FREE TESTOSTERONE

Free testosterone is a solid-phase, ¹²⁵I radioimmunoassay designed for its quantitative measurement in serum. It is intended strictly for in vitro use as an aid in the clinical diagnosis and management of hirsutism due to hyperandrogenism.

Testosterone circulates almost entirely bound to transport proteins: normally less than one percent is free. The principal transport protein for testosterone is known as sex hormone binding globulin (SHBG) or testosterone-estradiol binding globulin (TeBG), since it binds not only to testosterone but also to estradiol (and Dihydrotestosterone). Albumin and cortisol binding globulin (DBG) are the other testosterone transport proteins.

For three reasons, SHBG is the most important of these transport proteins. It caries, at least in females, a higher percentage of the testosterone in circulation than either albumin or CBG. Furthermore, it binds to testosterone with a much higher affinity than do the other two transport proteins. (The testosterone bound to albumin and CBG is collectively known as "Weakly bound" testosterone.) Finally, SHBG has a responsiveness, not associated with albumin, insofar as the SHBG level is sensitive to changes in the ration of circulating estrogens to circulating androgens. SHBG thus plays a greater role in determining the level of free testosterone in circulation.

In pregnancy, SHBG levels show a progressive increase that mirrors the rise in estradiol levels. Although the total testosterone level also shows some increase during pregnancy, the rise in estradiol, and hence also in SHBG, is more dramatic. The net result is a decrease in free testosterone as a percent of total testosterone. Women taking oral contraceptives likewise have increased SHBG levels, at least if they are taking high dose ethinyl estradiol preparations. Conversely, the administration of androgens to prepubertal boys, or the elevation of endogenous testosterone by HCG simulation, induces a significant decrease in the SHBG level. Obesity is also associated with a decrease in the SHBG level.

Other things being equal, we expect the concentration of free testosterone in circulation to increase if the testosterone level (T) increases or if the SHBG level decreases. The T/SHBG ratio, i.e. the ration of total testosterone to (the concentration or binding capacity of) SHBG, thus serves as a rough guide to the concentration of free testosterone in circulation. The T/SHBG ratio is sometimes referred to as the Testosterone Free Index (TFI).

The Testosterone Free Index is often increased in severe acne, male androgenic alopecia (balding), hirsutism and other conditions. A low SHBG level, often in combination with a normal total testosterone level, is a common finding in these conditions. An increase in the testosterone production rate typically induces a decrease in the SHBG level. This stimulates cellular uptake and metabolism of testosterone, by making more available in the free form. The result is that the total testosterone level is often normal, because the increased production rate is offset by an increased rate of clearance.

Total testosterone measurements have traditionally been used to help screen for hirsutism. In view of the mechanism just described, it is natural to expect free testosterone levels, measured directly or indexed by the T/SHBG ratio, to correlate better with hirsutism. Some investigators, notably Paulson, have found free testosterone to be overwhelmingly superior to total testosterone in screening for hirsutism. In his study of 32 hirsute women, only 44 percent had elevated total testosterone levels, while all 32 had elevated free testosterone levels. Not all investigators have achieved this decree of success. On balance, however, judging from the studies reviewed by Wu, it appears that free testosterone is at least marginally superior to total testosterone in this context. (The varied outcomes could possibly be due to differences in methodology and differences in the selection of patients.)