CRH to ACTH to cortisol: a three-tier cascade with stress input and negative feedback loop.
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HPA Axis Hormone Cascade
The hypothalamic-pituitary-adrenal (HPA) axis is the body's core stress-response circuit. A stressor activates the hypothalamus, which releases corticotropin-releasing hormone (CRH). CRH travels to the anterior pituitary and triggers ACTH secretion. ACTH reaches the adrenal cortex within minutes, driving cortisol production and release.
The cascade completes with a negative-feedback loop: cortisol suppresses both CRH release at the hypothalamus and ACTH sensitivity at the pituitary, preventing runaway cortisol elevation.
CRH is a 41-amino acid peptide secreted from the paraventricular nucleus of the hypothalamus. It binds CRH-R1 receptors on pituitary corticotroph cells, stimulating POMC cleavage and ACTH release into portal circulation.
ACTH binds melanocortin-2 receptors on adrenocortical cells, activating cAMP-PKA signaling and StAR protein to mobilize cholesterol into the steroidogenic pathway. Cortisol output rises within 15-20 minutes of the initial stressor.
Negative feedback operates at three timescales: fast (minutes, via membrane receptor), delayed (hours, via glucocorticoid receptor transcription), and slow (days-weeks, via hippocampal receptor downregulation in chronic stress).
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This hpa axis hormone cascade is an editorial illustration built to represent the concept accurately. Where it shows figures, they are typical or representative values chosen to make the relationship clear, not a single underlying dataset. The diagram and its explainer are reviewed and maintained centrally, and updated over time as understanding improves.
The three tiers of the HPA axis
The hypothalamic-pituitary-adrenal (HPA) axis is the body's central stress-response system, organized as a three-step cascade. The hypothalamus releases corticotropin-releasing hormone (CRH), which signals the anterior pituitary to release adrenocorticotropic hormone (ACTH), which in turn drives the adrenal cortex to release cortisol.
Each step amplifies and relays the signal, converting a brain-level stress input into a whole-body hormonal response. Cortisol then acts widely, raising blood glucose, modulating immune activity, and helping mobilize energy.
Negative feedback and daily rhythm
The axis is self-regulating through negative feedback: rising cortisol acts back on the hypothalamus and pituitary to suppress further CRH and ACTH release, keeping the system from overshooting. This feedback loop is what returns the axis toward baseline once a stressor passes.
Cortisol also follows a daily (circadian) rhythm, typically peaking in the early morning and falling to a low at night. Chronic stress can dysregulate this loop, and the axis is central to understanding conditions such as Cushing's and Addison's. This is general physiology, not medical advice.
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