What are the causes of elevated sex hormone‑binding globulin?

Causes of Elevated Sex Hormone-Binding Globulin (SHBG)

Elevated SHBG is primarily caused by hyperthyroidism, hepatic disease, aging, estrogen-containing medications, and certain anticonvulsants, with thyroid hormones and liver function being the most clinically significant regulators. 1

Primary Pathological Causes

Endocrine Disorders

• Hyperthyroidism is one of the most important causes of elevated SHBG, as thyroid hormones directly increase hepatic SHBG production through upregulation of hepatocyte nuclear factor-4alpha (HNF-4alpha) 1, 2
• Thyroid hormones (T3 and T4) increase SHBG by reducing cellular palmitate levels and increasing HNF-4alpha gene expression in hepatocytes, with effects becoming apparent after 4-5 days of exposure 2
• Hypogonadism in men is associated with elevated SHBG levels 3
• Androgen insensitivity syndrome results in high SHBG concentrations 3

Hepatic Disease

• Hepatic cirrhosis and chronic liver disease elevate SHBG levels due to altered hepatic synthetic function 1, 3
• Liver dysfunction disrupts the hypothalamic-pituitary axis and can lead to altered gonadotropin levels including FSH 1

Medication-Induced Elevation

Hormonal Medications

• Oral estrogens significantly increase SHBG production and can reduce IGF1 generation by the liver, confounding hormone assessments 4, 1
• Thyroid hormone replacement therapy increases SHBG levels 1, 3

Other Medications

• Anticonvulsants (certain types) elevate SHBG concentrations 1, 3

Physiological and Lifestyle Factors

Age-Related Changes

• Aging is associated with progressive increases in SHBG levels 1, 5

Lifestyle Factors

• Smoking is associated with elevated SHBG 1, 5

Nutritional Status

• Anorexia and altered nutritional status can affect SHBG levels, as SHBG is regulated by general metabolic factors and nutritional state 6, 7

Infectious Disease

• HIV/AIDS is associated with elevated SHBG levels 1, 5

Metabolic Regulation Mechanisms

Growth Hormone Pathway

• SHBG may be regulated primarily by growth hormone and somatomedin-C (IGF-1), with growth hormone promoting hepatic SHBG synthesis 6
• Sex steroids appear to have an indirect, modulating influence rather than direct primary regulation 6

Hepatocyte Nuclear Factor-4alpha (HNF-4alpha)

• HNF-4alpha is a key transcriptional regulator of SHBG production in response to metabolic changes in the liver 2
• Changes in cellular palmitate levels and fatty acid metabolism influence HNF-4alpha activity and subsequently SHBG production 2

Clinical Implications and Pitfalls

Diagnostic Considerations

• When SHBG is elevated, measure both total and free testosterone (or calculate free testosterone index) to accurately assess androgen status, as elevated SHBG reduces bioavailable testosterone despite potentially normal total testosterone 1, 8
• A free testosterone index (total testosterone/SHBG ratio) <0.3 indicates hypogonadism 1, 8

Common Pitfalls to Avoid

• Do not rely solely on total testosterone measurements when SHBG is elevated, as this can miss functional hypogonadism caused by reduced free testosterone 1
• Always consider thyroid function testing in patients with unexplained elevated SHBG, as hyperthyroidism is a major reversible cause 1, 3
• Review all medications including oral contraceptives, hormone replacement therapy, anticonvulsants, and thyroid medications that can elevate SHBG 1, 3
• In adolescents, oral estrogens can confound IGF1 detection accuracy by reducing hepatic IGF1 generation while simultaneously elevating SHBG 4

Special Populations

• In functional hypothalamic amenorrhea patients without polycystic ovarian morphology, higher SHBG levels correlate with higher FSH levels 1
• In men with erectile dysfunction who have failed phosphodiesterase-5 inhibitor therapy, both testosterone and SHBG should be measured concurrently to allow accurate interpretation of androgen status 1