Testosterone Replacement Therapy: Evidence, Benefits, and Safety in 2025
Testosterone replacement therapy (TRT) is indicated for men with confirmed hypogonadism—defined by consistent symptoms and two separate fasting, early-morning testosterone levels below the lower limit of normal.
The greatest likelihood of benefit occurs in men with markedly low testosterone accompanied by classical symptoms. [1][2]
When TRT Is Appropriate
Indications
Primary or secondary hypogonadism with symptoms such as low libido, erectile dysfunction, fatigue, anemia, or reduced muscle mass.
TRT is not recommended for isolated, age-related testosterone decline without clear symptoms or for men pursuing fertility, since exogenous testosterone suppresses spermatogenesis. [1][2]
Risks and Safety Considerations
Cardiovascular
The TRAVERSE trial (n = 5,246; mean follow-up 33 mo) found no increase in major adverse cardiovascular events (MACE)—myocardial infarction, stroke, or CV death—with TRT versus placebo (HR 0.96; 95% CI 0.78–1.17). [4]
Meta-analyses and position papers from the Androgen Society and Endocrine Society now conclude TRT is not associated with elevated MACE risk. [5][6]
However, TRAVERSE noted small upticks in atrial fibrillation, pulmonary embolism, and acute kidney injury, so ongoing vigilance is warranted. [4–6]
Thromboembolism
Absolute risk is low, but men with prior VTE events may require prophylactic measures or closer monitoring. [1]
Polycythemia
TRT can raise hematocrit and trigger erythrocytosis, increasing thrombotic risk—regular hematologic monitoring is essential. [3]
Prostate Health
Current data show no increased risk of prostate cancer or LUTS during TRT in screened populations, though high-risk men were excluded from trials.
Baseline and serial PSA and prostate evaluations remain standard. [1][2][3]
Other Adverse Effects
Gynecomastia, fluid retention, acne, elevated blood pressure, application-site reactions, testicular atrophy, infertility, and potential worsening of sleep apnea may occur. [3]
Monitoring Recommendations
PhaseEvaluationTimingTarget / ActionBaselineSymptoms, two early-morning testosterone levels, PSA, hematocrit, prostate examBefore therapyConfirm diagnosis, rule out contraindicationsFollow-upTestosterone, hematocrit, PSA, symptom review3, 6, 12 months, then annuallyMaintain testosterone in mid-normal range (≈ 350–750 ng/dL) [2][4]Formulation SelectionIM vs transdermal vs subcutaneousOngoingChoose based on preference, cost, adherence, and risk profile [3]
Long-Term Cardiovascular Safety: The 2025 Consensus
TRAVERSE (NEJM 2023): Non-inferior MACE rates vs placebo in high-risk men. [4]
Meta-analyses (2024): No signal for increased MACE, CV death, or stroke. [5][6][7][8]
Society positions: Both the Androgen Society and Endocrine Society endorse TRT as cardiovascularly safe in men with true hypogonadism, provided appropriate monitoring. [2][5]
Some studies note possible rises in atrial fibrillation and non-calcified coronary plaque, but these findings remain inconsistent. [6][8]
Clinical Summary
TRT is appropriate only for men with unequivocal hypogonadism and significant symptoms.
Benefits are most robust in sexual function, anemia correction, and lean mass gain, with modest effects on mood and physical performance.
Current high-quality data—including TRAVERSE and multiple meta-analyses—show no excess risk of major cardiovascular events when TRT is used judiciously.
Continued vigilance for arrhythmias, thromboembolism, and polycythemia remains critical.
Success depends on careful patient selection, thorough baseline evaluation, and structured follow-up.
References
Bhasin S, Snyder PJ. Testosterone Treatment in Middle-Aged and Older Men with Hypogonadism. N Engl J Med.2025;393(6):581-591. doi:10.1056/NEJMra2404637.
Bhasin S et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.
Diem SJ et al. Efficacy and Safety of Testosterone Treatment in Men. Ann Intern Med. 2020;172(2):105-118.
Lincoff AM et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117.
Morgentaler A et al. Androgen Society Position Paper on Cardiovascular Risk With Testosterone Therapy. Mayo Clin Proc. 2024;99(11):1785-1801.
Corona G et al. Cardiovascular Safety of Testosterone Replacement Therapy in Men: Updated Systematic Review and Meta-Analysis. Expert Opin Drug Saf. 2024;23(5):565-579.
Thirumalai A, Anawalt BD. Relationships Between Endogenous and Exogenous Testosterone and Cardiovascular Disease in Men. Rev Endocr Metab Disord. 2022;23(6):1305-1322.
Krishnan S et al. Testosterone Therapy and the Risk of Cardiovascular Disease in Older, Hypogonadal Men. Prog Cardiovasc Dis. 2024;84:14-18.
