HPA Axis and Cortisol Stress Response

The hypothalamic–pituitary–adrenal (HPA) axis coordinates the endocrine response to threat. Physical illness, injury, and psychological stress can activate neurons in the hypothalamic paraventricular nucleus, which release corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). CRH and AVP stimulate corticotrophs in the anterior pituitary to release adrenocorticotropic hormone (ACTH). ACTH travels through the circulation to the adrenal cortex, where it drives cortisol production. Cortisol then enters cells, binds intracellular glucocorticoid receptors, and changes gene transcription. Its effects help maintain glucose availability, support vascular responsiveness, and regulate immune and inflammatory activity during stress. The system is self-limiting. Rising cortisol feeds back to the hypothalamus and pituitary, reducing further CRH, AVP, and ACTH release. A useful analogy is a thermostat with a delayed response: the hypothalamus and pituitary send the heating signal, the adrenal cortex produces the output, and circulating cortisol tells the controller when to reduce the signal. If the adrenal cortex cannot produce enough cortisol, or if prolonged glucocorticoid therapy suppresses the upstream signal, the feedback loop cannot meet the body’s demand during illness. Acute HPA activation is adaptive. Persistent stress, severe...