What does a low dehydroepiandrosterone sulfate (DHEAS) level after a dexamethasone suppression test indicate regarding adrenal function?

DHEAS Response to Dexamethasone

Low DHEAS levels after dexamethasone suppression indicate either secondary adrenal insufficiency with ACTH deficiency or autonomous cortisol secretion from an adrenal adenoma—the key distinction is whether cortisol is suppressed (secondary AI) or remains elevated (autonomous secretion).

Interpretation in Secondary Adrenal Insufficiency

In patients with secondary adrenal insufficiency, DHEAS levels are characteristically low because ACTH deficiency reduces adrenal androgen production. 1

• DHEAS is decreased in approximately 95% of untreated patients with secondary adrenal insufficiency, making it more sensitive than cortisol for detecting ACTH deficiency 1
• The frequency of decreased DHEAS levels in secondary adrenal insufficiency is significantly higher than that of decreased cortisol levels 1
• Simultaneous measurement of DHEAS and cortisol improves diagnostic accuracy for secondary adrenal insufficiency 1
• DHEAS levels remain suppressed regardless of the underlying cause of secondary adrenal insufficiency 1

Interpretation in Autonomous Cortisol Secretion

In patients with adrenal incidentalomas producing autonomous cortisol, DHEAS levels are suppressed because the autonomous cortisol secretion suppresses ACTH, which in turn reduces DHEA/DHEAS production from the normal adrenal tissue. 2, 3

• Low DHEAS levels are found in 87.5% of patients with adrenocortical incidentalomas, serving as a marker of adrenocortical origin 2
• Higher post-dexamethasone cortisol concentrations correlate negatively with DHEAS levels (rs = -0.380, P = 0.006), indicating that greater cortisol autonomy produces more ACTH suppression and lower DHEAS 3
• DHEAS correlates positively with basal ACTH levels (rs = +0.456, P < 0.001), confirming that DHEAS production is ACTH-dependent 3
• All patients with Cushing's syndrome from adrenocortical adenoma have low DHEAS levels, whereas patients with Cushing's disease (pituitary source) have normal DHEAS 2

Differential Diagnosis Based on Cortisol Response

If Cortisol Is Suppressed After Dexamethasone:

• Low DHEAS with suppressed cortisol indicates secondary adrenal insufficiency 1
• Both hormones are low because ACTH deficiency reduces production of both cortisol and DHEAS 1
• This pattern confirms intact negative feedback and absent autonomous cortisol production 4

If Cortisol Remains Elevated After Dexamethasone:

• Low DHEAS with elevated post-dexamethasone cortisol indicates autonomous cortisol secretion from an adrenal source 2, 3
• The autonomous cortisol suppresses ACTH, which secondarily reduces DHEAS production from the contralateral normal adrenal 3
• Post-dexamethasone cortisol ≥50 nmol/L with ACTH <0.6 pmol/L or ACTH ratio <18% strongly suggests autonomous cortisol secretion 5

Physiologic Basis

Adrenal androgen secretion (DHEAS) is more sensitive to dexamethasone suppression than cortisol secretion because ACTH-stimulated DHEA levels are suppressed to a greater extent than ACTH-stimulated cortisol levels. 6

• Low-dose dexamethasone causes similar suppression of basal cortisol, DHA, and DHEAS, but ACTH-stimulated DHA is suppressed more than ACTH-stimulated cortisol 6
• This differential sensitivity means that subtle ACTH suppression will manifest as low DHEAS before cortisol becomes clearly abnormal 6
• DHEAS increases by 9% with each doubling of ACTH levels, demonstrating tight ACTH-dependence 5

Clinical Application

When evaluating post-dexamethasone hormone levels, measure both cortisol and DHEAS simultaneously, along with ACTH, to distinguish between secondary adrenal insufficiency and autonomous cortisol production. 1, 3, 5

• In secondary AI: cortisol <250 nmol/L, ACTH low or inappropriately normal, DHEAS low 7, 4
• In autonomous secretion: cortisol ≥50 nmol/L post-dexamethasone, ACTH suppressed (<0.6 pmol/L), DHEAS low 3, 5
• DHEAS correlates with midnight cortisol levels, providing additional evidence of circadian rhythm disruption in autonomous secretion 3

Critical Pitfall

Do not interpret low DHEAS after dexamethasone in isolation—the cortisol response determines whether this represents normal suppression, secondary AI, or autonomous secretion. 2, 3

• Low DHEAS can occur in primary adrenal failure with bilateral adrenal destruction, but this presents with elevated ACTH and low cortisol 2
• Always exclude primary adrenal insufficiency before attributing low DHEAS to secondary causes 2
• In adrenal incidentalomas, low DHEAS is a marker of adrenocortical origin (87.5% sensitivity) but requires correlation with post-dexamethasone cortisol to assess autonomy 2