CorticotropinReleasing

Corticotropin-releasing hormone (CRH), also known as corticotropin-releasing factor in older literature, is a hypothalamic peptide that initiates the vertebrate stress response through the hypothalamic-pituitary-adrenal (HPA) axis. In humans, CRH is a 41-amino-acid peptide produced primarily by neurons in the paraventricular nucleus of the hypothalamus. It is released into the hypophyseal portal circulation and acts on the anterior pituitary gland.

CRH binds to G protein–coupled receptors, predominantly CRHR1 and CRHR2, on pituitary corticotrophs. This stimulates transcription of the proopiomelanocortin (POMC) gene and the release of adrenocorticotropic hormone (ACTH). ACTH travels to the adrenal cortex, prompting the production and secretion of glucocorticoids, chiefly cortisol in humans. Cortisol then feeds back negatively to suppress CRH and ACTH production, helping maintain hormonal balance.

CRH receptors are distributed in the brain and peripheral tissues, with CRHR1 mainly in the brain and pituitary and CRHR2 in additional sites. CRH activity is modulated by CRH-binding protein (CRH-BP), which can influence the availability of CRH for receptor activation. The CRH system interacts with other neuropeptides, including the related peptides urocortins.

Clinical and research relevance includes diagnostic testing of the HPA axis. The CRH stimulation test uses exogenous CRH to evaluate ACTH and cortisol responses, helping differentiate pituitary from ectopic sources of ACTH in Cushing’s syndrome. Dysregulation of CRH signaling has been implicated in stress-related disorders such as depression and anxiety, stimulating investigation of CRH receptor–targeted therapies.