High SHBG of 95: Genetic Contribution
An SHBG level of 95 nmol/L has a genetic component, but acquired factors are far more commonly the primary drivers of elevated SHBG and should be systematically evaluated first. 1
Genetic Influence on SHBG Levels
While genetic factors do contribute to SHBG variation, they typically account for a modest portion of the overall level:
Specific SHBG gene polymorphisms have been identified that influence circulating SHBG levels, including the D327N point mutation in exon 8 and the pentanucleotide (TAAAA)n repeat polymorphism in the 5' untranslated region. 2
The D327N variant allele is associated with higher SHBG levels (36.9 ± 15.9 nmol/L for heterozygotes vs 31.1 ± 16.1 nmol/L for wild-type), representing approximately a 15-20% increase. 2
Polymorphisms in the SHBG gene promoter region predict serum SHBG levels in population studies of men, with statistically significant associations (P < 0.001). 3
However, even when genetic variants are present, BMI and metabolic status independently influence SHBG levels and often have a larger effect magnitude than genetic factors alone. 2
Acquired Causes Are More Common
The European Urology guidelines emphasize that very high SHBG is typically caused by acquired conditions rather than primary genetic disorders. 1 You must systematically evaluate:
- Hyperthyroidism - one of the most common causes of markedly elevated SHBG 1, 4
- Hepatic disease/cirrhosis - liver dysfunction increases SHBG production 1, 4
- Medications - anticonvulsants, estrogens, and thyroid hormone replacement elevate SHBG 1, 5
- Aging - SHBG naturally increases with age 1
- Smoking - associated with higher SHBG levels 1
- HIV/AIDS - can significantly elevate SHBG 1
Clinical Approach to SHBG of 95
Measure free testosterone or calculate the free testosterone index (total testosterone/SHBG ratio) to determine if functional hypogonadism is present, as elevated SHBG reduces bioavailable testosterone. 1, 6
A free testosterone index <0.3 indicates hypogonadism despite potentially normal total testosterone. 1, 5
Check thyroid function tests (TSH, free T4) immediately, as hyperthyroidism is a highly treatable cause of elevated SHBG. 1
Evaluate liver function tests (AST, ALT, bilirubin, albumin) to assess for hepatic disease. 1
Consider HIV testing in appropriate clinical contexts. 1
Key Clinical Pitfall
Relying solely on total testosterone measurements will miss functional hypogonadism caused by elevated SHBG, as the bound testosterone is not biologically active. 1, 6 Always assess free or bioavailable testosterone when SHBG is elevated, as symptoms of testosterone deficiency can occur despite normal total testosterone levels. 1
Bottom Line on Genetics
While genetic variants in the SHBG gene do exist and contribute to baseline SHBG levels, identifying and treating acquired causes is the most effective clinical approach to managing elevated SHBG. 1 Genetic testing for SHBG polymorphisms is not routinely recommended in clinical practice, as it rarely changes management compared to addressing modifiable acquired factors. 2, 3