What causes elevated sex hormone binding globulin (SHBG) levels?

Causes of Elevated Sex Hormone Binding Globulin (SHBG)

Elevated SHBG levels can be caused by hyperthyroidism, estrogen therapy, liver disease, aging, and certain medications, while decreased levels are associated with obesity, insulin resistance, and hyperandrogenism. Understanding these factors is crucial for accurate interpretation of hormone status and clinical management.

Primary Causes of Elevated SHBG

Hormonal Factors

• Thyroid Hormones: Hyperthyroidism significantly increases SHBG production 1, 2
• Estrogens: Oral estrogen therapy and high estrogen states increase SHBG levels 1
• Glucocorticoids: Elevated glucocorticoid levels can increase SHBG production 1

Medical Conditions

• Liver Disease: Liver dysfunction can alter SHBG production as the liver is the main site of SHBG synthesis 1
• Aging: Advanced age is associated with higher SHBG levels 1
• Anorexia/Malnutrition: Severe caloric restriction increases SHBG levels 3

Medications and Substances

• Oral Estrogens: Significantly increase SHBG production 1
• Anticonvulsants: Can elevate SHBG levels 1
• Alcohol Consumption: Chronic alcohol use increases SHBG levels 1
• Resmetirom: A thyroid hormone receptor-β agonist used for MASH treatment elevates SHBG levels 4

Clinical Significance of Elevated SHBG

Impact on Hormone Measurement

• Elevated SHBG can lead to misleadingly high total testosterone levels while free testosterone (the biologically active form) may be normal or low 4
• When evaluating low total testosterone in obesity, measuring morning serum free testosterone is essential as obesity-related decreases in testosterone are frequently due to low SHBG 4

Disease Associations

• Cardiovascular Disease: Higher SHBG levels are independently associated with increased risk of cardiovascular events in men 5
• Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD): SHBG elevation with resmetirom treatment is used as a marker of target engagement 4
• Polycystic Ovary Syndrome (PCOS): Typically shows decreased SHBG levels due to hyperandrogenism and insulin resistance 4

Diagnostic Approach

Laboratory Assessment

• Measure both total and free testosterone levels when SHBG is elevated 1
• Calculate free testosterone index (ratio of total testosterone to SHBG) to assess androgen status 1
• Evaluate thyroid function (TSH, free T4) as thyroid disorders commonly affect SHBG levels 1, 2
• Consider liver function tests as liver disease can alter SHBG production 1

Differential Diagnosis for Elevated SHBG

1. Hyperthyroidism: Check thyroid function tests (elevated free T4, suppressed TSH) 2
2. Liver Disease: Evaluate liver enzymes and function 1
3. Medication Effect: Review current medications, particularly estrogens and anticonvulsants 1
4. Aging: Consider age-related changes in hormone levels 1
5. Alcohol Use: Assess alcohol consumption patterns 1

Clinical Implications

Treatment Considerations

• When SHBG is elevated with normal free testosterone but low total testosterone, treatment should be guided by free testosterone levels and clinical symptoms rather than total testosterone alone 1
• In men with obesity and hypogonadism, testosterone replacement may improve metabolic parameters including fasting glucose, insulin resistance, and body composition 4
• For patients on resmetirom therapy, elevated SHBG serves as a biomarker of treatment response, with a 120% increase associated with positive treatment outcomes 4

Monitoring

• Regular monitoring of free testosterone levels rather than total testosterone alone is recommended when SHBG is elevated 1
• For patients on medications that affect SHBG (like resmetirom), monitor for potential effects on thyroid function and sex hormone levels 4

Understanding the causes and implications of elevated SHBG is essential for accurate hormone assessment and appropriate clinical management across various endocrine and metabolic conditions.