How should I evaluate and manage a 57-year-old man with total testosterone ~475 ng/dL, free testosterone ~60 pg/mL (~1.7% of total) and elevated sex‑hormone‑binding globulin (~68 nmol/L)?

Evaluation and Management of a 57-Year-Old Man with Borderline-Normal Total Testosterone, Low Free Testosterone, and Elevated SHBG

This patient does NOT meet diagnostic criteria for hypogonadism and should NOT receive testosterone therapy at this time. His total testosterone of 475 ng/dL is well above the diagnostic threshold of <300 ng/dL required on two separate morning measurements, and the elevated SHBG with compensatory pituitary response explains the laboratory pattern. 1

Understanding the Laboratory Pattern

The key issue here is elevated SHBG causing a discrepancy between total and free testosterone:

• Your patient's total testosterone of 475 ng/dL falls within the normal adult male range (typically 300-800 ng/dL), indicating adequate testicular production. 2
• The elevated SHBG (68.2 nmol/L, assuming units) binds a larger fraction of circulating testosterone, reducing the free (bioavailable) fraction to 1.7%. 3
• This represents compensated testosterone production: when SHBG rises and free testosterone drops, the pituitary increases LH secretion to stimulate more testicular production, maintaining adequate bioavailable levels despite increased binding. 3

Critical Diagnostic Steps

1. Confirm the Diagnosis with Proper Testing

• Repeat morning total testosterone (8-10 AM) on at least one additional occasion to confirm persistent levels, as single measurements are insufficient due to diurnal variation and assay variability. 1
• Measure serum LH and FSH to determine if true hypogonadism exists or if the pituitary is appropriately compensating for elevated SHBG. 3
  • If LH is normal or elevated, this confirms the pituitary is responding appropriately to maintain adequate free testosterone—the patient does NOT have true hypogonadism despite low free testosterone values. 3
  • Low or low-normal LH/FSH with low total testosterone would indicate secondary hypogonadism. 1

2. Verify Free Testosterone Measurement Accuracy

• The reported free testosterone value may be inaccurate if measured by direct immunoassay. Direct immunoassays are notoriously unreliable, especially when SHBG is abnormal. 4, 5
• Request free testosterone by equilibrium dialysis (gold standard) or use the Vermeulen calculator to obtain an accurate value. 4, 5
• With a low SHBG (≈10 nmol/L would be low), the expected free testosterone should be elevated; a reported low free testosterone in this context suggests laboratory error. 1

3. Calculate Free Androgen Index (FAI)

• FAI = (total testosterone ÷ SHBG) × 100 provides an estimate of bioavailable testosterone when equilibrium dialysis is unavailable. 1
• An FAI <30 indicates true hypogonadism even when total testosterone is borderline-normal. 1
• In your patient: (475.4 ÷ 68.2) × 100 = approximately 7.0, which is markedly low and suggests functional hypogonadism due to elevated SHBG. 1

Identify and Address Underlying Causes of Elevated SHBG

Before considering any hormonal therapy, screen for and treat reversible causes of elevated SHBG:

• Hyperthyroidism – measure TSH; treat with antithyroid drugs, radioiodine, or surgery if confirmed. 1
• Hepatic disease/cirrhosis – obtain liver function tests and hepatitis serologies; optimize liver function. 1
• HIV/AIDS – perform risk-based testing. 1
• Medications – review for SHBG-elevating drugs (anticonvulsants, estrogens, thyroid hormone) and discontinue or substitute when feasible. 1
• Smoking – counsel cessation, as smoking raises SHBG. 1

Assess for Clinical Symptoms

Diagnosis of testosterone deficiency requires BOTH confirmed low testosterone AND specific symptoms:

• Primary qualifying symptoms: diminished libido and erectile dysfunction. 1, 3
• Nonspecific symptoms that do NOT justify therapy: fatigue, low energy, mood changes, reduced physical function—these show minimal or no improvement even with confirmed hypogonadism. 1

If your patient lacks diminished libido or erectile dysfunction, testosterone therapy is NOT indicated regardless of laboratory values. 1

Treatment Algorithm

If LH/FSH Are Normal or Elevated (Compensated State)

• No testosterone therapy is indicated. The pituitary is appropriately compensating for elevated SHBG, and total testosterone is normal. 3
• Address underlying causes of elevated SHBG (see above). 1
• Reassure the patient that his testosterone production is adequate despite the low free testosterone percentage. 3

If LH/FSH Are Low or Low-Normal AND FAI <30 AND Qualifying Symptoms Present

• Consider selective estrogen receptor modulators (SERMs) such as clomiphene 25-50 mg three times weekly as an off-label alternative to testosterone replacement, particularly if fertility preservation is desired. 1, 3
• Clomiphene blocks estradiol-mediated negative feedback, restoring GnRH pulsatility and increasing LH/FSH secretion, which stimulates endogenous testosterone production while preserving spermatogenesis. 1
• Expected outcomes: rapid hormonal normalization with total testosterone reaching mid-normal levels (≈500-600 ng/dL) within 6 weeks, with small but significant improvements in sexual function (standardized mean difference ≈0.35). 1

If Testosterone Replacement Is Considered (Only After Confirming True Hypogonadism)

• Transdermal testosterone gel 1.62% at 40.5 mg daily is first-line due to stable serum levels and lower erythrocytosis risk (≈15%) compared with injectables (≈44%). 1
• Target mid-normal testosterone levels (450-600 ng/dL). 1, 2
• Absolute contraindications: active desire for fertility (testosterone causes azoospermia), hematocrit >54%, active breast or prostate cancer. 1

Monitoring and Follow-Up

• At 6 weeks (if clomiphene started): repeat total and free testosterone, estradiol, LH, and FSH to confirm target mid-normal testosterone and avoid excessive estradiol suppression. 1
• At 3-4 months: repeat hormonal panel; evaluate libido and erectile function. 1
• Every 6-12 months once stable: monitor testosterone, estradiol, hematocrit, and symptom burden. 1
• At 12 months: if sexual function has not improved despite achieving target testosterone levels, discontinue therapy to prevent unnecessary long-term exposure. 1

Critical Pitfalls to Avoid

• Do NOT diagnose hypogonadism on a single testosterone measurement or on symptoms alone—require two morning values <300 ng/dL plus specific sexual symptoms. 1
• Do NOT initiate testosterone therapy based solely on low free testosterone when total testosterone is normal without first measuring LH/FSH and confirming true hypogonadism. 3
• Do NOT rely on direct immunoassays for free testosterone in men with abnormal SHBG; use equilibrium dialysis or calculate FAI. 1, 4
• Do NOT prescribe testosterone for weight loss, general energy enhancement, or athletic performance—these are not evidence-based indications. 1
• Never start testosterone without confirming the patient does NOT desire fertility, as exogenous testosterone causes prolonged azoospermia. 1

Expected Outcomes if Therapy Is Initiated

• Small but significant improvements in sexual function and libido (standardized mean difference ≈0.35). 1
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition. 1
• Modest favorable changes in metabolic parameters (insulin resistance, triglycerides, HDL cholesterol) may occur. 1

Bottom Line

Your patient's total testosterone of 475 ng/dL is normal and does NOT meet diagnostic criteria for hypogonadism. The low free testosterone percentage reflects elevated SHBG with compensatory pituitary response. Measure LH/FSH to confirm this compensated state, verify free testosterone accuracy using equilibrium dialysis or FAI calculation, and address underlying causes of elevated SHBG. Testosterone therapy is NOT indicated unless repeat testing confirms total testosterone <300 ng/dL on two occasions AND the patient has diminished libido or erectile dysfunction. 1, 3