What is the best course of action to manage elevated Dehydroepiandrosterone sulfate (DHEA-s) levels with normal cortisol, thyroid, and Hemoglobin A1c (HbA1c) levels?

Management of Isolated DHEA-S Elevation

Rule out an androgen-secreting adrenal tumor immediately with adrenal CT imaging, as this is the most critical diagnosis to exclude when DHEA-S is elevated above the reference range. 1, 2

Immediate Diagnostic Priorities

The first step is urgent imaging to exclude malignancy, particularly since approximately 60% of androgen-secreting adrenocortical tumors present with evidence of adrenal steroid hormone excess. 2 Your patient's DHEA-S levels of 392-463 μg/dL (reference 84-378) represent mild-to-moderate elevation rather than the dramatically elevated levels typically seen with tumors, but imaging cannot be deferred. 2

Key Imaging Characteristics to Assess:

• Obtain adrenal CT with contrast washout protocol to evaluate for adenoma versus carcinoma 3, 1
• Suspect malignancy if tumor is >4-5 cm, has irregular margins, is internally heterogeneous, or shows poor contrast washout (<60% at 15 minutes) 3, 2
• On unenhanced CT, Hounsfield units >10 suggest possible malignancy and warrant enhanced imaging with washout assessment 3
• Look for adjacent lymph nodes, liver metastases, or local invasion 3

Clinical Assessment for Virilization

Examine carefully for signs of androgen excess that would heighten concern for a tumor: 2, 4

• Rapidly progressive hirsutism, acne, or male-pattern baldness
• Clitoromegaly or deepening voice
• Increased muscle mass or temporal balding
• Note: The absence of virilization does NOT exclude a tumor - 77% of women with elevated DHEA-S in one series were nonhirsute 5

Functional Testing

If imaging is negative for a mass, perform dexamethasone suppression testing to distinguish functional hypersecretion from autonomous production: 3, 6

• Administer dexamethasone 0.5 mg at bedtime for 2 weeks 4
• Recheck DHEA-S levels - marked suppression suggests functional adrenal hyperactivity rather than tumor 6, 4
• Failure to suppress raises concern for autonomous production and may warrant repeat imaging or further evaluation 3

Common Causes of Isolated DHEA-S Elevation

Once tumor is excluded, consider these etiologies:

Polycystic Ovary Syndrome (PCOS)

• DHEA-S is elevated in 34% of oligomenorrheic women and 60% of hirsute patients 4
• 50% of anovulatory infertility patients have elevated DHEA-S 5
• Some patients have mild 3β-hydroxysteroid dehydrogenase deficiency contributing to elevation 5

Functional Adrenal Hyperandrogenism

• Isolated bilateral adrenal DHEA-S hypersecretion can occur without other hormonal abnormalities 6
• This represents functional rather than neoplastic overproduction 6
• Responds to dexamethasone suppression 6, 4

Rare Genetic Variants

• Heterozygous mutations in steroid sulfatase (STS) or transporter proteins (BCRP) can cause isolated DHEA-S elevation 7
• Consider genetic testing only if other causes excluded and family history suggestive 7

Management Strategy

If Imaging Shows Adrenal Mass:

Surgical resection is first-line treatment: 1, 2

• Laparoscopic adrenalectomy for benign-appearing tumors (<4 cm, homogeneous, regular margins) 1, 2
• Open adrenalectomy for suspected malignancy (>4-5 cm, irregular margins, heterogeneous) 3, 1, 2

If No Mass Identified (Functional Hypersecretion):

Medical management with ketoconazole 400-1200 mg/day can inhibit adrenal steroidogenesis and reduce DHEA production 3, 1, 2

Monitoring requirements on ketoconazole: 1, 2

• Liver function tests regularly due to hepatotoxicity risk
• Periodic DHEA-S levels to assess treatment efficacy
• Watch for signs of adrenal insufficiency (fatigue, hypotension, hyponatremia) with excessive suppression

Alternative approach - low-dose dexamethasone: 4

• 0.5 mg at bedtime can suppress adrenal androgen production
• Monitor for iatrogenic Cushing's syndrome (weight gain, hypertension, hyperglycemia, bruising) 3

Critical Pitfalls to Avoid

• Never delay imaging when DHEA-S is elevated - rapidly progressive virilization strongly suggests malignancy requiring urgent intervention 2
• Do not confuse elevated DHEA-S with primary adrenal insufficiency, where DHEA levels are typically low rather than elevated 3, 1, 2
• Do not rely solely on presence or absence of virilization - many patients with elevated DHEA-S are nonhirsute 5
• Avoid assuming PCOS without excluding tumor - obtain imaging first before attributing elevation to functional causes 2, 4

Your Patient's Context

Given normal cortisol (excludes Cushing's syndrome), normal thyroid, and HbA1c 5.4% (excludes significant insulin resistance/diabetes), your patient likely has either: 3

1. Functional adrenal hyperandrogenism (most likely if imaging negative)
2. Small adrenal adenoma (requires imaging to exclude)
3. PCOS-related elevation (if oligomenorrheic or anovulatory)

The normal cortisol makes Cushing's syndrome unlikely, and the modest DHEA-S elevation (1.2-1.5× upper limit) is more consistent with functional hypersecretion than malignancy, but imaging remains mandatory. 3, 2