What are the causes of elevated Dehydroepiandrosterone (DHEA) levels in adults?

Causes of Elevated DHEA/DHEAS Levels

Elevated DHEA/DHEAS levels in adults require systematic evaluation for three primary pathological causes: non-classical congenital adrenal hyperplasia, polycystic ovary syndrome (PCOS), and androgen-secreting adrenal tumors, with the urgency of workup determined by the absolute DHEAS level and presence of virilization symptoms. 1, 2

Critical Thresholds for Urgency

• DHEAS >6000 ng/mL (16.3 μmol/L) demands urgent evaluation for adrenocortical carcinoma with immediate adrenal CT imaging 2, 3
• Age-specific thresholds requiring investigation: >3800 ng/mL for ages 20-29, >2700 ng/mL for ages 30-39 1, 3
• Rapidly progressive virilization symptoms escalate urgency regardless of absolute DHEAS level 2, 3

Primary Pathological Causes

Adrenal Tumors (Most Urgent)

• Androgen-secreting adrenocortical carcinomas present with virilization in approximately 60% of cases, including hirsutism, voice deepening, and oligomenorrhea/amenorrhea in women 2
• Peak incidence occurs in the fourth to fifth decades with a female-to-male ratio of 1.5:1 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
• Adrenal tumors account for 17-30% of cases with abnormal DHEAS levels 4, 5

Non-Classical Congenital Adrenal Hyperplasia

• Must be ruled out first, particularly when DHEAS exceeds age-specific thresholds 1, 2, 3
• Accounts for 32% of cases with low DHEAS (due to overtreatment) but can present with elevated levels when untreated 5, 6
• Characterized by hypertension with hypokalemia and virilization (11-beta-hydroxylase deficiency) or incomplete masculinization in males and primary amenorrhea in females (17-alpha-hydroxylase deficiency) 4

Polycystic Ovary Syndrome (Most Common in Reproductive-Age Women)

• PCOS is the most common cause of elevated androgens in reproductive-age women 3
• Pathogenesis involves accelerated pulsatile GnRH secretion, insulin resistance, and downstream metabolic dysregulation 1
• Diagnosed using 2 of 3 criteria: androgen excess, ovulatory dysfunction, and polycystic ovaries on ultrasound 3

Other Adrenal Causes

• Cushing's syndrome presents with rapid weight gain (central distribution), proximal muscle weakness, depression, and hyperglycemia 4
• Adrenoleukodystrophy in males can cause very high DHEAS without tumor; measure very long-chain fatty acids in serum when suspected 4, 2
• Primary adrenal insufficiency typically shows low DHEAS levels along with low cortisol and aldosterone 4

Associated Clinical Conditions

Metabolic and Cardiovascular

• Arterial hypertension is present in 26% of patients with high DHEAS levels 5
• Overweight/obesity occurs in 19% of cases with elevated DHEAS 5
• Significant correlation exists between DHEAS levels and body mass index, systolic and diastolic blood pressure 5

Other Associations

• Non-toxic goiter (17% of cases) 5
• Alopecia (9% of cases) 5
• Acromegaly (rare): presents with acral features, enlarging shoe/glove/hat size, headache, visual disturbances, and diabetes mellitus 4

Diagnostic Algorithm

Initial Clinical Assessment

• Evaluate for hyperandrogenism signs: hirsutism, acne, menstrual irregularities, androgenetic alopecia, infertility, voice deepening, clitoromegaly 1, 2, 3
• In prepubertal children: early-onset body odor, axillary/pubic hair, accelerated growth, advanced bone age, genital maturation 1
• Document rapidity of symptom progression (rapid progression strongly suggests malignancy) 2

Essential Laboratory Panel

• Free and total testosterone, DHEAS, androstenedione, LH, FSH 1, 2, 3
• 17-hydroxyprogesterone to screen for non-classical congenital adrenal hyperplasia 2, 3
• Morning ACTH and cortisol to distinguish adrenal from pituitary sources 2, 3
• Sex hormone binding globulin, free androgen index 1, 3
• Consider: prolactin, estrogen, progesterone, insulin, lipid levels, IGF-1 in selected cases 1, 2

Imaging Studies

• Adrenal CT scan when 21-hydroxylase antibodies are negative, DHEAS >6000 ng/mL, or clinical suspicion for adrenal tumor exists 4, 2, 3
• Transvaginal ultrasound to evaluate for polycystic ovaries and ovarian masses in females 1, 2, 3

Specialized Testing

• 2-day dexamethasone suppression test to distinguish functional from neoplastic causes of hyperandrogenism 1
• Measure very long-chain fatty acids in males to exclude adrenoleukodystrophy 4, 2
• 21-hydroxylase antibody testing for autoimmune adrenal disease 4

Critical Pitfalls to Avoid

• Do not delay imaging when rapidly progressive virilization symptoms are present, as this strongly suggests malignancy 2
• Do not assume PCOS without ruling out non-classical congenital adrenal hyperplasia and adrenal tumors first 1, 2, 3
• Remember that primary adrenal insufficiency causes low DHEAS, not high; hyponatremia is present in 90% of cases 4
• In treated congenital adrenal hyperplasia patients, DHEAS may be overly suppressed, limiting its value for monitoring therapy adequacy 6