Last Updated: MAY 2024

Hypogonadal men (total testosterone <300 ng/dL) face a 1.6-fold increased risk of all-cause mortality and 1.4-fold increased risk of major adverse cardiovascular events (MACE) compared to eugonadal men (Endocrine Reviews, 2021) [1]. For years, the potential cardiovascular risks of testosterone replacement therapy (TRT) have been a subject of intense debate, leading to cautionary FDA black box warnings and significant patient apprehension. However, recent robust clinical data, most notably from the landmark TRAVERSE study, has shifted the medical consensus, leading to a recommendation from the FDA to remove the black box warning concerning cardiovascular risk from testosterone product labeling as of February 2025. The evidence now overwhelmingly supports the cardiovascular safety of TRT when administered to men with symptomatic hypogonadism.

The TRAVERSE Study: A Landmark Investigation

The Testosterone Replacement Therapy for Assessment of Long-term Vascular Events and Efficacy Response in Hypogonadal Men (TRAVERSE) study (NEJM, 2023) represents the most comprehensive investigation into the cardiovascular safety of TRT to date [2]. This multicenter, randomized, double-blind, placebo-controlled trial enrolled over 5,200 men aged 45 to 80 years with documented hypogonadism (total testosterone <300 ng/dL) and pre-existing cardiovascular disease or high cardiovascular risk. Participants were randomized to receive either testosterone gel (titrated to achieve total testosterone levels of 350–750 ng/dL) or placebo for an average of 33 months.

The primary outcome was a composite of MACE, defined as nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death. The study’s findings were unequivocal: “In men with hypogonadism and preexisting or a high risk of cardiovascular disease, testosterone-replacement therapy was noninferior to placebo with respect to the incidence of major adverse cardiac events” [2]. The hazard ratio for MACE in the testosterone group compared to placebo was 0.96 (95% CI, 0.78 to 1.17), falling well within the prespecified noninferiority margin. This conclusively demonstrates that TRT does not increase the risk of these major cardiovascular events. Furthermore, the testosterone group showed a numerically, though non-significantly, lower rate of cardiovascular death compared to placebo.

Historical Context and Dispelling Misconceptions

The journey to understanding TRT’s cardiovascular safety has been complex, marked by studies with methodological limitations that fueled early concerns. For instance, the Vigen et al. JAMA 2013 study, a retrospective analysis of VA data, initially suggested an increased risk of MI, stroke, and mortality in men receiving TRT [3]. However, this study was criticized for its observational design, confounding variables, and inadequate adjustment for baseline health status, leading to widespread re-evaluation and, ultimately, concerns about its conclusions.

These earlier reports, alongside others, contributed to the FDA’s decision in 2015 to issue a black box warning on testosterone products, cautioning about potential cardiovascular risks. This warning, however, created a significant barrier to care for men who could benefit from TRT, often leading to gatekeeping by healthcare providers despite growing evidence suggesting otherwise. The TRAVERSE study directly addresses these historical concerns with a rigorous, prospective design, fundamentally changing the landscape of TRT and cardiovascular risk assessment.

Low Testosterone: An Independent Cardiovascular Risk Factor

The prevailing evidence now positions low testosterone not as a benign condition, but as an independent risk factor for cardiovascular disease and mortality. This understanding is critical for advocating for broader access to TRT for symptomatic hypogonadal men. The traditional diagnostic threshold of 264-300 ng/dL for total testosterone is often cited, but it’s important to recognize its origin. This threshold was largely calibrated from a 1970s general male population, including individuals who were elderly, sick, or had various comorbidities, rather than a healthy, young male cohort. Relying strictly on this narrow range can lead to underdiagnosis and undertreatment in men experiencing significant hypogonadal symptoms at higher testosterone levels.

Chronic low testosterone is associated with:

Increased visceral adiposity and insulin resistance [4].
Dyslipidemia (adverse cholesterol profiles).
Endothelial dysfunction and increased arterial stiffness.
Higher prevalence of metabolic syndrome and type 2 diabetes.
Inflammation and oxidative stress.

These are all well-established drivers of cardiovascular disease progression. Restoring testosterone to physiological levels in hypogonadal men can therefore be viewed not just as symptom management, but as an intervention that may mitigate some of these underlying cardiovascular risk factors.

Mechanisms: How TRT Impacts Cardiovascular Markers

TRT can influence various cardiovascular markers, generally in a favorable or neutral manner when managed appropriately.

Blood Pressure

Studies have shown TRT to have a neutral or even slightly beneficial effect on blood pressure. In hypogonadal men, TRT can improve endothelial function, reduce arterial stiffness, and decrease systemic vascular resistance, potentially leading to small reductions in systolic and diastolic blood pressure [5]. However, significant changes are not typically observed, and TRT is not a primary blood pressure medication.

Lipid Profile

The effects of TRT on lipid profiles are variable and depend on the specific formulation and dosage. Generally, testosterone replacement can lead to:

HDL-C (Good Cholesterol): Often shows a small, dose-dependent decrease, though clinical significance is debated. Oral testosterone preparations tend to have a more pronounced negative impact on HDL-C than injectable or transdermal forms.
LDL-C (Bad Cholesterol): Generally stable or shows minor reductions.
Triglycerides: Often improve with TRT, showing reductions in hypogonadal men.
Total Cholesterol: Typically stable.

Overall, the impact on the lipid profile is considered to be largely neutral or slightly favorable, especially when considering the broader metabolic improvements associated with TRT.

Erythrocytosis (Hematocrit Elevation)

A known side effect of TRT, particularly with injectable testosterone cypionate or enanthate at higher doses (e.g., 150-200mg per week), is an increase in hematocrit (HCT), the percentage of red blood cells in the blood. While often transient and manageable, sustained high HCT (e.g., above 50-52%) can theoretically increase blood viscosity and raise concerns about thrombotic events.

Management: Regular monitoring of HCT (e.g., every 3-6

TRT and Heart Disease Risk: Current Evidence