What is the management approach for a patient with low total testosterone levels despite normal free testosterone levels, considering potential symptoms of hypogonadism and underlying health conditions?

Management of Low Total Testosterone with Normal Free Testosterone

In patients with low total testosterone but normal free testosterone, testosterone replacement therapy is generally not indicated, as the normal free testosterone level indicates adequate bioavailable androgen activity and these patients are functionally eugonadal. 1

Understanding the Biochemical Discordance

This pattern typically reflects elevated sex hormone-binding globulin (SHBG), which binds testosterone and lowers the total testosterone measurement while free testosterone—the biologically active fraction—remains normal. 1, 2

Key physiologic principle: Free testosterone by equilibrium dialysis is the gold standard for assessing true androgen status when total testosterone is borderline or discordant with clinical presentation. 1, 3

Common causes of elevated SHBG include:

• Aging (SHBG increases progressively after age 60) 2
• Hyperthyroidism 2
• Hepatic disease 2
• HIV infection 2

Diagnostic Algorithm

Step 1: Confirm the Measurements

• Repeat morning (8-10 AM) total testosterone on a separate occasion to confirm persistently low levels 1, 3
• Measure free testosterone by equilibrium dialysis (not analog immunoassay methods, which are unreliable) 4, 1
• Measure SHBG to calculate free androgen index (total testosterone/SHBG ratio) 1

Step 2: Assess for True Hypogonadism

If free testosterone is normal (≥6.5 ng/dL), the patient does NOT have biochemical hypogonadism regardless of total testosterone level. 2

The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men, even for complaints of weight loss, fatigue, low energy, or diminished vitality. 1

Step 3: Evaluate Underlying Causes

If SHBG is elevated:

• Screen thyroid function (TSH, free T4) 2
• Assess liver function tests 2
• Consider HIV testing if risk factors present 2

Treatment Approach

When Testosterone Therapy is NOT Indicated

Testosterone replacement therapy should not be initiated when free testosterone is normal, as this represents functional eugonadism. 1

Critical evidence: The American College of Physicians found that testosterone therapy produces little to no effect on physical functioning, energy, vitality, or cognition even in men with confirmed biochemical hypogonadism. 1 In functionally eugonadal men with normal free testosterone, no benefit would be expected.

Address Underlying Conditions Instead

First-line management should focus on treating the underlying cause of elevated SHBG rather than prescribing testosterone. 1

• For hyperthyroidism: Treat with antithyroid medications or radioactive iodine; SHBG will normalize with euthyroid state 2
• For hepatic disease: Address underlying liver pathology; SHBG elevation reflects hepatic synthetic function 2
• For obesity-associated changes: Weight loss through low-calorie diets and regular exercise can improve the testosterone-to-SHBG ratio 1

Symptomatic Management

If the patient presents with sexual dysfunction despite normal free testosterone:

For erectile dysfunction: PDE5 inhibitors (sildenafil, tadalafil) are first-line therapy and do not require testosterone supplementation when free testosterone is normal. 1

For diminished libido: Investigate other causes including:

• Depression (consider screening with PHQ-9) 1
• Relationship factors 1
• Medications (SSRIs, beta-blockers, opiates) 5
• Sleep disorders 1

Critical Pitfalls to Avoid

Never initiate testosterone therapy based solely on low total testosterone without measuring free testosterone, especially in men over 60 years. 2 Studies show that 26.3% of men over 60 with erectile dysfunction have normal total testosterone with low free testosterone, but the reverse pattern (low total/normal free) also occurs and represents functional eugonadism. 2

Never use testosterone therapy to treat non-specific symptoms like fatigue, low energy, or depressed mood in eugonadal men. 1 Even in confirmed hypogonadism, testosterone produces minimal improvements in these domains (standardized mean difference of only 0.17 for energy/fatigue and -0.19 for depressive symptoms). 1

Do not assume that symptoms alone justify testosterone therapy. The European Association of Urology explicitly warns against using screening questionnaires or symptoms alone to diagnose hypogonadism due to lack of specificity. 1

When to Reconsider

If free testosterone subsequently falls below normal range (<6.5 ng/dL) on repeat testing AND the patient develops specific symptoms of hypogonadism (diminished libido, erectile dysfunction), then formal evaluation for testosterone replacement therapy would be appropriate. 1, 3

At that point, measure LH and FSH to distinguish primary from secondary hypogonadism, as this distinction has critical treatment implications including fertility preservation options. 1, 3