Testosterone replacement therapy and non‑major adverse cardiovascular event safety signals: Atrial fibrillation, acute kidney injury, and pulmonary embolism

Testosterone replacement therapy (TRT) is an effective treatment for male hypogonadism of defined etiology, but its safety profile continues to prompt clinical and regulatory scrutiny. Beyond major adverse cardiovascular events (MACE), attention has shifted toward clinically important non‑MACE outcomes, notably atrial fibrillation (AF), acute kidney injury (AKI), and venous thromboembolism, including pulmonary embolism (PE). The landmark TRAVERSE randomized safety trial in men with hypogonadism and established or high cardiovascular risk demonstrated non‑inferiority of TRT vs. placebo for MACE, but reported higher event rates of AF, AKI, and PE in the testosterone group. Observational datasets suggest a possible early venous thromboembolism risk window after TRT initiation (often within the first 3-6 months), although estimates vary and residual confounding remains a major limitation. In February 2025, the US Food and Drug Administration updated testosterone product labeling: the boxed warning for major cardiovascular events was removed, while a class‑wide warning regarding blood pressure increases was added based on ambulatory blood pressure monitoring data. This narrative review integrates randomized and real‑world evidence on TRT‑associated AF, AKI, and PE, translates these signals into practical guidance for patient selection and safety monitoring, and outlines key methodological and mechanistic priorities for future research. In contemporary practice, the objective is precision: select the right patient, aim for stable exposure, and follow a protocolized safety plan.