Assessment of free testosterone concentration

Testosterone (T) is strongly bound to sex hormone binding globulin and measurement of free T may be more appropriate than measuring total serum T, according to the free hormone theory. This view remains controversial and it has its detractors who claim that little extra benefit is gained than simply measuring total T, but it is endorsed by recent clinical practice guidelines for investigation of androgen disorders in both men and women. Free T measurement is very challenging. The gold standard equilibrium dialysis methods are too complex for use in routine clinical laboratories, assays are not harmonized and consequently there are no common reference intervals to aid result interpretation. The algorithms derived for calculating free T are inaccurate because they were founded on faulty models of testosterone binding to SHBG, however they can still give clinically useful results. To negate the effects of differences in binding protein constants, some equations for free T have been derived from accurate measurement of testosterone in large population studies, however a criticism is that the equations may not hold true in different patient populations. The free androgen index is not recommended for use in men because of inaccuracy at extremes of SHBG concentration, and in women it can also give inaccurate results when SHBG concentrations are low. If the free hormone hypothesis is to be believed, then calculated free testosterone may offer the best way forward but better equations are needed to improve accuracy and these should be derived from detailed knowledge of testosterone binding to SHBG. There is still much work to be done to improve harmonization of T and SHBG assays between laboratories because these can have a profound effect on the equations used to calculate free testosterone.