From the Guidelines
Total testosterone is generally better to measure for most clinical purposes, as it provides a comprehensive assessment of all testosterone in the bloodstream. However, free testosterone measurement can be more valuable in certain situations, particularly when conditions affect binding protein levels, such as obesity, liver disease, or when taking certain medications, as noted in studies 1. For example, in obesity, binding protein levels may be altered, making free testosterone a more accurate reflection of the biologically active hormone, as discussed in 1. The gold standard for measuring free testosterone is equilibrium dialysis, though this is expensive and not widely available, as mentioned in 1 and 1. Calculated free testosterone (derived from total testosterone and binding protein measurements) is a reasonable alternative, as suggested in 1 and 1. For initial evaluation of testosterone status, total testosterone is recommended, with free testosterone being a useful follow-up test when results are borderline or when binding protein abnormalities are suspected, as recommended in 1 and 1. Testing should ideally be done in the morning when levels are highest, and abnormal results should be confirmed with repeat testing before making treatment decisions, as advised in 1 and 1. Some key points to consider when measuring testosterone include:
- Total testosterone levels below 300 ng/dL are considered low, as stated in 1.
- Free testosterone measurement is essential in men with obesity, as noted in 1.
- Testosterone replacement therapy may be beneficial for men with hypogonadism, as discussed in 1 and 1.
- The method of testosterone replacement should be individualized for each patient, as suggested in 1. It's also important to consider the potential risks and benefits of testosterone therapy, including the possible increased risk of heart attack and stroke, as mentioned in 1. Overall, the choice between total and free testosterone measurement depends on the individual patient's circumstances and the clinical context, as emphasized in 1.
From the FDA Drug Label
Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free. Generally, the amount of this sex-hormone binding globulin in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life
The FDA drug label does not answer the question.
From the Research
Comparison of Free and Total Testosterone Measurement
- Free testosterone measurement may be more appropriate than total serum testosterone according to the free hormone theory 2
- However, free testosterone measurement is challenging and the gold standard equilibrium dialysis methods are too complex for routine clinical laboratories 2
- Calculated free testosterone may offer the best way forward, but better equations are needed to improve accuracy 2
Clinical Utility of Free Testosterone Measurement
- Measurement of free testosterone is important in the diagnosis of many diseases, including disorders of androgen deficiency in men and androgen excess in women 3
- Free testosterone is believed to be the metabolically active fraction, and its measurement can help prevent misdiagnosis and overtreatment of male hypogonadism 4
- Clinicians should be aware of the limitations of free testosterone calculations, particularly the lack of standardization 4
Methods for Measuring Free Testosterone
- Several methodologies are available for free testosterone measurement, including equilibrium dialysis, ultrafiltration, analog immunoassay, and calculated free testosterone based on measurement of total testosterone, SHBG, and albumin 3
- Liquid chromatography-tandem mass spectrometry is a promising new methodology for free testosterone measurement 3
- Equilibrium dialysis is considered the gold standard for measuring free testosterone, but it is not commonly available in clinical practice 5
Reference Ranges for Total and Free Testosterone
- Harmonized reference ranges for total testosterone can be applied to laboratories certified by the Centers for Disease Control and Prevention's Hormone Standardization (HoST) Program 5
- Reference intervals for calculated free testosterone vary depending on the equation used, and there is a need for standardization 6
- Age-stratified free testosterone reference ranges measured by equilibrium dialysis have been established, but more work is needed to improve harmonization of T and SHBG assays between laboratories 4