What is the management approach for a male with elevated Sex Hormone-Binding Globulin (SHBG) levels of 90 nmol/L without a known cause?

Management of Elevated SHBG (90 nmol/L) in Males

For a male with SHBG of 90 nmol/L without known cause, the priority is identifying the underlying etiology through targeted evaluation of thyroid function, liver disease, medications, and HIV status, followed by assessment of free testosterone to determine if functional hypogonadism exists despite potentially normal total testosterone levels. 1

Initial Diagnostic Approach

Measure Free or Bioavailable Testosterone

• Calculate free testosterone using total testosterone and SHBG measurements (Vermeulen equation) or measure free testosterone directly, as SHBG of 90 nmol/L significantly reduces bioavailable testosterone even when total testosterone appears normal 2
• A free testosterone index (total testosterone/SHBG ratio) <0.3 indicates functional hypogonadism requiring intervention 1
• Total testosterone alone is misleading in high SHBG states—the bound fraction is biologically unavailable 2, 3

Identify the Underlying Cause

The European Urology guidelines emphasize that very high SHBG (>60 nmol/L, which your patient exceeds) is typically acquired rather than genetic 1:

• Check thyroid function tests (TSH, free T4): Hyperthyroidism is a common cause of elevated SHBG 1, 4
• Evaluate liver function tests (AST, ALT, bilirubin, albumin): Hepatic disease elevates SHBG and can cause feminization in males through altered sex hormone metabolism 1, 5
• Review medication list: Anticonvulsants, estrogens, and thyroid hormone replacement increase SHBG 1, 4
• Consider HIV testing in appropriate clinical contexts, as HIV/AIDS is associated with elevated SHBG 1, 4
• Assess for smoking history: Smoking increases SHBG levels 1, 4

Clinical Context Matters

Assess for Hypogonadal Symptoms

If the patient has decreased libido, erectile dysfunction, reduced muscle mass, or fatigue 6:

• Measure morning total testosterone using an accurate assay 6
• Check LH and FSH levels to determine if compensatory pituitary response is occurring—elevated SHBG reduces free testosterone, which can trigger increased gonadotropin secretion 1
• The pituitary senses free testosterone, not total testosterone, so high SHBG can cause functional hypogonadism with compensatory LH/FSH elevation 1

Monitor for Feminization Signs

In liver disease specifically, high SHBG contributes to feminization 5:

• Examine for gynecomastia, palmar erythema, or vascular spiders 5
• The free estradiol/free testosterone ratio increases with high SHBG in cirrhosis, causing estrogen predominance 5

Treatment Strategy

Treat the Underlying Condition

The most effective approach is identifying and treating the cause of elevated SHBG rather than attempting to lower SHBG directly 1:

• Correct hyperthyroidism if present 1
• Manage liver disease appropriately 1, 5
• Discontinue or substitute medications that elevate SHBG when feasible 1
• Address HIV if diagnosed 1

Consider Testosterone Replacement if Indicated

If free testosterone is low and symptoms of hypogonadism are present 6:

• Testosterone replacement may be appropriate in symptomatic men with documented low free testosterone, even if total testosterone is normal 6
• Benefits include improved sexual function, well-being, muscle mass, and bone density 6
• Monitor carefully: Perform baseline digital rectal exam and PSA, then follow PSA every 3-6 months in the first year 6
• Check hematocrit/hemoglobin regularly as testosterone can increase these values 6
• Be aware that testosterone replacement in older men has been associated with increased cardiovascular events in some studies 6

Avoid Inappropriate Interventions

Do not use medications solely to lower SHBG 1:

• Growth hormone, glucocorticoids, and anabolic steroids decrease SHBG but should only be used when clinically indicated for other conditions 1
• These carry significant risks and are not justified for SHBG reduction alone 1

Key Clinical Pitfalls

• Relying on total testosterone alone misses functional hypogonadism caused by high SHBG—always assess free or bioavailable testosterone 1, 2
• SHBG varies widely in clinical populations (range 6-109 nmol/L in one men's health cohort), with 5.6% having SHBG >60 nmol/L 3
• In eugonadal men, higher SHBG is associated with lower non-SHBG-bound estradiol but slightly higher non-SHBG-bound testosterone, contradicting the "estrogen amplifier" theory 7
• Liver disease deserves special attention: The T/SHBG ratio correlates with free testosterone and can serve as a free testosterone index in cirrhosis 5

Monitoring Approach

If testosterone replacement is initiated 6:

• Efficacy evaluation with dose adjustment at 1-2 months 6
• Monitoring every 3-6 months for the first year, then annually 6
• Assess urinary symptoms, sleep apnea exacerbation, and gynecomastia 6
• Perform digital rectal examination 6
• Check testosterone, hematocrit/hemoglobin, and PSA 6
• Consider prostate biopsy if PSA rises >1.0 ng/mL in any year 6