What is Sex Hormone-Binding Globulin (SHBG)?

Sex Hormone-Binding Globulin (SHBG): Function and Clinical Significance

Sex hormone-binding globulin (SHBG) is a glycoprotein primarily synthesized in the liver that binds to and transports sex steroids such as testosterone and estradiol in the bloodstream, regulating their bioavailability to target tissues. 1

Structure and Production

• SHBG is a glycoprotein with high affinity for 17β-hydroxysteriod hormones, particularly testosterone and estradiol 2
• Primary site of synthesis is the liver, although research has shown it can also be produced in target tissues 3
• Plasma concentrations are regulated by multiple factors:
  • Androgen/estrogen balance
  • Thyroid hormones
  • Insulin
  • Dietary factors
  • Metabolic state

Physiological Functions

Primary Functions

• Transport of sex steroids in plasma
• Regulation of free vs. bound hormone distribution
• Major determinant of biologically active (free) hormone levels

Regulatory Mechanisms

• SHBG binds approximately 44-65% of circulating testosterone and 20-40% of circulating estradiol
• Only unbound (free) hormones can enter cells and exert biological effects
• SHBG possesses a specific receptor that can bind to cell membranes, suggesting a more complex role beyond simple transport 4

Factors Affecting SHBG Levels

Conditions That Increase SHBG

• Liver disease/cirrhosis 1, 5
• Hyperthyroidism
• Hypogonadism
• Androgen insensitivity
• Low BMI/malnutrition 5
• Estrogen therapy

Conditions That Decrease SHBG

• Obesity 5
• Metabolic syndrome
• Polycystic ovary syndrome (PCOS) 1
• Hypothyroidism
• Hyperprolactinemia
• Excess androgen activity
• Insulin resistance 1

Clinical Significance

Diagnostic Applications

• Assessment of androgen status:
  • In hirsutism and PCOS, low SHBG contributes to increased free testosterone despite potentially normal total testosterone levels 1
  • In liver disease, elevated SHBG can mask hypogonadism by elevating total testosterone while free testosterone remains low 1

SHBG as a Biomarker

• Low SHBG levels are associated with:
  • Insulin resistance
  • Type 2 diabetes risk
  • Cardiovascular disease risk 6
  • Metabolic syndrome 1

SHBG in PCOS

• Women with PCOS typically have lower SHBG levels 1
• Reduced SHBG contributes to higher free androgen index (FAI) and clinical hyperandrogenism
• SHBG measurement helps identify women with hirsutism who may respond better to estrogen therapy 2

SHBG in Liver Disease

• In advanced liver disease, SHBG synthesis initially increases, leading to higher bound testosterone and lower free testosterone 1
• With progression to decompensated cirrhosis, SHBG levels may ultimately decline 1
• The testosterone:SHBG ratio (<0.3) can indicate hypogonadism despite normal total testosterone levels 5

Laboratory Assessment

• Morning measurement (8-10 AM) is recommended due to diurnal variation 5
• Calculation of free testosterone using total testosterone and SHBG is more reliable than direct free testosterone assays 5
• Testosterone:SHBG ratio correlates well with both measured and calculated values of free testosterone 2
• When interpreting testosterone levels, SHBG should be considered to accurately assess androgen status 5

Clinical Applications

• Evaluation of mild disorders of androgen metabolism
• Assessment of true androgen status in conditions affecting SHBG (obesity, liver disease)
• Risk stratification for metabolic disorders
• Monitoring response to hormone therapy

In conclusion, SHBG is far more than just a transport protein—it plays a crucial role in regulating hormone bioavailability and serves as an important biomarker for various endocrine and metabolic conditions.