Testosterone Therapy After TRAVERSE: Rethinking Cardiovascular and Prostate Cancer Safety

For more than a decade, testosterone replacement therapy (TRT) has divided opinion in men’s health. A question that once appeared straightforward—how to treat the symptoms of late-onset hypogonadism—grew into one of urology’s longest-running safety debates. Concerns tracing back to Huggins’ castration experiments, coupled with a long-held fear that androgens fuel prostate cancer, led the Food and Drug Administration (FDA) to issue cardiovascular safety advisories in 2014-2015.^{1, 2} Enough new evidence has since accumulated to justify revisiting that debate. The clinically relevant question today is no longer simply whether TRT is safe or dangerous, but which patients can be treated with a reasonable expectation of safety, under what circumstances, and with what degree of monitoring. Two developments from the past 3 years drive this shift and deserve close attention from urologists who prescribe TRT. The first is the Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) trial, a phase 4, randomized, placebo-controlled, non-inferiority trial that enrolled men with hypogonadism who had either preexisting cardiovascular disease or a high-risk of developing it across 316 centers.³ Over an average follow-up of roughly 33 months, TRT proved non-inferior to placebo for the incidence of major adverse cardiovascular events. A prespecified sub-study reported that, among men carefully screened to exclude high prostate cancer risk, rates of high-grade and overall prostate cancer were low and statistically comparable, as were other prostate safety events.⁴ After reviewing TRAVERSE together with postmarketing outpatient blood pressure monitoring data, the FDA removed language on increased cardiovascular risk from the boxed warning in February 2025, while adding or strengthening its blood pressure warnings.⁵ By June 2026, the FDA had requested further labeling updates, including lifting the restriction on use for age-related hypogonadism and revising the safety information on prostate cancer and benign prostatic hyperplasia.⁶

None of these regulatory changes amounts to a blanket guarantee of safety. TRAVERSE offers reassurance within a specific, well-defined framework: men with confirmed hypogonadism and known or suspected high cardiovascular risk are treated with transdermal testosterone gels and followed for roughly 3 years.^{3, 4}

A 2026 systematic review and meta-analysis—arguably closer to the interests of an andrology readership—registered in PROSPERO, pooled data from 41 prospective randomized controlled trials involving 11,161 male patients. It found no significant increase in major cardiac adverse events [pooled odds ratio (OR) 0.83, 95% confidence interval (CI) 0.52-1.32], prostate cancer events (pooled OR 0.88, 95% CI 0.52-1.51), or clinically significant prostate cancer (pooled OR 1.13, 95% CI 0.39-3.26).⁷ Its authors pointed to variation linked to comorbidity but concluded that the existing evidence supports short- and medium-term safety, adding that long-term studies are still needed.

Read together, these findings point to a shift from reflexive risk avoidance toward evidence-based risk assessment in the post-TRAVERSE period (Table 1).

TABLE 1. From Risk Avoidance to Risk Management: The Evolving Paradigm of Testosterone Therapy Safety.

Clinical question	Old paradigm	Current evidence	Remaining uncertainty	Clinical implication
Cardiovascular safety	Substantial caution followed FDA safety communications concerning possible cardiovascular risk.1	TRAVERSE showed non-inferiority versus placebo for MACE in men with hypogonadism and pre-existing or high cardiovascular risk; subsequent meta-analyses found no significant increase in major cardiovascular outcomes.3,7	Long-term safety beyond approximately three years remains incompletely defined, and TRAVERSE did not establish safety across all formulations or risk groups.3,8,9	Cardiovascular concern alone should not prompt reflexive avoidance; assess baseline cardiovascular risk and monitor patients appropriately.9
Prostate cancer risk	The traditional androgen-dependent model led to broad concern that testosterone exposure could stimulate prostate cancer.2,13	In carefully screened men without known prostate cancer, TRAVERSE prostate-safety data and randomized-trial meta-analysis have not demonstrated a significant increase in prostate cancer events.4,7	Event numbers were low, high-risk men were excluded from TRAVERSE, and long-term oncological safety remains incompletely defined.4,7	Use individualized oncological risk assessment and guideline-concordant prostate surveillance rather than blanket reassurance.9
TRT after localized prostate cancer treatment	A history of prostate cancer has traditionally prompted substantial caution regarding TRT.	Recent evidence syntheses after definitive treatment, including radical prostatectomy, have not identified an increased biochemical-recurrence signal.10,11	Evidence is predominantly retrospective, heterogeneous, based on selected patients, and lacks long-term randomized data.10,11	Restrict treatment to carefully selected men and counsel explicitly about uncertainty; follow guideline-based PSA surveillance.9
Patient selection and monitoring	Safety discussions often focused on whether TRT itself was intrinsically “safe” or “dangerous.”	Contemporary trial and guideline evidence supports TRT within defined populations, physiological treatment targets, and structured monitoring.3,4,9	Real-world adherence, formulation-specific effects, and longer treatment exposure remain incompletely characterized.8,9	Shift from risk avoidance to evidence-based risk management: whom to treat, how to monitor, and when to reconsider therapy.

The European Expert Panel for Testosterone Research judged the TRAVERSE findings sufficient to reassure clinicians managing cardiovascular risk over the short and medium term. It also flagged long-term outcomes and the generalizability of these findings to other patient populations as gaps that the evidence has yet to close.⁸

A separate clinical concern involves testosterone therapy after treatment for localized prostate cancer—a scenario urologists often encounter—and TRAVERSE could not speak to it directly because men with a history of prostate cancer were excluded from its safety analyses.⁴ Current European Association of Urology (EAU) guidelines confine postoperative testosterone therapy to carefully selected men who are at low-risk of disease recurrence, show no evidence of recurrence, and have a prostate-specific antigen level of < 0.01 ng/mL after at least 1 year of follow-up; the safety of testosterone replacement in men on active surveillance or those treated non-surgically remains inadequately studied.⁹ The reviews available so far are more descriptive than conclusive. A 2025 scoping review of 12 studies found no increase in biochemical recurrence or cancer progression across any of them, although it cautioned that the studies were largely retrospective, varied considerably in design and sample size, and lacked long-term follow-up data.¹⁰ A 2026 systematic review and meta-analysis of men treated with testosterone replacement after radical prostatectomy reached a similar conclusion—the evidence was insufficient to show a rise in biochemical recurrence—although the 7 retrospective studies behind it (n = 398) limit how far any causal or generalizable claims can be pushed.¹¹ Set against the cardiovascular picture, the oncological safety of testosterone therapy after prostate cancer treatment remains considerably less certain. Guidelines are starting to catch up with this evidence. The EAU Guidelines on Sexual and Reproductive Health call for restoring testosterone to the individual’s normal physiologic range, with structured follow-up.⁹ Blood tests—testosterone and hematocrit—are advised at 3 months, 6 months, and 1 year after starting treatment and then annually; if hematocrit rises above 54%, dose adjustment, a temporary pause in treatment, or venesection may be needed.⁹ A large multicenter analysis of more than 25,000 testosterone measurements found no clinically significant seasonal variation in serum levels, so monitoring during treatment should not be timed to the season in which testing occurs.¹² Untreated prostate or breast cancer remains an absolute contraindication to TRT. Cardiovascular disease and poorly controlled congestive heart failure call for caution and close monitoring but do not by themselves rule out treatment, whereas severe lower urinary tract symptoms (IPSS > 19) are a relative contraindication given the absence of long-term safety data.⁹

For urologists, the takeaway is not that testosterone is universally safe, but that the available data now support a more precise, individualized risk assessment. Morgentaler and Traish’s saturation model explains why prostate tissue remains sensitive to androgens even at very low testosterone levels, with this sensitivity declining once androgen receptors become saturated.¹³ Physiologic testosterone replacement, on this basis, is not equivalent to excessive exogenous androgen exposure; unsupervised use of anabolic-androgenic steroids, by contrast, carries a markedly higher cardiovascular risk than guideline-directed TRT.¹⁴

A recent review also contributes to the evolving evidence base regarding the detection and monitoring of prostate cancer. This review highlights the potential of GI, synthetic imaging, automated lesion detection, and image quality enhancement to support more sensitive and personalized monitoring in men for whom testosterone therapy is being considered or who are currently receiving such treatment following prostate cancer treatment.¹⁵ This study points to how personalized, image-based prostate cancer monitoring may evolve in the coming years, which is an important direction for men who are considering or currently receiving testosterone therapy following prostate cancer treatment. Urology and andrology centers worldwide are well positioned to generate the next generation of evidence through multicenter, prospective, long-term registries that monitor treatment planning, dosing, treatment adherence, and outcomes, particularly among men undergoing treatment for localized prostate cancer. Until such data emerge, neither blanket assurance nor reflexive caution is warranted. The answer to the cardiovascular issue has largely been found; however, the answer to the oncological issue has not yet been found, and it is this asymmetry, rather than any single clinical trial, that should guide the decision to treat each patient individually.