Testosterone Pellets and Atherosclerosis
Testosterone pellets do not worsen atherosclerosis, but they carry higher cardiovascular risk than transdermal preparations due to fluctuating hormone levels and increased polycythemia risk—transdermal formulations should be preferred when testosterone replacement is indicated. 1, 2
Evidence from Recent High-Quality Studies
The 2024 American Heart Association/American Stroke Association guidelines provide reassurance that testosterone replacement does not increase atherosclerotic cardiovascular events in appropriately selected men. The TRAVERSE study (2023) demonstrated no significant difference in major adverse cardiac events or nonfatal stroke in men with confirmed hypogonadism treated with testosterone gel versus placebo over a mean of 21.7 months. 1 However, this study specifically examined testosterone gel, not pellets, and the guidelines explicitly note that "the effects of other testosterone formulations and routes of administration on the risk of stroke are not well studied." 1
Formulation-Specific Cardiovascular Risks
Injectable and implantable testosterone formulations (including pellets) carry substantially higher cardiovascular risk compared to transdermal preparations. 1, 2 The mechanisms underlying this increased risk include:
Fluctuating testosterone levels: Pellets and injections cause prolonged periods in both supratherapeutic and subtherapeutic ranges between doses, unlike the stable levels achieved with transdermal preparations 1, 2
Polycythemia risk: Injectable formulations demonstrate a 43.8% incidence of elevated hematocrit in comparative studies, which increases blood viscosity and could theoretically aggravate vascular disease 2
FDA regulatory concerns: In 2015, the FDA mandated labeling changes warning of possible increased risk of heart attack and stroke with testosterone preparations, with particular concern for non-transdermal formulations 1, 2
Relationship Between Testosterone and Atherosclerosis
The underlying relationship between testosterone and atherosclerosis appears protective rather than harmful. Low endogenous testosterone levels are inversely associated with carotid atherosclerosis in men with type 2 diabetes, with lower free testosterone correlating with greater intima-media thickness and plaque scores. 3 Physiologic testosterone replacement at appropriate doses does not worsen lipid profiles and may confer cardiovascular benefit through anti-inflammatory effects, improved vascular reactivity, and reduced pro-thrombotic factors. 4, 5
Clinical Recommendations for Testosterone Replacement
When testosterone replacement is medically indicated for confirmed hypogonadism, transdermal preparations should be strongly preferred over pellets or injections. 1, 2 If pellets are used despite higher risk:
Monitor hematocrit at 2-3 months after implantation and every 6-12 months thereafter, with more frequent monitoring given the high erythrocytosis risk 2
Target mid-normal testosterone levels (500-600 ng/dL) to minimize time in supratherapeutic ranges 2
Consider switching to transdermal preparations if cardiovascular concerns develop, despite higher cost 2
Avoid use in men with recent myocardial infarction, stroke, or advanced heart failure 6
Common Pitfalls
The primary pitfall is assuming all testosterone formulations carry equivalent cardiovascular risk. While the TRAVERSE study provides reassurance for testosterone gel, this evidence cannot be extrapolated to pellets or injections, which have distinct pharmacokinetic profiles and associated risks. 1, 2 Another pitfall is failing to distinguish between the effects of endogenous low testosterone (which correlates with increased atherosclerosis) versus exogenous testosterone replacement (which does not worsen atherosclerosis when given at physiologic doses via appropriate formulations). 4, 3