Does Intramuscular (IM) Testosterone increase the risk of Cardiovascular Disease?

From the Guidelines

Intramuscular (IM) testosterone therapy does not appear to significantly increase the risk of cardiovascular disease in most men, but may pose a slightly higher risk for certain populations, such as older men and those with pre-existing cardiovascular disease. The evidence regarding IM testosterone therapy and cardiovascular disease risk is mixed, but current data suggests a possible modest increase in risk for certain populations. IM testosterone formulations like testosterone cypionate or enanthate (typically dosed at 50-400mg every 1-4 weeks) may pose slightly higher cardiovascular risks compared to topical formulations due to the higher peak levels they create 1. This risk appears most significant in older men (over 65) and those with pre-existing cardiovascular disease. The potential mechanisms include increased red blood cell production (erythrocytosis), changes in cholesterol profiles, and possible effects on blood vessel function. Some key points to consider:

• Patients using IM testosterone should have regular monitoring of hematocrit levels (keeping below 54%), lipid profiles, and blood pressure 1.
• The risk appears dose-dependent, with higher doses and supraphysiologic levels carrying greater risk.
• For men with existing cardiovascular disease, lower doses and more frequent injections (to avoid extreme peaks) may be safer.
• The absolute risk increase for most healthy men appears small, but patients should discuss their individual risk factors with their healthcare provider before starting therapy. It's also important to note that the evidence for long-term safety is lacking, and most studies excluded men with recent cardiovascular disease 1. Therefore, it's essential to weigh the potential benefits and risks of IM testosterone therapy on an individual basis.

From the Research

Intramuscular Testosterone and Cardiovascular Disease

• The relationship between intramuscular (IM) testosterone and cardiovascular disease is complex and has been the subject of numerous studies 2, 3, 4, 5, 6.
• Some studies suggest that testosterone replacement therapy, including IM testosterone, may increase the risk of cardiovascular disease, particularly in older men or those with pre-existing heart disease 5.
• However, other studies have found that testosterone replacement therapy is noninferior to placebo with respect to the incidence of major adverse cardiac events in men with hypogonadism and preexisting or a high risk of cardiovascular disease 3.
• The evidence suggests that the risk of cardiovascular disease associated with IM testosterone may depend on various factors, including age, pre-existing medical conditions, and the presence of other risk factors for cardiovascular disease 2, 4, 5, 6.

Key Findings

• A 2019 review of epidemiological data and clinical trials found that the cardiovascular safety of testosterone replacement therapy remains unclear due to the lack of trials designed to assess cardiovascular events 2.
• A 2023 randomized controlled trial found that testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events in men with hypogonadism and preexisting or a high risk of cardiovascular disease 3.
• A 2014 cohort study found that the risk of non-fatal myocardial infarction was increased in men aged 65 years and older who were prescribed testosterone therapy, particularly in those with a prior history of heart disease 5.
• A 2011 review of the literature found that testosterone deficiency is associated with an increased risk of cardiovascular disease, and that replacement therapy may have beneficial effects on cardiovascular risk factors 4.

Mechanisms and Risk Factors

• Testosterone is known to affect various risk factors for cardiovascular disease, including vascular tone, vasoreactivity, and blood flow 6.
• The evidence suggests that the relationship between testosterone and cardiovascular disease is complex and may involve multiple mechanisms, including effects on lipid metabolism, blood pressure, and inflammation 2, 4, 6.
• The presence of other risk factors for cardiovascular disease, such as obesity, diabetes, and hypertension, may also influence the risk of cardiovascular disease associated with IM testosterone 2, 4, 5.