What does an elevated Dehydroepiandrosterone (DHEA) level indicate and what should the workup for this include?

Elevated DHEA: Clinical Significance and Workup

What Elevated DHEA Indicates

Elevated DHEA-S levels most commonly indicate androgen-secreting adrenal tumors (particularly adrenocortical carcinoma), polycystic ovary syndrome in women, non-classical congenital adrenal hyperplasia, or benign functional adrenal conditions—with DHEA-S >6000 ng/mL being a red flag for malignancy requiring urgent imaging. 1, 2

Primary Differential Diagnoses

• Adrenocortical carcinoma (ACC): Approximately 60% of ACCs present with evidence of adrenal steroid hormone excess, with androgen-secreting tumors causing virilization in women (hirsutism, deepening voice, oligo/amenorrhea) and estrogen effects in men (gynecomastia, testicular atrophy). 1

• Polycystic ovary syndrome (PCOS): In women, PCOS is the most common cause of elevated DHEA-S with normal cortisol, requiring evaluation for polycystic ovaries on pelvic ultrasound, menstrual irregularities, and insulin resistance. 2

• Non-classical congenital adrenal hyperplasia: Particularly 21-hydroxylase or 3β-hydroxysteroid dehydrogenase deficiency, which can present with elevated DHEA-S alongside elevated 17-hydroxyprogesterone. 1, 3, 4

• Benign functional adrenal conditions: Isolated DHEA-S hypersecretion is recognized as a benign functional condition, particularly in men, that responds to dexamethasone suppression. 2, 5

Essential Workup Components

Immediate Hormonal Evaluation

All patients with elevated DHEA require a comprehensive hormonal panel to differentiate between adrenal tumors, PCOS, and congenital adrenal hyperplasia. 1, 2

• Sexual steroids and steroid precursors (serum):

  • DHEA-S 1
  • 17-hydroxyprogesterone (to screen for non-classical CAH) 1, 2
  • Androstenedione 1
  • Testosterone (total and free) 1, 2
  • 17β-estradiol (in men and postmenopausal women only) 1
  • LH and FSH 2

• Glucocorticoid excess screening (minimum 3 of 4 tests):

  • 1 mg dexamethasone suppression test at 23:00 h 1
  • 24-hour urinary free cortisol 1
  • Basal serum cortisol 1
  • Basal plasma ACTH 1

• Mineralocorticoid excess screening (only if hypertension/hypokalemia present):

  • Serum potassium 1
  • Aldosterone/renin ratio 1

• 24-hour urine steroid metabolite examination: Can help differentiate adenomas from ACCs using steroid metabolomics patterns. 1

Critical Imaging Studies

DHEA-S >6000 ng/mL mandates urgent adrenal CT imaging to evaluate for adrenocortical carcinoma. 2

• CT or MRI of abdomen: CT is first-choice for suspected ACC; MRI preferred if pheochromocytoma suspected. 1

  • Benign tumors: Hounsfield units <10 on unenhanced CT, rapid washout on 15-minute delayed contrast-enhanced CT 1
  • Malignant features: Inhomogeneous appearance, irregular margins, irregular enhancement, size >4 cm 1, 2

• CT thorax: Essential for staging if ACC suspected. 1

• Optional advanced imaging:

  • FDG-PET (if malignancy suspected) 1
  • Bone scintigraphy (if skeletal metastases suspected) 1

Gender-Specific Considerations

In women with elevated DHEA-S and normal cortisol, PCOS evaluation takes priority unless DHEA-S is markedly elevated or virilization is present. 2

• For women: Pelvic ultrasound for polycystic ovaries, assessment of menstrual irregularities, evaluation for insulin resistance and metabolic syndrome. 2

• For men: Isolated DHEA-S hypersecretion is more likely benign, but symptomatic cases may require low-dose dexamethasone suppression trial. 2, 5

Management Algorithm Based on Findings

If Adrenal Mass Identified on Imaging

• Masses >4 cm or with suspicious features: Require surgical evaluation for possible adrenocortical carcinoma; open adrenalectomy recommended (not laparoscopic) as these tumors are prone to rupture. 1, 2

• Masses <4 cm with benign features: May be observed with repeat imaging and hormonal assessment in 3-6 months. 2

If No Mass Found

• Symptomatic hyperandrogenism: May be treated with low-dose dexamethasone suppression (80-90% symptom reduction). 2, 5

• Asymptomatic patients: Observe with repeat DHEA-S measurement in 3-6 months. 2

• Women with PCOS features: Manage according to PCOS guidelines with lifestyle modification, metformin for insulin resistance, and anti-androgens if needed. 2

Critical Pitfalls to Avoid

• Do not assume elevated DHEA-S is benign without imaging: DHEA-S >6000 ng/mL has high specificity for ACC and requires urgent evaluation. 2

• Do not rely on cortisol levels alone: Approximately 40% of ACCs are hormonally inactive and present only with tumor burden symptoms. 1

• Do not perform laparoscopic adrenalectomy for suspected ACC: These tumors are prone to rupture; open adrenalectomy is mandatory. 1

• Do not skip 17-hydroxyprogesterone measurement: This is essential to screen for non-classical CAH, which can present with isolated DHEA-S elevation. 1, 2

• In women, do not attribute all elevated DHEA-S to PCOS: Always obtain imaging if DHEA-S is significantly elevated or if any clinical signs of virilization are present. 1, 2