Too much or too little? Testosterone may raise AF risk at both extremes

Clinical takeaway: When prescribing testosterone replacement therapy (TRT), aim for physiologic rather than high-normal testosterone levels, and monitor for atrial fibrillation (AF) risk factors and rhythm disturbances, particularly in older men with cardiovascular comorbidities.

TRT use has expanded substantially in middle-aged and older men, while AF remains a major cause of stroke and long-term anticoagulant use. Although low testosterone has traditionally been viewed as a risk factor for AF, newer evidence suggests that excessive testosterone exposure may also increase arrhythmia risk.

An updated narrative review in the Journal of the Endocrine Society examined emerging evidence on the relationship between testosterone, TRT, and AF. Across epidemiologic, clinical, and mechanistic studies, the authors conclude that AF risk appears to follow a U-shaped pattern, with higher risk at both low and high testosterone levels and the lowest risk occurring within the mid-normal range.

The review highlights findings from the 2023 TRAVERSE randomized trial of 5,246 men with hypogonadism and elevated cardiovascular risk. While testosterone therapy did not increase major adverse cardiovascular events, AF occurred in 3.5% of men receiving TRT versus 2.4% receiving placebo, representing about a 50% higher incidence.

Supporting this U-shaped model, large population studies found increased AF risk among men with both low testosterone and high-normal testosterone levels. In one analysis of older men, AF risk was nearly doubled among those in the highest testosterone quintiles compared with men in the middle range. Laboratory studies published since 2025 further suggest distinct biologic mechanisms: low testosterone may promote abnormal calcium handling and triggered electrical activity, whereas high testosterone may alter cardiac potassium currents and facilitate AF-promoting reentry circuits.

The authors recommend individualized TRT, targeting total testosterone levels of roughly 350-550 ng/dL, using stable-release formulations when appropriate, correcting modifiable AF risk factors such as obesity and sleep apnea, and monitoring rhythm, hematocrit, blood pressure, and organ function. They caution that the proposed therapeutic range is based largely on observational evidence and has not yet been prospectively tested.

“Both too little and too much testosterone appear to raise the risk of atrial fibrillation, through separate biological mechanisms, which means the dose and the target level matter,” said co-author Rajat S. Barua, MD, PhD. “Treatment should be individualized and monitored.”

Source: Maligireddy AR, et al. (2026 Sep 1) J Endocr Soc. Association of Testosterone and Testosterone Replacement Therapy With Atrial Fibrillation: An Updated Review