What are the causes of high Sex Hormone-Binding Globulin (SHBG) levels and what constitutes elevated levels?

Causes of High Sex Hormone-Binding Globulin (SHBG) Levels in Males

The primary causes of elevated SHBG in males include hyperthyroidism, hepatic disease, aging, smoking, HIV/AIDS, and certain medications (especially estrogens, anticonvulsants, and thyroid hormones). 1

Normal SHBG Levels in Males

• Normal reference ranges vary by laboratory and assay method
• Generally, normal SHBG levels in adult males range from approximately 10-57 nmol/L
• Values above this range are considered elevated

Major Causes of Elevated SHBG

Endocrine Disorders

• Hyperthyroidism: Significantly increases SHBG production, with levels often 2-3 times normal 1, 2
• Hypogonadism: Associated with compensatory increases in SHBG 1
• Cushing syndrome: Generally decreases SHBG, but important to note for differential diagnosis 1

Physiological Factors

• Advanced age: SHBG increases progressively with aging in men 1
• Smoking: Associated with increased SHBG levels 1

Hepatic Conditions

• Liver cirrhosis: Impairs metabolism of SHBG, leading to elevated levels 1, 3
• Hepatitis: Can increase SHBG production 1

Medications and Substances

• Estrogens and estrogen-containing medications: Potently increase SHBG production 1
• Anticonvulsants: Elevate SHBG levels 1
• Thyroid hormone replacement: Excessive doses can increase SHBG 1

Other Conditions

• HIV/AIDS: Associated with elevated SHBG levels 1
• Anorexia nervosa and extreme caloric restriction: Can increase SHBG 1
• Endurance exercise/athletes: Associated with higher SHBG levels 1

Clinical Significance of Elevated SHBG

High SHBG levels have important clinical implications:

• Increased binding of testosterone, reducing free (bioavailable) testosterone levels 1
• May contribute to symptoms of hypogonadism despite normal total testosterone 1
• Can mask hyperandrogenic states in laboratory testing 4
• May serve as a marker for certain underlying conditions 5

Diagnostic Approach for Elevated SHBG

When elevated SHBG is identified:

1. Medication review: Assess for estrogens, anticonvulsants, thyroid hormone replacement
2. Thyroid function testing: TSH, free T4 to rule out hyperthyroidism
3. Liver function assessment: Complete hepatic panel
4. Consider HIV testing: Particularly in at-risk individuals
5. Measure total and free testosterone: To assess impact on androgen status

Degree of Elevation in Different Conditions

• Hyperthyroidism: Typically 2-3 times normal range (>100 nmol/L) 2
• Hepatic cirrhosis: Often 1.5-2 times normal range
• Medication-induced: Variable depending on medication and dosage
• Age-related: Gradual increase, typically 1-1.5 times the levels seen in younger men
• HIV/AIDS: Often moderately elevated (1.5-2 times normal)

Common Pitfalls and Caveats

• SHBG measurement should be interpreted in conjunction with total and free testosterone levels
• Isolated SHBG measurement without hormone assessment may lead to incorrect conclusions
• Normal SHBG levels in suspected hyperthyroidism may help distinguish true thyrotoxicosis from thyroid hormone resistance syndromes 2
• SHBG can be used as a marker to differentiate between true hyperthyroidism and conditions that mimic it 2
• Failure to consider medications as a cause of elevated SHBG is a common oversight

Remember that SHBG alterations affect the bioavailability of sex hormones, which may not be reflected in total hormone measurements alone.