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 sex hormones, particularly testosterone and estradiol, regulating their bioavailability in circulation and serving as an important biomarker in various clinical disorders. 1, 2

Structure and Function

• SHBG is a glycoprotein with high affinity for 17β-hydroxysteriod hormones, particularly testosterone and estradiol 3
• Primary functions:
  • Transport of sex steroids in plasma
  • Regulation of the distribution between protein-bound and free (bioavailable) hormone states
  • Modulation of hormone delivery to target tissues 2, 3

Synthesis and Regulation

• Primary site of synthesis: Liver 1, 2
• Additional production sites: Hypothalamus and pituitary in the brain 4
• Regulatory factors that increase SHBG levels:
  • Estrogens (including oral contraceptives)
  • Thyroid hormones
  • Aging
  • Anticonvulsants 2
• Regulatory factors that decrease SHBG levels:
  • Androgens
  • Insulin
  • Obesity
  • Certain dietary factors
  • Growth hormone 2, 5

Clinical Significance

Diagnostic Value

SHBG serves as an important biomarker in various clinical conditions:

1. Liver disease:

   • SHBG levels increase in chronic liver disease and hepatic cirrhosis in men 1
   • Levels rise with progression from compensated to decompensated cirrhosis, though they ultimately decline in advanced disease 1

2. Endocrine disorders:

   • High SHBG levels are found in:
     • Hyperthyroidism
     • Hypogonadism
     • Androgen insensitivity 3, 5
   • Low SHBG levels are found in:
     • Hypothyroidism (myxoedema)
     • Hyperprolactinemia
     • Syndromes of excessive androgen activity (including PCOS) 3, 5

3. Metabolic conditions:

   • Low levels in obesity and metabolic syndrome
   • SHBG serves as a mediator between various endocrine tissues 4

Role in Hormone Assessment

• SHBG concentration is a major factor in determining free vs. bound testosterone levels 2, 6
• Testosterone:SHBG ratios (Free Androgen Index) correlate well with both measured and calculated values of free testosterone 3
• Useful in evaluating mild disorders of androgen metabolism 3
• Helps identify women with hirsutism who are more likely to respond to estrogen therapy 3

Importance in Clinical Testing

• Measuring SHBG is essential when assessing testosterone levels, as high SHBG is the most common cause of normal total testosterone with low free testosterone 2
• In polycystic ovary syndrome (PCOS), SHBG measurement helps assess biochemical hyperandrogenism 1
• In men with advanced liver disease, SHBG levels affect the interpretation of testosterone measurements 1

Clinical Applications

• Androgen disorders: Essential for proper evaluation of hyperandrogenism and hypogonadism
• Liver disease: Helps assess hormonal changes in chronic liver disease
• Metabolic disorders: Serves as a biomarker in obesity and metabolic syndrome
• Cancer risk assessment: May have value in breast and prostate cancer evaluation 4, 5

Emerging Research

Recent findings suggest SHBG may have direct cellular effects:

• SHBG can bind to specific membrane receptors
• When unliganded SHBG binds to cell receptors and then encounters an active steroid, it can activate adenylate cyclase and increase intracellular cAMP
• This represents a potential additional mode of action for steroid hormones that doesn't require direct interaction with intracellular steroid receptors 7

SHBG's role extends beyond being a simple transport protein, with emerging evidence pointing to its importance as both a biomarker and a direct participant in cellular signaling pathways.