Can low cortisol and DHEA-S reflect reduced central HPA-axis drive?

Reduced central hypothalamic–pituitary–adrenal (HPA) signaling can plausibly produce low cortisol and low DHEA sulfate (DHEA-S) together. This pattern is physiologically coherent but is not, by itself, diagnostic of central adrenal insufficiency.

Clinical and physiologic evidence

• ACTH directly stimulates cortisol synthesis in the adrenal zona fasciculata and adrenal androgen production—including DHEA and circulating DHEA-S—primarily in the zona reticularis.
• In central adrenal insufficiency, impaired hypothalamic–pituitary signaling reduces ACTH secretion. Reduced ACTH can therefore decrease both cortisol and DHEA-S output.
• Mineralocorticoid production is comparatively preserved in central disease because aldosterone regulation depends predominantly on the renin–angiotensin system and potassium rather than ACTH.

Diagnostic interpretation

• Concurrently low cortisol and DHEA-S can increase suspicion for reduced central HPA-axis drive, but the pattern is nonspecific and cannot distinguish central from primary adrenal insufficiency.
• DHEA-S is an adjunctive marker, interpreted against age- and sex-adjusted reference ranges. Its age-related decline reduces the specificity of a low value.
• In the limited available diagnostic literature, DHEA-S sensitivity ranged from 70.3% to 86.7%, with reported specificity of 87.1%; these findings support supportive rather than standalone use.

Clinical implications

• Confirmation requires a properly timed morning cortisol measured with ACTH. Low cortisol with low or inappropriately normal ACTH supports a central process.
• Intermediate cortisol results commonly require dynamic testing. Cosyntropin testing can be falsely normal in recent-onset central ACTH deficiency, so timing and clinical context remain important.

Bottom line

• Low cortisol plus low DHEA-S is mechanistically compatible with reduced central ACTH/HPA-axis drive and can strengthen suspicion, but diagnosis requires ACTH, appropriately timed cortisol, and often dynamic assessment.