What is Sex Hormone-Binding Globulin (SHBG)?

What is Sex Hormone-Binding Globulin (SHBG)?

SHBG is a liver-produced glycoprotein that binds testosterone and estradiol with high affinity, regulating the amount of free (biologically active) sex hormones available to tissues. 1, 2

Primary Function and Mechanism

• SHBG acts as the major transport protein for sex steroids in blood, binding testosterone and estradiol with high specificity and reducing their free, bioavailable fractions 1, 3
• When SHBG binds testosterone, it decreases the amount of free testosterone available for biological activity, as only unbound hormone can enter cells and exert effects 1
• The pituitary gland senses free testosterone levels rather than total testosterone when regulating hormone production, meaning elevated SHBG can trigger compensatory increases in gonadotropins (FSH and LH) despite normal total testosterone 1

Site of Production

• SHBG is primarily synthesized in the liver, where its production is regulated by multiple metabolic and hormonal factors 2, 3, 4
• SHBG is also produced in the brain (hypothalamus and pituitary), where it is spatially related to oxytocin-producing neurons 4
• Recent evidence shows SHBG can be synthesized in target cells themselves, functioning as part of a novel steroid-signaling system independent of classical intracellular steroid receptors 5

Regulation of SHBG Levels

Factors That Increase SHBG:

• Aging, hyperthyroidism, hepatic disease, certain medications (anticonvulsants, estrogens, thyroid hormone), smoking, and HIV/AIDS all elevate SHBG levels 1, 3

Factors That Decrease SHBG:

• Obesity, insulin resistance, hypothyroidism, certain medications (glucocorticoids, testosterone, anabolic steroids), acromegaly, and Cushing's disease all lower SHBG levels 1, 6
• Insulin directly inhibits hepatic SHBG synthesis, making insulin resistance a powerful SHBG-lowering mechanism 6
• SHBG levels progressively decline as metabolic syndrome components accumulate in patients with type 2 diabetes 6

Clinical Significance and Disease Associations

In Polycystic Ovary Syndrome (PCOS):

• Low SHBG is characteristic of PCOS and contributes to increased free testosterone, worsening hyperandrogenic symptoms like hirsutism and acne 1, 6, 7
• Insulin resistance is the primary driver of low SHBG in PCOS patients, creating a vicious cycle of increased androgen bioavailability 6, 7
• Bariatric surgery in women with PCOS significantly improves SHBG levels along with other metabolic parameters 8

In Male Hypogonadism:

• Elevated SHBG can cause symptoms of testosterone deficiency despite normal total testosterone levels, a condition called functional hypogonadism 1
• A free testosterone index (total testosterone/SHBG ratio) <0.3 indicates hypogonadism and warrants consideration of testosterone replacement 1

In Metabolic Disease:

• Low SHBG levels negatively correlate with markers of non-alcoholic fatty liver disease (NAFLD) and insulin resistance 7
• SHBG may serve as an early biomarker for metabolic dysfunction and progression to conditions like PCOS 7

Clinical Measurement and Interpretation

• Both total and free testosterone should be measured when evaluating hypogonadism, especially when SHBG levels may be abnormal 1
• Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG, as the free hormone is what matters physiologically 1
• The free androgen index (FAI) or free testosterone index helps assess true androgen status by accounting for SHBG binding 8, 1

Common Clinical Pitfalls

• Not considering the impact of medications and medical conditions on SHBG levels can lead to incorrect interpretation of testosterone test results 1
• Failing to measure SHBG when total testosterone is borderline can miss significant androgen excess or deficiency 1
• In women with hirsutism, measuring SHBG helps identify those more likely to respond to estrogen therapy 3