How to treat a male patient with fatigue, low free testosterone, and normal total testosterone?

Treatment of Male Patients with Low Free Testosterone, Normal Total Testosterone, and Fatigue

Testosterone replacement therapy is recommended for men with low free testosterone levels even when total testosterone is normal, as this pattern is associated with hypogonadal symptoms including fatigue. 1, 2

Diagnostic Confirmation

• Confirm low free testosterone with repeat morning testing (between 8-10 AM)
• Measure sex hormone-binding globulin (SHBG) levels
• Check luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish primary from secondary hypogonadism
• Rule out other causes of fatigue (thyroid dysfunction, anemia, sleep apnea)

Treatment Options

Testosterone Replacement Therapy (First-line)

1. Injectable testosterone:

   • Testosterone cypionate/enanthate: 50-100 mg weekly
   • Testosterone undecanoate: 750 mg initially, followed by 750 mg after 4 weeks, then 750 mg every 10 weeks

2. Transdermal formulations:

   • Testosterone gel 1%: 50 mg daily (range 50-100 mg)
   • Testosterone gel 1.62%: 20.25-40.5 mg daily (range 20.25-81 mg)

Human Chorionic Gonadotropin (Alternative for fertility preservation)

• 500-1000 USP units three times weekly for 3 weeks, followed by same dose twice weekly for 3 weeks 3
• Consider if patient desires fertility preservation, as exogenous testosterone suppresses spermatogenesis

Non-pharmacological Interventions (Adjunctive)

• Regular aerobic exercise, particularly vigorous physical activity 4
• Weight loss for overweight/obese patients 5
• Adequate sleep hygiene
• Nutritional supplements with limited evidence:
  • Zinc supplementation
  • Vitamin D (if deficient)
  • Ashwagandha 6

Monitoring Protocol

• Check testosterone levels 2-3 months after starting therapy:

  • For injectable testosterone: measure midway between injections
  • For transdermal preparations: can be measured at any time
  • Target total testosterone: 450-600 ng/dL 1

• Regular monitoring once stable:

  • Testosterone levels every 6-12 months
  • Hematocrit (discontinue if >54%)
  • PSA (for men >40)
  • Symptom assessment

Special Considerations

• Obesity-related low free testosterone is often due to increased aromatization of testosterone to estradiol in adipose tissue 5
• Men with normal free testosterone despite low total testosterone typically do not exhibit hypogonadal symptoms 2
• Contraindications to testosterone therapy include:
  • Active prostate or breast cancer
  • Hematocrit >50%
  • Severe untreated sleep apnea
  • Severe lower urinary tract symptoms
  • Uncontrolled heart failure
  • Myocardial infarction or stroke within 6 months
  • Desire for fertility in the near term 1, 7

Treatment Algorithm

1. If free testosterone is low and symptoms are present → initiate testosterone replacement therapy
2. If fertility is desired → consider hCG instead of testosterone
3. If cardiovascular risk factors are present → consider transdermal rather than injectable formulations
4. If hematocrit rises above 50% → reduce dose or change formulation
5. If symptoms persist despite normalized testosterone levels → evaluate for other causes of fatigue

Testosterone replacement has demonstrated improvements in energy levels, fatigue, and vitality in men with low testosterone, which directly addresses the primary complaint of fatigue in these patients 5, 1.