Genetic Factors Affecting SHBG Levels
Genetic factors can cause SHBG levels to vary widely, with studies showing up to 20-fold differences between individuals, though there is no established upper limit specifically attributed to genetics alone.
Genetic Determinants of SHBG Levels
Genetic variations in the SHBG gene significantly influence circulating SHBG concentrations:
SHBG Gene Polymorphisms: Two main polymorphisms have been identified that affect SHBG levels:
Impact of Specific Genetic Variants:
- Carriers of the Asn327 allele show 14-20% higher SHBG levels compared to non-carriers 1, 3
- Carriers of six TAAAA-repeats demonstrate 19-26% higher SHBG levels across different age groups 3
- Homozygous carriers of six repeats show significantly higher SHBG levels (34.9 nmol/L) compared to nine-repeat homozygotes (21.5 nmol/L) 1
Clinical Range and Variability
Observed Range: Clinical data shows SHBG concentrations ranging from 6-109 nmol/L in men, representing nearly a 20-fold difference between lowest and highest values 4
Age-Related Differences:
- Younger men (≤54 years): Mean SHBG 27.7±13.3 nmol/L (range 6-88 nmol/L)
- Older men (≥55 years): Mean SHBG 36.6±15.8 nmol/L (range 11-109 nmol/L) 4
Non-Genetic Factors That Modify SHBG Levels
When evaluating elevated SHBG, consider these common non-genetic factors:
Factors that increase SHBG levels:
- Advanced age
- Smoking
- Hyperthyroidism
- Hepatic disease
- HIV/AIDS
- Medications (estrogens, anticonvulsants, thyroid hormones) 5
Factors that decrease SHBG levels:
- Obesity
- Insulin resistance
- Metabolic syndrome
- Polycystic ovary syndrome
- Cushing syndrome
- Medications (growth hormone, glucocorticoids, testosterone, anabolic steroids) 5
Clinical Implications
Diagnostic Considerations: When encountering unusually high SHBG levels:
- Rule out non-genetic causes first (especially medications, thyroid dysfunction, liver disease)
- Consider genetic testing for SHBG gene polymorphisms in cases with unexplained elevations
- Assess impact on free hormone levels, as high SHBG binds more testosterone, potentially contributing to symptoms of hypogonadism 5
Clinical Assessment:
- Measure both total and free testosterone levels to assess the impact on androgen status
- Screen for thyroid dysfunction
- Evaluate liver function
- Review medication history 5
The wide variability in SHBG levels due to genetic factors should be considered when interpreting hormone test results, particularly for testosterone and other sex hormones that bind to SHBG, as the portion bound to SHBG is generally considered biologically unavailable.