alone.

• Diagnosis requires compatible symptoms and consistently low testosterone levels on repeated laboratory testing.

• Other causes of low testosterone—including obesity, chronic illness, poor sleep, medication effects, and alcohol use—should be considered.

• Men receiving TRT require ongoing monitoring of testosterone levels, blood counts, prostate health, and potential adverse effects.

Expected Benefits

Clinical trials demonstrate benefits from TRT, but generally more modest than many advertisements have suggested.

Reported benefits include:

• Improved sexual desire and sexual activity.

• Small-to-moderate improvements in mood and energy.

• Increased lean body mass.

• Reduced fat mass.

• Improved metabolic parameters in some men.

However, randomized trials have not consistently shown major improvements in overall vitality, cognitive function, or physical performance.

Conclusion

The JAMA discussion highlights a growing consensus that testosterone deficiency is a legitimate medical condition that deserves proper diagnosis and treatment when appropriate. The TRAVERSE trial provides important reassurance that carefully monitored testosterone replacement by topical gel or patch, not by injection of synthetic testosterone, appears to be safe in appropriately selected men. At the same time, questions remain regarding long-term safety, prostate cancer risk in certain populations, arrhythmias, blood clots, and other potential adverse effects.

Before initiating testosterone therapy, men should undergo a thorough evaluation with repeated testosterone measurements and assessment of symptoms. Because obesity, sedentary lifestyle, poor sleep, chronic illness, and excessive alcohol use can contribute to low testosterone levels, non-pharmaceutical interventions should be implemented whenever possible. These include:

• Weight loss for overweight or obese individuals

• Regular resistance and aerobic exercise

• Optimization of sleep

• Reduction or cessation of alcohol consumption

• Management of metabolic disease and other underlying medical conditions

Low T men may also choose to discuss evidence-informed nutritional or botanical approaches with their physician. One example is Zeus (The Wellness Company), a combination botanical supplement designed to support healthy testosterone levels. However, unlike prescription testosterone therapy, botanical supplements generally have not been studied in large randomized outcome trials such as TRAVERSE, and their effects may vary among individuals. They should be viewed as health and wellness approach taken before a commitment to TRT is contemplated.

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Peter A. McCullough, MD, MPH

Chief Scientific Officer, The Wellness Company

https://www.twc.health/pages/focal-points

References

1. JAMA Medical News. Testosterone Therapy: Does New Evidence Warrant Broader Prescribing? Published online July 10, 2026. doi:10.1001/jama.2026.13149.

2. American Urological Association. Evaluation and Management of Testosterone Deficiency Guideline (2024). [auanet.org]

3. Traish AM, Miner MM, Morgentaler A, Zitzmann M. Testosterone Deficiency. American Journal of Medicine. 2011;124(7):578-587. [amjmed.com]

4. Corsini C, et al. Age-related decline in total testosterone levels among young men: insights from a large single-center observational study. IJIR: Your Sexual Medicine Journal. 2025. [nature.com]

5. Lincoff AM, Bhasin S, Flevaris P, Mitchell LM, Basaria S, Boden WE, Cunningham GR, Granger CB, Khera M, Thompson IM Jr, Wang Q, Wolski K, Davey D, Kalahasti V, Khan N, Miller MG, Snabes MC, Chan A, Dubcenco E, Li X, Yi T, Huang B, Pencina KM, Travison TG, Nissen SE; TRAVERSE Study Investigators. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023 Jul 13;389(2):107-117. doi: 10.1056/NEJMoa2215025. Epub 2023 Jun 16. PMID: 37326322.