What is the protocol for testosterone replacement therapy (TRT)?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Article Review Status
Submitted
Under Review
Approved

Last updated: May 7, 2025 • View editorial policy

From the Guidelines

Testosterone replacement therapy should only be considered for men with clinically low testosterone levels causing symptoms like fatigue, decreased libido, and reduced muscle mass, and not for those with age-related low testosterone without symptoms. The standard treatment involves testosterone administered via injections, gels, patches, or pellets, with the goal of restoring physiologic levels and improving symptoms. According to the American College of Physicians guideline 1, testosterone treatment is approved for replacement therapy in men with primary or secondary hypogonadism caused by disorders of the hypothalamus, pituitary gland, or testes. Some key points to consider when prescribing testosterone replacement therapy include:

  • Injectable testosterone cypionate or enanthate is typically given at 50-100mg weekly or 100-200mg every two weeks 2.
  • Topical gels like AndroGel or Testim (50-100mg daily) are applied to shoulders, upper arms, or abdomen.
  • Patches (Androderm, 2-6mg daily) are applied nightly to non-scrotal skin.
  • Pellets (Testopel, 150-450mg) are implanted subcutaneously every 3-6 months. Before starting therapy, baseline PSA and hematocrit should be checked, and regular monitoring includes testosterone levels, hematocrit, PSA, and liver function tests at 3-6 month intervals initially, then annually 1. Potential side effects include acne, fluid retention, breast enlargement, sleep apnea, and increased red blood cell production. It's essential to note that evidence for long-term safety is lacking, and most studies excluded men with recent cardiovascular disease 2. Therefore, testosterone replacement therapy should be prescribed with caution and only when the benefits outweigh the potential risks, and patients should be closely monitored for any adverse effects.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION Dosage and Administration for testosterone gel 1.62% differs from testosterone gel 1%. For dosage and administration of testosterone gel 1% refer to its full prescribing information. (2) Prior to initiating testosterone gel 1. 62%, confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range (2). Starting dose of testosterone gel 1.62% is 40.5 mg of testosterone (2 pump actuations or a single 40.5 mg packet), applied topically once daily in the morning. (2. 1) Dose adjustment: testosterone gel 1.62% can be dose adjusted between a minimum of 20.25 mg of testosterone (1 pump actuation or a single 20. 25 mg packet) and a maximum of 81 mg of testosterone (4 pump actuations or two 40.5 mg packets).

The testosterone replacement therapy using testosterone gel 1.62% should be initiated with a starting dose of 40.5 mg of testosterone, applied topically once daily in the morning. The dose adjustment can be made between 20.25 mg and 81 mg of testosterone, based on the pre-dose morning serum testosterone concentration. Key points to consider are:

  • Diagnosis confirmation: Confirm the diagnosis of hypogonadism by ensuring that serum testosterone has been measured in the morning on at least two separate days and that these concentrations are below the normal range.
  • Dose titration: The dose should be titrated based on the pre-dose morning serum testosterone concentration at approximately 14 days and 28 days after starting treatment or following dose adjustment.
  • Serum testosterone assessment: Serum testosterone concentration should be assessed periodically thereafter 3.

From the Research

Testosterone Replacement Therapy

  • Testosterone replacement therapy (TRT) is the standard treatment for male hypogonadism, and it has been shown to restore normal serum testosterone concentrations and relieve symptoms in most hypogonadal men 4.
  • The selection of the method depends on the patient's preference with advice from the physician, and dose adjustment is possible with most delivery methods 4.
  • TRT has been demonstrated to have a significant impact on the signs and symptoms of hypogonadism, but there are concerns about the increase in TRT and its potential adverse effects, particularly cardiovascular effects 5.

Benefits and Risks of Testosterone Replacement Therapy

  • TRT is associated with multiple benefits, including improved symptoms and signs of testosterone deficiency, such as decreased libido, erectile dysfunction, and loss of muscle and bone mass 6.
  • However, TRT is not a good option in men wishing to preserve fertility, nor in men with (a high risk of) prostate cancer, polycythemia, thrombophilia, and severe cardiovascular disease 7.
  • The use of hepatotoxic androgens must be avoided, and testosterone treatment induces reversible suppression of spermatogenesis 4.

Alternative Treatments for Central Hypogonadism

  • Alternative treatments for central hypogonadism include gonadotropins, clomiphene citrate, and tamoxifen, which can be used when fertility is desired in the near future or in men with contraindications to TRT 7.
  • However, the use of clomiphene citrate and tamoxifen is off-label, and data supporting their efficacy on hypogonadal symptoms are insufficient 7.

Dosage Regimens of Testosterone Replacement Therapy

  • Different dosage regimens of testosterone enanthate have been studied, and the most effective regimens appear to be 200 mg every 2 weeks and 300 mg every 3 weeks 8.
  • The aim of TRT is to increase serum testosterone levels to the physiologic range, and the routes of delivery approved for use in the Western world include buccal, nasal, subdermal, transdermal, and intramuscular (IM) 6.

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.