Testosterone therapy without clear evidence of symptomatic deficiency may be linked to higher long-term cardiovascular risk. Digest
Testosterone therapy is increasingly prescribed beyond men with confirmed testosterone deficiency, but its long-term cardiovascular safety in that setting is not well established. A new study compared long-term cardiovascular outcomes in men starting testosterone therapy with and without documented evidence of symptomatic testosterone deficiency.
You just missed this in your inbox
Every other week our Premium Members received this exact study plus Rhonda's practical commentary and 8+ other hand-picked papers.
Researchers used electronic health records from 358,957 men aged 30 to 75 who had started testosterone therapy. Available diagnoses and testosterone test results were used as evidence of hypogonadism, the clinical condition of testosterone deficiency with compatible symptoms or signs. For the main analysis, they matched 113,554 men without documented evidence of hypogonadism to the same number with documented evidence of hypogonadism. Cardiovascular outcomes were tracked for up to 10 years. The main outcome combined major cardiovascular events, including heart attack, ischemic stroke, cardiac arrest, and death from any cause. The researchers also analyzed each outcome separately, along with heart failure and pulmonary embolism, a sudden and dangerous blockage in a lung artery, most often caused by a blood clot traveling from the leg.
- About one in three men started testosterone therapy without documented evidence of hypogonadism.
- The combined risk of major cardiovascular events or death from any cause was higher in men without evidence of hypogonadism. Starting therapy without evidence of hypogonadism was associated with a 10-year estimated cumulative risk of 16.5% for heart attack, ischemic stroke, cardiac arrest, or death, compared with 11.8% among men with documented hypogonadism.
- Testosterone therapy was linked to nearly twice the risk of death from any cause in men without evidence of hypogonadism. It was associated with an estimated 10.7% cumulative risk of death from any cause by 10 years, compared with almost 6% among men with documented hypogonadism.
- The individual cardiovascular outcomes showed mixed results. Ischemic stroke, cardiac arrest, and heart failure were consistently higher among men without evidence of hypogonadism. Heart attack and pulmonary embolism were initially higher as well, but those associations disappeared after events from the first 90 days were excluded.
Testosterone can raise hematocrit, which measures the proportion of blood made up of red blood cells. This can make the blood thicker and potentially harder to circulate. The researchers therefore examined whether the higher cardiovascular risks they observed were also more pronounced in men with high hematocrit levels. Among men who started testosterone therapy without documented evidence of hypogonadism, those with higher levels had modestly greater risks of major cardiovascular events overall and of heart attack when analyzed separately. This does not prove that thicker blood caused these events, but it supports a plausible pathway involving restricted blood flow, a higher risk of clot formation, and greater strain on the heart. Testosterone may also affect blood pressure and fluid balance, which could further contribute to the observed risks.
Because this observational study lacked standardized repeated testosterone testing and symptom assessment, it cannot prove causation or confirm that every man classified without deficiency truly lacked hypogonadism. Nevertheless, the results reinforce confirming hypogonadism and reviewing cardiovascular risk with a clinician before starting testosterone therapy. In Aliquot #116, I discuss strategies to optimize testosterone levels.