What Is TRT?
Testosterone Replacement Therapy ยท Last reviewed by the OPTML clinical team on April 20, 2026
Testosterone replacement therapy (TRT) is the medical administration of exogenous testosterone to men with clinically low endogenous testosterone (hypogonadism). TRT is delivered via intramuscular or subcutaneous injection (testosterone cypionate/enanthate), topical gel, transdermal patch, or implantable pellets. The TRAVERSE trial (Lincoff AM et al., NEJM 2023), the largest cardiovascular safety study of TRT ever conducted, enrolling 5,246 men, found TRT non-inferior to placebo for major adverse cardiac events.
Indications
TRT is indicated for men with clinically diagnosed hypogonadism, consistent symptoms plus confirmed low morning total testosterone, typically below 300 ng/dL on two separate measurements. Common symptoms include fatigue, low libido, erectile dysfunction, depressed mood, loss of muscle mass, increased fat mass, and poor exercise recovery.
Primary vs. Secondary Hypogonadism
- Primary hypogonadism: testicular failure. LH and FSH are elevated.
- Secondary hypogonadism: impaired HPG signaling from the hypothalamus/pituitary. LH and FSH are low or inappropriately normal.
Forms of Testosterone
| Form | Route | Frequency |
|---|---|---|
| Testosterone cypionate | IM or subcutaneous injection | Weekly or twice-weekly |
| Testosterone enanthate | IM injection | Weekly |
| Testosterone gel (AndroGel, Testim) | Topical | Daily |
| Testosterone patch | Transdermal | Daily |
| Testopel pellets | Subcutaneous implant | Every 3-6 months |
| Nasal testosterone (Natesto) | Intranasal | 3x daily |
Typical Laboratory Monitoring
- Total testosterone (target: mid-to-high normal, commonly 600-900 ng/dL).
- Free testosterone.
- Estradiol (monitor for aromatization).
- Hematocrit (elevated hematocrit is the most common clinically significant side effect).
- PSA (prostate-specific antigen).
- SHBG, LH, FSH at baseline.
- Comprehensive metabolic panel + lipids.
Clinical Trial Evidence
TRAVERSE (Cardiovascular Safety, 2023)
A 4-year trial of 5,246 men with hypogonadism and preexisting or high CV risk. TRT was non-inferior to placebo for the composite of CV death, MI, and stroke. Adverse events observed more frequently on TRT: atrial fibrillation, pulmonary embolism, and acute kidney injury.
Testosterone Trials (2016)
Seven coordinated RCTs in men 65+ demonstrated improvements in sexual function, physical function (modest), mood, vitality, anemia, and bone density with 1 year of TRT.
Side Effects and Risks
- Erythrocytosis (elevated hematocrit/hemoglobin).
- Acne, oily skin.
- Sleep apnea worsening.
- Gynecomastia (from aromatization to estradiol).
- Suppressed endogenous testosterone production and reduced fertility, generally reversible after discontinuation but not guaranteed.
- Worsening of untreated prostate pathology (careful PSA monitoring).
TRT vs. Enclomiphene
Unlike exogenous TRT, enclomiphene (a selective estrogen receptor modulator) stimulates the pituitary to increase endogenous LH/FSH signaling, raising natural testosterone production while generally preserving fertility. Enclomiphene is typically preferred for men with secondary hypogonadism who wish to conceive.
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Start your consultation →References
- Lincoff AM, Bhasin S, Flevaris P, et al. Cardiovascular Safety of Testosterone-Replacement Therapy. N Engl J Med. 2023;389(2):107-117. [TRAVERSE]
- Snyder PJ, Ellenberg SS, Cunningham GR, et al. The Testosterone Trials: Seven Coordinated Trials of Testosterone Treatment in Elderly Men. Clin Trials. 2014;11(3):362-375.
- 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.
- American Urological Association. Evaluation and Management of Testosterone Deficiency: AUA Guideline. 2018.