What does it mean to have an elevated Dehydroepiandrosterone (DHEA) level with low cortisol levels?

Elevated DHEA with Low Cortisol: Diagnostic Interpretation

Direct Answer

This pattern of elevated DHEA (304) with low cortisol (5.1) is highly suspicious for primary adrenal insufficiency and requires immediate diagnostic workup with paired morning cortisol and ACTH measurements, followed by ACTH stimulation testing if needed. 1, 2

Why This Pattern Occurs

The combination of low cortisol with elevated (or inappropriately normal) DHEA contradicts the expected pattern in adrenal insufficiency, where both cortisol and DHEA-S should be low 1. This discordance suggests several possibilities:

Most Likely Explanations:

• Early or partial adrenal insufficiency - The adrenal glands may be failing selectively, with cortisol production impaired before DHEA production declines 1
• Laboratory timing issues - DHEA levels can vary significantly throughout the day and may not reflect true adrenal reserve 3
• Exogenous DHEA supplementation - If the patient is taking DHEA supplements, this would artificially elevate DHEA while cortisol remains low 4, 5
• Concurrent androgen-secreting process - Though less likely with low cortisol, an adrenal adenoma could theoretically produce excess DHEA while overall adrenal function is compromised 6

Critical Diagnostic Steps

Immediate Workup Required:

• Obtain early morning (8 AM) paired cortisol and ACTH levels - This is the first-line diagnostic test to distinguish primary from secondary adrenal insufficiency 1, 2
• Measure DHEA-S (not just DHEA) - DHEA-S is more stable and reliable than DHEA for assessing adrenal function 1, 3
• Check basic metabolic panel - Look for hyponatremia (present in 90% of cases) and hyperkalemia (present in ~50% of cases) 1, 2

Interpretation Guidelines:

• Cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH = diagnostic of primary adrenal insufficiency 1, 2
• Cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH = strong suspicion of primary adrenal insufficiency 1, 2
• Normal age- and sex-adjusted DHEA-S level practically rules out adrenal insufficiency 3
• Low DHEA-S with low cortisol confirms adrenal insufficiency 1, 3

ACTH Stimulation Test Protocol:

If initial results are equivocal, perform cosyntropin stimulation test 1, 2:

• Administer 0.25 mg cosyntropin (tetracosactide) IM or IV 1, 2
• Measure serum cortisol at baseline, 30 minutes, and optionally 60 minutes 2
• Peak cortisol <500 nmol/L (<18 μg/dL) is diagnostic of adrenal insufficiency 1, 2
• Peak cortisol >550 nmol/L (>20 μg/dL) is normal 2

Critical Pitfalls to Avoid

• Never delay treatment if acute adrenal crisis is suspected - Give IV hydrocortisone 100 mg immediately plus 0.9% saline infusion, even before diagnostic testing 1, 2
• Do not rely on electrolytes alone - Hyperkalemia is absent in 50% of cases, and some patients have completely normal electrolytes 1, 2
• Check for exogenous steroid use - Oral prednisolone, dexamethasone, or inhaled fluticasone can suppress cortisol and confound interpretation 1, 2
• Verify DHEA supplementation status - Many patients take over-the-counter DHEA supplements without reporting them 4, 5

If Adrenal Insufficiency is Confirmed

Establish Etiology:

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first - Autoimmunity accounts for ~85% of primary adrenal insufficiency in Western populations 1, 2
• If antibodies negative, obtain adrenal CT imaging - Evaluate for hemorrhage, tumors, tuberculosis, or structural abnormalities 1, 2
• In males with negative antibodies, check very long-chain fatty acids - Screen for adrenoleukodystrophy 1, 2

Treatment Approach:

• Glucocorticoid replacement: Hydrocortisone 15-25 mg daily in divided doses (first dose immediately upon waking, last dose at least 6 hours before bedtime) 1, 2
• Mineralocorticoid replacement: Fludrocortisone 50-200 mcg daily (only needed in primary adrenal insufficiency) 1, 2
• Patient education on stress dosing - Double or triple dose during illness, fever, or physical stress 2
• Provide emergency hydrocortisone 100 mg IM injection kit with self-injection training 2
• Medical alert identification required - Bracelet or necklace indicating adrenal insufficiency 1, 2

Alternative Consideration: Isolated DHEA Elevation

If cortisol is truly low but DHEA is genuinely elevated (not from supplementation), consider 6:

• Adrenal imaging with CT - DHEA-S >6000 ng/mL is a red flag for adrenocortical carcinoma 6
• Comprehensive androgen panel - Include free and total testosterone, androstenedione, 17-hydroxyprogesterone, LH, and FSH 6
• In women, evaluate for PCOS - Most common cause of isolated DHEA-S elevation with normal cortisol 6