The HPA Axis Explained: How Your Brain and Adrenal Glands Talk to Each Other

Cortisol does not appear out of nowhere when you are stressed. It is released through a specific, well-mapped signaling chain called the hypothalamic-pituitary-adrenal axis, or HPA axis, and understanding that chain is what makes it possible to tell which cortisol claims online are grounded in real physiology and which ones are not.

The HPA axis links three organs in a one-way relay. It starts in the hypothalamus, a small region at the base of the brain, which releases corticotropin-releasing hormone, or CRH, when it registers a stressor, whether that is a work deadline, an infection, or simply low blood sugar. CRH travels a short distance to the pituitary gland, prompting it to release adrenocorticotropic hormone, or ACTH, into the bloodstream. ACTH then reaches the adrenal glands, two small glands that sit above the kidneys, and signals their outer layer, the adrenal cortex, to produce and release cortisol. The entire relay, from brain to adrenal gland, typically takes only minutes.

What keeps this system from running unchecked is negative feedback. Once cortisol reaches a high enough level in the blood, it signals back to both the hypothalamus and the pituitary gland to reduce their output of CRH and ACTH, which in turn slows further cortisol release. It works something like a thermostat: the system activates, does its job, then dials itself back down once the target is reached. In a healthy, well-regulated axis, this is also why cortisol follows a daily rhythm, peaking shortly after waking and gradually tapering through the day, rather than staying elevated indefinitely.

Research on chronic stress has focused specifically on what happens when that feedback loop is disrupted, rather than on cortisol itself. Sustained activation of the HPA axis is associated with a state researchers call glucocorticoid receptor resistance, where tissues become less responsive to cortisol's normal regulatory signals. Counterintuitively, this can increase inflammation rather than reduce it, since cortisol's anti-inflammatory signaling is one of the functions that becomes blunted. A 2025 review in the International Journal of Molecular Sciences linked this kind of HPA axis dysregulation to effects across multiple body systems, not just skin, including cardiovascular, metabolic, and immune function.

This is also where a lot of popular explanations overreach. Mainstream endocrinology recognizes real, diagnosable conditions involving this axis, including Cushing's syndrome, too much cortisol, and Addison's disease, too little, both of which require medical testing to diagnose. What it does not recognize as a medical diagnosis is "adrenal fatigue," a term used in some wellness content to describe tired adrenal glands that supposedly can no longer keep up with stress; there is no accepted physiological mechanism or diagnostic test for it, a point covered in more depth elsewhere on this site.

None of this is a reason to treat everyday stress as dangerous. The HPA axis activating in response to a stressful moment and then returning to baseline is the system working exactly as designed. The more useful frame for evaluating wellness claims is specifically about what happens when that return to baseline is chronically interrupted, whether by ongoing psychological stress, poor sleep, or other sustained physical demands on the body.