How should I evaluate and treat an adult with low dehydroepiandrosterone sulfate (DHEAS) presenting with fatigue, low libido, and mood changes in the absence of diagnosed adrenal or pituitary disease?

Evaluation and Management of Low DHEAS in Adults with Fatigue, Low Libido, and Mood Changes

In adults with low DHEAS presenting with fatigue, low libido, and mood changes, you must first exclude adrenal insufficiency with morning cortisol and ACTH measurements, followed by cosyntropin stimulation testing if initial results are indeterminate—only after ruling out adrenal pathology should you consider DHEA replacement therapy as a pragmatic 6-month trial in women with persistent symptoms despite optimized management. 1, 2

Step 1: Rule Out Adrenal Insufficiency (Critical First Step)

Low DHEAS can be a marker of underlying adrenal pathology that requires immediate recognition and treatment. 3

Initial Diagnostic Workup

• Obtain morning (8 AM) serum cortisol and plasma ACTH simultaneously as your first-line tests to assess the hypothalamic-pituitary-adrenal axis. 2
• Measure basic metabolic panel (sodium, potassium, CO2, glucose) to identify electrolyte abnormalities commonly seen in adrenal insufficiency. 2
• Basal cortisol <250 nmol/L (<9 μg/dL) with elevated ACTH in acute illness is diagnostic of primary adrenal insufficiency. 2, 4
• Basal cortisol <400 nmol/L (<14.5 μg/dL) with elevated ACTH raises strong suspicion and warrants further testing. 2

When to Perform Cosyntropin Stimulation Test

• If morning cortisol is indeterminate (140-400 nmol/L or 5-14.5 μg/dL), proceed with cosyntropin stimulation testing to definitively rule in or rule out adrenal insufficiency. 2
• Administer 0.25 mg (250 mcg) cosyntropin IV or IM, with cortisol measurements at baseline, 30 minutes, and 60 minutes post-administration. 2
• Peak cortisol <500 nmol/L (<18 μg/dL) at either 30 or 60 minutes is diagnostic of adrenal insufficiency. 2
• Peak cortisol >550 nmol/L (>18-20 μg/dL) excludes adrenal insufficiency. 2

Critical Pitfall to Avoid

• Never delay treatment if the patient presents with unexplained hypotension, collapse, or severe gastrointestinal symptoms—give 100 mg IV hydrocortisone immediately plus 0.9% saline infusion at 1 L/hour, and draw cortisol/ACTH before treatment if possible. 2, 5
• Hyponatremia is present in 90% of newly diagnosed adrenal insufficiency cases, but the absence of hyperkalemia cannot rule out the diagnosis as it occurs in only ~50% of cases. 2, 5

Step 2: Determine Etiology if Adrenal Insufficiency is Confirmed

Primary vs. Secondary Adrenal Insufficiency

• Primary adrenal insufficiency: high ACTH with low cortisol, often with hyponatremia and hyperkalemia. 2
• Secondary adrenal insufficiency: low or inappropriately normal ACTH with low cortisol, without mineralocorticoid deficiency. 2

Etiologic Workup for Primary Adrenal Insufficiency

• Measure 21-hydroxylase (anti-adrenal) autoantibodies first, as autoimmunity accounts for ~85% of primary adrenal insufficiency cases in Western populations. 2
• If autoantibodies are negative, obtain CT imaging of the adrenals to evaluate for hemorrhage, tumors, tuberculosis, or other structural causes. 2
• In male patients with negative antibodies, assay very long-chain fatty acids (VLCFA) to check for adrenoleukodystrophy. 2

Step 3: Consider DHEA Replacement (Only After Excluding Adrenal Pathology)

Who Benefits from DHEA Replacement

• DHEA replacement is specifically indicated for women with primary adrenal insufficiency who have persistent lack of libido and/or low energy levels despite optimized glucocorticoid and mineralocorticoid replacement. 1
• The evidence for clinical benefit is limited, but a pragmatic approach is reasonable. 1

DHEA Replacement Protocol

• Offer a 6-month trial of oral DHEA 25 mg as a single daily dose to women with persistent symptoms. 1
• Guide dosing by measuring serum DHEAS, androstenedione, and testosterone levels in the morning prior to DHEA ingestion—maintain levels in the normal range. 1
• Continue DHEA only if clinically effective after 6 months; discontinue if no improvement. 1

Important Caveats About DHEA Replacement

• Long-term effects of DHEA replacement therapy are not known, so use with caution. 1
• DHEA replacement is not recommended for men with age-related low testosterone to improve energy, vitality, physical function, or cognition. 1
• Over-the-counter DHEA preparations lack pharmacokinetic and pharmacodynamic data and should be avoided in favor of pharmaceutical-grade products. 6

Step 4: Exclude Other Causes of Low DHEAS

Medication-Related Causes

• Exogenous corticosteroids (prednisone, prednisolone, inhaled fluticasone) suppress the HPA axis and cause iatrogenic secondary adrenal insufficiency with low DHEAS. 2
• Do not attempt diagnostic testing while the patient is on corticosteroids—wait until treatment is discontinued with adequate washout time. 2

Disease-Related Causes

• Low DHEAS is associated with multiple age-related conditions including atrial fibrillation, chronic obstructive lung disease, dementia, cancer, diabetes, hypothyroidism, osteoporosis, and inflammatory arthritis. 7, 8
• However, low DHEAS in elderly people is more a non-specific indicator of aging and health status than a risk indicator of specific diseases. 7
• In the context of adrenal incidentalomas, low DHEAS levels can be a marker of adrenocortical tumor and warrant further evaluation with CT imaging. 3

Reproductive Endocrine Disorders in Women

• In women with epilepsy or polycystic ovary syndrome (PCOS), measure DHEAS as part of the reproductive endocrine workup. 1
• DHEAS >3800 ng/mL in women aged 20-29 or >2700 ng/mL in women aged 30-39 should prompt evaluation for non-classical congenital adrenal hyperplasia. 1

Step 5: Management if No Adrenal Pathology is Found

When DHEA Replacement is NOT Indicated

• Do not initiate DHEA replacement in men with age-related low DHEAS to improve energy, vitality, physical function, or cognition—the evidence does not support this practice. 1
• In patients without adrenal insufficiency, low DHEAS alone does not warrant treatment unless the patient is a woman with persistent symptoms affecting quality of life. 1

Alternative Considerations

• Evaluate and treat other potential causes of fatigue, low libido, and mood changes including thyroid dysfunction, depression, sleep disorders, and chronic medical conditions. 1
• In men with sexual dysfunction and age-related low testosterone, consider testosterone replacement therapy according to established guidelines, but reevaluate symptoms within 12 months and discontinue if no improvement. 1