What you need to know about testosterone replacement therapy risks

Testosterone therapy can boost energy, muscle, and sex drive, but it is not a free upgrade. Here is a clear, evidence-based guide to testosterone replacement therapy risks so you can balance benefits and downsides with your doctor.

“Testosterone therapy can be life-changing for the right patient, but it is still a powerful hormone drug. The biggest mistake I see is men starting treatment without a solid diagnosis or a clear plan to watch for risks over time.”

Susan Carter, MD: Endocrinologist & Longevity expert

The relationship

Testosterone is the main male sex hormone that supports muscle mass, sex drive, red blood cell production, and mood. Testosterone replacement therapy, or TRT, means using prescription testosterone to raise low levels into a healthy range. It can be given as injections, gels, patches, or pellets.

Testosterone replacement therapy risks depend a lot on whether you truly have low testosterone, called hypogonadism. Meta analyses suggest that men with clear symptoms and total testosterone below about 350 ng/dL, or free testosterone below 100 pg/mL, are most likely to benefit from TRT and have a more favorable risk–benefit balance.^[1] Men with normal levels who use testosterone for “anti-aging” tend to face more risk for less gain.

Large clinical trials and observational studies show a mixed picture. Some earlier reports linked TRT to more heart attacks and strokes, but more recent randomized trials in properly diagnosed men do not show a major jump in cardiovascular events when therapy is monitored carefully.^[1] That means for many men, the main testosterone replacement therapy risks are not sudden crises, but slower shifts in blood counts, prostate symptoms, fertility, mood, or fluid balance that build over months and years.

How it works

To understand testosterone replacement therapy risks, it helps to see how external, or exogenous, testosterone changes several body systems at once.

Heart and blood vessels

Testosterone affects blood vessel tone, cholesterol levels, and blood thickness. A large trial program in older men with low testosterone found that TRT modestly improved walking distance and some sexual symptoms, but also increased coronary artery plaque volume on CT scans, a marker of atherosclerosis, even though short-term heart attack and stroke rates did not spike. Other meta analyses report no clear rise in major cardiovascular events in appropriately selected men, but some signal of risk in those with uncontrolled heart disease or very high doses.^[2]

A key cardiovascular risk of TRT is erythrocytosis, which means too many red blood cells, measured as a high hematocrit. This thickens the blood and could raise clot risk. Men on injectable testosterone, especially at higher doses, are more likely to develop hematocrit above 54 percent, the usual cutoff for concern.^[2]

Prostate and urinary tract

The prostate is a small gland under the bladder that helps make semen. It responds strongly to androgens, the family of hormones that includes testosterone. TRT can increase prostate size somewhat and may worsen urinary symptoms in men who already have benign prostatic hyperplasia, or BPH, which is noncancerous prostate enlargement that makes it harder to urinate.^[3]

Evidence so far does not show that TRT causes new prostate cancer in men without prior disease, but guidelines recommend avoiding TRT in men with active prostate cancer and using caution in those with a history of high-risk disease.^[3] Prostate specific antigen, or PSA, a blood marker used in prostate cancer screening, can rise slightly on TRT, so regular PSA checks are part of safe treatment.

Fertility and testicles

TRT can sharply reduce sperm production. The brain controls the testes with two hormones: luteinizing hormone, or LH, and follicle-stimulating hormone, or FSH. When you take external testosterone, the brain senses higher levels and turns down LH and FSH. This shrinks testicular production of both testosterone and sperm. Many men on TRT develop very low sperm counts, and some become temporarily infertile.^[4]

Younger men or those hoping to have children should be warned that TRT is not a male fertility treatment. In these cases, doctors may use drugs like clomiphene citrate or human chorionic gonadotropin, or hCG, to boost the body’s own testosterone and sperm output instead of shutting it down.

Skin, mood, and metabolism

TRT can convert to dihydrotestosterone, or DHT, a more potent androgen in hair follicles and skin, and to estradiol, a form of estrogen. This can cause oily skin, acne, and male pattern hair loss in men who are genetically prone. Fluid retention and mild weight gain can also appear, especially early in treatment.

Mood effects vary. Many men with genuine low testosterone report better energy, motivation, and less depressed mood on TRT.^[1] But some experience irritability, sleep disturbance, or swings in mood, particularly if levels peak and crash with long dosing intervals. Obstructive sleep apnea, a condition where breathing pauses during sleep, can worsen or newly appear in some men on TRT, likely due to upper airway changes and weight or fluid shifts.^[5]

Blood sugar and body composition

Several controlled studies suggest TRT in men with low testosterone and type 2 diabetes can modestly improve insulin sensitivity, the way cells respond to insulin, and reduce waist circumference by increasing lean muscle and lowering fat mass.^[6] However, these metabolic benefits must be weighed against testosterone replacement therapy risks such as higher hematocrit and potential heart strain in men with advanced cardiovascular disease.

Guidelines emphasize using a firm biochemical threshold, such as total testosterone under 350 ng/dL with symptoms, before starting TRT for metabolic reasons, and avoiding it in men with poorly controlled heart failure or recent heart attack.^[2]

Conditions linked to it

Testosterone replacement therapy risks show up most clearly in a few key areas that your doctor should review with you in detail.

Cardiovascular disease: Studies in older, frail men with high testosterone doses have shown more cardiovascular events, while more recent, better controlled trials in appropriately selected men do not show a large increase in heart attacks or strokes.^,[2] Men with recent heart attack, uncontrolled heart failure, or severe arrhythmias are usually advised to avoid or delay TRT.
Polycythemia and blood clots: Polycythemia means too many red blood cells. TRT can drive hematocrit above 52–54 percent, which increases blood viscosity and may raise the chance of clots in the legs, lungs, or brain.^[2] Injectable forms, higher doses, and smoking magnify this risk.
Prostate enlargement and cancer monitoring: TRT can worsen urinary obstruction in men with significant BPH and requires regular PSA and digital rectal exams to watch for prostate cancer signals.^[3] Current evidence suggests that TRT does not substantially raise new prostate cancer risk when men are screened appropriately, but it may accelerate existing, undetected tumors.
Infertility: Long-term TRT can suppress sperm production to near zero. In many men this is reversible within 6–12 months after stopping therapy, but recovery is not guaranteed, especially after prolonged use or in older age.^[4]
Sleep apnea and respiratory issues: TRT may aggravate obstructive sleep apnea, especially in men who are overweight, snore loudly, or already have mild disease.^[5] Worsening fatigue despite higher testosterone can be a clue.
Benign breast enlargement: Some men develop gynecomastia, or breast tissue growth, when testosterone converts to estrogen. This is usually mild but can be bothersome or tender.

Limitations note: Much of the long-term risk data for TRT comes from relatively short randomized trials and longer observational studies, which can be biased. That means some testosterone replacement therapy risks, especially over more than 5–10 years, are still being clarified, and recommendations may evolve as new studies are published.

Symptoms and signals

If you are on TRT or considering it, these are the main signs that testosterone replacement therapy risks might be showing up in your body.

Heart and circulation: new chest pressure or pain with activity; sudden shortness of breath; swelling in one leg; pounding or irregular heartbeat; sudden weakness or trouble speaking
Blood thickness: frequent headaches; flushed or reddish face; nosebleeds; visual changes like blurring; feeling unusually sluggish or “thick-headed”
Urinary and prostate: weaker urine stream; starting and stopping when you urinate; needing to go often, especially at night; burning or pain with urination; blood in urine or semen
Fertility and sexual health: difficulty conceiving with a partner after months of trying; shrinking testicles; changes in ejaculation volume; new breast tenderness or swelling
Sleep and breathing: loud snoring reported by a partner; gasping or choking during sleep; waking up unrefreshed; morning headaches; sudden daytime sleep attacks
Mood and energy: new anger or irritability; feeling “amped up” or restless; trouble falling or staying asleep; strong mood swings that feel different from your baseline
Skin and fluid balance: sudden acne flare, especially on back or shoulders; rapid weight gain over a few days; ankle or hand swelling; tight rings or shoes

Any sudden or severe symptom, especially chest pain, shortness of breath, or trouble speaking, is an emergency and warrants immediate medical care, not just a message to your prescribing clinic.

What to do about it

Managing testosterone replacement therapy risks starts before the first shot or gel application and continues as long as you stay on treatment.

Step 1: Get properly tested and diagnosed
Ask for at least two early morning total testosterone tests, done on different days, along with sex hormone–binding globulin, or SHBG, and free testosterone if your total level is borderline. Symptomatic men with total testosterone below 350 ng/dL or free testosterone below 100 pg/mL on repeat testing are most likely to benefit.^[1] A full workup should also include blood counts, PSA for men over about 40–50 years depending on guidelines, fasting glucose or A1c, lipids, and a focused exam of the prostate and testicles.
Step 2: Match therapy to your goals and risk profile
If you and your doctor decide to proceed, discuss the form of TRT. Gels and patches give more stable levels but require daily use and careful handling to avoid skin transfer to others. Injections are cheaper but can cause peaks and troughs and higher rates of high hematocrit.^[2] Men who want future fertility should usually avoid standard TRT and consider alternative medications that stimulate the body to make its own testosterone.
Step 3: Monitor, adjust, and never “set and forget”
Once on TRT, most guidelines advise checking testosterone, blood counts, and PSA at 3–6 months, then at least yearly if stable.^[2],[3] Ask your doctor exactly which numbers would make them lower the dose, pause therapy, or investigate further. Track your symptoms over time and bring concrete examples, not just “better” or “worse.”

Myth vs Fact

Myth: “Testosterone therapy always causes heart attacks.”
Fact: In men with documented low testosterone who are monitored closely, recent trials have not shown a large rise in major heart events, though caution is needed in men with serious heart disease.^,[2]
Myth: “TRT is a safe anti-aging shortcut for any tired man over 40.”
Fact: Using testosterone when your levels are normal brings more risk and fewer proven benefits. Lifestyle changes, sleep, stress management, and treating other conditions often help more with less downside.
Myth: “If I use testosterone, I cannot ever have children.”
Fact: TRT can sharply lower sperm counts while you are on it, but fertility often returns after stopping, especially in younger men. Still, it is not guaranteed, and men planning a family should avoid TRT or use fertility-preserving strategies.^[4]
Myth: “No lab monitoring is needed once I’m on a steady dose.”
Fact: Blood counts, PSA, and testosterone levels can drift over time. Regular labs and checkups are essential to catching testosterone replacement therapy risks early and adjusting course.

Alongside medical management, several habits can make TRT safer and, in some men with borderline levels, even delay or reduce the need for it:

Weight and exercise: Losing even 5–10 percent of body weight and doing regular resistance training can raise natural testosterone and improve how well your body uses TRT.^[6] For men who want to stay active while balancing hormones, hormone-friendly training techniques can support safer, more effective workouts.
Sleep: Aim for 7–9 hours per night. Treating sleep apnea with a CPAP machine can significantly improve testosterone and protect the heart.^[5]
Alcohol and tobacco: Cutting back on heavy drinking and quitting smoking lowers clot and heart risk and supports hormone balance. If you use nicotine, it is worth understanding how nicotine affects testosterone and cardiovascular health.
Medications and supplements: Tell your doctor about any anabolic steroids, over-the-counter “testosterone boosters,” or herbal products. Some can interact with TRT or strain the liver. Many men first try natural ways to increase testosterone or stacks like fadogia agrestis and tongkat ali, so be sure to review these with your clinician.

Bottom line

Testosterone replacement therapy can restore energy, strength, and sexual function for men with true hypogonadism, but it is not a simple vitamin shot. The main testosterone replacement therapy risks involve the heart and circulation, blood thickness, prostate and urinary symptoms, fertility, sleep apnea, and mood. When TRT is reserved for men with well-documented low levels, tailored to individual risk, and monitored with regular labs and exams, the benefits often outweigh the downsides. The safest plan is to treat testosterone like any other powerful medication: confirm you need it, understand the trade-offs, and partner with a clinician who will follow you closely for the long haul.

References

Bhasin S, Brito JP, Cunningham GR, et al. Testosterone Therapy in Men With Hypogonadism: An Endocrine Society Clinical Practice Guideline. The Journal of clinical endocrinology and metabolism. 2018;103:1715-1744. PMID: 29562364
Corona G, Maseroli E, Rastrelli G, et al. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert opinion on drug safety. 2014;13:1327-51. PMID: 25139126
Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. The Journal of urology. 2018;200:423-432. PMID: 29601923
Crosnoe LE, Grober E, Ohl D, et al. Exogenous testosterone: a preventable cause of male infertility. Translational andrology and urology. 2013;2:106-13. PMID: 26813847
Liu PY, Yee B, Wishart SM, et al. The short-term effects of high-dose testosterone on sleep, breathing, and function in older men. The Journal of clinical endocrinology and metabolism. 2003;88:3605-13. PMID: 12915643
Grossmann M, Hoermann R, Wittert G, et al. Effects of testosterone treatment on glucose metabolism and symptoms in men with type 2 diabetes and the metabolic syndrome: a systematic review and meta-analysis of randomized controlled clinical trials. Clinical endocrinology. 2015;83:344-51. PMID: 25557752
Corona G, Rastrelli G, Morgentaler A, et al. Meta-analysis of Results of Testosterone Therapy on Sexual Function Based on International Index of Erectile Function Scores. European urology. 2017;72:1000-1011. PMID: 28434676