From the Guidelines
When evaluating testosterone levels, measuring free or bioavailable testosterone provides more useful information than total testosterone alone, particularly in conditions where binding proteins may be altered, such as obesity, liver disease, or thyroid disorders. Testosterone in the blood exists in three forms: free, bioavailable, and bound to proteins. Free testosterone (1-2% of total) is unbound and immediately available for cellular action 1. Bioavailable testosterone includes both free testosterone and testosterone loosely bound to albumin (approximately 35-50% of total), which can become available to tissues. The remainder is tightly bound to sex hormone-binding globulin (SHBG) and is not readily available for use.
Some key points to consider when evaluating testosterone status clinically include:
- Measuring free or bioavailable testosterone is essential, especially in patients with conditions that alter binding proteins, such as obesity, as it provides more accurate information about the amount of testosterone available to tissues 1.
- Free testosterone is the most biologically active form and directly correlates with clinical symptoms of testosterone deficiency or excess.
- Albumin-bound testosterone, while not immediately active, can dissociate relatively easily and become available to tissues.
- Calculating free testosterone using total testosterone and SHBG measurements is often more practical and cost-effective than direct measurement of free testosterone, which requires specialized techniques 2.
In clinical practice, the diagnosis of testosterone deficiency requires both a low testosterone measurement as well as the presence of select symptoms and/or signs, with a total testosterone level below 300 ng/dL considered a reasonable cut-off in support of the diagnosis of low testosterone 2. The use of morning serum free testosterone measurement is essential in evaluating low total testosterone clinically in men with obesity. Additionally, clinicians should consider measuring total testosterone in patients with a history of unexplained anemia, bone density loss, diabetes, exposure to chemotherapy, exposure to testicular radiation, HIV/AIDS, chronic narcotic use, male infertility, pituitary dysfunction, and chronic corticosteroid use, even in the absence of symptoms or signs associated with testosterone deficiency 2.
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 main difference between testosterone free, bioavailable, and albumin-bound is the way testosterone is bound in the blood.
- Free testosterone is the 2% of testosterone that remains unbound in the plasma.
- Bioavailable testosterone refers to the fraction of testosterone that is available to bind to androgen receptors, which includes free testosterone and testosterone loosely bound to albumin.
- Albumin-bound testosterone is the fraction of testosterone that is loosely bound to albumin, which is the rest of the testosterone after subtracting the free and SHBG-bound fractions. 3
From the Research
Testosterone Levels and Replacement Therapy
- Testosterone levels decrease as men age, and a serum total testosterone level of less than 300 to 350 ng/dL on two separate morning blood samples is considered a low level 4.
- Testosterone replacement therapy (TRT) is used to improve symptoms and signs of testosterone deficiency, including decreased libido, erectile dysfunction, and loss of muscle and bone mass 5.
- The aim of TRT is to increase serum testosterone levels to the physiologic range, and numerous preparations and formulations have been developed to improve pharmacokinetics and patient compliance 5.
Forms of Testosterone
- There are different forms of testosterone, including free testosterone, bioavailable testosterone, and testosterone bound to albumin 6.
- Free testosterone is the fraction of testosterone that is not bound to proteins in the blood and is available to enter cells and exert its effects 6.
- Bioavailable testosterone refers to the fraction of testosterone that is available to enter cells, including both free testosterone and testosterone bound to albumin 6.
- Testosterone bound to albumin is the largest fraction of testosterone in the blood, but it is not available to enter cells and exert its effects 6.
Testosterone Replacement Therapy Formulations
- Various testosterone formulations are available, including topical gels, intramuscular injections, buccal, nasal, subdermal, and transdermal preparations 4, 7, 5.
- The choice of formulation depends on factors such as cost, patient preference, and individual patient needs 4, 7, 5.
- Long-acting injectable formulations, such as undecanoate testosterone, can improve patient compliance and provide stable testosterone levels 7.
Monitoring and Safety of Testosterone Replacement Therapy
- Patients receiving TRT require close monitoring to minimize the risks and maximize the benefits of therapy 4, 5, 6.
- The safety of long-term TRT in late-onset hypogonadism is not well established, and clinicians must consider the unique characteristics of each patient and make necessary adjustments in management 5.
- Potential risks of TRT include stimulation of prostate cancer, worsening symptoms of benign prostatic hypertrophy, liver toxicity, hyperviscosity, erythrocytosis, and worsening untreated sleep apnea or severe heart failure 6.