Does TRT Actually Improve Heart Health Markers?

A 2026 review found hypogonadal men carry worse vascular biomarkers and that TRT improves most of them. This primer explains what that means for men choosing a delivery method.

Does TRT actually improve heart health markers?

Testosterone replacement therapy (TRT) does appear to improve several measurable markers of cardiovascular health in men with low testosterone (hypogonadism), though the honest caveat is that most of this evidence comes from biomarkers, not from large trials tracking heart attacks and strokes. A 2026 review in the International Journal of Molecular Sciences found that hypogonadal men consistently show a worse vascular profile across multiple categories: elevated inflammatory proteins, stickier platelets, and fewer circulating repair cells in the bloodstream [1]. TRT improved most of these markers, though the authors were careful to note that head-to-head randomized trials comparing outcomes across formulations are still needed [1].

The specific markers that improved with TRT included:

• ▶hsCRP and IL-6 (inflammation signals in the blood, like a low-grade fever your arteries are running)
• ▶ICAM-1 and VCAM-1 (proteins that make vessel walls stickier and more prone to plaque buildup)
• ▶Endothelial progenitor cells, or EPCs (stem-cell-like repair crews your body sends to fix damaged vessel walls)
• ▶Von Willebrand factor (a clotting protein that, when elevated, signals vessel wall stress)

Men with type 2 diabetes and low testosterone tend to carry the most adverse cardiometabolic profiles in this space, though diabetes-related risk factors appear to be the dominant drivers of calculated cardiovascular risk rather than testosterone alone [2]. For a fuller picture of what low testosterone does to heart health over time, the relationship runs deeper than any single biomarker.

Understanding what these markers actually measure, and why they matter for vessel health, is where the mechanism gets interesting.

What vascular damage does low testosterone actually cause?

Low testosterone does not just make you feel tired; it changes the chemistry inside your arteries in measurable, specific ways. Hypogonadal men, meaning men whose testosterone has fallen below the range their bodies need, consistently show elevated levels of several inflammatory and vascular stress markers that cardiologists track when assessing heart risk [1].

Inflammation markers: hsCRP and IL-6

Two of the most important signals are hsCRP and IL-6. High-sensitivity C-reactive protein (hsCRP) is a protein your liver releases when inflammation is running in the background, the kind you cannot feel but that slowly roughens the inner lining of blood vessels. Interleukin-6 (IL-6) is a chemical messenger that your immune system uses to amplify inflammation. Think of IL-6 as a fire alarm that keeps ringing even when the fire is small, keeping your arteries in a low-grade state of irritation. Men with testosterone deficiency carry higher circulating levels of both [1]. You feel this not as chest pain, but as fatigue that does not resolve with rest, and a body that takes longer to recover from anything.

Endothelial dysfunction: ICAM-1, von Willebrand factor, and progenitor cells

The inner lining of every blood vessel is called the endothelium. When it is working well, it stays smooth and slippery. When it is not, three specific changes appear in hypogonadal men [1]:

• ▶ICAM-1 (intercellular adhesion molecule-1): a surface protein that makes blood vessel walls stickier, allowing inflammatory cells to latch on and start the process that leads to plaque.
• ▶Von Willebrand factor: a clotting protein; elevated levels mean the blood is primed to clot more readily, raising thrombotic risk.
• ▶Endothelial progenitor cells (EPCs): these are repair cells your bone marrow sends out to patch damaged vessel walls. Hypogonadal men have fewer of them circulating, which means the vessel's self-repair system is running short-handed.

A six-month randomized trial in diabetic men with erectile dysfunction found that [testosterone-raising] interventions improved endothelial parameters, with flow-mediated dilation correlating significantly with serum testosterone levels (R²=0.299; P<0.001) [3].

For a broader look at how these markers connect to cardiovascular risk, the full picture is covered in [low testosterone and heart health

How does TRT move these biomarkers, and what will you feel?

TRT does move the vascular biomarkers described above, and the 2026 review in the International Journal of Molecular Sciences synthesized exactly how [1]. The improvements are not marginal or theoretical. They map onto mechanisms your body will register over weeks to months.

What the 2026 review found across formulations

The review reported that testosterone replacement improves most of the circulating cardiovascular biomarkers elevated in hypogonadal men [1]. The pathways driving these changes include PI3K/Akt/eNOS signaling, a chain reaction that tells the cells lining your blood vessels to produce more nitric oxide, the molecule that keeps arteries relaxed and blood flowing freely. When nitric oxide production recovers, arterial stiffness eases and blood pressure tends to follow.

Testosterone deficiency decreases nitric oxide production by altering the expression and activity of nitric oxide synthase and by increasing ADMA expression, a compound that blocks nitric oxide synthase from doing its job [4]. TRT addresses this at the source, restoring the signal the vessel wall needs to stay flexible.

The review catalogued improvements across a broad biomarker set [1]:

• ▶EPCs (endothelial progenitor cells): Circulating counts rise with TRT. EPCs are the body's vascular repair crew; more of them means your arteries patch micro-damage faster.
• ▶hsCRP and IL-6: Both inflammatory markers fall. Lower IL-6 is felt as less background fatigue and faster recovery from exertion.
• ▶ICAM-1 and VCAM-1: These adhesion molecules, which help inflammatory cells stick to and damage artery walls, decrease, reducing the chronic irritation that precedes plaque formation.
• ▶Von Willebrand factor and endothelin-1: Both fall, meaning blood is less prone to clotting abnormally and arteries spend less time in a constricted state.

Translating biomarker shifts to real-world vascular benefit

The combined effect is an arterial environment that runs cooler, repairs faster, and clots less readily. For a patient, that often registers as better exercise tolerance and more consistent energy across the day.

For a fuller picture of what to expect as these changes accumulate, the first 90 days on TRT and the broader [benefits and side effects of hormone therapy for men](/blog/hormone-

Transdermal vs. intramuscular TRT: does the delivery method matter for your heart?

Yes, in one specific and clinically meaningful way: erythrocytosis risk.

Erythrocytosis risk and hematocrit

Erythrocytosis means your body is making too many red blood cells. Think of your bloodstream as a river: a healthy current carries oxygen efficiently, but pack in too many cells and the river turns sluggish, raising the risk of clots. Testosterone tells bone marrow to produce more red blood cells, which is partly why TRT raises energy and exercise capacity. The question is whether it pushes production too far.

Hematocrit, the percentage of your blood volume occupied by red blood cells, rises more sharply with intramuscular injections than with transdermal gels or creams. The reason is pharmacokinetics, the pattern of how a drug enters your bloodstream. Intramuscular injections create a large peak followed by a trough, and that peak repeatedly signals bone marrow to ramp up production. Transdermal delivery smooths the curve, so the signal to bone marrow is steadier and lower. A 2026 review in the International Journal of Molecular Sciences concluded that transdermal testosterone formulations "may offer advantages regarding hematological safety and more stable testosterone exposure" compared with intramuscular preparations [1]. You can read more about managing this specific risk in the guide to TRT and high hematocrit.

What the comparison table shows, and what it cannot prove

The honest caveat is this: the advantage for transdermal formulations rests on pharmacokinetic and hematological data, not on a randomized trial that counted heart attacks or strokes. Both [delivery methods improve vascular biomarkers](/blog/trt-delivery-methods-injections-vs-pellets-vs-cre

Who is most likely to benefit, and who should be cautious?

The benefit signal is strongest in men with confirmed hypogonadism whose vascular biomarkers are already running in the wrong direction: elevated hsCRP, reduced endothelial progenitor cells, and impaired endothelial function [1]. In that profile, correcting testosterone deficiency addresses a root cause of the vascular changes, not just a downstream number.

Men most likely to see meaningful improvement:

• ▶Symptomatic hypogonadism confirmed on two early-morning fasting samples, with SHBG and calculated free testosterone measured alongside total testosterone [5]
• ▶Elevated inflammatory markers (hsCRP, IL-6) alongside low testosterone, where the hormonal and vascular dysfunction are clearly coupled [1]
• ▶Men with insulin resistance or type 2 diabetes, where testosterone deficiency and cardiometabolic risk cluster together [2]

Men who warrant additional caution:

• ▶Those with pre-existing cardiovascular disease or a recent MACE event, where the risk-benefit calculation requires direct cardiologist input
• ▶Men with elevated hematocrit at baseline, where intramuscular formulations carry a higher erythrocytosis risk and transdermal delivery is preferable [1]
• ▶Polycythemia risk is real: hematocrit monitoring every three to six months is standard practice in any physician-supervised TRT protocol

The practical implication is that confirmed hypogonadism with measurable vascular dysfunction is a reasonable indication for TRT, while borderline testosterone with no metabolic context is a weaker one. For a longer view on cardiovascular safety across years of therapy, the evidence reviewed in Is TRT Safe Long-Term? and Is TRT Safe for Your Heart and Prostate? adds important context that biomarker studies alone cannot provide.

What to discuss with your clinician before choosing a TRT formulation

Bring the biomarker evidence to your appointment as a conversation-starter, not a prescription. The 2026 review in International Journal of Molecular Sciences documented that hypogonadal men carry elevated hsCRP, IL-6, ICAM-1, and reduced endothelial progenitor cells before therapy begins, and that TRT shifts most of those markers in a favorable direction [1]. Knowing your baseline values before starting gives you and your clinician a concrete way to track whether therapy is working beyond how you feel.

Before settling on a formulation, raise these points directly:

• ▶Baseline vascular labs: Ask for hsCRP and a full lipid panel alongside your testosterone panel. Understanding how to read your hormone lab report before the appointment makes that conversation more productive.
• ▶Hematocrit monitoring: Erythrocytosis, meaning blood that becomes thicker because too many red blood cells are being made, is more common with intramuscular than transdermal delivery [1]. Ask how often your hematocrit will be checked and what the threshold for a dose adjustment would be.
• ▶Formulation fit: Transdermal options may suit men who already carry cardiovascular risk factors, based on the pharmacokinetic and hematological evidence available, though head-to-head outcome trials are still lacking [1].
• ▶Confirmation of hypogonadism: Low or borderline testosterone should be confirmed on a second early-morning fasting sample before any formulation decision is made [5].

The evidence reviewed here supports a physician-supervised protocol built around shared decision-making, not a single best answer for every man. If you want to work through these questions with a clinician, booking a consultation is a reasonable next step.

MORE FROM THE JOURNAL