What is the significance of an elevated Dehydroepiandrosterone sulfate (DHEA-S) level in a female patient?

Elevated DHEA-S in Women: Clinical Significance and Management

Immediate Assessment Required

A DHEA-S level of 311 μg/dL (3,110 ng/mL) in a woman is moderately elevated and requires systematic evaluation to rule out adrenocortical carcinoma, non-classical congenital adrenal hyperplasia, and polycystic ovary syndrome, with the urgency of workup determined by the presence or absence of rapidly progressive virilization symptoms. 1, 2

Determining Clinical Urgency

High-Risk Features Requiring Immediate Imaging

• Rapidly progressive virilization (voice deepening, male-pattern baldness, clitoromegaly, increased muscle mass developing over weeks to months) strongly suggests malignancy and mandates immediate adrenal CT imaging regardless of DHEA-S level 1, 3
• While levels >6,000 ng/mL demand urgent evaluation for adrenocortical carcinoma, your patient's level of 3,110 ng/mL still warrants prompt investigation as approximately 60% of adrenocortical carcinomas present with virilization symptoms 1, 3

Standard-Risk Features

• Gradual onset hirsutism with male escutcheon pattern 1
• Menstrual irregularity (oligomenorrhea or amenorrhea) 1
• Absence of rapid symptom progression suggests benign etiology but does not exclude it 1

Diagnostic Algorithm

Initial Hormone Panel (Same Morning Blood Draw)

Order the following tests simultaneously: 1, 3, 2

• Total and free testosterone (ovarian vs. adrenal source)
• Androstenedione (rule out adrenal/ovarian tumor if >10.0 nmol/L)
• 17-hydroxyprogesterone (screen for non-classical congenital adrenal hyperplasia, which must be ruled out given DHEA-S exceeds age-specific thresholds)
• Morning ACTH and cortisol (distinguish adrenal from pituitary sources)
• LH and FSH (calculate LH/FSH ratio for PCOS assessment)
• Sex hormone binding globulin (SHBG) (calculate free androgen index)

Imaging Studies

Adrenal CT scan with contrast is indicated when: 1, 3, 2

• Clinical virilization is present (do not wait for hormone results)
• 21-hydroxylase antibodies are negative
• DHEA-S remains unexplained after initial hormone panel

Look for concerning features on CT: 1

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

Transvaginal ultrasound to assess for: 1, 2

• Polycystic ovaries (>10 peripheral cysts, 2-8 mm diameter)
• Ovarian masses

Differential Diagnosis in Order of Clinical Concern

1. Adrenocortical Carcinoma

• Peak incidence in fourth to fifth decades with female-to-male ratio of 1.5:1 1
• Approximately 60% present with virilization symptoms 1, 3
• Critical pitfall: Do not delay imaging when rapidly progressive virilization is present 3

2. Non-Classical Congenital Adrenal Hyperplasia

• Must be ruled out first, particularly when DHEA-S exceeds age-specific thresholds (>3,800 ng/mL for ages 20-29 or >2,700 ng/mL for ages 30-39) 3, 2
• Confirm with 17-hydroxyprogesterone and 21-hydroxylase antibodies 1, 3

3. Polycystic Ovary Syndrome (PCOS)

• Most common cause of elevated androgens in reproductive-age women, affecting 4-6% of women 1, 2
• Elevated DHEA-S found in 20-33% of PCOS patients, with higher prevalence in non-classic (B or C) phenotypes 4, 5
• Diagnose using 2 of 3 criteria: androgen excess, ovulatory dysfunction, and polycystic ovaries on ultrasound 2
• LH/FSH ratio >2, testosterone >2.5 nmol/L support diagnosis 1

4. Benign Adrenal Adenoma

• Less likely with this degree of elevation but possible 2
• Requires imaging to exclude 6

Management Based on Diagnosis

If Adrenal Mass Identified

• Unilateral adrenalectomy is recommended for adrenal masses causing androgen excess, with minimally-invasive surgery when feasible 6, 1
• If malignancy suspected (size >4-5 cm, irregular margins, heterogeneous appearance), open adrenalectomy is preferred as these tumors are prone to rupture 1

If PCOS Confirmed

Assess for metabolic complications: 1

• Fasting glucose/insulin ratio (ratio >4 suggests reduced insulin sensitivity)
• BMI and waist/hip ratio
• Address menstrual irregularity and metabolic dysfunction

If Non-Classical CAH Confirmed

• Refer to endocrinology for glucocorticoid management 1

If No Pathology Identified

• Repeat DHEA-S in 3-6 months to assess for progression if symptoms are mild 2

Important Clinical Pearls

• Positive predictive value of elevated DHEA-S for tumor is only 9% due to low frequency of the disorder, but negative predictive value is 100% 7
• Women with elevated DHEA-S in PCOS paradoxically have more favorable metabolic profiles (higher insulin sensitivity, better lipid profiles) compared to those with normal DHEA-S 8
• DHEA-S levels are age-dependent, declining by approximately 40% from the twenties to thirties 5
• In PCOS, elevated DHEA-S is generally part of generalized higher androgen production and is more common in non-classic phenotypes 5