Is a free testosterone (free T) calculator accurate at higher sex hormone-binding globulin (SHBG) levels?

Accuracy of Free Testosterone Calculators at Higher SHBG Levels

Free testosterone calculators are less accurate at higher SHBG levels, with calculated free testosterone (cFT) tending to overestimate actual free testosterone when SHBG is elevated.

Understanding Free Testosterone Calculation

Free testosterone represents the small fraction of total testosterone that is not bound to proteins and is considered the biologically active portion. The majority of testosterone circulates either:

• Tightly bound to sex hormone-binding globulin (SHBG) (60-70%)
• Weakly bound to albumin (30-40%)
• Unbound/free (1-2%)

Why SHBG Levels Matter

SHBG levels can be significantly altered by various conditions:

• Elevated SHBG conditions:

  • Advanced liver disease 1
  • Hyperthyroidism 2
  • Hypogonadism 2
  • Androgen insensitivity 2
  • Hepatic cirrhosis in men 2

• Decreased SHBG conditions:

  • Obesity 3
  • Insulin resistance 3
  • Hypothyroidism 2
  • Hyperprolactinemia 2
  • Syndromes of excessive androgen activity 2

Accuracy Issues with Free T Calculators at High SHBG

The accuracy of free testosterone calculations is compromised at higher SHBG levels for several reasons:

1. Mathematical limitations: Most calculators use simplified equations that assume constant binding affinity between testosterone and SHBG across all concentration ranges 4

2. Assay variability: The accuracy depends on the reliability of both total testosterone and SHBG measurements 5

3. Non-linear binding: At higher SHBG concentrations, the binding dynamics become more complex and less predictable 4

4. Lack of standardization: Different calculators use different algorithms, leading to inconsistent results 6

Evidence on Diagnostic Accuracy

According to a comprehensive systematic review and diagnostic meta-analysis published in Human Reproduction Update 1:

• Calculated free testosterone (cFT) had a sensitivity of 0.89 (95% CI: 0.69-0.96) and specificity of 0.83 (95% CI: 0.79-0.86)
• The diagnostic odds ratio was 38 (95% CI: 10-142)
• When SHBG levels are high, the accuracy of cFT decreases

The review also found that:

• cFT based on direct immunoassay methods had lower sensitivity (0.74) compared to LC-MS/MS methods (0.88)
• The accuracy of cFT varies depending on the assay method used for total testosterone measurement 1

Best Practices for Testosterone Assessment

When SHBG levels are elevated:

1. Preferred measurement methods:

   • Equilibrium dialysis or ultrafiltration (gold standard) for free testosterone 3, 4
   • LC-MS/MS for total testosterone measurement 1, 5

2. When using calculators:

   • Use calculators based on the Vermeulen equation rather than simple ratios like Free Androgen Index (FAI) 7
   • Interpret results with caution, especially at SHBG extremes 6
   • Consider using age-stratified reference ranges 6

3. Alternative approaches:

   • Bioavailable testosterone (free + albumin-bound) may be more clinically relevant in some cases 7
   • Consider measuring additional androgens when evaluating hyperandrogenism 1

Clinical Implications

For accurate assessment when SHBG is elevated:

• Recognize limitations: Be aware that calculated values may overestimate true free testosterone
• Confirm borderline results: When total testosterone is borderline and SHBG is high, direct measurement of free testosterone by equilibrium dialysis is recommended 3
• Consider the clinical context: Interpret results in conjunction with symptoms and other laboratory findings
• Calculate the free testosterone index: Total testosterone/SHBG ratio can provide additional information when free testosterone results are inconclusive 3

Conclusion

While free testosterone calculators are convenient and widely used, their accuracy diminishes at higher SHBG levels. For patients with conditions associated with elevated SHBG, direct measurement methods like equilibrium dialysis should be considered for more accurate assessment of androgen status, particularly when clinical decisions depend on precise free testosterone values.