From the Guidelines
The main difference between free and total testosterone is that free testosterone is the biologically active portion of the hormone, while total testosterone measures both bound and unbound forms, with free testosterone being more clinically relevant for diagnosing and treating conditions like hypogonadism. The distinction between these two forms is crucial because only free testosterone can enter cells and produce effects like muscle growth, libido, and other masculine characteristics. Total testosterone includes testosterone bound to proteins like sex hormone-binding globulin (SHBG) and albumin, as well as the free portion. Conditions such as obesity, liver disease, or thyroid disorders can affect binding proteins, leading to a situation where total testosterone appears normal while free testosterone is abnormal 1.
When testing hormone levels, total testosterone is commonly measured first, but free testosterone provides more accurate information about the hormone's actual biological activity. For instance, in men with diabetes who have symptoms or signs of hypogonadism, a morning total testosterone level should be measured, and if the levels are close to the lower limit, determining free testosterone concentrations either directly or through calculations using total testosterone, sex hormone-binding globulin, and albumin concentrations is reasonable 1.
Key points to consider include:
- Free testosterone is the biologically active form of the hormone.
- Total testosterone measures both bound and unbound forms.
- Conditions affecting binding proteins can lead to discrepancies between total and free testosterone levels.
- Both measurements are important for diagnosing and treating hypogonadism, with free testosterone being more clinically relevant.
- The relationship between free and total testosterone explains why some men with "normal" total testosterone levels may still experience symptoms of low testosterone if their free testosterone is insufficient 1.
In clinical practice, measuring both total and free testosterone levels is essential for accurately diagnosing hypogonadism and guiding treatment decisions, especially in patients with conditions that may affect hormone binding proteins, such as obesity or diabetes 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 main difference between free and total testosterone is the binding state.
- Total testosterone refers to the overall amount of testosterone in the blood, including both bound and free testosterone.
- Free testosterone is the small fraction (about 2 percent) of testosterone that is not bound to any proteins in the blood and is available to enter cells and exert its effects. The bound fraction (about 98 percent) is attached to a specific testosterone-estradiol binding globulin and is not available for immediate use by the body 2.
From the Research
Difference between Free and Total Testosterone
- Free testosterone refers to the fraction of testosterone that is not bound to proteins in the blood, such as sex hormone-binding globulin (SHBG) or albumin, and is considered the metabolically active form of testosterone 3.
- Total testosterone, on the other hand, includes all forms of testosterone in the blood, including both bound and free fractions 4.
- The majority of testosterone in the blood is bound to SHBG or albumin, with only a small percentage circulating as free testosterone 3.
- Measurement of free testosterone is important in the diagnosis of androgen deficiency disorders, such as hypogonadism in men, and androgen excess disorders, such as polycystic ovary syndrome and hirsutism in women 3.
Clinical Utility of Free Testosterone Measurement
- Free testosterone measurement can help prevent misdiagnosis and overtreatment of male hypogonadism, as low free testosterone levels have been associated with symptoms of androgen deficiency even in men with normal total testosterone levels 4.
- Calculated free testosterone (cFT) is often used as a proxy for free testosterone measurement, but its accuracy can be limited by the lack of standardization and the use of faulty models of testosterone binding to SHBG 5.
- The free androgen index is not recommended for use in men due to inaccuracy at extremes of SHBG concentration, and in women, it can also give inaccurate results when SHBG concentrations are low 5.
Comparison of Free and Total Testosterone Levels
- Free testosterone levels have been shown to correlate with clinical and biochemical parameters of androgen deficiency better than total testosterone levels, such as age, hematocrit, gonadotropins, and symptoms of erectile dysfunction and low libido 6.
- Total testosterone determination can misdiagnose hypogonadism in some cases, particularly in men with borderline total testosterone levels, highlighting the importance of measuring free testosterone levels for accurate diagnosis 6.
- Reference ranges for testosterone assays vary significantly among laboratories, and the use of poorly defined and variable reference values can affect how clinicians determine treatment 7.