For most men with genuinely low testosterone and existing heart risk factors, testosterone replacement therapy (TRT) does not appear to increase the rate of heart attacks or strokes. That was the central finding of the TRAVERSE trial, the largest randomized safety study of TRT ever conducted, published in 2023. But “no increase in major events” is not the same as “zero cardiovascular effects.” TRT shifts several things in the body that matter for heart health, and understanding which ones are benign, which are manageable, and which deserve genuine caution makes the difference between informed treatment and a gamble.
What the TRAVERSE Trial Actually Showed
Before TRAVERSE, doctors were working with contradictory data. A widely cited 2013 observational study of U.S. veterans who had undergone coronary angiography reported that men receiving testosterone had a higher combined rate of death, heart attack, and stroke compared to untreated men, with roughly a 29 percent increase in risk after adjustment.1JAMA. Association of Testosterone Therapy With Mortality, Myocardial Infarction, and Stroke in Men With Low Testosterone Levels That study had serious methodological issues (including a later correction and ongoing criticism about its statistical approach), but it was alarming enough that the FDA required testosterone products to carry a cardiovascular warning label and called for a dedicated safety trial.
TRAVERSE was the answer to that call. It enrolled over 5,200 men aged 45 to 80 who had both low testosterone and either established cardiovascular disease or multiple risk factors for it. Over an average follow-up of 33 months, about 7 percent of men in the testosterone group and about 7.3 percent in the placebo group experienced a major cardiovascular event such as heart attack, stroke, or cardiovascular death. The hazard ratio was 0.96, meaning the two groups were statistically indistinguishable in terms of major events.2PubMed. Cardiovascular Safety of Testosterone-Replacement Therapy A later review confirmed that the trial found no increase in major adverse cardiac events or prostate-related events, effectively addressing the FDA’s earlier concerns.3PubMed Central. Long Term Cardiovascular Safety of Testosterone Therapy: A Review of the TRAVERSE Study
That is reassuring as far as the big outcomes go. But TRAVERSE also revealed that testosterone treatment was associated with a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism compared to placebo.2PubMed. Cardiovascular Safety of Testosterone-Replacement Therapy These were secondary findings, not the primary endpoint, but they point to real cardiovascular effects that deserve attention even when the headline number looks clean.
Blood Clots and Venous Thromboembolism
One of the more consistent signals across TRT research is a link to blood clots in the veins, known as venous thromboembolism (VTE). A large case-crossover study found that men prescribed testosterone had roughly double the short-term risk of VTE regardless of whether they had a formal diagnosis of low testosterone.4JAMA Internal Medicine. Association of Testosterone Therapy With Risk of Venous Thromboembolism Among Men With and Without Hypogonadism A population-based study from the UK added nuance: the elevated risk was concentrated in the first six months of treatment, with a rate ratio of about 1.63 for new courses of testosterone. After six months, the risk essentially returned to baseline.5BMJ. Testosterone treatment and risk of venous thromboembolism: population based case-control study
Randomized trial data tell a slightly different story. A systematic review and meta-analysis pooling results from randomized controlled trials found no statistically significant increase in VTE, pulmonary embolism, stroke, heart attack, or mortality with testosterone therapy, though the confidence intervals were wide.6PubMed Central. Testosterone replacement therapy and vascular thromboembolic events: a systematic review and meta-analysis The discrepancy likely reflects two things. First, randomized trials tend to exclude men at the highest clot risk, so they may undercount events. Second, observational studies can be influenced by confounders that inflate the signal. The practical takeaway is that the clot risk is probably real but modest, especially in the early months of treatment, and it warrants monitoring rather than avoidance.
Why Hematocrit Matters
One mechanism behind the clot risk is well understood. Testosterone stimulates your bone marrow to produce more red blood cells. In men with low testosterone, that can initially be a benefit, correcting mild anemia. But if red blood cell production overshoots, a condition called erythrocytosis, your blood becomes thicker and stickier. Elevated hematocrit raises the risk of clots and can strain the cardiovascular system.7PubMed Central. Testosterone use causing erythrocytosis
This is the single most common lab abnormality seen with TRT. European experts recommend checking hematocrit every three to six months in the first year, then annually, and keeping levels below 54 percent to reduce thromboembolic risk. If hematocrit climbs above that threshold, dose reduction or temporary discontinuation is standard practice.8PubMed Central. Cardiovascular safety of testosterone therapy—Insights from the TRAVERSE trial and beyond: A position statement of the European Expert Panel for Testosterone Research In other words, this is a manageable side effect, not an unavoidable danger, but only if you and your doctor are actually watching for it.
Coronary Artery Plaque
One finding from TRAVERSE’s era that still generates concern comes from a sub-study of the Testosterone Trials (TTrials), which used CT imaging to measure coronary artery plaque in older men with low testosterone. Over 12 months, men receiving testosterone had a significantly greater increase in noncalcified plaque volume compared to men on placebo.9PubMed Central. Testosterone Treatment and Coronary Artery Plaque Volume in Older Men With Low Testosterone Noncalcified plaque is the type considered more vulnerable to rupture, so this was not a trivial observation.
A follow-up analysis of the same data found that the plaque progression was not uniform. It was particularly pronounced in men with a higher waist-to-hip ratio, a marker of abdominal obesity. For every 0.1 increase in waist-to-hip ratio, the effect of testosterone on plaque growth roughly doubled.10The Journal of Clinical Endocrinology & Metabolism. Biomarkers and Noncalcified Coronary Artery Plaque Progression in Older Men Treated With Testosterone This suggests that the cardiovascular landscape is not uniform: a lean man starting TRT may face different vascular effects than someone carrying significant abdominal fat. It also raises the question of whether managing weight alongside TRT could reduce this plaque signal, though that has not been directly tested.
How do you reconcile increased plaque with no increase in heart attacks? The TTrials plaque sub-study involved only about 170 men and lasted only one year. Plaque growth is a surrogate marker, not an outcome. It signals a process that could eventually lead to problems, but whether the modest increases observed translate into clinical events over years or decades is unknown. TRAVERSE, with its much larger sample and longer follow-up, did not find that excess events materialized. Still, the plaque data serve as a reasonable argument for periodic cardiovascular monitoring.
Atrial Fibrillation and the U-Shaped Risk
The atrial fibrillation (AF) signal in TRAVERSE was not isolated. A growing body of research suggests that the relationship between testosterone and AF risk follows a U-shaped curve: both very low and very high testosterone levels appear to increase the odds of developing this arrhythmia. Population-level studies and post-hoc analyses have converged on this pattern, with mechanistic data supporting distinct pathways at each end. Low testosterone disrupts calcium handling in heart cells, while high testosterone alters potassium currents in ways that shorten the heart’s electrical recovery period and can promote the kind of short-circuiting that leads to AF.11PubMed Central. Association of testosterone and testosterone replacement therapy with atrial fibrillation: an updated review
A Mendelian randomization study using genetic instruments found that genetically predicted higher total testosterone in men was associated with lower heart rate variability but showed no clear association with AF itself or with other ECG measures like QT interval or P-wave duration.12PubMed Central. Sex hormones and reproductive factors with cardiac arrhythmia and ECG indices: a mendelian randomization study The genetic picture is murkier than the observational one, which is typical for complex traits. The practical implication is that men starting TRT who already have risk factors for AF, such as obesity, sleep apnea, or heavy alcohol use, should be aware that their rhythm risk may nudge upward, and that overshooting the target testosterone range could amplify the effect.
Fluid Retention and Blood Pressure
Testosterone promotes salt and water retention, an effect that becomes more pronounced in older men. This can contribute to edema, elevate blood pressure, and in susceptible individuals, worsen congestive heart failure.13PubMed Central. Adverse Events Associated with Testosterone Administration The magnitude of this effect in standard therapeutic doses is usually modest, and most men on TRT do not develop clinically meaningful hypertension from it alone. But for men already on the borderline of blood pressure control, or those with existing heart failure, even a small fluid shift can tip the balance. Blood pressure monitoring during the first months of TRT is a basic precaution that is sometimes neglected.
How TRT Affects Cholesterol
The lipid story is genuinely mixed. Meta-analyses of trials in men with low testosterone have generally found that TRT lowers HDL cholesterol, the so-called “good” cholesterol. That sounds bad in isolation, but the same treatment also tends to lower total cholesterol and LDL cholesterol, the “bad” fraction.14PubMed Central. An update on testosterone, HDL and cardiovascular risk in men A study specifically in hypogonadal and elderly men found that testosterone replacement lowered total cholesterol and the LDL fraction without significantly decreasing HDL or its subfractions, suggesting the HDL-lowering effect is not universal and may depend on dose, formulation, and population.15PubMed. Effect of testosterone replacement therapy on lipids and lipoproteins in hypogonadal and elderly men
Part of what makes this complicated is that testosterone is partially converted to estradiol through an enzyme called aromatase, and estradiol has its own cardiovascular effects, some of which are protective. How much of testosterone’s vascular action comes from the hormone itself versus its conversion into estradiol acting on estrogen receptors is still an active area of investigation.16Oxford Academic (Endocrine Reviews). Androgens and Cardiovascular Disease The net effect on heart risk through lipid changes alone appears to be roughly neutral in most men, though your individual lipid response is worth tracking.
TRT in Men With Heart Failure
Counterintuitively, testosterone therapy has shown potential benefit in men with moderate heart failure. A meta-analysis of randomized trials found that testosterone supplementation improved exercise capacity, with treated men walking an average of 54 meters farther in a six-minute walk test than those on placebo. No significant adverse cardiovascular events were recorded across those trials.17PubMed. Testosterone supplementation in heart failure: a meta-analysis Individual trials have supported this, showing improvements in peak oxygen consumption, insulin sensitivity, and muscle strength in elderly men with chronic heart failure, without measurable changes in left ventricular function.18PubMed. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure Another placebo-controlled trial reported that about 35 percent of men on testosterone improved by at least one functional class, compared with 8 percent on placebo.19European Heart Journal. Testosterone therapy in men with moderate severity heart failure: a double-blind randomized placebo controlled trial
These are relatively small trials, and no one is proposing testosterone as a primary heart failure treatment. But the consistent direction of the exercise-capacity data is notable and complicates the simple narrative that testosterone is categorically risky for weak hearts. For men who are hypogonadal and also have stable heart failure, the discussion with a cardiologist may be more nuanced than a blanket “no.”
Endothelial Function
The lining of your blood vessels, the endothelium, plays a central role in cardiovascular health. Stiff, poorly reactive endothelium is a hallmark of early cardiovascular disease. A study of men starting TRT found that after three to six months, as average testosterone levels rose from about 203 to 511 ng/dL, measures of endothelial function improved significantly. The reactive hyperemia index, a gauge of how well blood vessels dilate in response to increased blood flow, went up, and the augmentation index, which reflects arterial stiffness, went down.20PubMed Central. Improvement of endothelial function following initiation of testosterone replacement therapy This is a single study with no control group, so it is not definitive. But it adds to the picture that TRT’s cardiovascular effects are not uniformly negative. There appear to be mechanisms pulling in both directions.
Low Testosterone Itself Is a Risk Factor
Any discussion of TRT’s heart risks needs to acknowledge the context: untreated low testosterone is not a cardiovascular blank slate. Multiple epidemiological studies have identified low testosterone as an independent risk factor for cardiovascular and all-cause mortality.21PubMed Central. Welcoming low testosterone as a cardiovascular risk factor A large individual-participant-data meta-analysis found that men with testosterone concentrations below about 213 ng/dL had higher all-cause mortality, and those below about 153 ng/dL had higher cardiovascular mortality specifically.22PubMed Central. Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men: Individual Participant Data Meta-analyses
This means the comparison is not “TRT versus perfect health.” It is “TRT versus remaining in a low-testosterone state that itself carries cardiovascular risk.” The question then becomes whether restoring testosterone to a normal range reduces that baseline risk, leaves it unchanged, or introduces new risks that offset the benefit. TRAVERSE suggests that major cardiac events are not increased. Whether TRT actually reduces the mortality associated with low testosterone has not been proven in a randomized trial, but the observational data at least argue that the untreated condition is not benign.
Injections, Gels, and Patches Are Not Interchangeable
How you take testosterone may matter as much as whether you take it. A large comparative safety study found that men who initiated testosterone injections had a 26 percent higher hazard of cardiovascular events (heart attacks, unstable angina, and strokes) and a 34 percent higher hazard of death compared to men using testosterone gels. Patches, by contrast, showed no significant difference from gels on any of these outcomes.23JAMA Internal Medicine. Comparative Safety of Testosterone Dosage Forms
The likely explanation is pharmacokinetic. Injections produce high peaks and low troughs in testosterone levels, whereas gels and patches deliver a steadier, more physiological release. Those peaks may drive bigger spikes in hematocrit, more fluid retention, and greater acute hemodynamic stress. Channeling bias is also possible: sicker patients or those with lower socioeconomic access may be more likely to receive injections. But the pattern has been seen consistently enough that formulation choice deserves a conversation with your prescriber, especially if you have existing cardiovascular risk factors.
Genetics and Individual Variation
Not every man responds to TRT the same way, and part of that variation appears to be genetic. The androgen receptor gene contains a repeating stretch of DNA called the CAG repeat. Men with shorter CAG repeats have androgen receptors that are more sensitive to testosterone, meaning the same blood level produces a stronger cellular response. In a study of men with surgically caused low testosterone, those with shorter CAG repeats experienced greater improvements in weight, blood sugar, blood pressure, triglycerides, and insulin resistance when treated with testosterone.24PubMed Central. Androgen Receptor Gene CAG Repeat Polymorphism Regulates the Metabolic Effects of Testosterone Replacement Therapy in Male Postsurgical Hypogonadotropic Hypogonadism Broader reviews confirm that this polymorphism influences a wide range of testosterone-dependent outcomes, from body composition to cardiovascular risk factors.25PubMed Central. Influence of CAG Repeat Polymorphism on the Targets of Testosterone Action
This is not something most clinicians currently test for, and it is not ready to guide prescribing decisions in routine practice. But it helps explain why two men with identical testosterone levels and similar health profiles can have very different experiences on TRT, including different cardiovascular responses. The era of personalized hormone therapy is not here yet, but the biological basis for it clearly exists.
When TRT Is Combined With PDE5 Inhibitors
Many men prescribed TRT also use medications for erectile dysfunction, particularly PDE5 inhibitors like sildenafil or tadalafil. The interaction between these drugs is pharmacologically interesting. Testosterone regulates the expression of the PDE5 enzyme in erectile tissue, so low testosterone can blunt the effectiveness of PDE5 inhibitors. Adding testosterone can restore their efficacy.26PubMed. Combining testosterone and PDE5 inhibitors in erectile dysfunction: basic rationale and clinical evidences
From a cardiovascular standpoint, this combination may actually carry an unexpected upside. A retrospective study of men with type 2 diabetes found that those using PDE5 inhibitors had substantially lower all-cause mortality, and when PDE5 inhibitors were combined with testosterone therapy, the mortality reduction was even greater.27PubMed. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins PDE5 inhibitors have vasodilatory and anti-inflammatory properties beyond their role in erections, so the finding is biologically plausible. It is observational, and healthier men may simply be more likely to seek treatment for erectile dysfunction, so a causal interpretation is premature. But it at least argues against the concern that combining these two commonly co-prescribed drug classes would compound cardiovascular risk.
Age and Baseline Health Shape the Risk Profile
In younger men with classic hypogonadism caused by identifiable diseases of the pituitary or testes, testosterone replacement has a well-documented benefit profile and a low frequency of adverse events.28Nature Reviews Endocrinology. Risks and benefits of testosterone therapy in older men The cardiovascular uncertainty concentrates in older men, particularly those over 65, where testosterone levels may decline as part of aging rather than from a specific disease. TRAVERSE enrolled men in this higher-risk bracket and found no excess major events, which is encouraging. But the trial lasted about three years, and cardiovascular disease develops over decades. Whether TRT in a 55-year-old is still neutral at the 10- or 15-year mark is a question no existing trial can answer.
Baseline health also modifies risk in ways that go beyond age. The plaque progression data suggest that abdominal obesity amplifies at least one negative vascular effect of testosterone. Fluid retention matters more if your blood pressure is already poorly controlled. Erythrocytosis matters more if you have sleep apnea, which independently raises hematocrit. The decision to start TRT is least complicated in a lean, otherwise healthy man with confirmed hypogonadism and symptoms. It gets progressively more complex as comorbidities stack up, not because TRT is proven dangerous in those men, but because the monitoring burden grows and the margin for error shrinks.
What Monitoring Looks Like in Practice
European expert guidelines based on post-TRAVERSE evidence recommend a structured monitoring schedule. In the first year, hematocrit should be checked every three to six months, alongside testosterone levels, a lipid panel, and PSA (prostate-specific antigen). After the first year, annual monitoring is generally sufficient if values have been stable. The key threshold to watch is a hematocrit above 54 percent, at which point dose adjustment is warranted.8PubMed Central. Cardiovascular safety of testosterone therapy—Insights from the TRAVERSE trial and beyond: A position statement of the European Expert Panel for Testosterone Research
Beyond labs, paying attention to symptoms is worthwhile. New-onset ankle swelling, unexplained shortness of breath, or episodes of heart pounding can be early signals of fluid retention, heart failure exacerbation, or atrial fibrillation, all effects that have some association with TRT. These do not mean you need to stop treatment, but they mean you need a conversation with your doctor sooner rather than later. The men who run into serious trouble on TRT are disproportionately those who are using it without medical oversight, obtaining testosterone from non-medical sources, or skipping follow-up bloodwork.