Endocrine

Does Testosterone Replacement Raise Cardiovascular Risk?

Quick answer

TRAVERSE (2023) showed testosterone replacement is non-inferior to placebo for MACE over a mean 33-month follow-up in middle-aged/older hypogonadal men with CV risk. Mild increases in AFib, pulmonary embolism, and AKI were observed. Confirm hypogonadism with two AM total testosterone levels <300 ng/dL plus symptoms before initiating; avoid in fertility-desiring men and those with prior VTE or prostate cancer.

Evidence review

Pivotal trials, effect sizes, and the populations they studied. PubMed identifiers link directly to the source.

TRAVERSE (2023)

PMID 37326322

5,246 men 45–80, symptomatic hypogonadism, CV risk factors

MACE 7.0% vs 7.3% (HR 0.96, non-inferior). AFib (3.5% vs 2.4%, p=0.02), PE (0.9% vs 0.5%), AKI slightly elevated.

Basaria et al. TOM (2010)

PMID 20592293

209 older men with mobility limitation

Stopped early due to CV adverse events on testosterone gel. Superseded by TRAVERSE but influenced historical caution.

Practical decision algorithm

IfThen
Symptomatic hypogonadism (two AM total T <300 ng/dL, libido/fatigue/low mood)Initiate topical (gel) or injectable testosterone. Target total T 400–700 ng/dL.
Baseline hematocrit ≥54%Do not initiate. If on therapy: hold until <50%, then restart lower dose.
Prior VTE or strong thrombophiliaAvoid. If therapy essential, consider topical over injectable (less supraphysiologic peaks).
Prostate cancer history (treated, >2 years remission)Shared decision with urology. No clear evidence of progression; monitor PSA closely.
Fertility desiredDo not use testosterone (suppresses spermatogenesis). Use clomiphene or hCG.

Guideline position

Endocrine Society hypogonadism guidelines (most recent full guideline 2018, with postmarket updates): treat symptomatic men with confirmed total T <300 ng/dL; counsel using TRAVERSE findings. AUA 2023 testosterone deficiency guideline: prior treated prostate cancer is not an absolute contraindication. FDA 2025 class-wide testosterone labeling update (post-TRAVERSE): boxed CV-risk language removed; increased blood-pressure, AFib, PE, and AKI signals noted.

Contraindications and cautions

  • Hematocrit >54%
  • Active prostate or breast cancer
  • Severe untreated OSA
  • Fertility desired
  • Prior VTE within 6 months (relative)

Frequently asked questions

Is the AFib signal in TRAVERSE clinically meaningful?
Absolute increase 1.1% over 33 months — modest. Counsel patients with CHA2DS2-VASc-raising features. Check baseline ECG and reassess if palpitations develop.
How often should I monitor hematocrit?
Baseline, 3 months, 6 months, then annually. If HCT >54%, hold therapy, consider phlebotomy, and restart at lower dose. Gels have lower HCT risk than injections.
Do I need to treat low-normal T (300–400 ng/dL)?
Only if symptomatic and secondary causes ruled out. A significant fraction of hypogonadism in middle age is obesity-related and reverses with weight loss.
What about PSA monitoring?
Baseline PSA and DRE, then at 3, 6, 12 months. PSA often rises 0.5–1 ng/mL in the first year. Urology referral for PSA rise >1.4 ng/mL, velocity >0.4/year, or new DRE findings.
Is topical or injectable preferred?
Topical (gel, solution) offers steady levels and lower HCT/AFib signal. Injectables are cheaper; long-acting (testosterone undecanoate) minimizes peaks but requires loading. Patient preference drives many decisions.

Further reading

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