What does Sex Hormone-Binding Globulin (SHBG) indicate about a person's health?

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

Sex hormone-binding globulin (SHBG) is a critical biomarker that provides valuable insights into hormonal balance, liver function, and metabolic health, serving as an important diagnostic tool for various endocrine and metabolic disorders.

What is SHBG?

SHBG is a glycoprotein primarily synthesized in the liver that binds to sex hormones, particularly testosterone and estradiol, with high affinity. Its main functions include:

• Regulating the bioavailability of sex steroid hormones in circulation
• Transporting sex hormones in plasma
• Determining the distribution between protein-bound (inactive) and free (active) hormone states

Clinical Significance of SHBG Levels

Liver Function

• SHBG is produced in the liver, making it a marker of hepatic synthetic function 1
• Levels rise in chronic liver disease, particularly in compensated cirrhosis
• With progression to decompensated cirrhosis, SHBG levels ultimately decline 1

Hormonal Status Assessment

• Low SHBG increases free testosterone, even when total testosterone is normal
• High SHBG decreases bioavailable testosterone, even when total testosterone appears adequate
• SHBG measurement helps calculate free androgen index (FAI), which correlates well with both measured and calculated values of free testosterone 2

Metabolic Health

• SHBG has an inverse association with:
  • Insulin resistance
  • Obesity
  • Metabolic syndrome
  • Type 2 diabetes 3

SHBG in Specific Conditions

Polycystic Ovary Syndrome (PCOS)

• Consistently lower SHBG levels are found in women with PCOS compared to controls 3
• Low SHBG is considered a biomarker for metabolic abnormalities in PCOS 4
• SHBG gene polymorphism is associated with PCOS risk 4
• Testosterone:SHBG ratio helps discriminate subjects with excessive androgen activity 2

Functional Hypothalamic Amenorrhea (FHA)

• Higher SHBG levels are typically seen in FHA compared to PCOS patients 1
• FHA patients often have low insulin levels and normal insulin sensitivity, which increases SHBG production 1

Liver Disease

• In men with advanced liver disease, SHBG rises while free testosterone declines 1
• SHBG synthesis is stimulated by estrogens, which are elevated in liver disease due to:
  • Increased peripheral conversion of androgens to estrogen
  • Portosystemic shunting 1
• High SHBG levels are found in hepatic cirrhosis in men 2

Other Conditions with Altered SHBG Levels

• High SHBG conditions:

  • Hyperthyroidism
  • Hypogonadism
  • Androgen insensitivity 2

• Low SHBG conditions:

  • Hypothyroidism (myxoedema)
  • Hyperprolactinemia
  • Syndromes of excessive androgen activity 2

Factors That Regulate SHBG Levels

Hormonal Factors

• Estrogens increase SHBG levels
• Androgens decrease SHBG levels
• Thyroid hormones increase SHBG levels 2

Metabolic Factors

• Insulin decreases SHBG production 5
• Obesity is associated with lower SHBG levels 5
• Caloric intake and energy balance affect SHBG regulation 5

Medications That Affect SHBG

• Increase SHBG:

  • Estrogens
  • Thyroid hormones
  • Oral contraceptives 2

• Decrease SHBG:

  • Androgens
  • Glucocorticoids 2

Clinical Applications of SHBG Measurement

Diagnostic Value

• Useful in evaluating mild disorders of androgen metabolism 2
• Helps identify women with hirsutism who are more likely to respond to estrogen therapy 2
• Serves as a marker for insulin resistance and metabolic syndrome 3

Treatment Monitoring

• SHBG levels can be used to monitor response to treatments in PCOS:
  • Metformin
  • GLP-1 receptor agonists
  • Oral contraceptives 4

Interpretation Considerations

Gender and Hormone Therapy

• For transgender individuals on gender-affirming hormone therapy (GAHT) for more than 1 year, SHBG should be interpreted based on their affirmed gender 1
• For those newly initiated on hormone therapy (<1 year), values may change over time 1
• For those who have stopped GAHT, within 3 months, laboratory values typically reflect their sex assigned at birth 1

Common Pitfalls in SHBG Interpretation

• Failure to consider the effect of medications (especially hormonal therapies)
• Not accounting for liver function when interpreting SHBG levels
• Overlooking the relationship between SHBG and insulin resistance
• Interpreting total testosterone without considering SHBG levels

Clinical Algorithm for SHBG Interpretation

1. Measure SHBG along with total testosterone when evaluating:

   • Suspected hyperandrogenism
   • Menstrual irregularities
   • Hirsutism
   • Infertility
   • Metabolic syndrome

2. Calculate free androgen index (FAI = Total testosterone × 100/SHBG)

3. Interpret based on clinical context:

   • Low SHBG + normal/high testosterone: Suspect PCOS, insulin resistance, or obesity
   • High SHBG + normal/low testosterone: Consider liver disease, hyperthyroidism, or estrogen effect
   • Normal SHBG + high testosterone: Look for androgen-secreting tumors
   • Normal SHBG + low testosterone: Consider primary hypogonadism

4. Follow up with appropriate testing based on SHBG findings:

   • Insulin resistance evaluation if SHBG is low
   • Liver function tests if SHBG is high
   • Thyroid function tests if SHBG is abnormal

By understanding the complex role of SHBG in hormonal regulation and its relationship with various clinical conditions, clinicians can better utilize this biomarker for diagnosis, treatment selection, and monitoring of endocrine and metabolic disorders.