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What to measure: Total versus free testosterone?
All clinical guidelines on hypogonadism require measurement of total testosterone as part of making the diagnosis of hypogonadism. However, according to the free hormone hypothesis, free testosterone is the fraction of serum testosterone that is active and exerts physiological effects. Therefore it has been argued that free testosterone is a more accurate indicator of true androgen status. However, the in-vivo relationship between free and SHBG-bound testosterone - as opposed to the in-vitro studies that the free hormone hypothesis is based on - is very complex.1
Older men commonly have low or low-normal total testosterone levels, but high SHBG and low free testosterone levels. Even if free testosterone levels may be a more accurate indicator of true androgen status, there are major problems with free testosterone assays.
Free testosterone assays offered by most laboratories are based on analog immunoassays, which underestimate free testosterone levels; the provided values are about 1/5 to 1/8 of free testosterone by equilibrium analysis or calculated. If free testosterone is evaluated, it should be measured using equilibrium analysis (the gold standard reference method), which is more expensive and not commonly available. The second-best option is to calculate free testosterone from total testosterone and SHBG measurements, using an algorithm.1 A good online calculator can be found at https://www.nebido.com/en/hcp/research/testosterone-tools/free-calculator.php
There are no generally accepted lower limits of normal for free testosterone. However, a free testosterone level below 220 pmol/L (64 pg/nl) may provide supportive evidence for testosterone treatment).
Goldman AL, Bhasin S, Wu FCW, Krishna M, Matsumoto AM, Jasuja R. A Reappraisal of Testosterone's Binding in Circulation: Physiological and Clinical Implications. Endocr Rev. 2017 Aug 1;38(4):302-324Return to content