Testosterone, Testosterone Replacement Therapy, and Cardiovascular Disease: A Contemporary Review.

Low endogenous testosterone is consistently associated with higher all-cause and cardiovascular mortality, but most plausibly marks multimorbidity rather than being causal.

• The review describes the association as consistent across the literature.
• The authors judge that low testosterone most plausibly acts as a marker of multimorbidity rather than a cause of cardiovascular disease.
• Whether low endogenous testosterone is causal for cardiovascular disease is described as contested.

TRAVERSE established that physiologic transdermal testosterone replacement therapy was noninferior to placebo for 3-point major adverse cardiovascular events (MACE) over about 3 years.

• Noninferiority was established within a permissive margin.
• The trial had a 61% discontinuation rate.
• The follow-up was approximately 3 years.

Noninferiority over 3 years should not be read as long-term clinical equivalence.

• Long-term exposure beyond the trial duration remains untested.
• The permissive noninferiority margin and high discontinuation rate (61%) limit interpretation.

Observational analyses linking testosterone normalization to lower mortality were not reproduced under randomization.

• The authors classify these observational associations as not confirmed in randomized trials.
• This applies to claims that normalizing testosterone reduces mortality.

Several safety outcomes remain unresolved: atrial fibrillation, pulmonary embolism, acute kidney injury, fracture, and noncalcified plaque progression.

• These are categorized as unresolved secondary signals in the review's evidence-tier structure.
• They were not settled by the primary randomized findings.

Blood pressure rises across the class of testosterone products, and on ambulatory monitoring the magnitude differs by individual product rather than by route.

• The blood pressure increase is described as a class effect.
• Differences in magnitude were observed on ambulatory blood pressure monitoring.
• Variation tracks the specific product rather than the route of administration.

Long-term exposure and nontransdermal formulations remain untested for cardiovascular safety.

• TRAVERSE tested physiologic transdermal testosterone only.
• The authors classify these as areas of evidentiary absence.

US labeling has moved in two opposing directions within 16 months, and the age-related-hypogonadism limitation of use is now proposed for removal.

• The review draws on primary regulatory documents as well as MEDLINE.
• The shifting labeling contributes to contested classification of TRT cardiovascular risk.

The review used a targeted narrative design with a prespecified 3-tier author-consensus evidence rating.

• Reporting followed the Scale for the Assessment of Narrative Review Articles (SANRA).
• MEDLINE and primary regulatory documents were searched from January 2000 through July 2026.
• Tiers separate established randomized findings, unresolved secondary signals, and evidentiary absence.

Safe TRT use requires appropriate patient selection, distinguishing pathologic hypogonadism from functional or age-associated low testosterone, mapping recommendations to evidentiary tiers, and multidisciplinary collaboration.

• The authors emphasize distinguishing pathologic from functional or age-associated low testosterone.
• Each clinical recommendation should be tied to its level of evidence.