At what upper values of total testosterone do free testosterone (FT) calculators become inaccurate?

Free Testosterone Calculator Accuracy at Upper Total Testosterone Values

Free testosterone calculators become inaccurate when total testosterone exceeds 800 ng/dL, particularly when SHBG is ≤30 nmol/L and albumin is ≤3.5 g/dL. 1

Understanding Free Testosterone Calculation Methods

• Free testosterone (FT) represents the biologically active form of testosterone unbound to sex hormone-binding globulin (SHBG) or albumin, making it a more sensitive indicator of hyperandrogenemia than total testosterone (TT) 2
• The gold standard for measuring free testosterone is equilibrium dialysis, but this method is too complex and resource-intensive for routine clinical use 2, 3
• Calculated free testosterone (cFT) using the Vermeulen equation is the most widely accepted alternative method, which estimates FT from TT and SHBG measurements 2, 4

Accuracy Limitations of Free Testosterone Calculators

• Free testosterone calculators show decreased accuracy when:

  • Total testosterone levels exceed the upper normal range (>800 ng/dL) 5, 6
  • SHBG levels are extremely low (≤30 nmol/L) combined with low albumin (≤3.5 g/dL) 1
  • During pregnancy or with very high estradiol levels that compete for SHBG binding sites 4

• The accuracy of calculated free testosterone is highly dependent on the specific assays used for measuring total testosterone and SHBG 7

Specific Conditions Affecting Calculator Accuracy

• When SHBG is ≤30 nmol/L combined with albumin ≤3.5 g/dL, the variance between calculated and actual free testosterone increases significantly, occurring in approximately 1.2% of clinical evaluations 1

• Liquid chromatography-tandem mass spectrometry (LC-MS/MS) measurements of total testosterone provide more accurate inputs for free testosterone calculations compared to direct immunoassays 2, 6

• The Vermeulen equation (cFT-V) overestimates free testosterone by approximately 19% (median ratio 1.19) compared to equilibrium dialysis, but is the most robust calculation method as it remains relatively independent of variations in SHBG, albumin, and testosterone levels 6

Clinical Implications

• For most clinical evaluations, using a fixed albumin value of 4.3 g/dL in free testosterone calculations is acceptable 1

• When total testosterone levels are very high or SHBG levels are extremely low, direct measurement of free testosterone by equilibrium dialysis is warranted for better accuracy 1, 6

• Free androgen index (FAI), calculated as 100×T/SHBG, is not recommended for use in men because of inaccuracy at extremes of SHBG concentration 3

Recommendations for Clinical Practice

• When evaluating patients with total testosterone levels exceeding 800 ng/dL, consider:

  • Using equilibrium dialysis for direct measurement of free testosterone 2, 3
  • Ensuring morning measurements as testosterone levels naturally fluctuate throughout the day 8, 5
  • Obtaining two separate morning measurements for accurate assessment 8, 5

• For patients with obesity who may have low SHBG but normal free testosterone, measurement of morning serum free testosterone by equilibrium dialysis is essential rather than relying on calculators 8, 5