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

Causes of Elevated Sex Hormone-Binding Globulin (SHBG)

Elevated SHBG levels are primarily caused by drugs (especially estrogens, anticonvulsants, and thyroid hormones), hyperthyroidism, hepatic disease, aging, smoking, and HIV/AIDS. 1

Primary Causes of Elevated SHBG

The European Association of Urology guidelines clearly outline the main factors associated with increased SHBG levels:

1. Medications

   • Anticonvulsants
   • Estrogens
   • Thyroid hormone replacement therapy 1

2. Medical Conditions

   • Hyperthyroidism 1, 2
   • Hepatic disease/liver disorders 1
   • HIV/AIDS 1

3. Physiological Factors

   • Advanced age 1
   • Smoking 1

Pathophysiological Mechanisms

SHBG is primarily produced by the liver and serves as a transport protein for sex steroids. Several mechanisms explain elevated SHBG:

• Liver function: As a liver-produced glycoprotein, hepatic disease alters SHBG production 1, 3
• Thyroid hormones: Thyroid hormone is a direct modulator of SHBG levels, with hyperthyroidism significantly increasing SHBG production 2
• Estrogen effects: Estrogens stimulate SHBG synthesis, explaining why oral contraceptives can cause persistently elevated SHBG levels 4

Clinical Significance of Elevated SHBG

Elevated SHBG has important clinical implications:

• Reduced bioavailable testosterone: High SHBG binds more testosterone, reducing free testosterone levels and potentially contributing to symptoms of hypogonadism 5
• Diagnostic marker: SHBG serves as a useful biomarker for various endocrine and metabolic disorders 3
• Persistent elevation: Research shows SHBG may remain elevated for extended periods (>120 days) after discontinuation of oral contraceptives 4

Conditions Associated with Low SHBG

For contrast, conditions associated with decreased SHBG include:

• Medications: Growth hormone, glucocorticoids, testosterone, anabolic steroids 1
• Endocrine disorders: Hypothyroidism, acromegaly, Cushing's disease 1
• Metabolic conditions: Obesity, insulin resistance, metabolic syndrome, type 2 diabetes 1, 6
• Liver conditions: Non-alcoholic fatty liver disease 1
• Other: Nephrotic syndrome 1

Clinical Evaluation

When evaluating elevated SHBG:

• Assess medication history, particularly oral contraceptives, hormone therapy, and anticonvulsants
• Screen for thyroid dysfunction with TSH and free T4 levels
• Evaluate liver function with comprehensive liver tests
• Consider HIV testing in high-risk individuals
• Measure total and free testosterone levels to assess the impact on androgen status

Pitfalls and Caveats

• SHBG elevation can mask underlying androgen excess by reducing free androgen levels
• In women with functional hypothalamic amenorrhea with polycystic ovarian morphology, SHBG levels may be lower than expected 1
• SHBG measurement should be interpreted in the context of total hormone levels, as it affects the bioavailable fraction of sex hormones
• Oral contraceptive use can cause prolonged elevation of SHBG even after discontinuation 4

Understanding the causes of elevated SHBG is essential for proper diagnosis and management of various endocrine and metabolic disorders, as it directly impacts the bioavailability of sex hormones.