Do low morning cortisol and low DHEA-S indicate reduced HPA-axis output without adrenal failure?

Co-occurring low-normal morning cortisol and low dehydroepiandrosterone sulfate (DHEA-S) levels represent a functional state of the hypothalamic-pituitary-adrenal (HPA) axis rather than structural endocrine pathology.

Clinical evidence and diagnostic thresholds

• Functional versus pathological states: Morning cortisol levels in the low-normal "grey zone" (typically 5–10 µg/dL) combined with low-normal DHEA-S indicate functional HPA-axis down-regulation rather than organ failure.
• Diagnostic boundaries: True adrenal insufficiency (failure) is a distinct pathological diagnosis. It requires much lower biochemical thresholds, specifically a morning serum cortisol below 3–5 µg/dL, a DHEA-S level strictly below 25 µg/dL, or confirmation via a dynamic cosyntropin (ACTH) stimulation test. Within-reference-range values do not satisfy these diagnostic criteria.

Mechanistic pathways and adrenal aging

• Androgen reserve depletion: DHEA-S is synthesized almost exclusively in the adrenal cortex under ACTH stimulation. Because of its long half-life, it serves as a stable marker of cumulative HPA-axis drive and adrenal androgen reserve.
• Role of age-related decline: In older adults, physiological adrenal aging (adrenopause) is characterized by a steep, progressive decline in DHEA-S production, which naturally reduces the adrenal androgen reserve.
• Functional adaptation: When paired with low-normal cortisol, this biomarker pattern reflects a functional adaptative state—often driven by chronic stress, burnout, or aging—rather than autoimmune or physical destruction of the adrenal cortex.

Bottom line

• Combined low-normal morning cortisol and DHEA-S point to a depleted adrenal androgen reserve and functional HPA-axis down-regulation—often secondary to normal adrenal aging—but they do not prove clinical adrenal failure, which requires strict sub-threshold biochemical markers and dynamic stimulation testing.