From the Guidelines
The main difference between total and free testosterone is that total testosterone measures all testosterone in the blood, while free testosterone measures only the unbound, biologically active portion. Total testosterone includes both bound testosterone (attached to proteins like sex hormone-binding globulin and albumin) and free testosterone, which typically represents only about 2-3% of the total. Free testosterone is the portion that can enter cells and produce effects in the body, making it a more accurate indicator of testosterone activity. When evaluating testosterone levels, both measurements provide valuable information:
- Total testosterone offers a comprehensive view of overall production,
- Free testosterone better reflects the hormone actually available to tissues. Conditions like obesity, liver disease, or thyroid disorders can affect binding proteins, causing discrepancies between total and free levels, as noted in the 2023 standards of care in diabetes 1. For this reason, doctors often measure both values when evaluating hormonal status, particularly in cases where symptoms of testosterone deficiency exist despite normal total testosterone levels, as recommended in the assessment of comorbidities in diabetes care 1. The relationship between these two measurements helps clinicians better understand hormonal balance and make appropriate treatment decisions, including the consideration of screening with a morning serum testosterone level in men with diabetes who have symptoms or signs of hypogonadism 1. In men who have total testosterone levels close to the lower limit, it is reasonable to determine free testosterone concentrations either directly from equilibrium dialysis assays or by calculations that use total testosterone, sex hormone binding globulin, and albumin concentrations, as suggested in the 2023 standards of care in 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. Circulating testosterone is primarily bound in the serum to sex hormone-binding globulin (SHBG) and albumin. Approximately 40% of testosterone in plasma is bound to SHBG, 2% remains unbound (free) and the rest is loosely bound to albumin and other proteins
The main difference between total and free testosterone is the way they are bound in the blood.
- Total testosterone refers to the overall amount of testosterone in the blood, including both bound and free testosterone.
- Free testosterone refers to the amount of testosterone that is not bound to any proteins in the blood, which is about 2% of the total testosterone. The majority of testosterone is bound to proteins such as sex hormone-binding globulin (SHBG) and albumin 2, 3.
From the Research
Difference between Total and Free Testosterone
- Total testosterone refers to the total amount of testosterone present in the blood, including both bound and free testosterone [ 4 ].
- Free testosterone, on the other hand, refers to the amount of testosterone that is not bound to proteins in the blood and is available to enter cells and exert its effects [ 4 ].
Measurement of Total and Free Testosterone
- Accurate measurement of total and free testosterone is essential for making the diagnosis of androgen disorders [ 4 ].
- Total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry [ 4 ].
- Free testosterone levels should be measured in men in whom alterations in binding protein concentrations are suspected or in whom total testosterone levels are only slightly above or slightly below the lower limit of the normal male range for testosterone [ 4 ].
Relationship between SHBG and Testosterone
- The level of sex hormone-binding globulin (SHBG) is highly positively correlated with the total testosterone level in untreated men presenting for evaluation of adult onset hypogonadism [ 5 ].
- However, no relationship was found between the level of SHBG and total testosterone among men who were being treated with a transdermal testosterone preparation [ 5 ].
Clinical Implications
- The diagnosis and management of adult onset male hypogonadism are controversial, and the treatment of male hypogonadism can no longer be downgraded and must become part of the cultural baggage of the endocrinologist [ 6 ].
- Testosterone replacement therapy can restore normal serum testosterone concentrations and relieve symptoms in most hypogonadal men [ 7 ].