What are the implications and management of elevated sex hormone binding globulin (SHBG) levels?

Elevated Sex Hormone Binding Globulin (SHBG)

Elevated SHBG requires identification and treatment of the underlying cause—most commonly hyperthyroidism, hepatic disease, aging, certain medications (estrogens, anticonvulsants, thyroid hormone), smoking, or HIV/AIDS—rather than direct SHBG-lowering interventions. 1

Clinical Implications of Elevated SHBG

The primary concern with elevated SHBG is functional hypogonadism despite normal total testosterone levels. When SHBG increases, a greater proportion of total testosterone becomes bound, decreasing free and bioavailable testosterone fractions that are biologically active. 1, 2

Impact on Hormone Bioavailability

• The pituitary gland senses free testosterone levels rather than total testosterone when regulating the hypothalamic-pituitary-gonadal axis 1
• This reduced negative feedback from decreased free testosterone can trigger compensatory increases in gonadotropins (FSH and LH) to stimulate more testosterone production 1
• In women with functional hypothalamic amenorrhea without polycystic ovarian morphology, higher SHBG levels are associated with higher FSH levels 1
• Free testosterone is the biologically active form unbound to SHBG or albumin, making it a more sensitive indicator than total testosterone 2

Diagnostic Approach

Both total and free testosterone must be measured when evaluating hypogonadism, especially when SHBG abnormalities are suspected. 1

• A free testosterone index (total testosterone/SHBG ratio) <0.3 indicates hypogonadism and may reflect compensatory mechanisms through increased gonadotropin secretion 1
• Calculated free testosterone can be estimated from total testosterone and SHBG measurements using the Vermeulen equation 2
• Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG 1

Identifying the Underlying Cause

Common Etiologies of Elevated SHBG

Systematically evaluate for these conditions: 1, 3, 4

• Hyperthyroidism: SHBG levels increase in thyrotoxicosis as thyroxine stimulates SHBG secretion by increasing mRNA concentrations 5
• Hepatic disease: Evaluate liver function tests, as chronic liver disease elevates SHBG and can disrupt the hypothalamic-pituitary axis 1, 5
• Medications: Estrogens, anticonvulsants, and thyroid hormone replacement increase SHBG 1, 3
• Aging: SHBG naturally increases with age 1
• HIV/AIDS: Consider HIV testing in appropriate clinical contexts 1
• Smoking: Associated with elevated SHBG levels 1

Conditions with Normal SHBG Despite Apparent Thyroid Excess

• SHBG levels remain normal in abnormal thyroid hormone transport syndromes and thyroid hormone resistance, which can be confused with thyrotoxicosis 5

Management Strategy

Primary Approach: Treat the Underlying Condition

Identifying and treating the underlying condition causing elevated SHBG is the most effective approach, rather than attempting to lower SHBG directly. 1

• Correct hyperthyroidism if present 5
• Optimize management of hepatic disease 1
• Review and adjust medications that may be elevating SHBG 1, 3
• Address modifiable risk factors like smoking 1

Pharmacological Considerations

Medications that decrease SHBG include growth hormone, glucocorticoids, and testosterone or anabolic androgenic steroids; however, these should only be used when clinically indicated for other conditions, not solely to lower SHBG. 1

• Testosterone administration can lower SHBG: in one study, testosterone enanthate reduced SHBG from 16.4 ± 2 to 4.3 ± 0.5 ng DHT bound/ml in Klinefelter's patients 6
• The effect on SHBG differs by treatment type: testosterone directly lowers SHBG, while hCG treatment may not change or may even increase SHBG levels 6

Clinical Pitfalls to Avoid

• Not considering the impact of medications and medical conditions on SHBG levels can lead to incorrect interpretation of testosterone test results 1
• Focusing only on total testosterone can be misleading; free or bioavailable testosterone measurements provide better insight into androgen status 2
• In women with hirsutism, low SHBG concentrations correlate negatively with body mass index and fasting insulin levels, suggesting insulin resistance 5
• SHBG can serve as a marker of insulin resistance and cardiovascular risk, with decreased SHBG associated with increased risk for non-insulin-dependent diabetes and overall mortality in postmenopausal women 5

Additional Clinical Utility

SHBG measurement is useful for: 5

• Correctly interpreting testosterone and estradiol serum concentrations
• Investigating androgen-estrogen balance in gonadal and sexual dysfunctions
• Assessing peripheral effects of hormones that regulate SHBG production
• Evaluating insulin resistance and cardiovascular risk