What is the significance of low free testosterone (42.5 pg/mL) and bioavailable testosterone (89.2 ng/dL) with normal Sex Hormone-Binding Globulin (SHBG) (27 nmol/L) and albumin (4.6 g/dL) in a patient with total testosterone of 289 ng/dL?

From the Guidelines

The patient's low free testosterone and bioavailable testosterone levels, despite normal SHBG and albumin levels, suggest hypogonadism, and testosterone replacement therapy (TRT) may be considered to improve symptoms, particularly sexual dysfunction, as suggested by the American College of Physicians guideline 1. The total testosterone level of 289 ng/dL is below the typical reference range for adult males, and the low free testosterone (42.5 pg/mL) and bioavailable testosterone (89.2 ng/dL) levels indicate a potential need for TRT.

• The normal SHBG (27 nmol/L) and albumin (4.6 g/dL) levels suggest that the issue is not with testosterone binding proteins, but rather with testosterone production.
• The American College of Physicians guideline recommends considering intramuscular rather than transdermal formulations when initiating testosterone treatment to improve sexual function in men with age-related low testosterone, as costs are considerably lower for the intramuscular formulation and clinical effectiveness and harms are similar 1.
• Treatment should be individualized, and patients should be monitored for potential side effects, such as polycythemia, acne, fluid retention, and potential prostate issues.
• Further evaluation of the pituitary-gonadal axis with LH and FSH testing would help determine if this is primary or secondary hypogonadism to guide additional treatment approaches.
• The ACP suggests that clinicians should reevaluate symptoms within 12 months and periodically thereafter, and discontinue testosterone treatment in men with age-related low testosterone with sexual dysfunction in whom there is no improvement in sexual function 1.

From the FDA Drug Label

Male hypogonadism, a clinical syndrome resulting from insufficient secretion of testosterone, has two main etiologies. Primary hypogonadism is caused by defects of the gonads, such as Klinefelter's syndrome or Leydig cell aplasia, whereas secondary hypogonadism is the failure of the hypothalamus (or pituitary) to produce sufficient gonadotropins (FSH, LH).

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 patient's low free testosterone (42.5 pg/mL) and bioavailable testosterone (89.2 ng/dL) despite normal SHBG (27 nmol/L) and albumin (4.6 g/dL) levels, with a total testosterone of 289 ng/dL, may indicate hypogonadism. The exact cause of the low testosterone levels cannot be determined from the provided information. Further evaluation, including assessment of gonadotropin levels, is necessary to determine the underlying etiology of the patient's condition 2.

From the Research

Testosterone Levels and Binding Proteins

• The user's total testosterone level is 289 ng/dL, which is within the normal range, but the free testosterone (42.5 pg/mL) and bioavailable testosterone (89.2 ng/dL) levels are low 3.
• The sex hormone-binding globulin (SHBG) level is 27 nmol/L, and the albumin level is 4.6 g/dL, both of which are within the normal range.
• According to a study published in 1983, the distribution of testosterone in plasma proteins can affect the levels of free testosterone, and albumin can take over the surplus of testosterone when SHBG is saturated 4.

Relationship Between Testosterone and SHBG

• A study published in 2020 found that baseline SHBG and age can identify clinical subgroups that respond differently to testosterone replacement therapy (TRT) 5.
• The study suggested that men with lower SHBG levels and younger age may respond better to TRT, while those with higher SHBG levels and older age may not benefit as much from the therapy.
• Another study published in 2008 found that low SHBG and testosterone levels were associated with erectile dysfunction in human immunodeficiency virus-infected men receiving testosterone and oxandrolone 6.

Clinical Significance of Free Testosterone

• The free hormone hypothesis suggests that the biological activity of a hormone is best reflected by its free concentration rather than its total concentration 3.
• A study published in 2022 emphasized the relevance of free testosterone in androgen physiology and suggested that calculated free testosterone can be a useful diagnostic tool for male hypogonadism 3.
• The study also highlighted the importance of considering free testosterone in the diagnosis of male hypogonadism, particularly in cases where total testosterone levels are borderline low or SHBG levels are altered 3.