Hypothalamic-Pituitary-Adrenal (HPA) Axis

The HPA axis is a three-tier cascade with feedback at every level. Corticotropin-releasing hormone from the paraventricular nucleus, with vasopressin as a co-secretagogue, reaches the anterior pituitary through the portal circulation and drives ACTH release from corticotrophs. ACTH acts on the adrenal cortex to produce cortisol, and cortisol feeds back to inhibit both CRH and ACTH. The suprachiasmatic nucleus imposes the circadian pattern on top, which is why the axis has a shape across the day rather than a single set point.

The tests map onto the tiers. For suspected adrenal insufficiency the insulin tolerance test remains the reference standard for central disease, because it demands a real physiological stress, documented hypoglycaemia, before asking the axis to respond; the short cosyntropin test is the safer and far commoner proxy, testing adrenal responsiveness instead. For suspected hypercortisolism the screening tests are the overnight low-dose dexamethasone suppression test, late-night salivary cortisol and urinary free cortisol, after which a plasma ACTH separates ACTH-dependent from adrenal causes.

Reading the axis therefore means reading a position in the cascade rather than a single hormone. Cortisol alone cannot distinguish a failing adrenal from a failing pituitary, and ACTH alone cannot say whether the adrenal can respond.

Where this goes wrong in practice is largely commercial. Adrenal fatigue is marketed as a diagnosis with salivary cortisol curves as its test, and the Endocrine Society has stated the condition is not supported by evidence; a wide daytime spread in cortisol is normal physiology, not a finding. Peptides and supplements are promoted as regulating or balancing the HPA axis without human trial data showing any such effect, and the phrase itself is not a measurable claim.