From the Guidelines
The difference between free and total testosterone is that free testosterone is the unbound, biologically active form that can interact with cells, while total testosterone includes both free testosterone and testosterone bound to proteins in the blood. Approximately 98% of testosterone in the bloodstream is bound, with about 65-80% bound to sex hormone-binding globulin (SHBG) and 20-30% bound to albumin, as noted in the context of evaluating hypogonadism in men with diabetes 1. Only about 1-2% of testosterone circulates as free testosterone. This distinction is clinically important because only free testosterone is immediately available to target tissues and exerts biological effects. When measuring testosterone levels, total testosterone is commonly tested first, but free testosterone measurement may provide more useful information in certain conditions where binding proteins are abnormal, such as obesity, liver disease, or thyroid disorders, as suggested by guidelines for the assessment of comorbidities in diabetes 1. The binding of testosterone to proteins serves to regulate hormone availability and extend its half-life in circulation, creating a reservoir of hormone that can be released as needed. Key points to consider in the evaluation of testosterone levels include:
- The importance of measuring total testosterone in the morning using an accurate and reliable assay in men with symptoms or signs of hypogonadism 1.
- The consideration of free testosterone levels, especially in men with total testosterone levels close to the lower limit, due to the potential impact of diabetes on sex hormone-binding globulin levels 1.
- The potential benefits of testosterone replacement in men with symptomatic hypogonadism, including improved sexual function, well-being, muscle mass and strength, and bone density, while also considering the potential risks and the need for further evaluation with tests such as luteinizing hormone and follicle-stimulating hormone levels 1.
From the FDA Drug Label
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 difference between free and total testosterone is that free testosterone refers to the 2% of testosterone that remains unbound in the plasma, while total testosterone refers to the overall amount of testosterone in the plasma, including the portions bound to SHBG, albumin, and other proteins.
- Approximately 40% of testosterone is bound to SHBG.
- Approximately 2% of testosterone remains unbound (free).
- The rest is loosely bound to albumin and other proteins. 2
From the Research
Difference between Free and Total Testosterone
- Free testosterone refers to the amount of testosterone that is not bound to any proteins in the blood, and is considered the metabolically active fraction 3.
- Total testosterone, on the other hand, refers to the total amount of testosterone in the blood, including both free and bound testosterone.
Percentage of Testosterone Bound
- Most testosterone circulates tightly bound to sex hormone-binding globulin (SHBG) or weakly bound to albumin, with only a minor amount circulating as free testosterone 3.
- The proportion of unbound testosterone can be increased by certain treatments, such as testosterone replacement therapy 4.
- It is estimated that approximately 60-70% of testosterone is bound to SHBG, 30-40% is bound to albumin, and only 1-2% is free 5.
Clinical Utility of Measuring Free and Total Testosterone
- 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.
- Total testosterone levels can be used to diagnose hypogonadism, but may not accurately reflect the amount of biologically active testosterone 6, 5.
- Calculated free testosterone (cFT) can be used as an alternative to direct measurement of free testosterone, and may be more accurate in certain cases 5.