Stress + circadian cortisol regulation. Hypothalamic CRH → anterior pituitary ACTH → adrenal cortex (zona fasciculata) cortisol. Negative feedback: cortisol → hypothalamus + pituitary (suppresses CRH + ACTH). Exogenous glucocorticoids suppress the entire axis — chronic high-dose Rx (>10-20 mg/d prednisone equivalent for >2-3 weeks) produces tertiary adrenal insufficiency that requires gradual taper. ACTH-stim test diagnoses primary vs secondary AI. Diurnal rhythm: ACTH + cortisol peak in early morning (~6-8am), trough at night (~midnight) — the basis for AM cortisol measurement and dexamethasone suppression test.
Organ Systems
endocrine
nervous
immune-hematologic
Pathway Steps
crh → acth — via hypothalamic CRH → anterior pituitary corticotrophs. Stress and circadian cues drive hypothalamic release of corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). This is the top of the stress axis, integrating neural inputs into an endocrine cascade with a strong diurnal rhythm (peak at waking).
acth → cortisol — via ACTH → adrenal cortex zona fasciculata; ACTH-R / MC2R signaling. ACTH stimulates the adrenal cortex (zona fasciculata) to synthesize and release cortisol, which mobilizes glucose, modulates immunity, and mediates the systemic stress response. Measuring cortisol with ACTH localizes the cause of Cushing’s or Addison’s disease.
cortisol → crh-suppression — via negative feedback at hypothalamus + pituitary. Cortisol feeds back negatively on the hypothalamus and pituitary to suppress CRH and ACTH, closing the loop and limiting the stress response. Exogenous glucocorticoids exploit and suppress this loop — chronic use causes adrenal suppression, so steroids must be tapered, not stopped abruptly.