Factors That Increase Sex Hormone-Binding Globulin (SHBG)
SHBG levels increase with aging, hyperthyroidism, hepatic disease, anticonvulsant medications (particularly enzyme-inducing agents), estrogen therapy, thyroid hormone supplementation, smoking, and HIV/AIDS. 1
Medication-Induced SHBG Elevation
Anticonvulsant Drugs
- Enzyme-inducing anticonvulsants are the most clinically significant medication class that raises SHBG levels. 2, 3
- Male epileptic patients on chronic anticonvulsant therapy demonstrate elevated SHBG concentrations alongside increased LH and FSH levels, indicating compensatory pituitary response to reduced free testosterone. 2
- The mechanism involves hepatic enzyme induction that stimulates SHBG synthesis in the liver. 3
- Both male and female patients on anticonvulsants show significantly elevated SHBG, which can lead to functional hypogonadism despite normal or even elevated total testosterone levels. 3
Hormonal Medications
- Estrogen therapy directly increases SHBG production. 1, 4
- Thyroid hormone supplementation elevates SHBG levels. 1
Endocrine Disorders
Hyperthyroidism
- Thyroid excess is a well-established cause of elevated SHBG. 1
- This represents a reversible cause that should be identified and treated to normalize SHBG levels. 1
Functional Hypothalamic Amenorrhea (FHA)
- Women with FHA without polycystic ovarian morphology demonstrate higher SHBG levels associated with correspondingly higher FSH levels. 1
- This pattern contrasts with FHA patients who have polycystic ovarian morphology, who show lower SHBG and lower FSH. 1
Hepatic Disease
- Chronic liver disease and cirrhosis paradoxically increase SHBG despite overall hepatic dysfunction. 1
- Liver disease disrupts the hypothalamic-pituitary axis, leading to altered gonadotropin levels including FSH elevation. 1
- Evaluating liver function tests is essential when investigating unexplained SHBG elevation. 1
Lifestyle and Environmental Factors
Smoking
- Cigarette smoking is associated with elevated SHBG levels. 1
Aging
- SHBG naturally increases with advancing age in both sexes. 1
- This age-related rise contributes to the decline in bioavailable testosterone seen in older men despite stable total testosterone. 1
Infectious Disease
HIV/AIDS
- HIV infection and AIDS are associated with elevated SHBG levels. 1
- HIV testing should be considered in appropriate clinical contexts when evaluating unexplained SHBG elevation. 1
Clinical Pitfalls to Avoid
- Do not rely solely on total testosterone measurements when SHBG is elevated, as this misses functional hypogonadism. 1, 5
- Always measure or calculate free testosterone (using total testosterone/SHBG ratio) when SHBG abnormalities are suspected. 5
- A free testosterone index <0.3 indicates hypogonadism regardless of total testosterone levels. 5
- Patients on anticonvulsants may have reduced sexual activity and symptoms of hypogonadism despite normal or elevated total testosterone due to SHBG-mediated reduction in free testosterone. 2
- Consider medication review as a reversible cause before pursuing other interventions. 1