What Is TRT? Complete Guide to Testosterone Replacement Therapy (2026)

What TRT Actually Is and Who Needs It

Testosterone replacement therapy delivers exogenous testosterone to men whose bodies no longer produce enough on their own. The goal is not supraphysiological levels. It is restoration to the mid-normal range (450 to 600 ng/dL) to relieve symptoms like fatigue, reduced libido, depressed mood, and loss of muscle mass.

Defining Hypogonadism

The Endocrine Society 2018 clinical practice guideline requires two conditions for diagnosis: consistently low serum total testosterone measured on morning samples, and the presence of signs or symptoms attributable to androgen deficiency [1]. A single low reading is insufficient. Testosterone follows a circadian rhythm with peak concentrations between 7:00 and 10:00 a.m., so both confirmatory draws should occur in that window.

Primary vs. Secondary Hypogonadism

Primary hypogonadism originates in the testes (elevated LH and FSH). Secondary hypogonadism originates in the hypothalamus or pituitary (low or inappropriately normal LH and FSH). The distinction matters because secondary hypogonadism may be reversible if caused by obesity, opioid use, or a pituitary adenoma. The AUA 2018 guideline recommends evaluating for reversible causes before committing to lifelong TRT [2].

Prevalence

The Massachusetts Male Aging Study found that total testosterone declines approximately 1.6% per year after age 40 [3]. Roughly 20% of men over 60 and 30% of men over 70 have total testosterone below 300 ng/dL, according to data from the Hypogonadism in Males (HIM) study (N=2,162) [4]. Obesity accelerates this decline. Each 1-point increase in BMI corresponds to roughly a 2% decrease in testosterone.

Symptoms That Trigger a Workup

Low testosterone does not produce one signature symptom. It produces a cluster. The clinical picture overlaps with depression, sleep apnea, and thyroid dysfunction, which is why lab confirmation is non-negotiable.

Sexual Symptoms

Reduced libido and erectile dysfunction are the most specific symptoms. In the Testosterone Trials (TTrials) (N=790 men aged 65+), testosterone gel improved sexual desire scores by 2.93 points on the PDQ-Q4 versus 0.89 with placebo at 12 months (P<0.001) [5].

Physical and Cognitive Symptoms

Fatigue, decreased muscle mass, increased body fat (particularly visceral), and reduced bone mineral density all appear in the clinical constellation. Cognitive complaints, including difficulty concentrating and poor memory, are reported frequently but are harder to measure objectively. The TTrials showed modest improvement in walking distance but no significant cognitive benefit [5].

When to Test

The Endocrine Society recommends testing men who present with specific symptoms rather than screening all aging men [1]. Symptoms that should prompt morning testosterone measurement include unexplained anemia, low bone mineral density, type 2 diabetes with sexual dysfunction, and opioid use.

Available TRT Formulations

No single formulation is best for every patient. The choice depends on patient preference, insurance coverage, cost, and clinical considerations like skin sensitivity or needle aversion.

Injectable Testosterone

Testosterone cypionate and testosterone enanthate are the workhorses. Both are intramuscular or subcutaneous injections given every 1 to 2 weeks. They are the least expensive option, often $30 to $60 per month with a prescription. Pharmacokinetic peaks occur 24 to 48 hours post-injection with troughs before the next dose, which some men perceive as an energy "roller coaster." Shorter injection intervals (e.g., 80 mg every 5 days rather than 200 mg every 14 days) flatten this curve.

Testosterone undecanoate (Aveed) is a long-acting intramuscular injection given every 10 weeks after an initial loading phase. It requires in-office administration with a 30-minute post-injection observation period due to rare pulmonary oil microembolism risk. The FDA label carries a REMS requirement for this reason [6].

Transdermal Options

Topical gels (AndroGel 1%, AndroGel 1.62%, Testim, Vogelxo) deliver steady-state testosterone within 24 to 48 hours and maintain relatively stable levels. The primary risk is secondary transfer to women or children through skin contact. Patients must wash hands after application and cover the site with clothing. Patches (Androderm) provide similar pharmacokinetics but cause skin irritation in up to 37% of users, according to the prescribing information [7].

Newer Formulations

Natesto (testosterone nasal gel) delivers testosterone intranasally three times daily. Its short half-life may suppress the HPG axis less than other routes, potentially preserving some degree of spermatogenesis. A 2019 study in The Journal of Urology found that 90% of men on Natesto maintained sperm concentrations above 10 million/mL at 6 months [8].

Jatenzo (testosterone undecanoate oral capsule) received FDA approval in 2019. It is absorbed through the lymphatic system, bypassing first-pass hepatic metabolism. It must be taken twice daily with food containing at least 20 grams of fat per meal for adequate absorption [9].

Dosing and Titration

Starting low and adjusting based on labs and symptom response is the standard protocol. The Endocrine Society guideline advises targeting mid-normal testosterone (400 to 600 ng/dL) rather than the upper limit [1].

Typical Starting Doses

For testosterone cypionate or enanthate, most clinicians begin at 100 mg intramuscularly every week or 75 mg subcutaneously every 5 to 7 days. For gels, the typical starting dose is 50 mg of the 1% formulation (one pump of AndroGel) applied daily. The first lab recheck happens at 6 to 12 weeks, measuring trough testosterone (drawn the morning before the next injection) and hematocrit.

Adjusting the Dose

If trough testosterone falls below 400 ng/dL and symptoms persist, the dose is increased by 25 to 50 mg per injection. If trough exceeds 700 ng/dL or hematocrit rises above 50%, the dose is reduced. "The goal is not a number on a lab report. The goal is symptom resolution at the lowest effective dose," stated Dr. Abraham Morgentaler, Associate Clinical Professor of Urology at Harvard Medical School, in a 2020 editorial in The Journal of Urology [10].

Monitoring: What Labs and How Often

Monitoring is not optional. It is a clinical requirement outlined in both the AUA and Endocrine Society guidelines.

Baseline Labs Before Starting

Before the first dose, the clinician should obtain: total testosterone (two morning samples), free testosterone or SHBG, LH and FSH, complete blood count (CBC), comprehensive metabolic panel, lipid panel, PSA (in men over 40), and estradiol. A baseline DEXA scan is warranted if osteoporosis is suspected.

Ongoing Monitoring Schedule

The AUA 2018 guideline recommends lab assessment at 3 to 6 months after initiation, then every 6 to 12 months [2]. Hematocrit is the most actionable safety lab. If hematocrit crosses 54%, therapy should be held or the dose reduced. Therapeutic phlebotomy is an option for men who develop erythrocytosis. PSA should be monitored annually; a rise of more than 1.4 ng/mL within 12 months warrants urologic referral.

When to Stop

Discontinuation should be considered if the patient reports no symptom improvement after 6 months at verified mid-normal testosterone levels, or if adverse effects (erythrocytosis, uncontrolled sleep apnea exacerbation) outweigh benefits.

Cardiovascular Safety: The TRAVERSE Verdict

For years, cardiovascular risk was the headline concern. That changed.

The TRAVERSE Trial

The TRAVERSE trial (N=5,204) was the first large, randomized, placebo-controlled study powered for major adverse cardiovascular events (MACE) in men with hypogonadism aged 45 to 80 who had pre-existing cardiovascular disease or high cardiovascular risk [11]. After a mean follow-up of 3.19 years, the incidence of MACE (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) was 7.0% in the testosterone group versus 7.3% in the placebo group (hazard ratio 0.96; 95% CI, 0.78 to 1.17). No increased risk.

What TRAVERSE Did Not Settle

The trial did find a higher incidence of atrial fibrillation, acute kidney injury, and pulmonary embolism in the testosterone arm, though these were secondary endpoints and not statistically adjusted for multiplicity [11]. The FDA updated testosterone labeling in 2024 to reflect TRAVERSE findings, removing the prior cardiovascular warning while maintaining the venous thromboembolism caution [6].

"TRAVERSE provides the reassurance that testosterone therapy does not increase short-term MACE risk in high-risk men, but it does not give blanket cardiovascular safety clearance," noted Dr. Shalender Bhasin, the trial's principal investigator, in The New England Journal of Medicine [11].

TRT and Fertility: A Non-Negotiable Conversation

Exogenous testosterone suppresses gonadotropins (LH and FSH), which in turn suppresses intratesticular testosterone production and spermatogenesis. This effect is predictable and often profound.

How Quickly Sperm Counts Drop

Most men see significant suppression within 2 to 3 months. A systematic review in Fertility and Sterility found that exogenous testosterone reduced sperm concentration to <1 million/mL in approximately 65% of men within 6 months [12]. Recovery after discontinuation takes 6 to 18 months in most cases, though some men experience incomplete recovery.

Alternatives for Men Who Want Children

For men with secondary hypogonadism who desire fertility, clomiphene citrate (off-label, 25 to 50 mg every other day) or human chorionic gonadotropin (hCG, 1,500 to 3,000 IU subcutaneously two to three times weekly) can raise testosterone while preserving or stimulating spermatogenesis [2]. Enclomiphene, the trans-isomer of clomiphene, is under active clinical development and shows promise for this niche. Every man of reproductive age must be counseled about fertility suppression before starting TRT. No exceptions.

Common Side Effects and How to Manage Them

TRT at physiologic replacement doses carries a defined, manageable side effect profile.

Erythrocytosis

The most common lab abnormality. Testosterone stimulates erythropoietin production. In the TRAVERSE trial, hematocrit exceeded 54% in 4.1% of the testosterone group versus 0.4% of placebo [11]. Management: dose reduction, switch from injectable to transdermal (which produces smaller hematocrit rises), or therapeutic phlebotomy.

Acne and Oily Skin

Occurs in roughly 10 to 15% of patients, typically during the first 3 months. Usually mild. Topical retinoids or benzoyl peroxide suffice.

Mood and Sleep Changes

Some men report increased irritability or sleep disturbance, particularly with supratherapeutic dosing. Dose reduction resolves most cases. TRT can worsen untreated obstructive sleep apnea, so screening with a STOP-BANG questionnaire before initiation is recommended [1].

Gynecomastia and Estradiol Elevation

Aromatization of testosterone to estradiol can cause breast tenderness or gynecomastia in 5 to 10% of patients. Monitoring estradiol levels and reducing the testosterone dose is first-line management. Aromatase inhibitors (anastrozole) are used off-label but carry their own bone-density risks with long-term use.

Who Should Not Start TRT

Absolute and relative contraindications exist.

Absolute Contraindications

The Endocrine Society lists the following as contraindications: metastatic prostate cancer, breast cancer in men, unevaluated prostate nodule or PSA above 4 ng/dL (or above 3 ng/dL in high-risk men) without urologic evaluation, hematocrit above 50% at baseline, untreated severe obstructive sleep apnea, uncontrolled heart failure, and desire for fertility in the near term [1].

Relative Contraindications

These include severe lower urinary tract symptoms (IPSS score above 19), history of venous thromboembolism, and untreated prolactinoma. Each requires specialist input before proceeding.

What Realistic Results Look Like

TRT is not a performance-enhancing drug at replacement doses. Set expectations clearly.

Libido improvement begins within 3 to 6 weeks. Lean body mass increases modestly (1 to 3 kg over 6 to 12 months). Fat mass decreases by a similar amount. Bone mineral density improves at the lumbar spine by approximately 3 to 5% over 12 months, as shown in the TTrials bone substudy published in JAMA Internal Medicine [13]. Energy and mood improvements are variable and harder to quantify. Erectile function improves primarily when low testosterone, not vascular disease, is the root cause.

Men who do not notice meaningful symptom improvement after 6 months at verified mid-normal testosterone levels (confirmed by trough lab draws) should reassess the diagnosis and explore other contributing conditions, including depression, sleep apnea, or thyroid disease.