Accuracy of Free Testosterone Calculators at High SHBG Levels
Free testosterone calculators remain accurate at high Sex Hormone-Binding Globulin (SHBG) levels, with calculated free testosterone (cFT) showing excellent diagnostic performance (sensitivity 0.89, specificity 0.83) across various SHBG concentrations. 1
Evidence on Free Testosterone Calculation Methods
Calculated Free Testosterone (cFT)
- cFT demonstrates high diagnostic accuracy with an AUC of 0.85 (95% CI: 0.81-0.88), making it a reliable biochemical marker for diagnosing hyperandrogenism even with varying SHBG levels 1
- The Vermeulen equation is the most commonly used formula for calculating free testosterone from total testosterone and SHBG measurements 1
- No threshold effect was observed for cFT (rho = -0.6, P = 0.2) by Spearman's correlation, confirming its reliability across different SHBG concentrations 1
Comparison with Other Methods
- cFT values calculated using the laws of mass action correlate extremely well with those obtained from equilibrium dialysis (r = 0.99; P < 0.0001), which is considered the gold standard 2
- Direct immunoassay methods for free testosterone show unacceptably high systematic bias and random variability compared to equilibrium dialysis (r = 0.81; P < 0.0001) 2
- Free Androgen Index (FAI), while simpler to calculate, varies as a function of SHBG levels and is not as reliable as cFT, especially at high SHBG concentrations 3
Influence of SHBG Levels on Testosterone Measurement
High SHBG Scenarios
- In conditions with high SHBG (such as liver disease), total testosterone measurements may appear normal while free testosterone is actually low 1
- SHBG synthesis is stimulated by estrogens and can be elevated in various conditions, including chronic liver disease 1
- Free testosterone index (FAI) becomes less reliable at high SHBG concentrations (>30 nmol/L), making cFT the preferred method in these scenarios 1
Assay Methods and Accuracy
- LC-MS/MS methods for measuring total testosterone (used in cFT calculations) demonstrate superior performance with sensitivity of 0.88 (95% CI: 0.80-0.93) and specificity of 0.87 (95% CI: 0.75-0.94) 1
- Direct immunoassays for total testosterone show lower sensitivity (0.74,95% CI: 0.64-0.82) and specificity (0.81,95% CI: 0.75-0.85) when used in cFT calculations 1
Clinical Applications and Recommendations
When to Use cFT vs. Other Methods
- When SHBG levels are high, cFT is more reliable than total testosterone or FAI for assessing true androgen status 1
- In liver disease patients where SHBG is often elevated, a ratio of total testosterone/SHBG (free testosterone index) <0.3 indicates hypogonadism, but cFT provides more accurate assessment 1
- For borderline total testosterone values (7.5-12 nmol/L), calculated indices of free testosterone are superior to total testosterone alone for diagnosing hypogonadism (AUC: 0.75 vs. 0.63) 4
Practical Considerations
- Multiple calculation methods exist (Sodergard, Nanjee-Wheeler, Vermeulen, and Ly-Handelsman equations), with the Vermeulen equation being most widely validated 5
- Spreadsheet-based calculation methods that account for competitive binding effects provide user-friendly approaches for estimating free hormone concentrations 6
- Morning sampling is important due to significant diurnal variation in testosterone levels 1
Potential Pitfalls and Limitations
- During pregnancy, estradiol occupies a substantial part of SHBG-binding sites, causing calculated free testosterone to be lower than actual values measured by equilibrium dialysis 3
- Different equations for calculating free testosterone can yield considerably different values (biases ranging from 5.8% to 56.0%), so consistency in method selection is important 5
- The accuracy of cFT depends heavily on the quality of the assays used for measuring total testosterone and SHBG 1