Elevated DHEA-S with Normal Cortisol: Clinical Significance
Elevated DHEA-S on two separate measurements with normal cortisol most commonly indicates either a benign functional adrenal condition, polycystic ovary syndrome (PCOS) in women, non-classical congenital adrenal hyperplasia, or—when markedly elevated—raises concern for an androgen-secreting adrenal tumor that requires immediate imaging evaluation. 1, 2
Immediate Risk Stratification Based on DHEA-S Level
The absolute value of DHEA-S determines your next steps:
DHEA-S >6000 ng/mL (16.3 μmol/L): This is a red flag for adrenocortical carcinoma and mandates urgent adrenal CT imaging to evaluate for an androgen-secreting tumor 2. These tumors present with hirsutism, voice deepening, and oligomenorrhea/amenorrhea in women 2.
**DHEA-S moderately elevated but <6000 ng/mL**: Compare to age-specific reference ranges. Levels >3800 ng/mL in patients aged 20-29 or >2700 ng/mL in those aged 30-39 warrant further workup for non-classical congenital adrenal hyperplasia 2.
Mildly elevated DHEA-S: Consider benign functional hypersecretion, PCOS (in women), or physiologic variation 3, 2.
Essential Diagnostic Workup
Rule Out Adrenal Tumors First
Since you have normal cortisol, this patient does not have typical Cushing's syndrome, where DHEA-S is characteristically suppressed in cortisol-secreting adenomas 4, 5. The combination of elevated DHEA-S with normal cortisol is the opposite pattern and suggests:
Obtain adrenal CT imaging if DHEA-S is significantly elevated or if any clinical signs of virilization are present 1, 2. The CUA/AUA guidelines recommend testing for androgen excess when adrenal incidentalomas are found or when virilization is suspected 1.
Assess for clinical hyperandrogenism: Look for hirsutism, acne, menstrual irregularities, androgenetic alopecia, clitoromegaly, voice deepening, or increased muscle mass 2. In men, isolated DHEA-S elevation without virilization is often a benign functional condition 3.
Complete Hormonal Evaluation
Order a comprehensive androgen panel 2:
- Free and total testosterone
- Androstenedione
- 17-hydroxyprogesterone (to screen for non-classical CAH)
- LH and FSH
- Sex hormone-binding globulin (SHBG)
Consider 24-Hour Urinary Free Cortisol
Even though serum cortisol is normal, if any clinical signs of hypercortisolism are present (central obesity, striae, easy bruising, proximal muscle weakness), obtain 24-hour urinary free cortisol to definitively exclude subtle cortisol excess 3. Some patients with mild autonomous cortisol secretion (MACS) can have normal random cortisol but abnormal dexamethasone suppression 1.
Functional Testing
2-day dexamethasone suppression test: This distinguishes functional from neoplastic causes of hyperandrogenism 2. Benign functional DHEA-S elevation should suppress with dexamethasone, while adrenal tumors typically do not 2.
Measure ACTH level: Normal or elevated ACTH with elevated DHEA-S suggests ACTH-driven adrenal androgen production (as seen in non-classical CAH or PCOS), while suppressed ACTH suggests autonomous adrenal secretion from a tumor 1, 6.
Gender-Specific Considerations
In Women
- PCOS is the most common cause of elevated DHEA-S with normal cortisol 2. Evaluate for polycystic ovaries on pelvic ultrasound, menstrual irregularities, and insulin resistance 2.
- Non-classical congenital adrenal hyperplasia (21-hydroxylase deficiency) should be ruled out with 17-hydroxyprogesterone measurement 2.
In Men
- Isolated DHEA-S hypersecretion is recognized as a benign functional condition and is rarer than in women 3.
- If asymptomatic, observation may be appropriate 3.
- If symptomatic (acne, increased libido, or other androgenic effects), consider low-dose dexamethasone 0.125-0.25 mg nightly 3.
Special Diagnostic Considerations
Adrenoleukodystrophy in Males
In males with very high DHEA-S without an identifiable tumor, measure very long-chain fatty acids to screen for adrenoleukodystrophy, a rare X-linked disorder that can cause isolated DHEA-S elevation 2.
Age-Related Context
DHEA-S naturally declines with age 4, 5. In elderly patients, what appears "elevated" may actually represent preserved adrenal androgen production. Conversely, in younger patients, even borderline elevations warrant investigation 4.
Management Based on Findings
If Imaging Shows an Adrenal Mass
- Masses >4 cm or with suspicious features (heterogeneous, irregular borders, >10 HU on non-contrast CT) require surgical evaluation for possible adrenocortical carcinoma 1.
- Functional adrenal lesions with androgen excess should be referred for surgical consideration 1.
If No Mass is Found
- Symptomatic hyperandrogenism: Consider low-dose dexamethasone suppression (0.125-0.25 mg nightly) if symptoms are bothersome 3.
- Asymptomatic: Observation with repeat DHEA-S measurement in 3-6 months is reasonable 3.
- PCOS or non-classical CAH: Treat the underlying condition per endocrine guidelines 2.
Critical Pitfalls to Avoid
- Do not assume normal cortisol excludes all adrenal pathology: Androgen-secreting tumors can produce DHEA-S without cortisol excess 1, 2.
- Do not ignore markedly elevated DHEA-S (>6000 ng/mL): This mandates imaging to exclude malignancy 2.
- Do not forget age-adjusted reference ranges: DHEA-S declines significantly with age, so interpretation must be age-appropriate 4, 5.
- In women on estrogen replacement therapy: Estrogen can alter SHBG and confound androgen interpretation 7. Consider this when evaluating the clinical significance of elevated androgens.