What are the cardiovascular risks and management strategies for a patient with a history of cardiovascular events or significant risk factors starting testosterone replacement therapy (TRT)?

Testosterone Replacement Therapy Does NOT Increase Cardiovascular Risk When Properly Prescribed

Based on the highest quality evidence from the 2023 TRAVERSE trial, testosterone replacement therapy does not increase the risk of heart attacks, strokes, or cardiovascular events in appropriately selected men with confirmed hypogonadism. 1 The American Heart Association/American Stroke Association provides a Class 2a recommendation that testosterone therapy is reasonable and does not increase stroke risk, even in men with preexisting cardiovascular disease. 1

Patient Selection Criteria for Safe TRT Initiation

TRT should only be initiated in men meeting ALL of the following criteria:

• Age 45-80 years 1
• Two separate fasting morning testosterone levels <300 ng/dL 1
• Documented hypogonadism symptoms (decreased libido, erectile dysfunction, fatigue, diminished muscle mass, or reduced bone density) 2
• Documented medical cause of hypogonadism 1

The FDA specifically mandates that safety and efficacy in age-related hypogonadism have not been established, making confirmed organic hypogonadism essential. 3

Cardiovascular Effects: The Evidence

Neutral to Beneficial Effects on Cardiac Function

The evidence demonstrates testosterone has neutral to potentially beneficial cardiovascular effects. 2, 1 Men with chronic stable angina treated with transdermal testosterone showed greater angina-free exercise tolerance compared to placebo controls, and direct coronary artery injection of physiologic testosterone increased coronary artery diameter and blood flow. 2

Lipid Profile Effects Are Neutral

Physiologic replacement doses of testosterone show no clinically significant worsening of lipid profiles. 2 A meta-analysis of intramuscular testosterone esters found HDL levels were unchanged in 15 of 18 studies, total cholesterol was reduced in 5 studies and unchanged in 12, and LDL was unchanged or reduced in 14 of 15 studies. 2 Only supraphysiologic doses (600 mg weekly, well above replacement range) caused significant HDL reduction. 2

Critical Risk: Erythrocytosis and Blood Viscosity

The primary cardiovascular concern with TRT is erythrocytosis (elevated hematocrit), NOT direct cardiac toxicity. 2, 1 Elevated hematocrit increases blood viscosity and could aggravate coronary, cerebrovascular, or peripheral vascular disease, particularly in elderly patients. 2

Formulation-Specific Erythrocytosis Risk

• Intramuscular injections: 43.8% risk of elevated hematocrit (>52%) 2
• Transdermal preparations: 3-18% risk depending on dose 1, 4
• Oral testosterone undecanoate: FDA contraindicated for age-related hypogonadism due to blood pressure increases 1, 4

Injectable testosterone carries substantially higher cardiovascular risk than transdermal preparations due to fluctuating hormone levels causing prolonged time in both supratherapeutic and subtherapeutic ranges. 2, 4

Management Algorithm for Patients with Cardiovascular Disease or Risk Factors

Step 1: Formulation Selection

Strongly prefer transdermal testosterone gel over injections or pellets for all patients, especially those with cardiovascular disease or risk factors. 2, 1, 4 Transdermal preparations produce stable testosterone levels and have the lowest erythrocytosis risk. 2

Step 2: Dosing Strategy

• Starting dose: 50 mg daily (one tube/packet or 4 pump actuations) applied to shoulders and/or upper arms 3
• Target testosterone level: 500-600 ng/dL (mid-normal range) to minimize supraphysiologic exposure 2, 4
• Measure testosterone at 2-3 months after initiation or dose change 2
• For transdermal preparations, measure at any time; for injections, measure midway between doses 2

Step 3: Monitoring Protocol

Mandatory monitoring parameters:

• Hematocrit at 2-3 months, then every 6-12 months 1, 4
• PSA and prostate examination periodically 3
• Lipid panel periodically 3
• Blood pressure at each visit, given small increases (3-5 mmHg systolic) possible 4

If hematocrit exceeds 52%: Consider dose reduction, increased phlebotomy frequency, or formulation switch from injection to transdermal. 2

Step 4: Special Cardiovascular Considerations

For patients with preexisting coronary artery disease, cerebrovascular disease, or peripheral arterial disease, the 2023 TRAVERSE trial provides definitive evidence that TRT does not increase stroke risk. 1 However, monitor for:

• Venous thromboembolism (VTE) including DVT and PE 3
• Fluid retention in patients with preexisting cardiac, renal, or hepatic disease (though rarely clinically significant) 2, 3
• Worsening heart failure symptoms if edema develops 3

Common Pitfalls to Avoid

Pitfall 1: Using injectable testosterone in high-risk patients. The 43.8% erythrocytosis rate with injections versus 3-18% with transdermal preparations makes injections inappropriate for most cardiovascular patients. 2, 1

Pitfall 2: Prescribing TRT for age-related decline without confirmed hypogonadism. The FDA has not established safety for this indication, and the 2015 FDA warning specifically addressed concerns about inappropriate prescribing. 2, 3

Pitfall 3: Failing to monitor hematocrit. Given the high erythrocytosis risk, especially with non-transdermal formulations, hematocrit monitoring is non-negotiable. 2, 1, 4

Pitfall 4: Overattributing mild edema to dangerous cardiovascular effects. Fluid retention is listed as a potential risk but is "rarely of clinical significance" in clinical practice. 2, 4

Pitfall 5: Using oral testosterone undecanoate. This formulation is FDA-contraindicated for age-related hypogonadism due to demonstrated blood pressure increases. 1, 4

Contraindications

Absolute contraindications per FDA labeling:

• Known or suspected prostate or breast carcinoma 3
• Pregnancy (causes fetal harm) 3

Relative contraindications requiring careful risk-benefit assessment:

• Untreated severe sleep apnea 3
• Severe untreated heart failure 3
• Hematocrit >50% at baseline 2

Key Takeaway for Clinical Practice

The cardiovascular safety concerns that emerged from earlier observational studies have been refuted by the 2023 TRAVERSE trial, the highest quality evidence available. 1 When TRT is prescribed for confirmed hypogonadism using transdermal preparations at physiologic doses with appropriate monitoring, it does not increase cardiovascular risk and may provide benefits. 2, 1 The real cardiovascular danger lies in erythrocytosis from injectable formulations and inappropriate prescribing without confirmed hypogonadism. 2, 1