What is the approach to managing a patient with low free testosterone and normal total serum testosterone?

Management of Low Free Testosterone with Normal Total Testosterone

For patients with low free testosterone but normal total testosterone, a comprehensive evaluation is necessary, followed by testosterone replacement therapy if clinically indicated based on symptoms and confirmed laboratory findings.

Diagnostic Approach

• Confirm low free testosterone with a second morning measurement (between 8-10 AM) as testosterone levels show diurnal variation with highest levels in the morning 1
• Free testosterone should be measured by equilibrium dialysis or calculated using validated formulas that incorporate total testosterone, sex hormone-binding globulin (SHBG), and albumin concentrations 2, 1
• Measure serum luteinizing hormone (LH) levels to help establish the etiology of testosterone deficiency (primary vs. secondary hypogonadism) 2
• Total testosterone measurement alone is not sufficient to rule out hypogonadism when free testosterone is low, as it has low specificity for the biochemical diagnosis of hypogonadism 3

Clinical Assessment

• Document symptoms associated with low testosterone, including:

  • Reduced energy, endurance, physical performance
  • Fatigue, depression, reduced motivation
  • Poor concentration, impaired memory
  • Reduced sex drive, changes in erectile function
  • Infertility 2, 1

• Perform targeted physical examination for signs of low testosterone:

  • Body habitus and virilization status
  • Body mass index/waist circumference
  • Gynecomastia
  • Testicular evaluation (size, consistency)
  • Prostate examination 2, 1

Additional Testing

• Serum prolactin levels should be measured in patients with low testosterone combined with low or low/normal LH levels to screen for hyperprolactinemia 2
• Consider measuring estradiol in patients who present with breast symptoms or gynecomastia 2
• Men with testosterone levels <150 ng/dL in combination with low or low/normal LH should undergo pituitary MRI regardless of prolactin levels 2
• Prior to testosterone therapy, measure hemoglobin/hematocrit and assess for cardiovascular disease risk factors 2

Treatment Approach

• If free testosterone is confirmed low on at least two separate assessments and symptoms are present, testosterone replacement therapy is indicated 1, 4
• Treatment options include:
  • Transdermal preparations (gel, patch)
  • Intramuscular injections
  • Implantable testosterone pellets 1
• The goal of therapy is to achieve testosterone levels in the mid-normal range 4

Special Considerations

• In obese patients, low free testosterone with normal total testosterone may occur due to altered SHBG levels and increased aromatization of testosterone to estradiol in adipose tissue 1, 5
• Men interested in fertility should have a reproductive health evaluation performed prior to testosterone replacement therapy, as exogenous testosterone can suppress spermatogenesis 2

Monitoring

• After initiating treatment, monitor testosterone levels at 2-3 months to ensure normal serum testosterone concentrations are achieved 1
• Monitor for potential adverse effects including polycythemia (hematocrit >50%), worsening of sleep apnea, lower urinary tract symptoms, and cardiovascular events 4

Pitfalls and Caveats

• Screening questionnaires alone are not recommended for identifying candidates for testosterone therapy due to variable specificity and sensitivity 2, 1
• Free androgen index correlates poorly with calculated free testosterone and may overestimate free testosterone at low SHBG concentrations 6
• Total testosterone between 280 and 350 ng/dL is not sensitive enough to reliably exclude hypogonadism when free testosterone is low 3