Differential Diagnoses for Elevated DHEA/DHEAS
The primary differential diagnoses for elevated DHEA or DHEAS include polycystic ovary syndrome (PCOS), non-classical congenital adrenal hyperplasia (NCAH), adrenal or ovarian androgen-secreting tumors, and isolated adrenal DHEAS hypersecretion. 1
Initial Clinical Assessment
When evaluating elevated DHEA/DHEAS, look for specific clinical manifestations:
In Adult Women
- Hirsutism, acne, androgenetic alopecia, menstrual irregularities (oligomenorrhea/amenorrhea), infertility 1
- Clitoromegaly and truncal obesity in severe cases 1
- Rapidly progressive virilization suggests androgen-secreting neoplasm 2
In Prepubertal Children
- Early-onset body odor, premature axillary or pubic hair, accelerated growth, advanced bone age, genital maturation 1
Primary Differential Diagnoses
1. Polycystic Ovary Syndrome (PCOS)
- Most common cause of hyperandrogenism in women 2
- DHEAS elevated in approximately 20% of hyperandrogenic women 3
- Pathogenesis involves accelerated GnRH pulsatility, insulin resistance, and metabolic dysregulation 1
- Higher androgen levels when polycystic ovaries demonstrated on imaging 3
2. Non-Classical Congenital Adrenal Hyperplasia (NCAH)
- Must be ruled out, particularly when DHEAS exceeds age-specific thresholds: >3800 ng/ml (ages 20-29) or >2700 ng/ml (ages 30-39) 1
- Consider in patients with premature adrenarche 4
- Evaluate with appropriate hormonal testing including 17-hydroxyprogesterone 1
3. Androgen-Secreting Neoplasms
Adrenal Tumors
- Suspect when DHEAS >16.3 μmol/L (6000 ng/ml), though this threshold has low positive predictive value (specificity 98%) 2
- Androgen-secreting adrenal carcinomas may present with hirsutism, voice deepening, oligomenorrhea/amenorrhea in women 5
- Malignancy suspected if tumor >5 cm, inhomogeneous with irregular margins, or local invasion 5
- CT imaging of adrenals recommended when antibodies negative 5
Ovarian Tumors
- Total testosterone >8.7 nmol/L (250 ng/dl) has 100% sensitivity but only 9% positive predictive value for ovarian neoplasm 2
- Ovarian hilar cell tumors present with rapidly progressive virilization 2
- Pelvic ultrasound indicated for evaluation 1
4. Isolated Adrenal DHEAS Hypersecretion
- Rare functional disorder with bilateral adrenal DHEAS hypersecretion without tumor 6
- Responds to dexamethasone suppression, suggesting functional rather than neoplastic etiology 6
- Consider in differential when imaging negative and other causes excluded 6
5. Genetic/Enzymatic Disorders
- Steroid sulfatase (STS) deficiency or transporter protein defects can cause very high DHEAS without tumor 4
- Adrenoleukodystrophy in males—measure very long-chain fatty acids in serum 5
- X-linked conditions with primary adrenal insufficiency and hypogonadotropic hypogonadism (NR0B1/DAX1 mutations) 5
Diagnostic Algorithm
Laboratory Evaluation
Initial hormone panel should include: 1
- Free and total testosterone
- DHEAS
- Androstenedione
- LH and FSH
Additional testing in selected cases: 1
- 17-hydroxyprogesterone (for NCAH)
- Sex hormone binding globulin (SHBG)
- Prolactin, estrogen, progesterone
- Insulin, lipid levels, IGF-1
Functional Testing
- 2-day dexamethasone suppression test quantitatively predicts degree of testosterone suppression and helps distinguish functional from neoplastic causes 3
- Overnight dexamethasone test less precise 3
- Dexamethasone suppression distinguishes functional adrenal hyperplasia from autonomous tumor production 5, 6
Imaging Studies
- Adrenal CT scan when 21-hydroxylase antibodies negative 5
- Transvaginal ultrasound for polycystic ovaries in females 1
- MRI when CT inconclusive 4
Critical Pitfalls to Avoid
Screening testosterone and DHEAS for tumors has poor cost-effectiveness due to low positive predictive value (9% for testosterone >250 ng/dl, unable to calculate for DHEAS due to rarity) 2. Clinical evaluation alone often sufficient for screening, with imaging reserved for specific indications 2.
In primary adrenal insufficiency, DHEAS levels are LOW, not elevated 5. Do not confuse this presentation with the differential for elevated DHEAS.
Amenorrheic women have higher testosterone levels than those with regular cycles 3, which helps stratify risk but does not definitively distinguish etiologies.
Chronic low-dose prednisone therapy suppresses androgens in many hyperandrogenic women, but pretreatment DHEA/DHEAS levels do NOT predict testosterone response to therapy 3. The 2-day dexamethasone test is superior for predicting treatment response 3.