Testosterone Replacement Therapy: Benefits, Risks, and Who It's For

Testosterone replacement therapy (TRT) has become one of the most discussed topics in men's health. Prescriptions have increased dramatically over the past two decades, driven in part by direct-to-consumer marketing and the rise of men's health clinics. For men with genuine testosterone deficiency, TRT can meaningfully improve quality of life. But it is not a universal solution, it carries real risks, and the decision to start treatment should be based on careful evaluation rather than marketing.

Who Is TRT For?

TRT is indicated for men with clinical hypogonadism — a combination of consistently low testosterone levels (typically below 300 ng/dL on at least two morning blood draws) and symptoms attributable to testosterone deficiency. Both elements are required. A low number without symptoms, or symptoms without a low number, does not meet the diagnostic threshold that major medical organizations recommend for initiating treatment.

The Endocrine Society's clinical practice guidelines specify that TRT should be considered for men with:

• Confirmed low total testosterone (below 300 ng/dL) on two separate morning measurements
• Signs and symptoms consistent with testosterone deficiency (decreased libido, erectile dysfunction, fatigue, loss of muscle mass, depressed mood, decreased bone density)
• No contraindications to therapy

TRT is generally not recommended for men who are trying to conceive (it suppresses sperm production), men with untreated severe obstructive sleep apnea, men with active or recently treated prostate or breast cancer, men with hematocrit above 50 percent, or men with uncontrolled heart failure.

Delivery Methods

Testosterone can be administered through several routes, each with distinct advantages and drawbacks:

Intramuscular Injections

Testosterone cypionate and testosterone enanthate are the most commonly used injectable forms. They are typically administered every one to two weeks, either by a healthcare provider or self-injected. Injections are effective and inexpensive but produce fluctuating levels, with a peak shortly after injection and a trough before the next dose. Some men experience mood swings or energy fluctuations in sync with these peaks and troughs. More frequent dosing (e.g., weekly or twice weekly) can reduce this variability.

Topical Gels and Solutions

Transdermal testosterone (applied daily to the skin) provides more stable blood levels than injections. Products are applied to the shoulders, upper arms, or abdomen. The main concerns are transfer to others through skin contact (particularly children and female partners) and variable absorption rates. Gels are more expensive than generic injectable testosterone.

Transdermal Patches

Testosterone patches also provide steady delivery but are less commonly used due to skin irritation at the application site, which affects a significant percentage of users.

Subcutaneous Pellets

Testosterone pellets are implanted under the skin (typically in the hip or buttock area) and release testosterone slowly over three to six months. They provide consistent levels and do not require daily or weekly administration. The downsides include the need for a minor office procedure for insertion, occasional pellet extrusion, and infection risk at the insertion site.

Nasal Gel

A testosterone nasal gel is applied inside the nostrils two to three times daily. It avoids the skin transfer risk of topical gels but requires multiple daily applications and may cause nasal irritation.

Oral Testosterone

An oral formulation of testosterone undecanoate was approved in the United States in 2019. Older oral testosterone formulations were associated with liver toxicity, but the newer formulation is absorbed through the lymphatic system rather than the portal circulation, reducing hepatic risk. It must be taken with food and twice daily.

What the Evidence Shows: Benefits

The best evidence for TRT efficacy comes from the Testosterone Trials (TTrials), a set of seven coordinated placebo-controlled studies in men aged 65 and older with testosterone below 275 ng/dL. Results, published between 2016 and 2017, showed the following benefits after one year of treatment:

Sexual Function

The most consistent and largest effect was on sexual function. Men receiving testosterone reported improvements in sexual desire, erectile function, and overall sexual activity compared to placebo. This finding is consistent across multiple other studies and is the best-supported benefit of TRT.

Physical Function

Testosterone-treated men showed modest improvements in walking distance (the six-minute walk test). The effect was statistically significant but small in magnitude. Other studies have shown improvements in lean body mass and reductions in fat mass, though the effects on actual physical performance measures like strength are more variable.

Mood

In the TTrials, testosterone treatment improved mood as measured by the Patient Health Questionnaire (PHQ-9) compared to placebo, but only in men who had mild depressive symptoms at baseline. The effect was modest. TRT is not a substitute for antidepressant therapy or psychotherapy in men with clinical depression.

Bone Density

One year of testosterone treatment significantly increased bone mineral density and estimated bone strength, particularly in the spine and hip. Whether this translates to reduced fracture risk over the long term has not been established in clinical trials, but the bone density improvement is consistent and meaningful.

Anemia

Testosterone treatment corrected unexplained anemia in a significantly higher proportion of men compared to placebo. This effect was large and clinically relevant.

What the Evidence Shows: Risks

TRT is not risk-free. The following risks are documented and should be discussed with your provider before starting treatment.

Erythrocytosis (Elevated Red Blood Cells)

TRT stimulates red blood cell production. In some men, this leads to erythrocytosis, an elevation in hematocrit above normal levels (typically above 50 to 54 percent, depending on the reference). Elevated hematocrit increases blood viscosity and may increase the risk of blood clots, stroke, and cardiovascular events. This is the most common reason for dose adjustment or discontinuation of TRT. Regular monitoring of hematocrit (typically every 3 to 6 months initially, then annually) is required.

Cardiovascular Risk

The cardiovascular safety of TRT has been debated extensively. The TRAVERSE trial, a large randomized controlled trial published in the New England Journal of Medicine in 2023, enrolled over 5,000 men aged 45 to 80 with hypogonadism and established or high risk for cardiovascular disease. After a mean follow-up of 33 months, testosterone treatment did not increase the incidence of major adverse cardiovascular events compared to placebo. However, it did not decrease them either.

This is reassuring but does not provide a clean bill of health. The study population was carefully monitored, and men at the highest risk were excluded. Real-world use, where monitoring may be less rigorous, may carry different risk profiles. Men with pre-existing cardiovascular disease should discuss the implications with their cardiologist.

Prostate Effects

TRT does not cause prostate cancer based on current evidence. However, it can stimulate growth of existing prostate tissue, including pre-existing but undetected prostate cancer. The Endocrine Society recommends prostate cancer screening (PSA and digital rectal exam) before starting TRT and monitoring during treatment. Significant PSA increases during TRT should prompt urological evaluation.

Fertility Suppression

Exogenous testosterone suppresses the hypothalamic-pituitary- gonadal axis, reducing the production of LH and FSH. This in turn reduces or eliminates sperm production. For men who are trying to conceive or who may want children in the future, TRT is generally contraindicated. Alternatives such as clomiphene citrate or human chorionic gonadotropin (hCG), which stimulate endogenous testosterone production while preserving spermatogenesis, may be considered in these cases.

Skin Reactions

Acne and oily skin are common side effects, particularly with injections that produce supraphysiologic peak levels. Topical formulations can cause irritation at the application site.

Sleep Apnea

TRT may worsen pre-existing obstructive sleep apnea. Men with symptoms of sleep apnea should be evaluated and treated for this condition before or concurrent with TRT initiation.

Monitoring During Treatment

Responsible TRT requires ongoing monitoring. The Endocrine Society recommends:

• Testosterone levels measured 3 to 6 months after starting treatment to ensure they are in the target range (typically mid-normal)
• Hematocrit checked at 3 to 6 months, then annually, with dose reduction or temporary cessation if hematocrit exceeds 54 percent
• PSA at 3 to 12 months, then annually
• Bone density assessment at 1 to 2 years if osteoporosis was present at baseline
• Assessment of symptom response to ensure treatment is actually providing benefit

If a provider prescribes TRT without a plan for regular monitoring, that is a red flag.

What TRT Cannot Do

It is important to be realistic about what TRT can and cannot accomplish. TRT is not:

• A substitute for exercise and healthy eating
• A weight loss drug (though it may modestly reduce fat mass)
• A performance enhancer for men with normal testosterone
• A cure for depression
• A fountain of youth

Men with genuine hypogonadism can expect meaningful improvements in specific symptoms, particularly sexual function. But TRT is one component of health management, not a comprehensive solution. Men who combine TRT with attention to sleep, exercise, diet, and stress management will see better outcomes than men who rely on TRT alone.

Making the Decision

The decision to start TRT should be a collaborative one between you and your provider. It should be based on confirmed low testosterone, documented symptoms, exclusion of other causes, and a clear understanding of both the potential benefits and the risks. It should include a monitoring plan and a willingness to reassess if the expected benefits do not materialize.

If you are considering TRT, come prepared with questions: What is my testosterone level, and has it been confirmed? What other causes of my symptoms have been ruled out? What delivery method do you recommend, and why? What monitoring will we do? What are the specific risks for someone with my health profile?

Informed patients make better decisions, and better decisions lead to better outcomes.