What is the difference between free testosterone and total testosterone?

From the Guidelines

Total testosterone level is the preferred initial measurement for diagnosing testosterone deficiency, with a cut-off value of below 300 ng/dL, as recommended by the American Urological Association guideline 1. When evaluating testosterone levels, both total and free testosterone measurements have value. Total testosterone is typically used for initial screening and is more widely available and standardized. However, free testosterone provides a more accurate picture of biologically available hormone, especially in conditions where binding proteins may be altered, such as obesity, liver disease, thyroid disorders, and aging 1. Key points to consider when measuring testosterone levels include:

• The diagnosis of low testosterone should be made only after two total testosterone measurements are taken on separate occasions, with both conducted in an early morning fashion 1.
• The clinical diagnosis of testosterone deficiency is only made when patients have low total testosterone levels combined with symptoms and/or signs, such as reduced energy, reduced endurance, diminished work and/or physical performance, fatigue, and changes in erectile function 1.
• Clinicians should consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use, even in the absence of symptoms or signs associated with testosterone deficiency 1. Ideally, both total and free testosterone tests should be considered for a complete assessment, particularly when total testosterone is borderline or when symptoms of low testosterone exist despite normal total levels 1.

From the FDA Drug Label

Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about two percent is free Testosterone in plasma is 98 percent bound to a specific testosterone-estradiol binding globulin, and about 2 percent is free

The free testosterone concentration is about 2 percent of the total testosterone in plasma, while the remaining 98 percent is bound to a specific testosterone-estradiol binding globulin.

• The distribution of testosterone between free and bound forms is determined by the amount of sex-hormone binding globulin (SHBG) in the plasma.
• The free testosterone concentration determines its half-life 2, 3.

From the Research

Testosterone Free vs Total

• The difference between free and total testosterone is crucial in diagnosing testosterone deficiency 4.
• Total testosterone levels of less than 8 nmol/l highly support a diagnosis of hypogonadism, whereas levels greater than 12 nmol/l are likely to be normal 4.
• The grey zone between 8 and 12 nmol/l requires further evaluation and assessment of free or non-sex hormone-binding globulin-bound (bioavailable) testosterone 4.
• Free testosterone is the biologically active form of testosterone, and its levels can be affected by various factors, including age, obesity, and certain medical conditions 5, 6.
• The diagnosis of hypogonadism should be based on both clinical history and examination as well as biochemical assessment of serum testosterone levels, including both total and free testosterone 4.

Diagnosis and Treatment

• The clinical manifestations of testosterone deficiency occur as a result of decreased serum androgen concentrations or activity, regardless of whether there is an identified underlying etiology 6.
• Symptomatic men with total testosterone levels lower than 12 nmol/L or 350 ng/dL should be treated with testosterone therapy 6.
• A trial of testosterone therapy in symptomatic men with total testosterone levels higher than 12 nmol/L or 350 ng/dL can be considered based on clinical presentation 6.
• Testosterone replacement therapy (TRT) has been shown to improve symptoms and signs of testosterone deficiency, including decreased libido, erectile dysfunction, and depressed mood 7, 8.

Safety and Risks

• There is no compelling evidence that testosterone treatment increases the risk of developing prostate cancer or that its use is associated with prostate cancer progression 5, 6, 8.
• The weight of evidence indicates that testosterone therapy is not associated with increased cardiovascular risk 6.
• Polycythemia is a potential cardiovascular-related adverse event associated with testosterone therapy, but follow-up of controlled trials is limited to 3 years 5.
• Mild erythrocytosis can be a common side effect of TRT, but thromboembolic events have rarely been reported in the literature 8.