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Subject: Testosterone, Total, Free, Bioavailable
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Testosterone circulates in the blood of men and women in several forms. In healthy adults, approximately 44% of circulating testosterone is specifically bound to sex hormone–binding globulin (SHBG), 50% is nonspecifically bound to albumin, and 3–5% is bound to cortisol-binding globulin, indicating that only 2–3% is unbound and free. Current methods available to evaluate the androgen status include measurement of total testosterone, free testosterone by direct immunoassays, equilibrium dialysis, HPLC-MS, SHBG, calculated free (non–SHBG- and nonalbumin-bound) testosterone, and bioavailable (non–SHBG-bound) testosterone. In most, but not all clinical conditions, a measurement of total testosterone is adequate for the evaluation of a patient. It is widely believed that SHBG-bound testosterone is not readily available to most tissues, whereas albumin-bound and free testosterones are bioavailable. Because SHBG concentrations can be influenced by many factors (e.g., decreased by obesity, testosterone treatment, and hypoandrogenic female conditions such as polycystic ovary syndrome; increased by aging, pregnancy, and estrogen therapy), there are clinical situations in which measured concentrations of total testosterone may not reflect the bioavailable concentrations or the clinical status of the patient. In these circumstances, a supplemental test assessing bioavailable and free testosterone is helpful in clinical decision making.
Normal range: see Table 16.75.
Evaluation of gonadal hormonal function
Adrenal virilizing tumor causing premature puberty in boys or masculinization in women
Idiopathic hirsutism (inconclusive)
Stein-Leventhal syndrome: variable; increased when virilization is present
Ovarian stromal hyperthecosis
Use of certain drugs that alter thyroxine-binding globulins may also affect testosterone-binding globulins; however, the free testosterone level is not affected
Primary hypogonadism (e.g., orchiectomy)
Secondary hypogonadism (e.g., hypopituitarism)
Klinefelter syndrome levels lower than in normal male individual but higher than in normal female and orchiectomized male
Total (but not free) testosterone decreased due to decreased SHBG (e.g., cirrhosis, chronic renal disease)
Due to the availability of many different forms of testosterone assays, as well as the confusion in the literature regarding their clinical relevance, there is a lack of consistency for its measurement in routine clinical situations. The earliest approaches to the measurement of free testosterone were equilibrium dialyses and ultrafiltration. These assays were very cumbersome for routine use.
Indirect measurement of free testosterone using isotope-labeled testosterone was one of the earlier methods proposed and widely used. The endocrine society recently reported a review of the evidence that the analog-based free testosterone immunoassays should be avoided because of the problems with accuracy and sensitivity. Free testosterone measurements by calculation using algorithms based on the law of mass action, which requires total testosterone, SHBG, and albumin concentrations, have excellent correlations with physical separation measures.
Testosterone exhibits significant circadian variations in young men, and early morning samples are recommended.