From the Guidelines
Total testosterone is the preferred measurement for diagnosing and managing testosterone deficiency, as it is the most widely available and standardized test. When evaluating testosterone levels, it is essential to consider the clinical context and symptoms presented by the patient. Total testosterone measures all testosterone in the blood, including that bound to proteins, and is the primary test used for diagnosis and monitoring of testosterone therapy 1. The goal of testosterone therapy is to achieve a total testosterone level in the middle tertile of the normal reference range, which is typically between 450-600 ng/dL 1. Some may argue that free testosterone is more accurate for assessing testosterone activity, as it measures the unbound, biologically active hormone. However, total testosterone is still the most widely used and accepted test for diagnosing and managing testosterone deficiency. Key points to consider when evaluating testosterone levels include:
- Total testosterone levels should be measured on two separate occasions, in the early morning, to confirm the diagnosis of low testosterone 1
- The diagnosis of testosterone deficiency requires both a low testosterone measurement and the presence of symptoms and/or signs 1
- Clinicians should consider measuring total testosterone in patients with a history of certain medical conditions, such as unexplained anemia, bone density loss, or diabetes, even in the absence of symptoms or signs associated with testosterone deficiency 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 correct answer is total testosterone, as the drug label discusses the levels of testosterone in the blood, including both bound and unbound (free) testosterone, but the primary focus is on the total testosterone concentration, which includes both free and bound testosterone 2.
From the Research
Testosterone Measurement
- Total testosterone and free testosterone are two different measures of testosterone levels in the body 3, 4, 5, 6, 7
- Total testosterone refers to the total amount of testosterone present in the blood, including both bound and unbound testosterone 3, 7
- 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, 5, 7
Comparison of Total and Free Testosterone
- Studies have shown that free testosterone levels are increased disproportionately during testosterone treatment, as the proportion of unbound testosterone is increased by all three treatments (intramuscular injection, oral testosterone undecanoate, and subcutaneous testosterone pellets) 3
- The predicted changes in free testosterone fraction during testosterone replacement therapy exhibited a non-linear relationship with changes in each of total testosterone, dihydrotestosterone, and estradiol concentrations 4
- Age was a strong predictor of LH suppression during testosterone replacement, and the effect could not be explained by obesity, SHBG, or higher levels of total or non-SHBG testosterone or estradiol during treatment 5
Clinical Significance
- Accurate measurement of total and free testosterone is essential for making the diagnosis of androgen disorders 7
- Total testosterone should ideally be measured in a fasting state in the morning using a reliable assay, such as liquid chromatography tandem mass spectrometry, in a laboratory that is certified by an accuracy-based benchmark 7
- 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 7
Relationship between SHBG and Testosterone
- The level of SHBG was highly positively correlated with the total testosterone level in untreated men presenting for evaluation of AOH, but no relationship was found between the level of SHBG and total testosterone among men who were being treated with a transdermal testosterone preparation 6
- The level of SHBG was inversely proportional to BMI in both the untreated and the testosterone-treated men 6