Testosterone, atrial fibrillation, and a debate built on conflicting data
A narrative review in World Journal of Men’s Health takes on a question that has followed testosterone therapy for years: does treatment in hypogonadal men increase the risk of atrial fibrillation, or does testosterone deficiency itself set the stage for arrhythmia? The answer in this review is not a simple yes or no. The authors argue that the weight of contemporary evidence points in the opposite direction from the concern that often dominates the conversation: low circulating testosterone appears more consistently linked to AF, while testosterone therapy has not convincingly been shown to raise arrhythmia risk in a causal way.
Atrial fibrillation is not a minor rhythm disturbance. It carries risk for stroke, heart failure, cognitive decline, and excess mortality, and it emerges from a web of structural, electrophysiologic, ionic, and molecular changes. In that setting, endocrine status matters because testosterone participates in cardiovascular homeostasis. The review describes testosterone as a sex steroid that supports cardiomyocyte function and vascular smooth muscle physiology, regulates endothelial nitric oxide synthase, and downregulates nuclear factor kappa-light-chain-enhancer of activated B cells, or NF-κB. In practical biologic terms, those actions support an anti-inflammatory, antifibrotic, and vasoprotective milieu. Reduced testosterone may push atrial tissue toward fibrosis, impaired gap junction communication, and autonomic imbalance — changes that can favor arrhythmia initiation and maintenance.
The evidence base, however, is uneven.
Why some studies raised concern about testosterone therapy
The review identifies several studies that have been interpreted as suggesting a higher AF risk with testosterone therapy or higher circulating testosterone levels. One recent retrospective analysis from the TriNetX Research Network compared 117,908 cis men with hypogonadism treated with testosterone against a 1:1 propensity-score matched group not receiving treatment. After 5 years, testosterone-treated men had a lower risk of myocardial infarction, but higher risks of AF and acute pulmonary embolism/deep vein thrombosis, with no difference in stroke or mortality. On its face, that combination of findings could make testosterone look proarrhythmic.
But the review immediately presses on the brakes. The apparent association sits on shaky ground because important confounders were not accounted for. Diabetes, hypertension, chronic obstructive pulmonary disease, obstructive sleep apnea, periodontal disease, congestive heart failure, peripheral vascular disease, coronary artery disease, hyperthyroidism, rheumatic and nonrheumatic valve disease, structural heart disease, cardiomyopathy, body mass index, low-density lipoprotein, and medication use such as aspirin, beta-blockers, and statins were not included in the analysis. In AF research, omission of those variables can easily tilt the apparent direction of risk. A treatment can look culpable when the real drivers are the diseases clustered around the men receiving it.
A similar issue shadows the broader literature summarized in the review. The table of studies includes the Multi-Ethnic Study of Atherosclerosis, the prospective ARIC cohort, a randomized clinical trial, a post-hoc analysis of ASPREE participants, and the TriNetX retrospective study. Some found that higher endogenous testosterone or testosterone treatment tracked with greater incident AF, but the review treats those signals cautiously because observational associations do not resolve causality. Higher hormone levels may simply be a marker of healthier survivors, different prescribing patterns, or unmeasured baseline risk rather than the mechanism of arrhythmia itself.
Low testosterone appears more consistently tied to arrhythmia risk
The stronger thread running through the review is the association between testosterone deficiency and incident AF. Across a larger number of studies, low circulating testosterone was linked to greater AF incidence, while testosterone therapy in hypogonadal men did not increase AF risk. Some reports even suggest a protective association when testosterone levels are restored or maintained in the physiologic range.
This pattern fits biologic plausibility. Testosterone deficiency may worsen atrial fibrosis and disturb the electrical coupling needed for coordinated conduction. It may also amplify inflammation through pathways such as NF-κB and reduce the vascular and endothelial support that helps stabilize cardiac structure over time. In older men already burdened by hypertension, metabolic disease, sarcopenia, or frailty, low testosterone may be less a bystander than part of the substrate that permits AF to emerge.
The review also points to studies in which higher endogenous testosterone was associated with AF in men, including long-term cohort analyses such as MESA and ARIC, as well as a post-hoc analysis from ASPREE. Those findings keep the debate alive. But the authors place them in context: these studies were not designed with AF as the primary endpoint, and the rhythm outcome was usually secondary or tertiary. Without a trial built around AF from the outset, the signal remains difficult to interpret.
The missing trial design issue at the center of the debate
Atrial fibrillation has not been the primary outcome in any of the clinical trials discussed. That matters because rhythm endpoints require prespecified surveillance, standardized adjudication, and careful accounting for competing cardiovascular risks. When AF appears late in the hierarchy of outcomes, the result is vulnerable to noise from ascertainment bias and confounding by comorbidity.
The review’s central clinical point is blunt: the field still lacks accurate data anchored by trials that deliberately test AF risk as the main question. Until that happens, the debate will remain unsettled, not because the biologic question is trivial, but because the available studies are not built to answer it cleanly.
For clinicians treating hypogonadal men, the practical implication is restraint rather than alarmism. Testosterone therapy should not be presumed to trigger AF on the basis of mixed observational findings alone, especially when low testosterone itself may be part of the arrhythmic substrate. Yet the literature also does not justify complacency. Men with hypogonadism often carry overlapping cardiovascular and metabolic risks, and those conditions can distort any association between hormone replacement and arrhythmia.
A review that asks for better evidence, not louder debate
The authors conclude that the contemporary evidence more often links low testosterone with higher AF incidence than it links testosterone therapy with harm. Their position is not that the question has been settled, but that the current balance of data does not support a simple narrative in which testosterone replacement drives atrial fibrillation in hypogonadal men.
What remains unresolved is whether future trials will finally isolate testosterone’s arrhythmic effect from the burden of comorbidity that surrounds men prescribed therapy. Until then, AF will stay in the realm of association rather than proof, and the strongest clinical demand is for studies designed with rhythm outcomes at the center rather than at the margins.