Elevated DHEA-Sulfate: Clinical Significance and Diagnostic Approach
Elevated DHEA-sulfate (DHEAS) indicates excessive adrenal androgen production and requires systematic evaluation to identify the underlying cause, which ranges from benign conditions like polycystic ovary syndrome to serious pathology including androgen-secreting tumors and non-classical congenital adrenal hyperplasia.
Primary Clinical Significance
Elevated DHEAS reflects increased adrenal androgen secretion and serves as a marker for several distinct pathophysiologic processes 1:
- In primary adrenal insufficiency, DHEAS levels are characteristically LOW, not elevated 2
- Elevated levels suggest adrenal hyperfunction or androgen excess syndromes 1
Major Causes to Consider
Non-Classical Congenital Adrenal Hyperplasia
- This must be ruled out first, particularly when DHEAS exceeds age-specific thresholds (>3800 ng/ml for ages 20-29, >2700 ng/ml for ages 30-39) 1
- Represents subtle defects in adrenal steroidogenesis that manifest with androgen excess 3
- ACTH stimulation testing reveals compromised steroidogenesis in approximately 61% of hirsute women, even when basal DHEAS levels appear normal 3
Polycystic Ovary Syndrome (PCOS)
- PCOS involves accelerated pulsatile GnRH secretion, insulin resistance, and metabolic dysregulation 1
- DHEAS is elevated in only 20-34% of women with PCOS-related oligomenorrhea 4, 5
- Importantly, 75.8% of hyperandrogenic women have elevated testosterone, while only 20% have elevated DHEAS 4
Androgen-Secreting Tumors
- Very high DHEAS levels (>16.3 μmol/L or 6000 ng/ml) raise concern for adrenal tumors 6, 7
- However, the positive predictive value of elevated DHEAS for detecting tumors is extremely low due to the rarity of these neoplasms 7
- Clinical presentation (rapid virilization, severe symptoms) is more predictive than absolute DHEAS levels 7
Other Causes
- Rare genetic variants affecting steroid sulfatase or transporter proteins (BCRP, MRP2) can cause markedly elevated DHEAS without tumor 6
Diagnostic Approach
Clinical Assessment
Look for specific signs of hyperandrogenism 1:
In prepubertal children:
- Early-onset body odor
- Premature axillary or pubic hair
- Accelerated growth velocity
- Advanced bone age
- Genital maturation 1
In postpubertal females:
- Menstrual irregularities (oligomenorrhea, amenorrhea)
- Hirsutism (modified Ferriman-Gallwey score ≥6)
- Androgenetic alopecia
- Acne
- Infertility
- Clitoromegaly (suggests tumor)
- Truncal obesity 1, 4
Laboratory Evaluation
Initial hormone panel should include 1:
- Free and total testosterone
- DHEAS
- Androstenedione
- Luteinizing hormone (LH)
- Follicle-stimulating hormone (FSH)
Additional testing in selected cases 1:
- 17-hydroxyprogesterone (for 21-hydroxylase deficiency)
- ACTH stimulation test if non-classical CAH suspected 3
- Sex hormone binding globulin (SHBG)
- Free androgen index
- Insulin and glucose (for metabolic assessment)
Critical caveat: Basal DHEAS levels do NOT predict which patients have adrenal enzyme defects—ACTH stimulation testing is required 3. Additionally, 13% of patients with clinical hyperandrogenism have normal levels of all androgens measured 4.
Imaging Studies
- Pelvic ultrasound to evaluate for polycystic ovaries in females with suspected PCOS 1
- Adrenal CT or MRI only if DHEAS is markedly elevated (>6000 ng/ml) or clinical features suggest tumor (rapid virilization, severe symptoms) 7
- Routine imaging for tumor screening is NOT cost-effective given the low prevalence and poor positive predictive value of elevated DHEAS alone 7
Clinical Implications for Management
- Identifying the specific cause determines treatment strategy 1
- For non-classical CAH: Consider glucocorticoid therapy (chronic low-dose prednisone can suppress androgens in many patients) 4
- For PCOS: Address insulin resistance, metabolic factors, and ovulatory dysfunction 1
- Dexamethasone suppression testing (2-day protocol) can predict response to chronic glucocorticoid therapy better than basal DHEAS levels 4
Key Pitfalls to Avoid
- Do not assume elevated DHEAS alone indicates adrenal tumor—the positive predictive value is only 9% even at levels >250 ng/dl testosterone 7
- Do not rely solely on basal DHEAS to exclude adrenal enzyme defects—61% of women with hirsutism have abnormal ACTH stimulation tests despite normal basal steroids 3
- Do not overlook that 13.3% of clinically hyperandrogenic women have normal levels of all measured androgens 4
- Remember that amenorrheic women have higher testosterone levels than those with regular cycles, affecting interpretation 4