What causes mid-range normal total testosterone but notably high free testosterone levels?

Causes of Normal Total Testosterone with High Free Testosterone

The most common cause of normal total testosterone with high free testosterone is decreased sex hormone-binding globulin (SHBG) levels, which allows more testosterone to circulate in its free, biologically active form. 1

Understanding Testosterone Distribution

Testosterone in the bloodstream exists in three forms:

• Tightly bound to SHBG (approximately 44%)
• Weakly bound to albumin (approximately 54%)
• Free/unbound testosterone (approximately 2%)

Only the free testosterone is considered biologically active and available to tissues 1, 2.

Causes of Decreased SHBG

Several conditions can lead to decreased SHBG levels while maintaining normal total testosterone:

1. Obesity/Metabolic Syndrome

   • Excess adipose tissue reduces SHBG production
   • Insulin resistance decreases hepatic SHBG production

2. Insulin Resistance/Type 2 Diabetes

   • Hyperinsulinemia suppresses SHBG synthesis in the liver

3. Hypothyroidism

   • Reduced thyroid hormone levels decrease SHBG production

4. Glucocorticoid Excess/Cushing's Syndrome

   • Elevated cortisol suppresses SHBG synthesis

5. Androgen Use/Abuse

   • Exogenous androgens can suppress SHBG production

6. Nephrotic Syndrome

   • Protein loss can alter the binding protein balance

7. Certain Medications

   • Glucocorticoids, growth hormone, and certain anticonvulsants can reduce SHBG

Clinical Significance

This pattern (normal total testosterone with high free testosterone) is clinically important because:

• Free testosterone represents the biologically active fraction 2
• Symptoms of androgen excess may occur despite normal total testosterone levels
• In men with suspected hypogonadism, total testosterone alone may miss cases where free testosterone is abnormal 3

Diagnostic Approach

When encountering this pattern:

1. Confirm the laboratory findings

   • Ensure testosterone measurements were performed with reliable methods 2
   • Morning samples (before 10 AM) provide the most accurate assessment

2. Measure SHBG levels

   • Low SHBG will confirm the suspected mechanism

3. Screen for underlying conditions

   • Evaluate for metabolic syndrome, diabetes, thyroid disorders
   • Review medication history
   • Consider hormonal disorders

4. Consider clinical context

   • Assess for symptoms of androgen excess or deficiency
   • The clinical significance depends on the patient's presentation

Important Considerations

• The relationship between total and free testosterone is not always predictable 3
• Total testosterone between 280-350 ng/dL is not sensitive enough to reliably exclude hypogonadism 3
• In certain populations (like HIV patients), SHBG levels are commonly altered, making free testosterone measurement particularly important 4

Measurement Methods

When evaluating free testosterone:

• Equilibrium dialysis and ultrafiltration are reference methods
• Calculated free testosterone (using total testosterone, SHBG, and albumin) is clinically acceptable
• Direct analog immunoassays for free testosterone may be less reliable 2

Remember that normal ranges for testosterone levels are:

• Total Testosterone: 300-950 ng/dL
• Free Testosterone: 50-200 pg/mL
• SHBG: 10-50 nmol/L 1