Management of Abnormal SHBG Levels
Identify and Treat the Underlying Cause
The most effective approach to managing abnormal SHBG levels is to identify and treat the underlying condition causing the abnormality, rather than attempting to directly manipulate SHBG itself. 1
When SHBG is Elevated
Elevated SHBG is typically caused by acquired conditions rather than primary genetic disorders. 1 The following conditions should be systematically evaluated:
Endocrine Causes
Hyperthyroidism: Check TSH, free T4, and free T3. Correct hyperthyroidism if present, as thyroid hormones directly stimulate SHBG production. 1, 2 In overt hyperthyroidism, SHBG levels are markedly elevated (mean 141.6 nmol/L in Graves' disease vs. 48.3 nmol/L in euthyroid controls). 2
Hypogonadism in men: Measure morning total testosterone (8-10 AM) using an accurate assay in men with decreased libido, erectile dysfunction, reduced muscle mass, or fatigue. 1 When total testosterone is near the lower limit of normal, determine free testosterone by equilibrium dialysis or calculate it using total testosterone, SHBG, and albumin. 1
Hepatic Disease
- Evaluate liver function tests (AST, ALT, alkaline phosphatase, bilirubin, albumin, PT/INR) as hepatic disease can elevate SHBG. 1 In advanced liver disease with cirrhosis, the mechanism is complex: elevated estrogen from portosystemic shunting suppresses the hypothalamic-pituitary axis, leading to hypogonadotropic hypogonadism, testicular atrophy, and elevated SHBG. 3
Medications and Other Factors
- Review medications: Anticonvulsants, estrogens, and thyroid hormone replacement can increase SHBG. 1, 3
- Smoking status: Smoking is associated with elevated SHBG. 1
- HIV/AIDS: Consider HIV testing in appropriate clinical contexts. 1
- Aging: SHBG naturally increases with age. 1
When SHBG is Low
Low SHBG is commonly associated with metabolic conditions and androgen excess:
Metabolic Causes
Obesity and insulin resistance: Low SHBG is found in obese patients regardless of androgen status. 4 In obesity-related hypogonadism, men often have low total testosterone due to low SHBG but may have normal free testosterone levels. 3
Type 2 diabetes: Insulin resistance and hyperinsulinemia suppress SHBG production. 4
Endocrine Causes
Hypothyroidism: Check TSH and free T4. In manifest hypothyroidism, SHBG is significantly decreased (mean 24.9 nmol/L vs. 48.3 nmol/L in controls). 2
Polycystic ovary syndrome (PCOS): Low SHBG is a significant risk marker in PCOS and contributes to increased free testosterone, worsening hyperandrogenic symptoms. 1 In women with hirsutism or irregular menses, evaluate for PCOS with total testosterone, SHBG, and calculate the free androgen index. 5
Hyperprolactinemia: Check prolactin levels as this condition lowers SHBG. 6
Medications
- Glucocorticoids, testosterone, and anabolic steroids decrease SHBG. 1 These should only be used when clinically indicated for other conditions, not solely to lower SHBG. 1
Assess Androgen Status Accurately
Critical Measurement Principles
Both total and free testosterone should be measured when evaluating hypogonadism, especially when SHBG levels may be abnormal. 5, 1
Free testosterone index (FTI): Calculate as total testosterone divided by SHBG. A ratio <0.3 indicates hypogonadism. 1
Avoid the pitfall: Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG. 1 Conversely, in obesity with low SHBG, total testosterone may be low while free testosterone remains normal. 3
Testosterone Replacement in Men with Elevated SHBG
When symptomatic men have documented low free testosterone (even if total testosterone is normal due to elevated SHBG), testosterone replacement may be appropriate. 1 Benefits include improved sexual function, well-being, muscle mass, and bone density. 1
Monitoring Requirements for Testosterone Therapy
- Baseline: Digital rectal exam and PSA. 1
- First year: Check PSA every 3-6 months, monitor hematocrit/hemoglobin regularly. 1
- Ongoing: Monitor every 3-6 months in the first year, then annually, assessing urinary symptoms, sleep apnea exacerbation, gynecomastia, testosterone levels, hematocrit/hemoglobin, and PSA. 1
- Red flag: Consider prostate biopsy if PSA rises >1.0 ng/mL in any year. 1
Special Clinical Scenarios
Testicular Atrophy with High SHBG
Do not attribute testicular atrophy solely to elevated SHBG. 3 The atrophy results from suppression of the hypothalamic-pituitary axis by elevated estrogens (in liver disease) or other causes of hypogonadotropic hypogonadism, not from SHBG elevation itself. 3 SHBG is a consequence, not the cause. 3
Women with Functional Hypothalamic Amenorrhea
In patients with functional hypothalamic amenorrhea without polycystic ovarian morphology, higher SHBG levels are associated with higher FSH levels. 1 This reflects the underlying hypothalamic-pituitary dysfunction rather than a direct effect of SHBG. 1