FREE TESTOSTERONE

Clinical Significance:

Testosterone, a C-18 steroid, is the most potent naturally secreted androgen. In normal postpubertal males, testosterone is secreted primarily by the testes with only a small amount derived from peripheral conversion of 4- or 5-androstene-3beta,17beta-dione (ASD). In adult women, it has been estimated that more than 50 % of serum testosterone is derived from peripheral conversion of ASD secreted by the adrenal glands and ovaries, with the remainder derived from direct secretion of testosterone by these glands.

Testosterone circulates in plasma either freely or bound to plasma proteins. The binding proteins include the specific SHBG and non specific proteins such as albumin. In men, testosterone circulates bound 44% – 65% to SHBG and 33%- 50% to albumin, whereas in women, testosterone is bound to 66 %-78 % to SHBG and 20 % -30 % to albumin. The bioavailable testosterone is equal to about 35 % of the total, or the free plus the albumin bound.

When measuring testosterone levels, it is most important to look at the level of free testosterone, because it is the free (not bound to protein) testosterone found in the blood serum that is the active one. The FAI can be used to estimate physiologically active testosterone. This index is calculated as the ratio of total testosterone divided by SHBG (both expressed in the same units) and multiplied by 100 to yield numerical results comparable in free testosterone concentration.

In most men and women, >50% of total circulating testosterone is bound to sex hormone-binding globulin, SHBG, and most of the rest is bound to albumin. SHBG-bound testosterone is not readily available for intracellular complex formation because of SHBG’s high binding affinity for testosterone. Thus, testosterone-bound SHBG is considered to be biologically inactive. Albumin has a much lower binding affinity for testosterone but binds a significant portion of the total testosterone because albumin is present at much higher plasma concentrations than SHBG. The rapid dissociation of “weakly bound” testosterone from albumin, together with a relatively long transit time of albumin through target tissue capillary beds, result in the availability of essentially all albumin-bound testosterone for steroid-receptor interaction. The sum of the free- and albumin-bound testosterone is often referred to as bioavailable testosterone. The concentration of testosterone in the various free and bound forms is essentially a function of total testosterone concentration and the relative concentrations of SHBG and albumin. It can be predicted that increased SHBG will decrease the concentration of both free and bioavailable testosterone for a given total testosterone concentration. The free androgen index can be used to estimate physiologically active testosterone.