Is high serum testosterone with high Sex Hormone-Binding Globulin (SHBG) normal?

High Serum Testosterone with High SHBG: Clinical Significance and Evaluation

High serum testosterone with high SHBG is typically not a clinical concern, as the elevated SHBG may be a compensatory mechanism to maintain appropriate levels of bioavailable testosterone. 1

Understanding the Relationship Between Testosterone and SHBG

Sex Hormone-Binding Globulin (SHBG) is a glycoprotein that binds to sex hormones, particularly testosterone, regulating their bioavailability. When SHBG levels are elevated, the body may increase total testosterone production to maintain adequate free testosterone levels as a compensatory mechanism.

Key points about this relationship:

• SHBG binds approximately 44-65% of circulating testosterone, making it unavailable to tissues
• Free testosterone (1-2% of total) and albumin-bound testosterone (33-54%) constitute the bioavailable fraction
• The free testosterone index (ratio of total testosterone/SHBG) is a better indicator of gonadal status than total testosterone alone 1

Clinical Significance

When evaluating testosterone status, it's important to consider:

1. Free testosterone or calculated free testosterone (cFT) - This represents the biologically active portion and is more clinically relevant than total testosterone alone
2. Free testosterone index - A ratio of total testosterone/SHBG <0.3 indicates hypogonadism, while normal or elevated values suggest adequate bioavailable testosterone 1

Common Causes of Elevated SHBG

Several conditions can cause elevated SHBG levels:

• Liver disease - SHBG is produced in the liver, and liver dysfunction can lead to increased production 1
• Hyperthyroidism - Thyroid hormones increase SHBG production 1, 2
• Advanced age - SHBG levels naturally increase with aging 1, 2
• Alcohol use - Associated with high SHBG levels 1
• Medications - Estrogens, oral contraceptives, and some anticonvulsants can increase SHBG 2

Diagnostic Approach

When evaluating high testosterone with high SHBG:

1. Calculate free testosterone or free testosterone index - This helps determine if bioavailable testosterone is normal despite elevated total testosterone 1

2. Evaluate for underlying causes of elevated SHBG:

   • Check thyroid function (TSH, free T4)
   • Assess liver function (ALT, AST, bilirubin)
   • Review medication history
   • Consider alcohol consumption patterns

3. Measure luteinizing hormone (LH) - This helps establish the etiology of any testosterone abnormality 3

Clinical Implications

• High testosterone with high SHBG often results in normal free testosterone levels, which typically doesn't require intervention
• Focus should be on identifying and addressing any underlying condition causing elevated SHBG
• Treating elevated total testosterone when free testosterone is normal may lead to adverse effects without clinical benefit 1

Potential Pitfalls

• Relying solely on total testosterone without considering SHBG can lead to incorrect clinical conclusions 1
• Significant between-kit variability exists in testosterone measurement, particularly for samples with high SHBG levels 4
• Failure to measure morning testosterone levels can lead to falsely low results due to diurnal variation 1

Follow-up Recommendations

• If asymptomatic with normal free testosterone/index, routine monitoring may be sufficient
• If an underlying condition is identified (e.g., hyperthyroidism, liver disease), treat the primary condition
• Follow-up testing in 3-6 months is reasonable if asymptomatic, with earlier follow-up if symptomatic 1

Remember that the goal of evaluation is to determine if there is a true hormonal imbalance affecting tissue exposure to testosterone, rather than focusing solely on laboratory values.