What is the maximum level of Sex Hormone-Binding Globulin (SHBG) in men with polymorphisms?

Maximum SHBG Levels in Men with Polymorphisms

In men with SHBG gene polymorphisms, SHBG levels can reach up to 109 nmol/L, with significant variability based on specific genetic variants. 1

Genetic Factors Affecting SHBG Levels

SHBG levels in men are significantly influenced by genetic polymorphisms, with two main variants having the greatest impact:

1. (TAAAA)n Microsatellite Repeat Polymorphism:

   • Located in the SHBG gene promoter region
   • Six different alleles with 6-11 repeats have been identified 2
   • Men with shorter repeats (particularly 6 repeats) show significantly higher SHBG levels compared to those with longer repeats (9 repeats) 3
   • The difference can be substantial: up to 19-26% higher SHBG levels in carriers of six TAAAA-repeats compared to non-carriers across different age groups 4

2. Asp327Asn (D327N) Polymorphism:

   • Point mutation in exon 8 of the SHBG gene
   • Carriers of the Asn327 variant (particularly Asn/Asn homozygotes) demonstrate SHBG levels approximately 14-25% higher than those with the wild-type allele 4, 3
   • This variant delays SHBG half-life in circulation, contributing to higher serum concentrations 3

Age-Related Variations in SHBG Levels

Age significantly affects SHBG concentrations in men with polymorphisms:

• Younger men (≤54 years):

  • Mean SHBG: 27.7±13.3 nmol/L
  • Range: 6-88 nmol/L
  • Only 2.2% have SHBG >60 nmol/L 1

• Older men (≥55 years):

  • Mean SHBG: 36.6±15.8 nmol/L
  • Range: 11-109 nmol/L
  • 9% have SHBG >60 nmol/L 1

Clinical Implications

The wide variability in SHBG levels has important clinical implications:

1. Free Testosterone Assessment:

   • Free testosterone is the most accurate measurement for assessing testosterone status when SHBG levels vary significantly 5
   • Calculated free testosterone shows superior sensitivity (89%) compared to total testosterone (74%) 5

2. Diagnostic Considerations:

   • The free testosterone index (ratio of total testosterone/SHBG) is a better indicator of gonadal status than total testosterone alone 5
   • A ratio of <0.3 indicates hypogonadism 5

3. Treatment Decisions:

   • Relying solely on total testosterone without considering SHBG can lead to incorrect clinical conclusions 5
   • High testosterone with high SHBG is not typically a clinical concern, as elevated SHBG may compensate to maintain appropriate bioavailable testosterone levels 5

Monitoring Recommendations

For men with known SHBG polymorphisms resulting in elevated SHBG:

1. Use free testosterone or free androgen index for more accurate assessment of androgenic status
2. Consider the impact of other factors that can further increase SHBG:
   • Liver disease
   • Hyperthyroidism
   • Certain medications (estrogens, anticonvulsants)
   • Alcohol use 5

Pitfalls to Avoid

1. Misinterpreting Total Testosterone: High total testosterone with high SHBG may still result in normal free testosterone levels
2. Unnecessary Treatment: Treating elevated total testosterone when free testosterone is normal may lead to adverse effects without clinical benefit 5
3. Ignoring Genetic Factors: Failing to consider the contribution of genetic polymorphisms when interpreting SHBG and testosterone results

By understanding the significant impact of SHBG polymorphisms on hormone levels, clinicians can better interpret laboratory results and make more appropriate treatment decisions for men with suspected hormonal imbalances.