What are the considerations for a patient with a normal Adrenocorticotropic hormone (ACTH) level, normal dexamethasone suppression test, but elevated Dehydroepiandrosterone sulfate (DHEA-S) level?

Elevated DHEA-S with Normal ACTH and Normal Dexamethasone Suppression Test

This presentation most likely represents isolated adrenal DHEA-S hypersecretion, a benign functional adrenal condition that does not require aggressive intervention but warrants exclusion of androgen-secreting tumors and non-classical congenital adrenal hyperplasia (NCCAH).

Initial Assessment and Interpretation

Your patient's DHEA-S level of 503 μg/dL is mildly elevated (normal upper limit typically ~350-430 μg/dL depending on age and sex), but the normal ACTH and normal dexamethasone suppression test effectively rule out Cushing's syndrome and suggest this is not a cortisol-driven process 1.

Key Diagnostic Considerations

• DHEA-S is primarily of adrenal origin in both men and women, making this an adrenal-source hyperandrogenism 2
• The normal dexamethasone suppression test indicates the DHEA-S elevation is suppressible, which strongly suggests a functional rather than neoplastic etiology 3
• When DHEA-S is over 600 μg/dL, an androgen-secreting adrenal cortical adenoma becomes the primary concern 2. Your patient's level of 503 μg/dL is below this threshold but still warrants imaging consideration

Critical Exclusions Required

1. Rule Out Androgen-Secreting Adrenal Tumor

• Obtain adrenal CT imaging if DHEA-S >600 μg/dL or if there are signs of virilization (rapid onset severe hirsutism, clitoromegaly, voice deepening, male-pattern baldness) 1, 2
• At 503 μg/dL with normal dexamethasone suppression, tumor is less likely, but consider imaging if clinical hyperandrogenism is severe or rapidly progressive 1

2. Exclude Non-Classical Congenital Adrenal Hyperplasia (NCCAH)

• Measure basal 17-hydroxyprogesterone (17-OHP) level, ideally in the morning 1
• If 17-OHP is elevated (>200 ng/dL), perform ACTH stimulation test with 17-OHP measurement at baseline and 60 minutes post-cosyntropin 1
• NCCAH due to 21-hydroxylase deficiency presents with oligomenorrhea and hyperandrogenism similar to PCOS but shows elevated 17-OHP 1

3. Confirm Absence of Cushing's Syndrome

• Your normal dexamethasone suppression test already excludes this effectively 1
• If any clinical signs of hypercortisolism are present (central obesity, striae, easy bruising, proximal muscle weakness), consider 24-hour urinary free cortisol as additional confirmation 4, 5

Most Likely Diagnosis: Isolated DHEA-S Hypersecretion

• This is a recognized benign functional condition where the adrenal glands bilaterally hypersecrete DHEA-S without tumor or enzymatic defect 3
• The dexamethasone suppressibility confirms the functional nature of this alteration 3
• This condition has been documented in both males and females and represents a form of functional adrenal hyperandrogenism 3, 6

Clinical Context Matters

If Patient is Female with Hirsutism/Acne:

• 85% of hirsute women with adequate dexamethasone suppression have an adrenal component to their hyperandrogenism (either pure adrenal or mixed adrenal-ovarian) 6
• DHEA-S elevation is the most common finding in hirsute patients, present in 76% of cases 6
• Low-dose dexamethasone (0.125-0.375 mg nightly) can effectively suppress DHEA-S to <200 μg/dL in most patients 7
• Mean effective dose is 0.256 mg daily: 25% respond to 0.125 mg, 50% to 0.250 mg, and 20% to 0.375 mg 7

If Patient is Male:

• Isolated DHEA-S hypersecretion is rarer but documented 3
• Consider whether any clinical manifestations warrant treatment versus observation

Recommended Diagnostic Algorithm

1. Measure 17-OHP to exclude NCCAH 1
2. Check total testosterone level - if testosterone is twice the upper limit of normal, this increases concern for tumor 2
3. Consider adrenal CT imaging if:
   • DHEA-S >600 μg/dL 2
   • Rapid onset or severe virilization 1
   • Testosterone markedly elevated 2
4. If all above are negative, diagnosis is isolated functional DHEA-S hypersecretion 3

Management Approach

• If asymptomatic or minimal symptoms: Observation with periodic monitoring of DHEA-S levels is reasonable 3
• If symptomatic hyperandrogenism (hirsutism, acne): Consider low-dose dexamethasone 0.125-0.25 mg nightly 7
• Monitor for adverse effects of glucocorticoid therapy if treatment initiated, though low doses are generally well-tolerated 7

Important Pitfalls to Avoid

• Do not assume PCOS without excluding NCCAH - both present with oligomenorrhea and hyperandrogenism 1
• Do not ignore rapid progression or virilization - these mandate tumor exclusion regardless of DHEA-S level 1
• Remember that SHBG levels affect interpretation - if SHBG is elevated (from medications like tamoxifen, hyperthyroidism, or liver disease), total testosterone may appear falsely elevated 2
• Conversely, low SHBG (from obesity, metabolic syndrome) can mask hyperandrogenism with normal total testosterone 2