Testosterone Injections and Coronary Artery Disease Risk
The evidence regarding testosterone injections and coronary artery disease is conflicting, but the FDA mandated labeling changes in 2015 warning of possible increased cardiovascular risk, and testosterone injections specifically appear to carry higher cardiovascular risk than transdermal formulations, particularly in older men with existing cardiovascular disease. 1
Regulatory Position and Safety Concerns
The FDA required labeling changes in 2015 to inform healthcare professionals and patients of a possible increased risk of heart attack and stroke with testosterone preparations used to treat age-related hypogonadism. 1, 2 This regulatory action was based on conflicting safety data that emerged from multiple studies. 1
Injection-Specific Cardiovascular Risks
Testosterone injections are associated with greater cardiovascular risk compared to transdermal preparations (gels and patches). 1 The proposed mechanisms for this increased risk include:
Fluctuating testosterone levels: Injections cause patients to spend increased time in both supratherapeutic and subtherapeutic ranges between doses, unlike the more stable levels achieved with transdermal preparations. 1
Acute post-injection risk: A 2018 case-crossover study found that testosterone injections were associated with increased risk of adverse cardiovascular events (myocardial infarction, stroke, or unstable angina) in the immediate post-injection period for older Medicare patients (OR = 1.45,95% CI: 1.07-1.98), though not in younger commercially insured men. 3 This association was either greatly attenuated or absent when evaluating all testosterone formulations combined. 3
Erythrocytosis risk: Injections carry substantially higher risk of polycythemia compared to transdermal preparations—43.8% of injection users versus 15.4% of transdermal patch users developed elevated hematocrit in one comparative study. 1 Erythrocytosis increases blood viscosity and could aggravate vascular disease in coronary, cerebrovascular, or peripheral circulation. 1
Contradictory Evidence
However, multiple professional societies and substantial safety data support testosterone use when appropriately prescribed. 1 Key counterpoints include:
Study limitations: The increased cardiovascular risk demonstrated in some studies may be related to high-risk patient populations receiving therapy and lack of appropriate comparator groups, rather than testosterone itself. 1
Beneficial effects: A 2015 Mayo Clinic review found that mortality and incident coronary artery disease are inversely associated with serum testosterone concentrations, and several randomized controlled trials in men with coronary artery disease reported improved function with testosterone compared to placebo. 4
Direct coronary effects: Acute administration studies showed testosterone induces coronary artery dilation, increases coronary blood flow, and has anti-ischemic effects in men with established coronary artery disease. 5, 6
Neutral lipid effects: Testosterone replacement at physiologic doses does not worsen lipid profiles. 1
High-Risk Study Findings
A 2013 JAMA study of 8,709 male veterans with low testosterone who underwent coronary angiography found that testosterone therapy was associated with increased risk of the composite outcome of all-cause mortality, MI, and stroke (25.7% vs 19.9% at 3 years, absolute risk difference 5.8%). 7 This effect was present regardless of whether patients had underlying coronary artery disease. 7
Clinical Recommendations
Given the conflicting evidence but regulatory warnings and injection-specific risks, transdermal testosterone preparations should be preferred over injections for most hypogonadal men. 1
When testosterone therapy is used:
Avoid in high-risk populations: Exercise particular caution in older men (>65 years) and those with established cardiovascular disease, where injection-related risks appear highest. 3
Monitor hematocrit closely: Check at 2-3 months after initiation and every 6-12 months thereafter, with more frequent monitoring for injection users given their 43.8% risk of erythrocytosis. 1 Institute dose reduction, withholding, or therapeutic phlebotomy if hematocrit exceeds 52%. 1
Target mid-normal testosterone levels: For injections, measure levels midway between doses targeting 500-600 ng/dL to minimize time in supratherapeutic ranges. 1
Consider formulation switch: If injections are necessary due to cost or adherence issues but cardiovascular concerns exist, consider switching to transdermal preparations despite higher cost. 1