What is the evaluation and treatment process for low total and free testosterone levels?

Evaluation and Treatment of Low Total and Free Testosterone Levels

Testosterone replacement therapy (TRT) should only be initiated after confirming consistently low testosterone levels (<300 ng/dL) on at least two separate morning measurements, and should be targeted to achieve levels in the middle tertile of the normal range (450-600 ng/dL). 1

Diagnostic Approach

Laboratory Assessment

• Measure total testosterone on at least two separate mornings to confirm consistently low levels (<300 ng/dL) 1, 2
• Testing should be performed:
  • In a fasting state
  • Before 11:00 AM (to account for diurnal variation) 3, 4
  • Using accurate methodology (preferably liquid chromatography-tandem mass spectrometry) 2, 3
• Normal ranges:
  • Total testosterone: 300-950 ng/dL
  • Free testosterone: 50-200 pg/mL 1

When to Measure Free Testosterone

• Measure free testosterone when:
  • Total testosterone levels are borderline (slightly above or below the lower limit)
  • Alterations in binding proteins are suspected 3
• Free testosterone should ideally be measured by equilibrium dialysis method, not analog immunoassay 2, 5

Clinical Evaluation

• Assess for symptoms:
  • Reduced energy and fatigue
  • Depression and poor concentration
  • Irritability
  • Reduced sex drive
  • Infertility 1
• Physical examination should include:
  • Body habitus and BMI
  • Virilization status
  • Gynecomastia
  • Testicular size
  • Prostate examination 1

Treatment Approach

Indications for TRT

• Confirmed low testosterone levels (<300 ng/dL) on multiple morning measurements
• Presence of specific symptoms of testosterone deficiency
• Primary goal: improve sexual function, energy, vitality, physical function, or cognition 1

Contraindications for TRT

• Breast or prostate cancer
• Hematocrit >50%
• Severe untreated sleep apnea
• Severe lower urinary tract symptoms
• Uncontrolled heart failure
• Current or future fertility desires 1

Dosing and Administration

• Initial dosing:
  • Starting dose typically 40.5 mg daily for gel formulations 6
  • Adjust dosing to achieve total testosterone levels in the middle tertile of normal range (450-600 ng/dL) 1
• Administration routes:
  • Transdermal (gel, patch)
  • Intramuscular injections
  • Buccal tablets
  • Note: Intramuscular testosterone is associated with greater LH suppression than transdermal formulations 1

Monitoring Protocol

• Initial monitoring (3-6 months):

  • Total testosterone levels
  • Hematocrit
  • PSA
  • Symptom response 1

• Long-term monitoring (annually):

  • Total testosterone (target: 450-600 ng/dL)
  • Hematocrit (discontinue if >54%)
  • PSA (in men ≥40 years; biopsy if >4.0 ng/mL or increases >1.0 ng/mL/year)
  • Symptom evaluation 1

Treatment Discontinuation

• Discontinue TRT if:
  • No improvement in sexual function within 12 months
  • Hematocrit exceeds 54% (consider therapeutic phlebotomy)
  • Development of contraindications 1

Potential Adverse Effects

• Erythrocytosis (increased red blood cell count)
• Fluid retention
• Prostate effects (increased PSA)
• Mood swings
• Hypertension
• Skin irritation
• Gynecomastia
• Potential blood clots
• Suppression of natural testosterone production 1, 6

Lifestyle Modifications

• Weight management
• Regular exercise
• Mediterranean diet
• Limit alcohol consumption to less than 21 units per week 1

Important Clinical Considerations

• TRT should not be prescribed for men with normal testosterone levels as it can lead to suppression of natural production 1
• The FDA-approved testosterone gel formulations are designed to restore physiologic testosterone levels, with target ranges of 300-1000 ng/dL 6
• Men with type 2 diabetes often have lower testosterone levels and may benefit from TRT, but require careful monitoring 7
• When evaluating borderline testosterone levels, consider the significant intra-individual variability that can occur 4