What causes elevated Dehydroepiandrosterone (DHEA) levels?

Causes of Elevated DHEA/DHEAS Levels

Elevated DHEA/DHEAS levels most commonly result from polycystic ovary syndrome (PCOS), non-classical congenital adrenal hyperplasia, or androgen-secreting adrenal tumors, with the latter requiring urgent exclusion when levels are markedly elevated (>6000 ng/ml) or accompanied by virilization. 1, 2

Primary Pathological Causes

Adrenal Tumors (Most Critical to Exclude)

• Androgen-secreting adrenocortical carcinomas present in approximately 60% of cases with adrenal steroid hormone excess and virilization symptoms including hirsutism, voice deepening, and oligomenorrhea/amenorrhea in women 3, 2
• Malignancy should be suspected when tumors are >4-5 cm, have irregular margins, are lipid-poor, fail to wash out on contrast-enhanced CT, or secrete multiple hormones 2
• Peak incidence occurs in the fourth to fifth decades with a female-to-male ratio of 1.5:1 3
• Evaluate patients with DHEAS >16.3 μmol/L (6000 ng/ml) urgently for adrenal carcinomas using adrenal CT imaging 1, 2

Non-Classical Congenital Adrenal Hyperplasia

• Must be ruled out first, particularly when DHEAS exceeds age-specific thresholds: >3800 ng/ml for ages 20-29 or >2700 ng/ml for ages 30-39 1, 4
• Inherited defects in steroid biosynthesis enzymes (particularly 21-hydroxylase deficiency) can produce a PCOS-like phenotype 5
• Measure 17-hydroxyprogesterone levels and consider ACTH stimulation testing for diagnosis 1

Polycystic Ovary Syndrome (PCOS)

• Approximately 20-30% of PCOS women demonstrate excess adrenal precursor androgen production 5
• Pathogenesis involves accelerated pulsatile GnRH secretion, insulin resistance, and metabolic dysregulation 1, 4
• Women with PCOS and elevated DHEAS show generalized exaggeration in adrenal steroidogenesis in response to ACTH stimulation 5

Rare Causes

• Isolated DHEAS hypersecretion of functional (non-tumor) nature can occur, confirmed by dexamethasone suppression and bilateral adrenal secretion on selective venous sampling 6
• Adrenoleukodystrophy in males can cause very high DHEAS without tumor; measure very long-chain fatty acids in serum when suspected 1
• Genetic variants affecting steroid sulfatase or transporter proteins (BCRP, MRP2, OATP) may impair DHEAS metabolism and clearance 7

Diagnostic Algorithm

Clinical Assessment

In prepubertal children: Look for early-onset body odor, premature axillary or pubic hair, accelerated growth velocity, advanced bone age, and genital maturation 1, 4

In postpubertal females: Evaluate for hirsutism, acne, menstrual irregularities, androgenetic alopecia, clitoromegaly, truncal obesity, and infertility 1, 4, 2

For suspected Cushing syndrome: Assess for weight gain, proximal muscle weakness, hypertension, psychiatric disturbances, centripetal obesity, purple striae, buffalo hump, and hyperglycemia 3, 2

Laboratory Evaluation

• Initial hormone panel must include free and total testosterone, DHEAS, androstenedione, LH, and FSH 1, 4
• Measure morning ACTH and cortisol to distinguish adrenal from pituitary sources 2
• Check 17-hydroxyprogesterone to screen for non-classical congenital adrenal hyperplasia 1
• Consider additional testing: sex hormone binding globulin, free androgen index, prolactin, insulin, glucose, and lipid levels in selected cases 1, 4

Imaging Studies

• Obtain adrenal CT scan when 21-hydroxylase antibodies are negative or when DHEAS >6000 ng/ml to evaluate for adrenal tumors 1, 2
• Perform transvaginal ultrasound to assess for polycystic ovaries in females with suspected PCOS 1

Functional Testing

• 2-day dexamethasone suppression test distinguishes functional from neoplastic causes of hyperandrogenism 1
• Failure to suppress suggests adrenal tumor; appropriate suppression indicates functional excess 6

Critical Pitfalls to Avoid

• Do not delay imaging when rapidly progressive virilization symptoms are present, as this strongly suggests malignancy 2
• DHEAS measurement has limited value for monitoring treatment adequacy in congenital adrenal hyperplasia, as levels are disproportionately suppressed even with adequate therapy 8
• Extra-adrenal factors (obesity, insulin levels, ovarian secretions) play limited roles in PCOS-associated DHEAS elevation 5
• Heterozygous genetic variants in steroid metabolism enzymes or transporters typically do not cause clinically significant DHEAS elevation unless combined with other mutations 7