Elevated DHEA-S: Clinical Significance and Management
Primary Interpretation
Elevated DHEA-S indicates adrenal androgen excess and requires systematic evaluation to distinguish between benign conditions like PCOS and serious pathology such as adrenocortical carcinoma. 1, 2
The clinical approach depends critically on the degree of elevation and associated symptoms. DHEA-S serves as a marker for adrenal hyperfunction, with different thresholds suggesting different underlying pathologies. 1
Initial Clinical Assessment
Key Signs and Symptoms to Evaluate
Look for specific manifestations of androgen excess:
- In women: Hirsutism, androgenetic alopecia, acne, male-pattern baldness, menstrual irregularities (oligomenorrhea), and clitoromegaly 1, 2
- Signs of virilization (concerning for malignancy): Deepening voice, increased muscle mass, rapid progression of symptoms 3, 2
- In children: Early-onset body odor, premature axillary or pubic hair, accelerated growth velocity, advanced bone age, and genital maturation 1
- Associated endocrine features: Truncal obesity, hypertension, hyperglycemia (suggesting Cushing's syndrome) 2
The rapidity of symptom onset is critical—sudden or rapidly progressive virilization strongly suggests an androgen-secreting tumor and requires urgent imaging. 4, 5
Differential Diagnosis by DHEA-S Level
Moderate Elevations (Most Common)
Polycystic ovary syndrome (PCOS) is the most common cause, affecting 4-6% of women, characterized by menstrual irregularity, hirsutism, acne, and often obesity. 2, 6
- DHEA-S has moderate diagnostic accuracy for PCOS with sensitivity and specificity around 70-75% 6
- Clinical diagnosis based on Rotterdam criteria is often sufficient for moderate elevations with typical PCOS features 2
Non-classical congenital adrenal hyperplasia (NCAH) must be excluded, particularly when DHEA-S exceeds age-specific thresholds (>3800 ng/mL for ages 20-29, >2700 ng/mL for ages 30-39). 1
Very High Elevations (>8.7 nmol/L testosterone or markedly elevated DHEA-S)
Very high DHEA-S levels raise concern for adrenocortical carcinoma (ACC), which accounts for more than half of androgen hypersecretion cases. 3
- Malignancy should be suspected if the tumor is larger than 3 cm, has irregular morphology, is lipid-poor, or secretes multiple hormones 3
- Total testosterone >8.7 nmol/L (250 ng/dL) has 100% sensitivity but only 9% positive predictive value for androgen-secreting neoplasms 5
- DHEA-S >16.3 μmol/L (6000 ng/mL) warrants aggressive tumor evaluation, though specificity is 98% 5
Diagnostic Workup Algorithm
Initial Hormone Panel (All Patients)
Obtain the following tests to characterize the androgen excess: 1
- Free and total testosterone
- LH and FSH
- Sex hormone binding globulin (SHBG) and free androgen index
- 17-hydroxyprogesterone (early morning, follicular phase) to screen for NCAH 4
Additional Testing Based on Clinical Context
For suspected Cushing's syndrome (truncal obesity, hypertension, glucose intolerance): 3, 2
- 1 mg overnight dexamethasone suppression test
- 24-hour urinary free cortisol
- Morning ACTH level
For metabolic assessment in PCOS: 1
- Fasting insulin and glucose
- Lipid panel
Imaging Studies
Adrenal CT or MRI is mandatory when: 3, 2, 6
- DHEA-S is very high (>16.3 μmol/L or >6000 ng/mL)
- Rapid symptom progression
- Signs of virilization present
- Suspected ACC based on clinical features
Pelvic ultrasound in women to evaluate ovarian pathology, particularly for PCOS diagnosis or to exclude ovarian tumors. 2, 6
Important caveat: The positive predictive value of biochemical screening alone for tumors is low (9% for testosterone >8.7 nmol/L), so clinical judgment regarding imaging is paramount. 5 However, the negative predictive value is 100%, meaning normal levels effectively exclude tumors. 5
Management Strategies
For PCOS-Related Elevation (Most Common Scenario)
Weight loss is first-line therapy for overweight or obese patients with PCOS-related DHEA-S elevation. 2, 6
Hormonal contraceptives regulate menstrual cycles and reduce androgen effects. 2, 6
Metformin or other insulin-sensitizing agents if insulin resistance is documented. 2, 6
Anti-androgen therapy (spironolactone) for persistent hirsutism or acne despite above measures. 2, 6
For Non-Classical CAH
A significant decrease in testosterone and DHEA-S with a 2-day dexamethasone suppression test confirms NCAH. 4
- Treatment typically involves low-dose glucocorticoid replacement if symptomatic
For Suspected or Confirmed Adrenal Tumors
When ACC is suspected based on imaging characteristics (>3 cm, irregular morphology, lipid-poor, multiple hormone secretion), open adrenalectomy is recommended as these tumors are prone to rupture. 3
For benign cortisol-secreting adenomas with clinical Cushing's syndrome, unilateral adrenalectomy via minimally invasive surgery is indicated. 3
- Postoperative corticosteroid supplementation is required until HPA axis recovery 3
For Premature Adrenarche in Children
Regular monitoring without specific treatment is appropriate, with follow-up every 6-12 months to assess growth velocity, bone age, and pubertal development. 6
Monitoring and Follow-Up
Repeat DHEA-S measurements every 3-6 months until normalized or stable. 2, 6
Monitor clinical symptoms of androgen excess and assess for treatment response (improvement in hirsutism, acne, menstrual regularity). 2, 6
Long-term follow-up for persistent elevations is essential to detect evolving pathology, particularly in cases where initial workup was negative for tumors. 2, 6
Critical Pitfalls to Avoid
Do not rely solely on biochemical thresholds for tumor diagnosis—clinical presentation (rapidity of onset, virilization) is equally important. 4, 5
Do not miss Cushing's syndrome in patients with recent-onset hyperandrogenism and accompanying hypercortisolism features. 4
Do not forget to exclude hyperprolactinemia in women with recent oligomenorrhea and mild hyperandrogenism. 4
Do not assume all elevated DHEA-S is pathologic—rare cases of isolated DHEA-S hypersecretion of functional (non-neoplastic) nature exist, confirmed by dexamethasone suppression. 7