From the Guidelines
The testosterone to free testosterone ratio is approximately 100:1 to 200:1 in healthy adult males. This ratio is crucial in understanding the biologically active portion of testosterone that is available to bind to receptors in tissues, as opposed to the total testosterone level which includes both bound and free testosterone 1. The majority of testosterone in the bloodstream is bound to proteins like sex hormone-binding globulin (SHBG) and albumin, limiting its bioavailability.
Key Factors Influencing the Ratio
- Aging: can decrease the ratio due to increased SHBG levels
- Obesity: can decrease the ratio due to increased aromatization of testosterone to estrogen
- Liver disease: can affect the production of SHBG and albumin, thereby altering the ratio
- Thyroid disorders: can influence the production of SHBG, affecting the ratio
- Certain medications: can alter the levels of SHBG, albumin, or testosterone itself, changing the ratio When evaluating testosterone status, both total and free testosterone measurements are valuable as they provide complementary information - total testosterone gives an overall picture of production, while free testosterone indicates how much is actually available for biological activity 1. Abnormal ratios may suggest underlying health conditions even when total testosterone levels appear normal.
Clinical Implications
- Monitoring the testosterone to free testosterone ratio can help in the early detection of hypogonadism or other conditions affecting testosterone levels
- Adjusting the ratio through treatment, such as testosterone replacement therapy, can improve symptoms and quality of life in individuals with hypogonadism 1
- Understanding the factors that influence the ratio can guide clinicians in making informed decisions about patient care and management.
From the FDA Drug Label
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 testosterone to free testosterone ratio is approximately 50:1 or 40:1.8 (considering 2% of testosterone is free), as about 2% of testosterone remains unbound (free) and around 40% is bound to SHBG, with the rest bound to other proteins. 2
From the Research
Testosterone to Free Testosterone Ratio
- The ratio of testosterone to free testosterone is approximately 98:2, with about 2% of total testosterone being free testosterone 3.
- Most of the circulating testosterone is bound to albumin and sex hormone-binding globulin (SHBG), whereas free testosterone accounts for a small fraction of total testosterone 3, 4.
- The free testosterone concentration can be calculated using various equations, including the Sodergard, Nanjee-Wheeler, Vermeulen, and Ly-Handelsman equations, which can provide clinically useful estimates of free testosterone concentration 3.
- However, these equations have limitations and can yield varying results, with mean biases ranging from 5.8 to 56.0% 3.
- 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.
Measurement of Free 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 4.
- Various 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 4.
- However, these methods have limitations, and there is a need for better equations to improve accuracy and harmonization of T and SHBG assays between laboratories 5.