What is the management approach for a female patient with significantly elevated Dehydroepiandrosterone sulfate (DHEA-S) levels?

Management of DHEA-S 311 μg/dL in a Woman

A DHEA-S level of 311 μg/dL (3110 ng/mL) in a woman requires urgent evaluation for adrenocortical carcinoma with immediate adrenal CT imaging, as this level is significantly elevated and approaches the threshold that strongly suggests malignancy. 1

Immediate Risk Stratification

Your patient's DHEA-S level of 311 μg/dL (3110 ng/mL) is concerning and requires urgent action. The American College of Endocrinology recommends evaluating patients with DHEAS >6000 ng/ml urgently for adrenal carcinomas, and while your patient is below this threshold, the level is still markedly elevated and warrants immediate investigation. 1

Critical Red Flags to Assess Immediately

• Rapidly progressive virilization symptoms (voice deepening, male-pattern baldness, clitoromegaly, increased muscle mass) strongly suggest malignancy and should not be delayed. 1
• Menstrual irregularity (oligomenorrhea or amenorrhea) is common with androgen-secreting tumors. 1
• Hirsutism with male escutcheon pattern. 2
• Timeline of symptom onset - rapid progression over weeks to months favors malignancy over benign conditions. 1

Diagnostic Algorithm

Step 1: Complete Hormone Panel (Obtain Immediately)

Order the following tests on the same morning blood draw: 1

• Free and total testosterone
• Androstenedione (rule out adrenal/ovarian tumor if >10.0 nmol/L) 2
• LH and FSH (calculate LH/FSH ratio)
• 17-hydroxyprogesterone (screen for non-classical congenital adrenal hyperplasia)
• Morning ACTH and cortisol (distinguish adrenal from pituitary sources)

Step 2: Imaging Studies

Obtain adrenal CT scan with contrast immediately - do not wait for hormone results if clinical virilization is present. 1 Look for:

• Tumor size >4-5 cm (highly suspicious for malignancy) 1
• Irregular margins or heterogeneous appearance 1
• Lipid-poor lesions that fail to wash out on contrast-enhanced CT 1
• Multiple hormone secretion 1

Obtain transvaginal ultrasound to assess for polycystic ovaries (>10 peripheral cysts, 2-8 mm diameter) and ovarian masses. 2, 1

Step 3: Rule Out Non-Classical Congenital Adrenal Hyperplasia

This must be excluded first, particularly since age-specific thresholds are exceeded (>3800 ng/ml for ages 20-29 or >2700 ng/ml for ages 30-39). 1 The 17-hydroxyprogesterone level will guide this assessment. 1

Differential Diagnosis by DHEA-S Level

Your Patient's Level (3110 ng/mL):

Most likely diagnoses in order of concern:

1. Adrenocortical carcinoma - approximately 60% present with virilization symptoms; peak incidence in fourth to fifth decades with female-to-male ratio of 1.5:1. 1

2. Non-classical congenital adrenal hyperplasia - must be ruled out with 17-hydroxyprogesterone and 21-hydroxylase antibodies. 1

3. Polycystic ovary syndrome (PCOS) - affects 4-6% of women in general population; characterized by LH/FSH ratio >2, testosterone >2.5 nmol/L, and polycystic ovaries on ultrasound. 2

4. Benign adrenal adenoma - less likely with this degree of elevation but possible. 1

Management Based on Findings

If Adrenal Mass Identified:

Unilateral adrenalectomy is recommended for adrenal masses causing androgen excess, with minimally-invasive surgery when feasible. 3 However, if malignancy is suspected (size >4-5 cm, irregular margins, heterogeneous), open adrenalectomy is preferred as these tumors are prone to rupture. 2

If No Mass Found and PCOS Diagnosed:

• Assess for metabolic complications: fasting glucose/insulin ratio (ratio >4 suggests reduced insulin sensitivity), BMI, waist/hip ratio. 2
• Mid-luteal phase progesterone (<6 nmol/L indicates anovulation). 2
• Address menstrual irregularity and metabolic dysfunction. 2

If Non-Classical CAH Confirmed:

• Refer to endocrinology for glucocorticoid management. 1

Critical Pitfalls to Avoid

• Do not delay imaging when rapidly progressive virilization is present - this strongly suggests malignancy and requires immediate evaluation. 1
• Do not assume PCOS without excluding adrenal pathology first - the positive predictive value of elevated androgens for tumors is low (9%), but missing a malignancy has devastating consequences. 4
• Do not measure DHEA-S post-ictally in patients with epilepsy - this can falsely elevate levels. 2
• Do not ignore medication history - valproate can cause modest testosterone elevation and PCOS-like syndrome. 2

Special Considerations

In males with very high DHEAS, measure very long-chain fatty acids in serum to rule out adrenoleukodystrophy, which can cause elevated DHEAS without tumor. 1 This is not applicable to your female patient but important to note for differential diagnosis.

The combination of heterozygous mutations in steroid sulfatase and BCRP genes has been reported to cause very high DHEAS without tumor in rare cases, but this should only be considered after excluding all other pathology. 5