DHEA vs DHEA-S Testing: Key Differences
DHEA and DHEA-S are distinct molecules with fundamentally different clinical utilities—DHEA-S should be measured as a second-line test for hyperandrogenism when first-line testosterone tests are negative, while DHEA testing has limited clinical application and is rarely used in routine practice. 1
Biochemical and Metabolic Differences
Molecular Characteristics
- DHEA-S is the sulfated, hydrophilic storage form that circulates as the most abundant steroid hormone in human blood, while DHEA is the unconjugated, lipophilic active form 2, 3
- DHEA has a rapid metabolic clearance rate of approximately 2000 L/day, whereas DHEA-S clears much more slowly at only 13 L/day, making DHEA-S levels more stable for laboratory measurement 2
- DHEA-S does NOT freely convert back to DHEA in the liver, challenging the traditional concept of interconversion—studies show that intravenous DHEA-S administration fails to increase serum DHEA levels, while oral DHEA readily converts to DHEA-S 4
Conversion Pathways
- Only 6% of DHEA re-enters circulation as DHEA-S, but 60-70% of DHEA-S can theoretically re-enter as DHEA (though hepatic conversion is minimal) 2
- DHEA can be directly converted to downstream androgens (androstenedione, testosterone, dihydrotestosterone) and aromatized to estrogens, while DHEA-S requires desulfation first 2, 4
Clinical Diagnostic Performance
For PCOS Diagnosis
- DHEA-S has poor diagnostic accuracy for PCOS with pooled sensitivity of 0.75 and specificity of only 0.67, yielding an AUC of 0.77—significantly inferior to total testosterone (AUC 0.87), calculated free testosterone (AUC 0.85), and free androgen index (AUC 0.87) 5, 1
- DHEA testing is not recommended for PCOS evaluation and lacks established diagnostic thresholds in current guidelines 5, 6
Assay Method Impact
- For DHEA-S, direct immunoassays have sensitivity 0.67 and specificity 0.70, while LC-MS/MS methods improve sensitivity to 0.82 but reduce specificity to 0.57 5, 1
- For DHEA, direct immunoassays show sensitivity 0.67 and specificity 0.70, while LC-MS/MS achieves sensitivity 0.82 but specificity drops to 0.57 7
Clinical Indications
When to Order DHEA-S
- Measure DHEA-S as a second-line test when total testosterone and free testosterone are normal but clinical suspicion for hyperandrogenism remains high 1, 6
- Order DHEA-S when clinical signs of virilization are present to evaluate for adrenal androgen excess 1
- DHEA-S serves as an indicator of adrenal androgen function and is superior to urinary 17-ketosteroid measurements for assessing adrenal androgen secretion 8
When to Order DHEA
- DHEA testing has extremely limited clinical utility in routine endocrine evaluation and is not recommended as part of standard hyperandrogenism workup 5, 6
- DHEA measurement may be considered in research settings but lacks validated clinical applications in diagnostic algorithms 7
Age-Related Considerations
Reference Range Requirements
- DHEA-S levels decline approximately 2% per year, reaching maximum concentrations between ages 20-30 years 1
- Age-adjusted reference ranges are mandatory for DHEA-S interpretation—failure to use age-specific norms leads to overdiagnosis of elevation 1
- DHEA-S levels in healthy individuals over 90 years are five-fold lower than in young adults (geometric mean 404-551 ng/mL in nonagenarians vs 2824-3110 ng/mL in those under 40) 9
Critical Clinical Pitfalls
Common Errors to Avoid
- Never use DHEA-S as a first-line test for PCOS due to poor specificity and low prevalence of elevation 1
- Do not assume DHEA-S reflects bioavailable DHEA—the lack of hepatic conversion means DHEA-S is not a circulating storage pool for DHEA regeneration 4
- A low DHEA-S alone cannot establish adrenal insufficiency and requires confirmation with dynamic testing 1
- DHEA-S can be used to screen for adrenal suppression from exogenous steroids, as low levels accompany iatrogenic adrenal suppression 3