Do you initiate treatment for hypogonadism based on free testosterone levels alone?

Free Testosterone Testing in Hypogonadism Treatment Initiation

Free testosterone should not be used as the sole criterion for initiating testosterone replacement therapy in hypogonadism, but it is a better index of gonadal status than total testosterone when available and should be part of a comprehensive diagnostic workup. 1

Diagnostic Approach for Hypogonadism

Initial Assessment

• Measure total testosterone as the best screening test for suspected hypogonadism 1, 2
• Morning measurement is essential due to significant diurnal variation in testosterone levels 1
• If total testosterone is low, free testosterone levels should be obtained 3

Interpreting Testosterone Results

• Total testosterone levels:

  • <8 nmol/L (<230 ng/dL): Strongly supports hypogonadism diagnosis

  • 12 nmol/L (>350 ng/dL): Likely normal

  • 8-12 nmol/L (230-350 ng/dL): "Grey zone" requiring further evaluation with free testosterone 2

• Free testosterone assessment:

  • Free testosterone index (total testosterone/SHBG ratio) <0.3 indicates hypogonadism 1
  • Free testosterone is particularly important when SHBG levels may be altered (e.g., in alcoholics, liver disease) 1

When to Use Free Testosterone Testing

Free testosterone measurement is particularly valuable in the following scenarios:

• When total testosterone is in the borderline/grey zone (8-12 nmol/L)
• When SHBG levels may be abnormal:
  • Liver disease (SHBG often elevated)
  • Obesity (SHBG often decreased)
  • Alcoholism (SHBG often elevated) 1
• When symptoms of hypogonadism are present despite normal total testosterone

Additional Diagnostic Workup

For comprehensive assessment, include:

• LH/FSH levels to differentiate primary from secondary hypogonadism 1
• SHBG levels when measuring total testosterone 1
• Prolactin levels if testosterone is low or libido is decreased 1
• Morning measurement of testosterone to account for diurnal variation 1

Treatment Decision Algorithm

1. Assess symptoms of hypogonadism (decreased libido, fatigue, reduced muscle mass, etc.)
2. Measure morning total testosterone
3. If total testosterone is low (<300 ng/dL or <10.4 nmol/L):
   • Measure free testosterone
   • Measure LH/FSH and prolactin
4. Consider treatment if:
   • Symptomatic hypogonadism AND
   • Total testosterone <300 ng/dL OR
   • Free testosterone below lower limit of normal 3

Clinical Pearls and Pitfalls

• Free testosterone is a better index of gonadal status than total testosterone but cannot be measured by all laboratories 1
• The prevalence of low testosterone in men with erectile dysfunction varies from 12.5% to 35%, making routine testing controversial 1
• The American College of Physicians does not recommend for or against routine hormonal blood tests in erectile dysfunction management due to insufficient evidence 1
• Testosterone therapy should be considered in the context of overall health, including bone health, cardiometabolic function, and sexual function 1
• Hypogonadal men with osteoporosis should usually be treated with an established anti-osteoporosis medication, regardless of whether testosterone therapy is instituted 1
• 76-84% of men with low free testosterone levels report symptoms of androgen deficiency, suggesting clinical relevance of free testosterone measurements 4

In conclusion, while free testosterone should not be the sole criterion for initiating treatment, it provides valuable diagnostic information, especially when total testosterone results are equivocal or when conditions affecting SHBG levels are present.