Testosterone Replacement Therapy Shows a Favorable Cardiovascular and Systemic Safety Profile When Properly Prescribed

Why Testosterone Safety Matters

Testosterone replacement therapy, often shortened to TRT, is one of the most discussed treatments in men’s health. It can improve symptoms in men with confirmed testosterone deficiency, but it has also been surrounded by concerns about heart attack, stroke, blood clots, prostate cancer, and long-term safety.

The current evidence is more reassuring than many patients realize, but it also requires careful interpretation. Testosterone therapy is not a casual wellness supplement. It is a prescription hormone therapy that should be used for men with consistent symptoms, properly documented low testosterone, appropriate screening, physiologic dosing, and follow-up monitoring.

The most important distinction is between testosterone replacement and testosterone misuse. Testosterone replacement is intended to restore testosterone into a normal physiologic range in men with hypogonadism. Supraphysiologic dosing, anabolic steroid use, and testosterone use in men without a clear diagnosis are different situations and should not be assumed to share the same safety profile.

For appropriately selected men, the best available evidence suggests that TRT has a generally favorable cardiovascular and systemic safety profile. Major adverse cardiac events do not appear to be increased when therapy is used properly. At the same time, several safety issues still require monitoring, including erythrocytosis, blood pressure, venous thromboembolism risk, atrial fibrillation, prostate surveillance, fertility suppression, and sleep apnea.

Who Was Studied in the Major Safety Trial?

The most important modern cardiovascular safety trial is TRAVERSE, a large randomized trial of testosterone therapy in men with hypogonadism and either established cardiovascular disease or high cardiovascular risk.

This matters because earlier testosterone safety debates were limited by smaller studies, inconsistent definitions, observational bias, and mixed populations. TRAVERSE was designed specifically to evaluate cardiovascular safety in a high-risk group.

The trial enrolled middle-aged and older men who had symptoms of hypogonadism and two fasting testosterone levels below 300 ng/dL. Participants were treated with testosterone gel or placebo, with dosing adjusted to maintain testosterone in a physiologic range.

That design is important. The trial did not study men using testosterone for bodybuilding, athletic enhancement, anti-aging without a confirmed diagnosis, or supraphysiologic dosing. The reassuring safety data apply best to men who resemble the study population: symptomatic men with confirmed low testosterone, treated and monitored appropriately.

Major Cardiovascular Events

The main concern patients often ask about is whether testosterone therapy increases heart attack, stroke, or cardiovascular death. These outcomes are often grouped as major adverse cardiovascular events, or MACE.

TRAVERSE found that testosterone therapy was not associated with an increased risk of MACE compared with placebo. The curves for cardiovascular outcomes were very similar between groups, which provided the strongest randomized evidence to date that properly prescribed TRT does not increase major cardiovascular events in men with confirmed hypogonadism.

This is clinically important because many men with low testosterone also have obesity, insulin resistance, sleep apnea, diabetes risk, hypertension, dyslipidemia, or known cardiovascular disease. These men already need cardiovascular risk management. The question is whether physiologic testosterone replacement adds additional MACE risk. The best available randomized evidence suggests it does not.

That does not mean testosterone therapy is a cardiovascular prevention drug. TRT should not be prescribed to reduce cholesterol, prevent heart attacks, or treat cardiovascular disease. It means that when TRT is medically indicated, current evidence does not show an increase in major adverse cardiovascular events when patients are appropriately selected and monitored.

Blood Pressure

The FDA has updated testosterone labeling to reflect a possible increase in blood pressure. This change followed review of TRAVERSE and postmarket ambulatory blood pressure monitoring studies.

The blood pressure effect appears modest for many men, but it still matters. A 2 to 4 mmHg rise in systolic blood pressure may be clinically meaningful in patients who already have hypertension, kidney disease, cardiovascular disease, sleep apnea, or multiple risk factors.

Blood pressure should be measured before therapy and monitored after treatment begins. If blood pressure rises, the response may include lifestyle changes, sleep apnea treatment, dose adjustment, medication review, or antihypertensive therapy when appropriate.

This is one reason testosterone therapy should be integrated into preventive care rather than prescribed in isolation.

Erythrocytosis and Hematocrit

Erythrocytosis is one of the most consistent adverse effects of testosterone therapy. It occurs when testosterone stimulates red blood cell production, raising hemoglobin and hematocrit.

A mild increase in hematocrit is expected in some men. However, excessive elevation can increase blood viscosity and may contribute to thrombotic risk, especially in patients with other risk factors. This is why CBC monitoring is essential.

Erythrocytosis risk varies by dose, route, baseline health, sleep apnea, smoking, dehydration, altitude, and individual sensitivity. Injectable testosterone, especially higher-dose or less frequent regimens that create peaks, may carry a higher erythrocytosis risk than some transdermal approaches.

A practical monitoring plan usually includes a baseline CBC, repeat testing after starting therapy or changing dose, and ongoing monitoring. If hematocrit rises too high, management may include lowering the dose, changing injection frequency, switching formulation, treating sleep apnea, addressing smoking or dehydration, or temporarily holding therapy.

The goal is not simply to raise testosterone. The goal is to optimize testosterone safely.

Venous Thromboembolism and Pulmonary Embolism

Venous thromboembolism, or VTE, includes deep vein thrombosis and pulmonary embolism. This remains one of the more unsettled areas in testosterone safety.

Randomized trial data have not consistently shown a clear VTE increase, but the confidence intervals are wide and the number of events is relatively small. TRAVERSE found a higher incidence of pulmonary embolism in the testosterone group, which keeps this issue clinically relevant.

Observational studies have been mixed. Some suggest no major increase, while others suggest a short-term increase in VTE risk after testosterone initiation, especially during the first 3 to 6 months. The risk may be higher in men with underlying thrombophilia, prior VTE, elevated hematocrit, smoking, obesity, cancer, immobility, or other clotting risk factors.

This does not mean TRT is contraindicated for every man with cardiovascular risk. It means the clotting history matters. Men with prior VTE, known thrombophilia, unexplained clotting events, or strong family history should be evaluated carefully before starting therapy. New leg swelling, calf pain, chest pain, shortness of breath, coughing blood, or sudden unexplained symptoms require urgent evaluation.

Atrial Fibrillation and Heart Rhythm

TRAVERSE reported more atrial fibrillation in men receiving testosterone than placebo. This does not prove that TRT causes atrial fibrillation in every patient, but it is a safety signal that deserves attention.

Atrial fibrillation is more common with aging, obesity, sleep apnea, hypertension, alcohol use, cardiovascular disease, and metabolic dysfunction. Many of these factors are also common in men seeking testosterone evaluation.

Before starting TRT, clinicians should ask about palpitations, known arrhythmias, sleep apnea, alcohol intake, stimulant use, thyroid disease, and cardiovascular history. During treatment, new palpitations, irregular heart rhythm, chest discomfort, unexplained shortness of breath, dizziness, or reduced exercise tolerance should be evaluated.

This is another reason that testosterone therapy works best when it is part of comprehensive men’s health care, not a stand-alone injection protocol.

Acute Kidney Injury Signal

TRAVERSE also reported a higher incidence of acute kidney injury in the testosterone group. The reason for this signal is not fully established, but it reinforces the need to consider kidney health, hydration, blood pressure, medications, and comorbid disease.

Patients with chronic kidney disease, uncontrolled hypertension, diabetes, heavy NSAID use, dehydration risk, or multiple medications should be monitored carefully. Baseline and follow-up CMP testing can help track kidney function and liver markers.

TRT should not be treated as unsafe for every patient with kidney risk, but kidney function should be part of the monitoring plan.

Metabolic and Body Composition Benefits

Testosterone therapy can provide meaningful metabolic and body composition benefits in men with true hypogonadism. Low testosterone is associated with increased fat mass, reduced lean mass, insulin resistance, lower energy, reduced physical activity, and worse cardiometabolic risk factors.

When testosterone is restored into a physiologic range, many men experience improvements in lean mass, reduced fat mass, improved waist circumference, better exercise response, and improved energy. Some studies show improvements in insulin resistance, fasting glucose, hemoglobin A1c, triglycerides, and body composition, particularly in men with type 2 diabetes, metabolic syndrome, or obesity-related hypogonadism.

These benefits are not automatic and should not be oversold. Testosterone therapy is most effective when paired with resistance training, aerobic conditioning, adequate protein intake, body composition monitoring, sleep optimization, and treatment of metabolic risk factors.

A man who starts testosterone but remains sedentary, sleeps poorly, has untreated sleep apnea, drinks heavily, and eats a low-protein diet is unlikely to see the same benefit as a man who combines TRT with a structured training and metabolic plan.

Lipids and Cardiovascular Risk Reduction

Testosterone therapy can cause favorable changes in lipid markers, including a reduction in LDL, but it should not be used to treat dyslipidemia or reduce cardiovascular risk.

Patients with high LDL, high ApoB, high triglycerides, hypertension, insulin resistance, or strong family history need standard cardiovascular prevention. This may include nutrition changes, exercise, weight management, statins, ezetimibe, PCSK9 inhibitors, blood pressure medications, diabetes medications, smoking cessation, and sleep apnea treatment when appropriate.

TRT may support body composition and energy in men with hypogonadism, but it does not replace evidence-based cardiovascular risk management.

Prostate Cancer Risk

Many men worry that testosterone therapy causes prostate cancer. Current evidence does not show an increased risk of prostate cancer in carefully screened men treated with physiologic testosterone replacement.

The dedicated prostate-safety analysis from TRAVERSE found low and similar rates of high-grade prostate cancer, any prostate cancer, acute urinary retention, invasive BPH procedures, and new lower urinary tract symptom medications in the testosterone and placebo groups. Testosterone modestly increased PSA, especially early, but did not appear to worsen urinary symptom scores in the studied population.

This is reassuring, but it has limits. TRAVERSE excluded men at higher prostate cancer risk, including men with a history of prostate cancer, concerning prostate findings, high PSA, or severe lower urinary tract symptoms. The follow-up period was also not long enough to answer every lifetime prostate cancer question.

The best interpretation is balanced: TRT has not been shown to cause prostate cancer in appropriately screened men, but prostate screening remains important. Baseline PSA, digital rectal exam when appropriate, symptom review, and follow-up PSA monitoring should be individualized based on age, risk factors, family history, race, prior PSA patterns, and urology guidance.

Men with known prostate cancer, unexplained PSA elevation, prostate nodules, or high-risk findings should be evaluated before testosterone therapy is considered.

Prostate Enlargement and Urinary Symptoms

Testosterone can modestly increase PSA and may influence prostate tissue, but physiologic TRT has not consistently been shown to worsen lower urinary tract symptoms in appropriately selected men.

Patients should still be monitored for urinary changes. Symptoms such as weak stream, incomplete emptying, frequent urination, nighttime urination, urgency, urinary retention, blood in the urine, or pelvic pain should be evaluated.

Men with severe lower urinary tract symptoms may need treatment of prostate enlargement, bladder dysfunction, pelvic floor dysfunction, sleep apnea, fluid timing issues, or other contributors before or during TRT.

Fertility and Testicular Function

One of the most important systemic risks of testosterone therapy is fertility suppression. Exogenous testosterone suppresses LH and FSH signaling from the pituitary gland. This can reduce intratesticular testosterone and sperm production.

Men who want future fertility should discuss this before starting TRT. Options may include semen analysis, sperm banking, hCG, clomiphene or enclomiphene in selected patients, reproductive urology referral, or delaying testosterone depending on goals.

Testosterone therapy can improve symptoms, but it can also reduce sperm production. This is not a minor detail. Fertility planning should be part of informed consent for men of reproductive age.

Sleep Apnea

Sleep apnea is common in men with obesity, insulin resistance, fatigue, low testosterone symptoms, high blood pressure, nighttime urination, and poor recovery. It can also contribute to low testosterone and erectile dysfunction.

TRT may worsen untreated sleep apnea in some patients or amplify erythrocytosis risk when nighttime oxygen levels are low. Patients with loud snoring, witnessed apneas, morning headaches, daytime sleepiness, resistant hypertension, or unexplained fatigue should be screened.

Treating sleep apnea can improve energy, testosterone physiology, blood pressure, metabolic health, erectile function, and recovery. For many men, TRT and sleep care should be considered together.

Who Should Be More Cautious With TRT?

Testosterone therapy requires more caution in men with recent heart attack or stroke, unstable cardiovascular disease, prior venous thromboembolism, known thrombophilia, untreated severe sleep apnea, uncontrolled hypertension, elevated hematocrit, unexplained PSA elevation, prostate nodule, active prostate cancer, severe lower urinary tract symptoms, or active fertility goals.

Caution does not always mean TRT is impossible. It means the risks, timing, alternatives, and monitoring plan need to be individualized. In some cases, treatment should be delayed until a condition is stabilized. In others, a different formulation or lower dose may be safer.

What Proper Monitoring Looks Like

Safe TRT depends on monitoring. A responsible plan usually begins with confirming the diagnosis. Testosterone should generally be measured in the morning, repeated, and interpreted alongside symptoms, SHBG, free testosterone when appropriate, LH, FSH, prolactin, estradiol, medication history, sleep, and metabolic health.

Baseline evaluation may include CBC, CMP, lipid panel, A1c or glucose markers, blood pressure, PSA when appropriate, sleep apnea screening, fertility discussion, and cardiovascular risk assessment.

After starting treatment, follow-up should assess symptoms, testosterone levels, hematocrit, blood pressure, estradiol when relevant, PSA when appropriate, acne, mood, sleep, libido, erectile function, urinary symptoms, and adverse effects.

The goal is physiologic replacement, not simply the highest number possible.

A Practical Risk-Benefit Framework

TRT is most appropriate when three conditions are met.

First, the patient has symptoms consistent with testosterone deficiency. These may include low libido, erectile dysfunction, fatigue, low motivation, reduced muscle mass, increased fat mass, poor recovery, anemia, low bone density, or depressed mood.

Second, laboratory testing confirms low testosterone on more than one occasion, with interpretation of free testosterone and SHBG when appropriate.

Third, the patient has been screened for major contraindications and understands the monitoring plan, fertility implications, and realistic benefits.

When these conditions are met, the cardiovascular and prostate safety data are generally reassuring. When these conditions are not met, the risk-benefit balance becomes less favorable.

What Patients Should Avoid

Patients should avoid unsupervised testosterone use, supraphysiologic dosing, combining TRT with anabolic steroids or SARMs, using testosterone solely for weight loss, skipping lab monitoring, ignoring fertility goals, donating blood repeatedly without addressing the cause of high hematocrit, or continuing therapy despite concerning symptoms without evaluation.

Patients should also avoid assuming that testosterone will fix every symptom. Fatigue, low libido, brain fog, weight gain, poor recovery, and erectile dysfunction can also come from sleep apnea, depression, thyroid disease, diabetes, medication effects, alcohol, chronic stress, pelvic floor dysfunction, cardiovascular disease, or relationship factors.

The best men’s health care evaluates the whole system.

Bottom Line

For men with confirmed hypogonadism treated to physiologic levels, testosterone replacement therapy has a generally favorable safety profile. The strongest modern cardiovascular trial data show no increase in major adverse cardiovascular events, and prostate safety data are reassuring in carefully screened men.

The remaining safety issues are manageable but important. Erythrocytosis, modest blood pressure increases, possible early VTE risk, atrial fibrillation signal, pulmonary embolism signal, acute kidney injury signal, fertility suppression, sleep apnea, and prostate monitoring all require attention.

TRT works best when it is part of comprehensive care: diagnosis confirmation, physiologic dosing, monitoring, resistance training, metabolic optimization, cardiovascular risk management, sleep evaluation, and fertility counseling when relevant.

At the Performance Medicine Institute, we take a comprehensive approach to testosterone therapy by combining symptom assessment, lab-guided diagnosis, cardiovascular risk review, body composition testing, prostate monitoring when appropriate, sleep evaluation, fertility counseling, and individualized treatment planning. Contact us to schedule an evaluation.

References

• Ayele HT, Brunetti VC, Renoux C, Tagalakis V, Filion KB. Testosterone replacement therapy and the risk of venous thromboembolism: a systematic review and meta-analysis of randomized controlled trials. Thromb Res. 2021;199:123-131.
• Bhasin S, Brito JP, Cunningham GR, et al. Testosterone therapy in men with hypogonadism: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-1744.
• Bhasin S, Lincoff AM, Nissen SE, et al. Effect of testosterone on progression from prediabetes to diabetes in men with hypogonadism. JAMA Intern Med. 2024;184(4):353-362.
• Bhasin S, Travison TG, Pencina KM, et al. Prostate safety events during testosterone replacement therapy in men with hypogonadism: a randomized clinical trial. JAMA Netw Open. 2023;6(12):e2348692.
• Corona G, Rastrelli G, Di Pasquale G, Sforza A, Mannucci E, Maggi M. Testosterone and cardiovascular risk: meta-analysis of interventional studies. J Sex Med. 2018;15(6):820-838.
• Li SY, Zhao YL, Yang YF, et al. Metabolic effects of testosterone replacement therapy in patients with type 2 diabetes mellitus or metabolic syndrome: a meta-analysis. Int J Endocrinol. 2020;2020:4732021.
• Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular safety of testosterone-replacement therapy. N Engl J Med. 2023;389(2):107-117.
• Mendias CL, Awan TM. Increasing skeletal muscle mass and strength during incretin-based weight loss. Obes Pillars. 2026 Aug 10;19:100317.
• Morgentaler A, Dhindsa S, Dobs AS, et al. Androgen Society position paper on cardiovascular risk with testosterone therapy. Mayo Clin Proc. 2024;99(11):1785-1801.
• Newman CB, Blaha MJ, Boord JB, et al. Lipid management in patients with endocrine disorders: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2020;105(12):dgaa674.
• Snyder PJ, Bhasin S, Cunningham GR, et al. Effects of testosterone treatment in older men. N Engl J Med. 2016;374(7):611-624.
• Walker RF, Zakai NA, MacLehose RF, et al. Association of testosterone therapy with risk of venous thromboembolism among men with and without hypogonadism. JAMA Intern Med. 2020;180(2):190-197.