How to manage a patient with normal total testosterone, low free testosterone, and low sex hormone-binding globulin (SHBG) with a normal body mass index (BMI)?

Management of Normal Total Testosterone with Low Free Testosterone and Low SHBG in Non-Obese Patients

In a patient with normal BMI, normal total testosterone, low free testosterone, and low SHBG, you should NOT initiate testosterone replacement therapy, as this represents a measurement artifact rather than true hypogonadism—the patient is biochemically eugonadal and testosterone therapy is explicitly contraindicated in eugonadal individuals. 1

Understanding the Biochemical Pattern

This specific pattern (normal total testosterone, low free testosterone, low SHBG) is fundamentally different from true hypogonadism:

• Low SHBG causes proportionally lower total testosterone while maintaining normal free (bioavailable) testosterone, which is the physiologically active form 2
• When SHBG is low, the calculated or measured free testosterone may appear falsely low using certain assays, but the actual bioavailable testosterone reaching tissues remains adequate 3
• The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men, even for symptoms of fatigue, low energy, or other non-specific complaints 1

Diagnostic Workup Required

Step 1: Confirm the Diagnosis with Proper Testing

• Repeat morning total testosterone measurements (8-10 AM) on two separate occasions to establish whether true hypogonadism exists 1, 3
• Measure free testosterone by equilibrium dialysis, the gold standard method, rather than relying on calculated values when SHBG is abnormal 1, 3
• Calculate the free testosterone index (total testosterone/SHBG ratio), with values >0.3 indicating eugonadism despite low SHBG 1

Step 2: Measure LH and FSH

• The American Urological Association recommends measuring serum LH in all patients with suspected testosterone deficiency (Strong Recommendation; Evidence Level: Grade A) 4
• Normal or elevated LH with normal total testosterone confirms eugonadism and rules out secondary hypogonadism 4
• This single test is the most important to guide further workup and prevent inappropriate testosterone therapy 4

Clinical Interpretation in Normal BMI Patients

The absence of obesity makes this case particularly important to recognize:

• In obese patients, low SHBG with low total testosterone but normal free testosterone represents obesity-associated secondary hypogonadism, where both total and free testosterone must decline for symptoms to develop 5
• In non-obese patients with normal BMI, isolated low SHBG with normal total testosterone almost never represents true hypogonadism 5
• Research demonstrates that symptomatic androgen deficiency develops only when both total AND free testosterone decline concurrently 5

What NOT to Do

• Never initiate testosterone therapy based on symptoms alone without confirmed biochemical hypogonadism (total testosterone <300 ng/dL on two occasions) 1, 3
• Never diagnose hypogonadism using calculated free testosterone when SHBG is low—equilibrium dialysis is required for accurate assessment 3, 6
• Never skip LH measurement, as this is the critical test to distinguish true hypogonadism from eugonadism 4
• Approximately 20-30% of men receiving testosterone in clinical practice do not have documented low testosterone, representing inappropriate prescribing 1

Alternative Evaluation for Symptoms

If the patient has symptoms (fatigue, low libido, erectile dysfunction), investigate alternative causes:

• Evaluate for sleep disorders, thyroid dysfunction, anemia, and vitamin D deficiency 1
• Assess for metabolic syndrome and cardiovascular risk factors 1
• Screen for depression and other mood disorders, as testosterone produces minimal improvements in depressive symptoms even in confirmed hypogonadism (SMD -0.19) 1
• Evaluate for primary sexual dysfunction with consideration of PDE5 inhibitors if erectile dysfunction is present 1

Expected Outcomes if Testosterone Were Inappropriately Given

The evidence is clear that testosterone therapy in eugonadal men provides no benefit:

• Little to no effect on physical functioning, energy, vitality, or cognition even in confirmed hypogonadism 1
• Minimal improvements in energy and fatigue (SMD 0.17) that are not clinically meaningful 1
• The European Association of Urology explicitly recommends against testosterone therapy in eugonadal men for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1

Critical Pitfall to Avoid

The most common error is misinterpreting low calculated free testosterone in the setting of low SHBG as indicating hypogonadism when total testosterone is normal. This represents a measurement artifact, not true androgen deficiency. In a patient with normal BMI, this pattern almost certainly indicates eugonadism, and testosterone therapy would be contraindicated and potentially harmful (risk of erythrocytosis, cardiovascular events, and permanent suppression of fertility). 1, 7, 3