How should I evaluate and manage a patient with elevated sex hormone‑binding globulin and symptoms of low free testosterone?

Evaluation and Management of Elevated SHBG with Symptoms of Low Free Testosterone

Understanding the Diagnostic Challenge

When SHBG is elevated, total testosterone may appear normal or borderline-low while free testosterone—the biologically active fraction—is genuinely reduced, creating "functional hypogonadism." This discordance occurs because SHBG binds testosterone with high affinity, reducing the proportion available to tissues 1, 2.

Key Diagnostic Principles

• Equilibrium dialysis combined with LC-MS/MS is the only FDA-cleared method for accurately measuring free testosterone, but it is not routinely available in commercial laboratories 3
• When equilibrium dialysis is unavailable, calculate the Free Androgen Index (FAI) = (total testosterone ÷ SHBG) × 100 to estimate bioavailable testosterone 3
• FAI < 30 indicates true hypogonadism even when total testosterone appears borderline-normal 3
• Direct immunoassays for free testosterone are unreliable when SHBG is abnormal and should be avoided 3

Diagnostic Algorithm

Step 1: Confirm Biochemical Hypogonadism

• Obtain two separate morning total testosterone measurements (8-10 AM) on different days to account for diurnal variation and assay variability 4, 3
• Measure SHBG, LH, and FSH simultaneously to distinguish primary from secondary hypogonadism and calculate FAI 4, 3
• Request free testosterone by equilibrium dialysis if available; otherwise rely on calculated FAI 3

Interpretation thresholds:

• Total testosterone < 300 ng/dL on both measurements = confirmed hypogonadism 4, 3
• Total testosterone 231-346 ng/dL (gray zone) with FAI < 30 = functional hypogonadism likely 3
• Total testosterone > 350 ng/dL but FAI < 30 with diminished libido = SHBG-mediated functional hypogonadism may justify treatment 3

Step 2: Identify the Cause of Elevated SHBG

Common causes of elevated SHBG include:

• Liver disease (especially cirrhosis) 3, 1
• Hyperthyroidism 1, 2
• Aging 4
• Medications (estrogens, anticonvulsants, thyroid hormones) 1
• Low insulin states (lean body habitus) 2, 5

Essential workup:

• Thyroid function tests (TSH, free T4) to exclude hyperthyroidism 1, 2
• Liver function tests and hepatic ultrasound if cirrhosis suspected 3, 1
• Review medication list for SHBG-elevating drugs 1

Step 3: Assess Qualifying Symptoms

Testosterone therapy is justified primarily for:

• Diminished libido (primary indication) 4, 3
• Erectile dysfunction (primary indication) 4, 3

Symptoms with minimal or no proven benefit from testosterone:

• Fatigue, low energy, or reduced vitality (standardized mean difference only 0.17) 3
• Depressive symptoms (less-than-small improvement, SMD -0.19) 3
• Physical functioning or cognition (little to no effect) 4, 3

Treatment Approach

Address Underlying Causes First

Before initiating testosterone therapy, treat reversible causes of elevated SHBG:

• If hyperthyroid: normalize thyroid function with antithyroid medication or radioiodine; SHBG will decline as thyroid hormones normalize 1, 2
• If cirrhotic: optimize liver disease management; testosterone therapy carries theoretical hepatocellular carcinoma risk and requires careful discussion 3
• If medication-induced: discontinue or substitute SHBG-elevating drugs when feasible 1

Testosterone Replacement Therapy

If free testosterone remains low (FAI < 30) after addressing reversible causes AND the patient has diminished libido or erectile dysfunction, initiate testosterone therapy 4, 3.

Preferred formulation:

• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line due to stable day-to-day levels and lower erythrocytosis risk (15.4% vs 43.8% with injectables) 4, 3

Alternative formulations:

• Testosterone cypionate or enanthate 100-200 mg every 2 weeks if cost is prohibitive (annual cost $156 vs $2,135 for gel) 3
• Monitor testosterone levels midway between injections (days 5-7) targeting mid-normal range 500-600 ng/dL 3

Expected Outcomes

Realistic expectations to discuss with patients:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 4, 3
• Modest quality of life improvements, primarily in sexual domains 3
• Little to no benefit for energy, physical function, mood, or cognition 4, 3

Monitoring Requirements

Initial monitoring (first year):

• Testosterone levels at 2-3 months after initiation, then every 3-6 months 4, 3
• Hematocrit at each visit—withhold treatment if >54% and consider phlebotomy in high-risk cases 4, 3
• PSA in men ≥40 years—refer for urology if PSA rises >1.0 ng/mL in first 6 months or >0.4 ng/mL/year thereafter 3

Long-term monitoring (after stabilization):

• Testosterone, hematocrit, and PSA every 6-12 months 4, 3
• Reassess symptoms at 12 months—discontinue if no improvement in sexual function 3

Critical Pitfalls to Avoid

• Never diagnose hypogonadism based on total testosterone alone when SHBG is elevated—always calculate FAI or measure free testosterone by equilibrium dialysis 3
• Never use direct immunoassays for free testosterone in the setting of abnormal SHBG; results are unreliable 3
• Never initiate testosterone without confirming the patient does not desire fertility—testosterone causes azoospermia; use gonadotropin therapy (hCG + FSH) instead for fertility preservation 4, 3
• Never expect meaningful improvements in energy, physical function, or cognition even with confirmed hypogonadism and treatment 4, 3
• Never skip investigation for reversible causes (hyperthyroidism, liver disease, medications) before committing to lifelong testosterone therapy 1, 2

Special Considerations

In men with cirrhosis and elevated SHBG:

• Use free testosterone index (total testosterone/SHBG ratio < 0.3) to define hypogonadism in this population 3
• Discuss theoretical risk of hepatocellular carcinoma before initiating testosterone 3
• Prefer transdermal formulations to minimize hepatic first-pass effects 3

In men with hyperthyroidism:

• Defer testosterone therapy until thyroid function is normalized; SHBG and testosterone levels may correct spontaneously 1, 2
• SHBG levels are normal in thyroid hormone resistance syndromes, helping differentiate these from true thyrotoxicosis 2