For most men with diagnosed hypogonadism, testosterone replacement therapy (TRT) appears reasonably safe over years of use, though it carries specific risks that require ongoing monitoring. The largest randomized trial to date, the TRAVERSE trial with over 5,200 men, found no increase in heart attacks or strokes compared to placebo. But “safe” comes with caveats: TRT reliably suppresses fertility, thickens the blood, and may worsen sleep apnea. Whether the tradeoff makes sense depends on your individual health profile and how closely you’re being monitored.
What the TRAVERSE Trial Settled About Heart Risk
For years, the biggest fear around long-term TRT was cardiovascular danger. Earlier observational studies sent mixed signals, and the FDA added a warning label in 2015. The TRAVERSE trial, published in the New England Journal of Medicine in 2023, was designed specifically to answer this question. It enrolled 5,246 men aged 45 to 80 who already had cardiovascular disease or were at high risk for it, then followed them for a mean of 33 months.
The results: 7.0% of men on testosterone experienced a major cardiac event (heart attack, stroke, or cardiovascular death) compared to 7.3% on placebo. The hazard ratio was 0.96, meaning the risk was statistically equivalent. This was strong enough to meet the threshold for “noninferiority,” the formal statistical standard that TRT is no worse than placebo for heart outcomes.
That said, the trial did flag three concerns. Men on testosterone had higher rates of atrial fibrillation (an irregular heart rhythm), acute kidney injury, and pulmonary embolism (blood clots in the lungs). These weren’t the primary endpoints, so the trial wasn’t designed to measure them precisely, but they showed up consistently enough to warrant attention. If you have a history of blood clots or heart rhythm problems, these findings are especially relevant to discuss with your doctor.
Blood Thickening Is the Most Common Side Effect
Testosterone stimulates your bone marrow to produce more red blood cells. This is actually one reason men naturally have higher red blood cell counts than women. But on TRT, this effect can overshoot, pushing your hematocrit (the percentage of your blood made up of red blood cells) into a range that increases clotting risk. The medical term is erythrocytosis, and it’s the most predictable side effect of long-term therapy.
How often it happens depends partly on the formulation. In the TRAVERSE trial, which used a topical gel, fewer than 1% of men exceeded a hematocrit of 54%, the threshold where guidelines recommend stopping treatment or performing a blood draw to thin things out. But in another large trial using injectable testosterone, 22% of participants hit that threshold, and 5% had to discontinue entirely. Injections tend to produce higher peak testosterone levels, which drives more red blood cell production.
Both the European Academy of Andrology and the British Society for Sexual Medicine agree that hematocrit should stay below 54%. This is why regular blood work, typically every 6 to 12 months once you’re stable on TRT, is non-negotiable. If your levels creep up, your provider will lower the dose, switch formulations, or schedule a therapeutic blood draw.
Prostate Cancer Risk Hasn’t Materialized
The worry that testosterone fuels prostate cancer goes back decades, rooted in the observation that cutting off testosterone causes existing prostate cancers to shrink. The logic seemed straightforward: more testosterone, more cancer. But the data haven’t supported that leap.
In studies tracking men on TRT, the rate of prostate cancer has been 9.2 cases per 1,000 person-years, compared to 8.3 per 1,000 person-years in men not taking testosterone. That difference isn’t statistically significant. A UK retrospective study followed 1,365 men on testosterone for up to 20 years and found 14 cases of prostate cancer, a rate of about 1 case per 212 person-years of follow-up, which aligns with background rates in the general male population.
This doesn’t mean testosterone is protective or that monitoring is unnecessary. PSA levels (a prostate marker) often rise modestly in the first year of TRT, and your provider will track them. But the long-standing fear that TRT meaningfully increases your odds of developing prostate cancer hasn’t held up under scrutiny.
Fertility Suppression Is Predictable and Usually Reversible
This is one of the most important things men starting TRT don’t always hear clearly: exogenous testosterone shuts down your body’s own production, and with it, sperm production. The median time for sperm counts to drop below 1 million per milliliter is just 3.5 months. For context, a normal count is above 15 million. Many men on TRT become functionally infertile while on treatment.
The good news is that recovery after stopping is well-documented in clinical trial settings. About 67% of men recover a sperm count of 20 million per milliliter within 6 months of stopping TRT. By 12 months, that figure rises to 90%, and by 24 months, essentially 100% recover in trial data. However, longer duration of use, older age, and individual variation can all slow recovery. Men who’ve been on TRT for many years outside of controlled trials may not bounce back as quickly or completely.
If you’re considering TRT and want to preserve fertility, this is a conversation to have before starting. There are strategies your provider can use, but once you’re on standard TRT, sperm production will decline.
Liver and Kidney Safety With Modern Formulations
Liver damage is a legitimate concern with certain oral anabolic steroids, specifically the older formulations chemically modified to survive passing through the liver (known as 17-alpha alkylated compounds). These are the ones historically linked to cholestasis, liver tumors, and elevated liver enzymes.
The injectable testosterone esters used in standard TRT (cypionate and enanthate) are a different class entirely. Multiple studies, including controlled trials with supraphysiologic doses, have found no changes in liver enzymes. A systematic review of testosterone therapy in transgender men across six studies found liver function values “changed minimally or not at all, no levels rising above the upper limits of normal for men.” An autopsy study of 52 patients who received injectable testosterone for years found no liver tumors or structural liver damage.
In short, if you’re using standard injectable or topical testosterone as prescribed, liver toxicity is not a realistic concern. The TRAVERSE trial did note a signal for acute kidney injury, which deserves further attention, but this hasn’t been a consistent finding across other studies.
Sleep Apnea Can Worsen
Testosterone appears to worsen obstructive sleep apnea in susceptible men. Several studies have documented increases in the apnea-hypopnea index (the number of breathing interruptions per hour of sleep) and decreases in oxygen saturation during sleep. The mechanism likely involves testosterone’s effects on the body’s response to low oxygen and high carbon dioxide levels during sleep, which can blunt the reflexes that keep your airway open.
If you already snore heavily, feel unrested despite adequate sleep, or have been diagnosed with sleep apnea, this is worth monitoring. Untreated sleep apnea carries its own cardiovascular risks, so worsening it with TRT could offset some of the therapy’s benefits.
Bone Density Improves Over Time
One clear long-term benefit of TRT is improved bone density. In men with low testosterone, the skeleton gradually loses mineral content, increasing fracture risk. Testosterone replacement reverses this. In a study following men for an average of 7.5 years on TRT, bone density at the lumbar spine increased by about 0.62% per year, and at the hip by about 0.25% per year. These are modest annual gains, but they compound over years and represent a meaningful reduction in fracture risk, particularly for older men.
What Long-Term Monitoring Looks Like
The safety of long-term TRT isn’t just about the drug itself. It’s about the monitoring that goes with it. Most guidelines recommend blood work every 6 to 12 months once you’re on a stable dose, checking hematocrit, PSA, testosterone levels, and basic metabolic markers. The first year typically involves more frequent checks as your dose is adjusted.
The men who run into trouble on TRT tend to be the ones who aren’t being monitored: those self-prescribing, using underground sources, or seeing providers who write a prescription and never follow up. With appropriate oversight, the manageable risks (blood thickening, sleep apnea changes, PSA shifts) get caught early enough to adjust course. Without it, those same risks can quietly escalate.