Interpreting Free vs Serum Testosterone in Diagnosing Hypogonadism
Free testosterone measurement is the most accurate method for diagnosing hypogonadism, especially in conditions that affect sex hormone-binding globulin (SHBG) levels, as it represents the biologically active fraction available to tissues. 1
Understanding Testosterone Measurements
Types of Testosterone Measurements
- Total Testosterone: Includes both bound (to SHBG and albumin) and free testosterone
- Free Testosterone: Approximately 2% of total testosterone that is biologically active and available to tissues
- Bioavailable Testosterone: Free testosterone plus albumin-bound testosterone
- Free Androgen Index (FAI): Calculated ratio of total testosterone to SHBG
Normal Reference Ranges
| Testosterone Level | Normal Range |
|---|---|
| Total Testosterone | 300-950 ng/dL |
| Free Testosterone | 50-200 pg/mL |
| SHBG | 10-50 nmol/L |
Diagnostic Approach for Hypogonadism
When to Measure Free Testosterone
- When total testosterone is borderline low (280-350 ng/dL) 2
- In conditions affecting SHBG levels:
- High SHBG states: Liver disease, hyperthyroidism, aging, HIV, estrogen use
- Low SHBG states: Obesity, insulin resistance, hypothyroidism, glucocorticoid use
Interpretation Algorithm
Initial screening: Measure morning total testosterone
Measure free testosterone when:
- Total testosterone is borderline (280-350 ng/dL)
- Suspected SHBG abnormalities exist
- Clinical symptoms of hypogonadism are present despite normal total testosterone
Determine type of hypogonadism by measuring LH and FSH:
- High LH/FSH with low testosterone: Primary hypogonadism
- Low/normal LH/FSH with low testosterone: Secondary hypogonadism
Clinical Pearls and Pitfalls
Key Considerations
- Total testosterone alone has poor specificity for diagnosing hypogonadism except at very low levels (<150 ng/dL) 2
- Free testosterone calculation methods vary significantly, with the Vermeulen equation being commonly recommended 3
- Morning measurements are essential due to diurnal variation in testosterone levels
Common Pitfalls
- Relying solely on total testosterone: May miss hypogonadism in patients with altered SHBG levels
- Using Free Androgen Index: Correlates poorly with calculated free testosterone (r²=0.21-0.46) and overestimates free testosterone when SHBG is low 3
- Single measurements: Testosterone should be measured on at least two separate morning occasions before confirming diagnosis 4
- Ignoring clinical symptoms: Laboratory values should always be interpreted in the context of clinical presentation
Special Populations
- Aging males: SHBG increases with age, making free testosterone measurement particularly important 5
- Obese men: Have lower SHBG levels, potentially masking hypogonadism if only total testosterone is measured
- Liver disease: Causes elevated SHBG, which may result in normal total testosterone despite low free testosterone 1
Treatment Considerations
- Testosterone replacement therapy should target mid-normal range values 1
- Monitor pre-dose morning serum testosterone at approximately 14 and 28 days after starting treatment 1
- Target range for total testosterone: 450-600 ng/dL 1
- Monitor hematocrit, PSA, and other parameters regularly during treatment 1
Remember that diagnosing hypogonadism requires both biochemical evidence of low testosterone (preferably free testosterone in borderline cases) and consistent clinical symptoms.