What does it mean if Dehydroepiandrosterone sulfate (DHEA-s) and cortisol are both elevated?

Elevated DHEA-S and Cortisol: Clinical Interpretation

When both DHEA-S and cortisol are elevated together, this most commonly indicates either an acute stress response, systemic inflammation, or—if markedly elevated—raises concern for an adrenal tumor, particularly adrenocortical carcinoma. 1, 2

Primary Diagnostic Considerations

Acute Stress or Inflammatory Response

• Both cortisol and DHEA-S rise together during acute physiological stress, as they are co-synthesized in the adrenal cortex and released coordinately in response to ACTH stimulation 3, 2
• In acute inflammatory states (such as endotoxin exposure), cortisol typically rises more dramatically than DHEA, creating an increased cortisol-to-DHEA ratio approximately 4 hours after the inflammatory stimulus 2
• This dissociation—where cortisol increases disproportionately relative to DHEA—is a normal physiological response to achieve adequate cortisol levels during acute inflammation 2

Adrenal Tumor Screening (Critical Red Flag)

• DHEA-S >6000 ng/mL is a red flag for adrenocortical carcinoma and mandates urgent adrenal CT imaging to evaluate for an androgen-secreting tumor 1
• The combination of significantly elevated DHEA-S with elevated cortisol suggests the need to rule out adrenal tumors first, particularly if there are any clinical signs of virilization or Cushing's syndrome 1
• Adrenal CT imaging should be obtained if DHEA-S is significantly elevated or if any clinical signs of virilization are present 1

Algorithmic Diagnostic Approach

Step 1: Assess the Magnitude of Elevation

• If DHEA-S >6000 ng/mL: Obtain urgent adrenal CT imaging to evaluate for adrenocortical carcinoma 1
• If cortisol >275 nmol/L (>10 μg/dL) on morning testing: Consider further evaluation for Cushing's syndrome with dexamethasone suppression testing or late-night salivary cortisol 4

Step 2: Evaluate Clinical Context

• Recent acute illness, infection, or physiological stress: Likely represents normal coordinated adrenal stress response; consider repeat testing after resolution of acute stressor 3, 2
• Chronic elevation without clear stressor: Proceed with comprehensive hormonal evaluation and imaging 1

Step 3: Obtain Comprehensive Hormonal Panel

• Order free and total testosterone, androstenedione, 17-hydroxyprogesterone, LH, and FSH to characterize the pattern of androgen excess 1
• Measure ACTH to differentiate ACTH-dependent from ACTH-independent causes 5
• Consider 24-hour urinary free cortisol or late-night salivary cortisol if Cushing's syndrome is suspected 4

Step 4: Imaging and Further Workup

• If adrenal mass found on CT: Masses >4 cm or with suspicious features require surgical evaluation for possible adrenocortical carcinoma 1
• If no mass found: Consider non-classical congenital adrenal hyperplasia (measure 17-hydroxyprogesterone), PCOS in women, or functional adrenal hyperandrogenism 1

Gender-Specific Considerations

In Women

• Evaluate for PCOS with pelvic ultrasound, assessment of menstrual irregularities, and insulin resistance screening 1
• PCOS is the most common cause of isolated DHEA-S elevation with normal cortisol, but concurrent cortisol elevation suggests a different etiology 1

In Men

• Isolated DHEA-S hypersecretion can be a benign functional condition, but concurrent cortisol elevation warrants more aggressive evaluation 1

Critical Pitfalls to Avoid

• Do not assume both elevations are benign without imaging: Adrenocortical carcinoma can present with both cortisol and DHEA-S hypersecretion 1
• Do not rely on electrolyte abnormalities alone: The absence of hyponatremia or hyperkalemia does not exclude significant adrenal pathology 5
• Consider medication effects: Exogenous steroids (including inhaled fluticasone) can suppress the HPA axis and confound cortisol interpretation, though they would typically lower rather than raise endogenous cortisol 5, 4
• Timing matters: Morning cortisol and DHEA-S measurements are preferred for initial evaluation to capture peak physiological levels 5

Management Based on Findings

If Imaging Shows Adrenal Mass

• Masses >4 cm or with suspicious radiographic features require surgical evaluation 1
• Refer to endocrine surgery for consideration of adrenalectomy 1

If No Mass and Symptomatic Hyperandrogenism

• Consider low-dose dexamethasone suppression therapy, which can reduce symptoms in 90% of cases 1
• Monitor with repeat DHEA-S measurement in 3-6 months 1

If Asymptomatic with Mild Elevation

• Observe with repeat DHEA-S and cortisol measurement in 3-6 months 1
• Ensure acute stressors have resolved before repeat testing 2