What is sex hormone binding globulin (SHBG)?

What is Sex Hormone-Binding Globulin (SHBG)?

Sex hormone-binding globulin (SHBG) is a liver-synthesized glycoprotein that binds and transports sex steroids—primarily testosterone and estradiol—in the bloodstream, thereby regulating the amount of free (biologically active) hormone available to tissues. 1, 2

Primary Function and Clinical Significance

• SHBG binds testosterone and estradiol with high affinity, reducing the fraction of these hormones that circulate in the free, bioavailable form 3, 2
• Free testosterone is a better indicator of true gonadal status than total testosterone, particularly when SHBG levels are abnormal, because only the unbound hormone can enter cells and exert biological effects 1
• The liver is the primary site of SHBG production, though it has also been identified in the brain (hypothalamus and pituitary) 4

How SHBG Affects Hormone Availability

• When SHBG levels increase, a greater proportion of total testosterone becomes bound, decreasing the free and bioavailable testosterone fractions 3
• The pituitary gland primarily senses free testosterone levels rather than total testosterone when regulating the hypothalamic-pituitary-gonadal axis 3
• This means elevated SHBG can cause symptoms of testosterone deficiency despite normal total testosterone levels, because the free fraction is reduced 3
• Testosterone occupies most SHBG binding sites in men, while estradiol binding is much lower in all subjects 5

Factors That Increase SHBG Levels

• Aging, hyperthyroidism, hepatic disease/liver cirrhosis, certain medications (anticonvulsants, estrogens, thyroid hormone), smoking, and HIV/AIDS all increase SHBG levels 1, 3
• These conditions can lead to functional hypogonadism by reducing free testosterone despite normal or even elevated total testosterone 3

Factors That Decrease SHBG Levels

• Obesity (particularly central/abdominal obesity), insulin resistance, hypothyroidism, high-dose glucocorticoids, growth hormone, testosterone, anabolic steroids, acromegaly, and Cushing's disease all decrease SHBG levels 1, 3
• Polycystic ovary syndrome (PCOS) is strongly associated with low SHBG levels, and lower SHBG is a significant risk marker for PCOS 1, 6
• In PCOS, low SHBG contributes to increased free testosterone, worsening hyperandrogenic symptoms 7, 6

Clinical Assessment and Interpretation

• Measure morning total testosterone along with either free testosterone (by equilibrium dialysis) or calculate the free androgen index (total testosterone divided by SHBG) to accurately assess androgen status 7, 1
• A free testosterone index (total testosterone/SHBG ratio) less than 0.3 indicates hypogonadism 1, 3
• Free testosterone assays using analog methods available at most local laboratories have limited reliability and should be avoided 7
• Both total and free testosterone should be measured when evaluating hypogonadism, especially when SHBG levels may be abnormal due to medications, liver disease, thyroid disorders, or metabolic conditions 1, 3

SHBG as a Disease Biomarker

• SHBG levels are altered in multiple disease states including hyper- and hypoandrogenism, thyroid disorders, pituitary diseases, liver disorders, metabolic syndrome, and breast/prostate cancer 4, 8
• In PCOS, SHBG levels in controls are significantly higher than in PCOS patients, making it a useful biomarker for diagnosis and treatment monitoring 6
• SHBG measurement is particularly useful in evaluating mild disorders of androgen metabolism and identifying women with hirsutism who are more likely to respond to estrogen therapy 2
• The testosterone:SHBG ratio correlates well with measured and calculated free testosterone values and helps discriminate subjects with excessive androgen activity from normal individuals 2

Common Clinical Pitfalls

• Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG, where patients have symptoms despite "normal" total testosterone 3
• Not considering the impact of medications (anticonvulsants, estrogens, glucocorticoids, thyroid hormone) and medical conditions (liver disease, thyroid disorders, obesity) on SHBG levels can lead to incorrect interpretation of testosterone results 1, 3
• Direct immunoassay methods for free testosterone are highly inaccurate due to low serum concentrations and should not be used 7