What is the appropriate protocol for initiating Testosterone Replacement Therapy (TRT)?

Protocol for Initiating Testosterone Replacement Therapy (TRT)

The appropriate protocol for initiating Testosterone Replacement Therapy (TRT) requires comprehensive evaluation, including two morning testosterone measurements, assessment of symptoms, and screening for contraindications before starting treatment with a target testosterone level in the mid-normal range (450-600 ng/dL). 1

Initial Evaluation and Diagnosis

• Before initiating TRT, clinicians should confirm testosterone deficiency with two separate morning total testosterone measurements 1
• A serum total testosterone level below 300-350 ng/dL on two separate morning blood samples is considered diagnostic of low testosterone 2
• Patients should have both laboratory evidence of low testosterone AND clinical symptoms of testosterone deficiency to qualify for treatment 2
• For men with obesity, morning free testosterone by equilibrium dialysis should be measured on at least 2 separate assessments 1

Pre-Treatment Assessment

Required Laboratory Tests

• Hemoglobin/hematocrit (baseline measurement required) 1
• PSA for men over 40 years of age 1
• Assessment of cardiovascular disease risk factors (both fixed and modifiable) 1

Clinical Evaluations

• Reproductive health evaluation for men interested in fertility 1
• Digital rectal examination for men over 40 1
• Assessment of voiding symptoms using tools like the International Prostatic Symptoms Score 1
• Evaluation for sleep apnea 1

Contraindications to TRT

• Carcinoma of the breast or known/suspected carcinoma of the prostate 3
• Men currently trying to conceive 1
• Recent cardiovascular events (within 3-6 months) 1
• Hematocrit exceeding 50% (consider withholding therapy until etiology is investigated) 1

Treatment Options and Selection

Available Formulations

• Transdermal preparations (gels, patches)
• Intramuscular injections
• Implantable pellets
• Buccal and nasal formulations 4

Formulation Selection Factors

• Transdermal preparations provide more stable day-to-day testosterone levels 1
• Injectable testosterone is associated with greater treatment-induced increases in hemoglobin/hematocrit 1
• Patient preference may favor gels (71%) for convenience and ease of use, while cost considerations may favor injections 1
• Annual cost differences are substantial: $2,135.32 for transdermal vs. $156.24 for intramuscular formulations (2016 Medicare data) 1

Dosing and Administration

Transdermal Gel Protocol

• Apply to clean, dry, intact skin of upper arms and shoulders only 3
• Starting dose typically 40.5-60.75 mg daily 3
• Dose adjustments based on pre-dose morning total serum testosterone concentration:

  • 750 ng/dL: Decrease daily dose

  • 350-750 ng/dL: No change
  • <350 ng/dL: Increase daily dose 3
• Avoid showering or swimming for at least 2 hours after application 3

Injectable Protocol

• Typically administered every 1-2 weeks depending on formulation 1
• Peak serum levels occur 2-5 days after injection 1
• Levels often return to baseline by 10-14 days after injection 1
• For monitoring, measure levels midway between injections, targeting mid-normal values (500-600 ng/dL) 1

Target Testosterone Levels and Monitoring

• Aim for total testosterone levels in the middle tertile of the normal reference range (450-600 ng/dL) 1
• First follow-up visit at 1-2 months to assess efficacy and consider dose adjustments 1
• Subsequent monitoring at 3-6 month intervals for the first year, then yearly thereafter 1
• For transdermal preparations, levels can be measured at any time 1
• If hematocrit rises above the reference range, consider temporarily withholding therapy, reducing dosage, or performing phlebotomy 1

Safety Monitoring

• Monitor PSA in men over 40 years according to standard prostate cancer screening guidelines 1
• If hematocrit exceeds 54% during treatment, intervention is warranted (dose reduction or temporary discontinuation) 1
• Monitor for gynecomastia or breast symptoms, which are uncommon but may occur 1
• Assess for cardiovascular events, especially in men with pre-existing risk factors 1

Patient Counseling

• Inform patients that TRT may improve erectile function, sex drive, anemia, bone mineral density, lean body mass, and depressive symptoms 1
• Discuss the long-term impact on spermatogenesis for men interested in future fertility 1
• Advise that TRT will likely reduce testicular size and compromise fertility during treatment 1
• Explain the need for long-term monitoring and potential risks 1

Common Pitfalls and Caveats

• Avoid 17-alpha-alkylated oral testosterone due to risk of liver toxicity 1
• Be aware that injectable testosterone is associated with greater increases in hemoglobin/hematocrit than other formulations 1
• For men on exogenous testosterone planning future reproduction, testosterone cessation should occur well in advance of conception attempts 1
• Evidence on long-term benefits or harms of testosterone treatment is lacking due to limited follow-up in studies 1
• Commercially manufactured testosterone products should be prescribed rather than compounded testosterone 1