Testosterone Cypionate Cardiovascular Impact Long-Term

What the long-term evidence actually covers

TRAVERSE was a randomized, double-blind, placebo-controlled noninferiority trial in 5,246 men aged 45 to 80 with symptoms of hypogonadism, two fasting testosterone levels below 300 ng/dL, and existing or high risk of cardiovascular disease. Men received daily 1.62% testosterone gel, adjusted to keep levels between 350 and 750 ng/dL, or placebo gel. Mean treatment lasted 21.7 months and mean follow-up 33.0 months [1].

The primary endpoint was the first cardiovascular death, nonfatal heart attack, or nonfatal stroke. It occurred in 182 men (7.0%) on testosterone and 190 men (7.3%) on placebo, hazard ratio 0.96 with a 95% CI of 0.78 to 1.17. Noninferiority required the upper confidence limit to fall below 1.5, and it did [1]. About 61% of participants stopped the study gel or placebo before the end.

FDA reviewed those results and said TRAVERSE did not demonstrate a new safety signal or trend in adverse cardiovascular outcomes [3]. On February 28, 2025, the agency asked sponsors to add the TRAVERSE results to all testosterone labels, remove boxed-warning language about an increased risk of adverse cardiovascular outcomes, and add a blood pressure warning to products that lacked one [4].

The trial did not test cypionate. TRAVERSE used a gel, and no cardiovascular outcome trial of that size exists for injectable testosterone [1].

What the cypionate label says about the heart

Depo-Testosterone, the branded testosterone cypionate injection, has no boxed warning [2]. Its warnings section still carries the pre-TRAVERSE language: long-term clinical safety trials have not been conducted to assess cardiovascular outcomes, epidemiologic studies and randomized trials have been inconclusive for major adverse cardiovascular events, some studies but not all have reported an increased risk, and patients should be informed of this possible risk [2].

The same label says testosterone can increase blood pressure, which can increase cardiovascular risk over time, that blood pressure should be monitored periodically especially in men with hypertension, and that testosterone products are not recommended in men with uncontrolled hypertension [2]. Serious cardiac, hepatic or renal disease is listed as a contraindication, and the label warns that edema, with or without congestive heart failure, may be a serious complication in men with pre-existing cardiac, renal or hepatic disease [2].

Label wording differs by product. The Azmiro (cypionate) and Xyosted (enanthate) labels describe TRAVERSE and no longer carry the older paragraph about inconclusive cardiovascular data; the Depo-Testosterone and generic enanthate labels checked still do.

Testosterone cypionate is a prescription product; HealthRX.com offers testosterone cypionate by prescription.

Blood pressure

FDA required ambulatory blood pressure monitoring studies for testosterone products, and the completed studies confirmed an increase in blood pressure with all of them, class-wide [4].

Where a product ran an ambulatory study, its label carries numbers. The Xyosted label, for a weekly subcutaneous testosterone enanthate autoinjector rather than cypionate, reports an average rise of 3.9/1.5 mm Hg systolic/diastolic at week 12 in 62 men with usable recordings, 3.9/1.3 mm Hg in men already on blood pressure medicine, and 10% of men in the 1-year study starting or changing an antihypertensive medicine. The Depo-Testosterone blood pressure paragraph carries no ambulatory numbers [2], and Xyosted's figures are not cypionate's figures.

The Xyosted label also notes that prescription and nonprescription analgesics and cold medicines known to raise blood pressure may add to the effect.

Hematocrit and red blood cells

Androgens stimulate red blood cell production by enhancing production of erythropoietic stimulation factor, and polycythemia is listed among the adverse reactions of testosterone cypionate [2]. The Depo-Testosterone label says to check hemoglobin and hematocrit periodically during long-term use, and notes that increased red blood cell mass may raise thromboembolic risk [2]. The Xyosted label directs hematocrit checks about every 3 months: if hematocrit becomes elevated, stop until it falls, and if it rises again after restarting, stop permanently. The Azmiro label gives the same stop, restart, stop-permanently rule.

Route matters. A network meta-analysis of 29 placebo-controlled randomized trials in 3,393 men found that every formulation raised mean hematocrit versus placebo: intramuscular enanthate or cypionate by 4.0% (95% CI 2.9 to 5.1), oral testosterone undecanoate by 4.3%, gel by 3.0%, intramuscular undecanoate by 1.6%, and patch by 1.4%. Intramuscular enanthate or cypionate rose significantly more than patch; the other comparisons were not significantly different [5].

A retrospective single-center review of 178 hypogonadal men followed for 3 years found erythrocytosis, defined there as hematocrit above 50%, in 66.7% of men on injectable testosterone versus 12.8% on gels and 35.1% on pellets. The injection group was younger (mean 42.5 versus about 54 years) and started with a higher hematocrit, and the study was not randomized [6].

Reviews put the overall risk in context: men on testosterone replacement had a 315% greater risk of erythrocytosis above 0.52 hematocrit than controls, with short-acting injectables showing the highest incidence, while the link between erythrocytosis and thromboembolic events remains unclear [7][8].

Blood clots

The Depo-Testosterone label describes postmarketing reports of deep vein thrombosis and pulmonary embolism in people using testosterone products, says to evaluate leg pain, swelling, warmth or redness and acute shortness of breath for those events, and says to discontinue testosterone if a venous thromboembolic event is suspected [2]. Venous thromboembolism appears in the label's list of adverse reactions [2].

In TRAVERSE, venous thromboembolism occurred in 1.7% of men on testosterone gel versus 1.2% on placebo, with deep vein thrombosis at 0.6% versus 0.5% and pulmonary embolism at 0.9% versus 0.5% [1]. Those are gel figures from a population selected for cardiovascular risk.

Atrial fibrillation and other events reported in TRAVERSE

Beyond the primary endpoint, several events were reported more often with testosterone gel than placebo: nonfatal arrhythmias requiring intervention in 5.2% versus 3.3%, atrial fibrillation in 3.5% versus 2.4%, acute kidney injury in 2.3% versus 1.5%, and bone fracture in 3.5% versus 2.5% [1].

Coronary plaque in older men: the Testosterone Trials substudy

A substudy of the Testosterone Trials measured coronary plaque by CT angiography in 170 of the trial's 788 men, all aged 65 or older with an average testosterone level below 275 ng/dL, randomized to testosterone gel or placebo gel for 12 months; 138 men had data for the primary analysis [9].

Noncalcified plaque volume rose from a median of 204 to 232 mm3 on testosterone and from 317 to 325 mm3 on placebo, an estimated difference of 41 mm3 (95% CI 14 to 67; P=.003). Total plaque volume rose by an estimated 47 mm3 more on testosterone (95% CI 13 to 80; P=.006) [9]. The study was built to test whether testosterone slowed plaque progression; plaque volume increased more on testosterone instead. It was a 12-month imaging study in older men, not an event trial.

Supraphysiologic doses: what the abuse data show

Illicit anabolic steroid use at high doses is a different setting from prescribed replacement. In a cross-sectional study of 140 male weightlifters aged 34 to 54, 86 of whom had at least 2 years of cumulative anabolic steroid use, users had lower left ventricular ejection fraction (52% versus 63%), lower early diastolic relaxation velocity (9.3 versus 11.1 cm/second), and higher coronary plaque volume (P=0.012) than nonusers. Longer cumulative steroid exposure was associated with more plaque [10].

The cypionate label addresses the same territory: testosterone has been abused, typically at doses above those recommended and alongside other anabolic steroids, and serious cardiovascular and psychiatric adverse reactions can result [2].

What remains unknown

Whether the higher hematocrit seen with injections translates into more heart attacks, strokes or clots over years has not been settled, and reviews describe the erythrocytosis-to-clot link as inconclusive [8]. The 2018 Endocrine Society guideline advises against starting testosterone in men with uncontrolled heart failure or a heart attack or stroke within the previous 6 months, and recommends monitoring symptoms, testosterone levels, hematocrit and prostate cancer risk during the first year [11].