From the Guidelines
Both free and total testosterone measurements are crucial, but total testosterone is typically measured first as a screening test for testosterone deficiency, and free testosterone is more biologically active and provides better insight into the hormone's actual availability to tissues. When evaluating testosterone levels, it is essential to consider both total and free testosterone, as they serve different purposes. Total testosterone represents all testosterone in the blood, including bound and unbound forms, while free testosterone, which is the unbound portion (about 2-3% of total testosterone), is more biologically active and provides better insight into the hormone's actual availability to tissues.
Key Points to Consider
- Total testosterone is typically measured first as a screening test for testosterone deficiency.
- Free testosterone testing is particularly valuable when total testosterone results are borderline or when conditions exist that affect sex hormone binding globulin (SHBG) levels, such as obesity, liver disease, or thyroid disorders.
- The interpretation of these values should always be done in the context of symptoms and clinical presentation, as normal ranges vary by age and laboratory.
- Both measurements together provide the most comprehensive assessment of testosterone status, especially when evaluating conditions like hypogonadism or monitoring hormone replacement therapy.
Clinical Practice Recommendations
According to the American Urological Association guideline 1, clinicians should adjust testosterone therapy dosing to achieve a total testosterone level in the middle tertile of the normal reference range. The goal of testosterone therapy is the normalization of total testosterone levels combined with improvement in symptoms or signs. In clinical practice, doctors often start with total testosterone and then measure free testosterone if needed for clarification, as recommended by the American College of Physicians 1. However, the most recent and highest quality study, the American Urological Association guideline 1, provides the most up-to-date recommendations for the evaluation and management of testosterone deficiency. Therefore, total testosterone should be measured first, and free testosterone should be measured when total testosterone results are borderline or when conditions exist that affect SHBG levels.
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 Generally, the amount of this sex-hormone binding globulin (SHBG) in the plasma will determine the distribution of testosterone between free and bound forms, and the free testosterone concentration will determine its half-life In responsive tissues, the activity of testosterone appears to depend on reduction to dihydrotestosterone (DHT), which binds to cytosol receptor proteins The steroid-receptor complex is transported to the nucleus where it initiates transcription events and cellular changes related to androgen action.
Free testosterone is needed for the activity of testosterone to depend on reduction to dihydrotestosterone (DHT), which binds to cytosol receptor proteins.
- The free testosterone concentration will determine its half-life.
- Total testosterone levels are not directly relevant to the activity of testosterone, as 98% of testosterone is bound to sex-hormone binding globulin (SHBG) and only about 2% is free 2. However, the amount of SHBG will determine the distribution of testosterone between free and bound forms 3.
From the Research
Testosterone Measurement
- Total testosterone and free testosterone are two different measures of testosterone in the body 4, 5, 6, 7
- Free testosterone is the metabolically active fraction of testosterone, and its measurement is important in the diagnosis of androgen deficiency in men and androgen excess in women 7
- 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 5, 6, 7
Clinical Utility of Free Testosterone
- Measurement of free testosterone is useful in the diagnosis of hypogonadism in men and polycystic ovary syndrome and hirsutism in women 7
- Calculated free testosterone (CFT) can be used as an alternative to direct measurement of free testosterone, but its accuracy can vary depending on the equation used 5, 6
- The free androgen index is not recommended for use in men due to inaccuracy at extremes of SHBG concentration, and can also give inaccurate results in women with low SHBG concentrations 6
Analytical Aspects of Measurement
- Equilibrium dialysis and ultrafiltration are reference methods for measuring free testosterone, but are not practical for routine clinical use 7
- Analog immunoassay and calculated free testosterone based on measurement of total testosterone, SHBG, and albumin are alternative methods for measuring free testosterone 7
- Liquid chromatography-tandem mass spectrometry is a new methodology for measuring free testosterone that may offer improved accuracy and precision 7
Testosterone Replacement Therapy
- Testosterone replacement therapy (TRT) can decrease serum gonadotropins and intratesticular testosterone, and impair spermatogenesis 8
- Concomitant administration of low-dose human chorionic gonadotropin (hCG) with TRT may help preserve spermatogenesis and fertility in hypogonadal men 8
- Monitoring of serum testosterone levels, including free testosterone, is important during TRT to ensure adequate treatment and minimize side effects 4, 8