Corticotropin-releasing hormone signaling axis (CRH axis)

The Corticotropin-releasing hormone (CRH) signaling axis is a central neuroendocrine pathway that coordinates the physiological and behavioral response to stress (UniProt P06850). It comprises the CRH ligand, its two primary G protein-coupled receptors, CRHR1 and CRHR2, and the CRH-binding protein (CRHBP) (UniProt P34998, Q13324). Upon activation by stress, CRH is secreted by the hypothalamus and binds to CRHR1 in the anterior pituitary, stimulating the release of adrenocorticotropic hormone (ACTH), which subsequently induces glucocorticoid production in the adrenal glands (StatPearls, Physiology, Corticotropin Releasing Hormone). Dysregulation of this axis is a hallmark of several endocrine and psychiatric disorders; for instance, in congenital adrenal hyperplasia (CAH), the lack of cortisol-mediated negative feedback results in chronic CRH and ACTH overproduction, driving adrenal hyperplasia and androgen excess (PubMed PMC9103555). Pharmacological modulation of the axis primarily focuses on small-molecule CRHR1 antagonists, such as crinecerfont and tildacerfont, which are designed to normalize ACTH and adrenal androgen levels (Neurocrine Biosciences, 2024; Spruce Biosciences, 2024). Additionally, the axis has been investigated as a therapeutic target for anxiety, depression, and irritable bowel syndrome, reflecting its broad role in mediating stress-related pathologies.

Other names

CRH systemCRF signaling pathwayHypothalamic-pituitary-adrenal axisCRH-CRHR1 axisCorticotropin-releasing factor signaling axis

Antagonism of the Corticotropin-releasing hormone receptor 1 (CRHR1) to inhibit the secretion of adrenocorticotropic hormone (ACTH) and reduce subsequent adrenal steroid production.