What is the appropriate work‑up for low dehydroepiandrosterone sulfate (DHEA‑S) and pregnenolone in an adult male?

Work-up for Low DHEA-S and Pregnenolone in Men

In men with low DHEA-S and pregnenolone levels, the primary work-up focuses on evaluating for primary adrenal insufficiency (PAI) as the most clinically significant cause, requiring measurement of morning cortisol, ACTH, aldosterone, and plasma renin activity to confirm the diagnosis. 1, 2

Initial Diagnostic Approach

The work-up should prioritize identifying adrenal insufficiency, as this is a life-threatening condition requiring immediate treatment:

Core Laboratory Tests

• Morning (8-10 AM) serum cortisol: Low cortisol (<138 nmol/L or <5 μg/dL) suggests adrenal insufficiency 1
• Plasma ACTH: Elevated ACTH (>2x upper limit of normal) confirms primary adrenal insufficiency rather than secondary causes 1
• Aldosterone and plasma renin activity (PRA): Low aldosterone with elevated PRA indicates mineralocorticoid deficiency characteristic of PAI 1
• Serum electrolytes: Look for hyponatremia and hyperkalemia, which suggest mineralocorticoid deficiency 1

Confirmatory Testing if Initial Results Suggest PAI

• ACTH stimulation test: If morning cortisol is borderline (138-500 nmol/L), perform cosyntropin stimulation test to definitively diagnose adrenal insufficiency 1
• Morning testosterone level: Check total and free testosterone by equilibrium dialysis, as men with PAI often have concurrent hypogonadism 1

Secondary Evaluation

Thyroid Function Assessment

• TSH and free T4: Hypothyroidism causes decreased DHEA-S and pregnenolone levels through reduced steroid synthesis 3
• Serum concentrations of DHEA, DHEA-S, and pregnenolone sulfate are all significantly lower in hypothyroid patients compared to controls 3

Additional Hormonal Testing

• Luteinizing hormone (LH) and follicle-stimulating hormone (FSH): If testosterone is low, measure these to distinguish primary from secondary hypogonadism 1
• Sex hormone-binding globulin (SHBG): Essential in men with obesity or borderline testosterone, as low SHBG can falsely lower total testosterone 1

Imaging Studies

When to Order Adrenal Imaging

• Adrenal CT or MRI: Obtain if PAI is confirmed to identify structural causes (autoimmune adrenalitis, hemorrhage, infiltrative disease, metastases) 1, 2
• Pituitary MRI: Consider if secondary adrenal insufficiency is suspected (low ACTH with low cortisol) 1

Clinical Context Assessment

Key Historical and Physical Examination Findings

Look for specific signs and symptoms that guide the work-up:

• Symptoms of adrenal insufficiency: Fatigue, weight loss, hypotension, salt craving, hyperpigmentation (in PAI specifically) 1
• Symptoms of hypogonadism: Decreased libido, erectile dysfunction, reduced muscle mass, decreased energy 1
• Signs of hypothyroidism: Cold intolerance, constipation, weight gain, bradycardia 3
• Medication review: Glucocorticoids, opioids, and other medications can suppress the hypothalamic-pituitary-adrenal axis 1

Important Caveats

Measurement Considerations

• Use LC-MS/MS when available: Immunoassays for DHEA-S show significant standardization problems with slopes ranging from 0.84 to 1.28 compared to mass spectrometry 4, 5
• Timing matters: Draw morning samples (8-10 AM) for cortisol and testosterone to ensure accurate interpretation 1
• Cholesterol autoxidation artifact: Be aware that inappropriate sample handling can cause artifactual DHEA and pregnenolone from cholesterol breakdown 6

Clinical Pitfalls to Avoid

• Do not assume isolated DHEA-S deficiency is benign: Low DHEA-S is a characteristic finding in PAI, which has significant morbidity and mortality if untreated 1, 2
• Do not overlook obesity as a confounder: Obesity lowers total testosterone through decreased SHBG; always check free testosterone in men with obesity 1
• Do not delay treatment if PAI is confirmed: This is a medical emergency requiring immediate glucocorticoid and mineralocorticoid replacement 1

Treatment Implications

If PAI is confirmed with low DHEA-S:

• DHEA replacement in men with PAI: Unlike women, men with PAI typically do not require DHEA supplementation as testicular testosterone production provides adequate androgens 1, 2
• Focus on glucocorticoid and mineralocorticoid replacement: Hydrocortisone 15-25 mg daily in divided doses and fludrocortisone 0.05-0.2 mg daily are the priorities 1
• Consider DHEA trial only if: Persistent symptoms despite optimized replacement therapy, though evidence of benefit in men is limited 1, 2