What causes decreased testosterone levels in patients on testosterone replacement therapy (TRT)?

Causes of Decreased Testosterone Levels During Testosterone Replacement Therapy

The most common causes of decreased testosterone levels in patients on testosterone replacement therapy (TRT) include medication non-adherence, improper administration technique, increased aromatization to estradiol in adipose tissue, and pituitary/hypothalamic dysfunction. 1

Primary Causes of Low Testosterone During TRT

1. Medication-Related Factors

• Non-adherence to prescribed regimen

  • Missed doses or incorrect timing of administration
  • Improper application technique with topical formulations
  • Inconsistent injection schedule with intramuscular formulations

• Formulation-specific issues

  • Transdermal preparations:

    • Poor absorption through skin
    • Washing off gel before complete absorption
    • Skin irritation leading to reduced application area 1

  • Intramuscular injections:

    • Testing testosterone levels at trough rather than mid-cycle
    • Improper injection technique
    • Inadequate dosing intervals 1

  • Oral preparations:

    • Variable absorption and bioavailability
    • First-pass liver metabolism reducing effectiveness 2

2. Physiological Factors

• Increased aromatization

  • Conversion of testosterone to estradiol in adipose tissue
  • More common in obese patients (BMI >30) 1
  • Creates negative feedback on hypothalamic-pituitary axis

• Altered sex hormone-binding globulin (SHBG) levels

  • Changes in SHBG affect free testosterone availability
  • Obesity decreases SHBG levels 1

• Hypothalamic-pituitary-gonadal axis suppression

  • Exogenous testosterone causes feedback inhibition
  • May lead to testicular atrophy and reduced endogenous production 2, 3

3. Drug Interactions

• Medications that can lower testosterone levels:

  • Corticosteroids (concurrent use requires careful monitoring) 2
  • Opioids/narcotics (chronic use) 1
  • Certain anticonvulsants
  • Some antidepressants

• Medications affecting metabolism:

  • Oral vitamin K antagonists (warfarin) - altered metabolism 2
  • Medications that induce hepatic enzymes

Diagnostic Approach

When testosterone levels are unexpectedly low during TRT, follow this algorithm:

1. Verify measurement technique:

   • Confirm blood was drawn in early morning (between 8-10 AM) 1
   • Ensure proper timing relative to dose administration
     • For injections: measure midway between injections
     • For transdermal: levels can vary (peak 6-8 hours after application) 1

2. Evaluate medication adherence:

   • Review administration technique
   • Assess frequency of missed doses

3. Laboratory assessment:

   • Measure luteinizing hormone (LH) levels 1
   • Check estradiol levels, especially if gynecomastia present 1
   • Measure prolactin if LH is low/normal 1
   • Consider SHBG measurement in obese patients 1

4. Rule out comorbidities:

   • Pituitary disorders 1
   • Sleep apnea (can be exacerbated by TRT) 1
   • Liver or kidney dysfunction

Management Strategies

Based on the identified cause:

1. For adherence issues:

   • Simplify regimen if possible
   • Consider switching formulations based on patient preference
   • Provide detailed administration instructions

2. For physiological causes:

   • If high estradiol: Consider dose adjustment or addition of aromatase inhibitor in select cases
   • If obesity-related: Recommend weight loss interventions
   • If SHBG abnormalities: Focus on free testosterone levels rather than total

3. For drug interactions:

   • Review medication list and consider alternatives when possible
   • Adjust testosterone dosing as needed
   • More frequent monitoring when on interacting medications 2

Common Pitfalls to Avoid

• Inadequate monitoring: Failure to check testosterone levels 2-3 months after initiation or dose changes 1
• Improper timing of blood tests: Not accounting for pharmacokinetics of specific formulation
• Focusing only on total testosterone: Free testosterone may be more relevant, especially in obesity 1
• Missing pituitary pathology: Failing to evaluate for prolactinoma or other pituitary disorders in patients with persistently low testosterone despite adequate TRT 1
• Overlooking medication interactions: Particularly with corticosteroids and anticoagulants 2

Special Considerations

• Patients with BMI >30 may have increased aromatization of testosterone to estradiol 1
• Patients with sleep apnea may experience worsening symptoms on TRT 1
• Patients using testosterone for non-medical purposes (abuse) may develop dependence and withdrawal symptoms upon discontinuation 3

By systematically evaluating these potential causes, clinicians can identify and address the specific factors contributing to decreased testosterone levels during TRT, improving treatment outcomes and patient quality of life.