What are the levels of Sex Hormone-Binding Globulin (SHBG) in men with genetic polymorphism?

Sex Hormone-Binding Globulin (SHBG) Levels in Men with Genetic Polymorphisms

Normal and Elevated SHBG Levels Due to Genetic Factors

Men with genetic polymorphisms in the SHBG gene can have significantly elevated SHBG levels, with values potentially 20-26% higher than non-carriers, which impacts testosterone bioavailability and clinical interpretation of hormone testing. 1

Genetic Polymorphisms Affecting SHBG Levels

• The (TAAAA)n microsatellite repeat in the SHBG gene promoter is strongly associated with SHBG levels:

  • Carriers of six TAAAA repeats demonstrate 19-26% higher SHBG levels compared to non-carriers across different age groups 1
  • This effect is consistent across young, middle-aged, and elderly men 1

• The Asp327Asn missense mutation (rs1799941) in exon 8 of the SHBG gene:

  • Associated with approximately 14% higher SHBG levels in middle-aged men 1
  • Contributes to genetically determined variation in total testosterone levels 2

Range of SHBG Values in Clinical Populations

• Clinical data shows remarkably wide distribution of SHBG concentrations:

  • Mean SHBG in a general male population: 31.8±15.2 nmol/L 3
  • Range: 6-109 nmol/L (nearly 20-fold difference between lowest and highest values) 3
  • Approximately 5.6% of men have SHBG levels >60 nmol/L 3

• Age-related differences:

  • Younger men (≤54 years): Mean SHBG 27.7±13.3 nmol/L (range 6-88 nmol/L) 3
  • Older men (≥55 years): Mean SHBG 36.6±15.8 nmol/L (range 11-109 nmol/L) 3
  • SHBG levels are significantly higher in older men (p<0.001) 3

Clinical Impact of Genetic SHBG Variations

Effect on Testosterone and Other Hormones

• Carriers of SHBG gene polymorphisms show:

  • 9-22% higher total testosterone levels compared to non-carriers 1
  • Altered dihydrotestosterone (DHT) levels 2
  • Changes in androgen metabolite levels (5α-androstane-3α,17β-diol glucuronides) 2

• Despite higher SHBG, free testosterone levels are only modestly affected:

  • Slight increase in free testosterone in middle-aged carriers 1
  • No significant difference in free testosterone in young and elderly men 1

Diagnostic Considerations

• High SHBG can mask true testosterone status by binding more testosterone, leaving less bioavailable 4
• Calculate free testosterone index (total testosterone/SHBG ratio) for better assessment of hypogonadism 4
• Morning total testosterone is an initial screening test, but free testosterone by equilibrium dialysis is critical for accurate assessment, especially with abnormal SHBG levels 4

Clinical Recommendations for Men with Genetically High SHBG

1. Always measure SHBG levels when assessing testosterone status in men suspected of testosterone deficiency 5, 4

2. Use free testosterone measurements rather than total testosterone alone when SHBG levels are abnormal 4

3. Calculate free testosterone index (total testosterone/SHBG ratio) with a ratio <0.3 indicating hypogonadism 4

4. Consider the impact of age on SHBG interpretation, as levels naturally increase with age 3

5. Be aware of the wide normal range of SHBG in clinical populations when interpreting results 3

Pitfalls in SHBG Interpretation

• Relying solely on total testosterone measurements can lead to misdiagnosis of hypogonadism in men with genetically high SHBG 4
• Failing to consider genetic factors when interpreting SHBG and testosterone results may lead to inappropriate treatment decisions 1
• Not accounting for the age-related increase in SHBG when evaluating older men 3

Conclusion

Genetic polymorphisms in the SHBG gene can significantly elevate SHBG levels in men by 20-26% compared to non-carriers. This genetic variation contributes to the wide range of SHBG values observed clinically (6-109 nmol/L) and affects total testosterone levels. When evaluating men with suspected hypogonadism, measuring both SHBG and free testosterone is essential for accurate diagnosis, especially in those with potentially genetically determined high SHBG levels.