In men with elevated endogenous testosterone or testosterone therapy, does high testosterone worsen the severity of illnesses such as prostate cancer, cardiovascular disease, COVID‑19, or other conditions?

Does High Testosterone Make Illnesses More Severe?

No, elevated endogenous testosterone does not make illnesses more severe, and the evidence shows that naturally high testosterone levels are not associated with clinically significant morbidity. In fact, higher endogenous testosterone may have neutral to beneficial effects on cardiovascular disease, does not cause prostate cancer, and does not increase COVID-19 severity or risk.

Cardiovascular Disease

Men with naturally elevated testosterone levels do not experience worse cardiovascular outcomes. The evidence consistently demonstrates a neutral to potentially beneficial cardiovascular effect:

• Multiple studies show that men with established cardiovascular disease have lower testosterone levels than men with normal angiograms, suggesting low testosterone—not high testosterone—is associated with worse cardiovascular health 1
• In the Rotterdam Study, men in the highest two-thirds of testosterone levels had age-adjusted relative risks of severe aortic atherosclerosis of 0.4 and 0.2 compared to men in the lowest third 1
• Men with chronic stable angina treated with testosterone showed greater angina-free exercise tolerance than placebo controls, and direct coronary artery injection of physiologic testosterone increased coronary artery diameter and blood flow 1
• The 2023 TRAVERSE trial provides Level 1 evidence that testosterone therapy does not increase stroke risk even in men with preexisting cardiovascular disease 2

One important caveat: A single retrospective cohort study of veterans with coronary disease found increased risk for combined mortality, MI, and stroke (HR 1.29) with testosterone therapy, but this was in men receiving exogenous testosterone, not those with naturally elevated endogenous levels 1

Prostate Cancer

High testosterone does not cause prostate cancer or make it more severe. This is one of the most important misconceptions to correct:

• Of 12 prospective studies examining stored plasma samples, only one suggested any relation between testosterone and prostate cancer, and this was only after simultaneous adjustment for four other hormones—of clinically uncertain significance 1
• Prospective studies found no difference in testosterone levels between men who developed prostate cancer 7-25 years later and those who did not 1
• No observational studies in the American College of Physicians systematic review reported an increased risk for prostate cancer with testosterone therapy 1
• A comprehensive review of 45 articles found contradictory findings largely due to disparate methodologies, with most studies not adhering to professional society guidelines on testosterone measurements 3

The key distinction: While testosterone can stimulate growth of existing prostate cancer (which is why it's contraindicated in men with known prostate cancer), it does not cause prostate cancer 1, 4

COVID-19

High testosterone does not worsen COVID-19 severity or increase infection risk:

• In the TRAVERSE trial of 5,204 men, neither baseline nor on-treatment testosterone, estradiol, and dihydrotestosterone levels prior to COVID-19 differed significantly between men with and without COVID-19 diagnosis 5
• The 3-year Kaplan-Meier incidence of COVID-19 was 8.0% in the testosterone replacement therapy group versus 8.6% in placebo (P = .823) 5
• COVID-19-related hospitalizations (38.5% vs 32.8%, P = .222) and deaths (12.8% vs 8.9%, P = .247) were similar in testosterone-treated and placebo groups 5
• Testosterone replacement therapy did not affect the risk of COVID-19 infection 5

Important nuance: While low testosterone during acute COVID-19 infection is associated with worse outcomes, this represents a consequence of severe illness rather than a causal factor. More than 50% of men who recovered from COVID-19 still had low testosterone at 7-month follow-up, with higher comorbidity burden predicting lower probability of testosterone recovery 6

Other Conditions and General Safety

Men with naturally elevated endogenous testosterone (>800 ng/dL) do not experience clinically significant adverse effects:

• In a National Health and Nutrition Examination Survey analysis of 3,673 men, only 4% had testosterone >800 ng/dL 7
• Men with elevated testosterone had similar rates of sleep disorders, urinary symptoms, and depression compared to men with normal testosterone (300-800 ng/dL) 7
• While men with elevated testosterone had higher hematocrit (βi 1.30,95% CI 0.69-1.90), AST, and ALT, these differences were not clinically significant 7

Critical Distinction: Endogenous vs. Exogenous Testosterone

The risks associated with testosterone therapy (exogenous administration) differ from naturally elevated endogenous levels:

• Erythrocytosis occurs in 3-18% with transdermal testosterone therapy and up to 44% with intramuscular injections, but this is a dose-dependent effect of exogenous administration 1, 2, 8
• The FDA mandated labeling changes in 2015 warning of possible increased cardiovascular risk with testosterone preparations, particularly in patients with existing cardiovascular disease 9
• Testosterone therapy requires monitoring for hematocrit elevation, fluid retention in heart failure patients, and prostate changes—but these are concerns for therapeutic administration, not naturally high levels 1, 4

Clinical Bottom Line

High endogenous testosterone is not pathologic and does not require intervention. The evidence challenges the assumption that elevated testosterone worsens disease severity. In fact, low testosterone—not high testosterone—is consistently associated with worse cardiovascular outcomes, more severe COVID-19, and higher mortality. The risks discussed in testosterone therapy guidelines apply to exogenous supplementation, particularly at supraphysiologic doses or with injectable formulations that cause erythrocytosis, not to men with naturally elevated testosterone levels 1, 7.