What does an elevated Dehydroepiandrosterone sulfate (DHEAS) level indicate in a 36-year-old female patient with hirsutism?

Elevated DHEAS in a 36-Year-Old Female with Hirsutism

In a 36-year-old woman with hirsutism, an elevated DHEAS primarily indicates increased adrenal androgen production, most commonly from polycystic ovary syndrome (PCOS), but markedly elevated levels (>600 μg/dL or >6000 ng/mL) should prompt urgent evaluation for adrenocortical carcinoma or other androgen-secreting tumors. 1, 2, 3

Primary Diagnostic Considerations

Most Common Cause: PCOS

• PCOS accounts for approximately 95% of hyperandrogenism cases and affects 10-13% of women globally, making it the overwhelmingly most likely diagnosis in this clinical scenario 4, 1
• Only 8-33% of PCOS patients actually have elevated DHEAS when age-adjusted reference ranges are used, meaning DHEAS is not a first-line diagnostic marker for PCOS due to poor specificity compared to total or free testosterone 1
• The International PCOS Guidelines recommend DHEAS only as a second-line test when total testosterone and free testosterone are not elevated but clinical suspicion remains high 1

Critical Red Flags Requiring Urgent Evaluation

Immediate imaging with adrenal CT is mandatory if: 2, 3

• DHEAS >600 μg/dL (some sources use >6000 ng/mL as the threshold for urgent concern) 3
• Rapid onset of virilization (developing over weeks to months rather than years) 2
• Presence of severe virilization signs: clitoromegaly, voice deepening, or male-pattern baldness 4, 2
• Very high total testosterone (>8.7 nmol/L or 250 ng/dL) combined with elevated DHEAS 5

Age-Specific DHEAS Thresholds

For this 36-year-old patient, DHEAS >2700 ng/mL warrants investigation for non-classical congenital adrenal hyperplasia 4, 2

• Age 20-29: >3800 ng/mL is abnormal 4
• Age 30-39: >2700 ng/mL is abnormal 4
• DHEAS levels peak between ages 20-30 and decline steadily thereafter, so age-adjusted reference ranges are essential 1

Differential Diagnosis by Source

Adrenal Sources (DHEAS typically elevated)

1. Adrenocortical carcinoma (ACC): ACC is responsible for more than half of androgen hypersecretion cases and should be suspected with DHEAS >600 μg/dL, tumors >4-5 cm, irregular margins, or heterogeneity on imaging 4, 2
2. Non-classical congenital adrenal hyperplasia: Suggested by DHEAS exceeding age-specific thresholds; confirm with 17-hydroxyprogesterone measurement and ACTH stimulation testing 2, 6
3. Functional adrenal hyperandrogenism: Revealed by ACTH stimulation testing showing subtle steroidogenic defects; 61% of hirsute women in one study had such defects 6

Ovarian Sources (DHEAS may be normal or mildly elevated)

1. PCOS: Most common cause; typically presents with gradual onset hirsutism, oligomenorrhea, and acne without severe virilization 1
2. Ovarian androgen-secreting tumors: Rare but important; typically present with testosterone >8.7 nmol/L and rapid virilization 5
3. Ovarian hyperthecosis: Associated with insulin resistance and normal DHEAS despite elevated testosterone 3

Important caveat: While DHEAS is presumed to be exclusively of adrenal origin, rare cases of ovarian sex cord-stromal tumors can produce markedly elevated DHEAS despite the lack of sulfotransferase in ovarian tissue 7

Recommended Diagnostic Algorithm

Step 1: First-Line Hormonal Testing (Morning Sample)

• Total testosterone and free testosterone by LC-MS/MS (TT sensitivity 74%, specificity 86%; FT sensitivity 89%, specificity 83%) 4, 1
• If LC-MS/MS unavailable, calculate free androgen index (FAI = total testosterone/SHBG ratio) 1
• DHEAS (already obtained in this case) 1
• LH and FSH (LH/FSH ratio >2 suggests PCOS) 1

Step 2: Additional Hormonal Evaluation

• 17-hydroxyprogesterone to rule out non-classical congenital adrenal hyperplasia, particularly since DHEAS exceeds age-specific threshold 2
• Prolactin and TSH to exclude hyperprolactinemia and thyroid disease 1, 2
• Androstenedione if testosterone levels are normal but clinical suspicion remains high (sensitivity 75%, specificity 71%) 1

Step 3: Metabolic Screening

• Fasting glucose and 2-hour oral glucose tolerance test for insulin resistance and diabetes 1, 2
• Fasting lipid panel for cardiovascular risk assessment 1, 2

Step 4: Imaging Studies (Based on Hormonal Results)

Obtain adrenal CT scan if: 2

• DHEAS >600 μg/dL (or >6000 ng/mL depending on units)
• Clinical signs of severe virilization
• 17-hydroxyprogesterone negative for congenital adrenal hyperplasia

Obtain pelvic ultrasound for: 2

• Suspected PCOS (look for >10 peripheral cysts 2-8 mm diameter)
• Elevated testosterone with normal DHEAS (suggests ovarian source)

Step 5: Advanced Testing if Indicated

• ACTH stimulation test if subtle adrenal steroidogenic defects suspected; basal DHEAS levels do not predict ACTH response 6
• Dexamethasone suppression testing to distinguish functional from neoplastic causes when imaging shows adrenal masses 4, 8
• Adrenal vein sampling for lateralization if surgical intervention considered 4

Clinical Pitfalls to Avoid

1. Do not rely solely on DHEAS for diagnosis: Basal DHEAS levels are not predictive of the underlying cause and may be misleading; 13 patients with defective steroidogenesis had normal DHEAS in one study 6

2. Do not assume all elevated DHEAS is adrenal: Rare ovarian tumors can produce DHEAS despite conventional teaching 7

3. Do not use direct immunoassay for free testosterone: Poor accuracy at low serum concentrations; use equilibrium dialysis or calculated FAI instead 1

4. Do not ignore SHBG fluctuations: SHBG is reduced with obesity, metabolic syndrome, and family history of diabetes, affecting interpretation of total testosterone and FAI 3, 8

5. Do not screen with DHEAS alone for tumors: The positive predictive value of elevated DHEAS for neoplasm is extremely low (specificity 98% but only 2.3% of patients with testosterone >8.7 nmol/L actually had tumors) 5

Management Implications

If PCOS is confirmed (most likely in this case): 1

• Combined oral contraceptives as first-line treatment to regulate cycles and reduce hyperandrogenism
• Lifestyle modifications including diet and exercise for weight management
• Screen for and manage metabolic complications, particularly insulin resistance

If adrenal tumor suspected: 4

• Unilateral adrenalectomy for confirmed ACC; minimally invasive surgery when feasible
• Open adrenalectomy if malignancy suspected (tumors >5 cm, irregular margins, local invasion)
• Postoperative corticosteroid supplementation required until HPA axis recovery

If non-classical congenital adrenal hyperplasia confirmed: 8

• Glucocorticoid therapy may reduce hirsutism, acne, and normalize menses in patients with dexamethasone-suppressible hyperandrogenemia