corticotropin-releasing hormone

**Synthesis and release** - Produced by parvocellular neurons of the paraventricular nucleus (PVN) of the hypothalamus. It is released into the hypophyseal portal system at the median eminence. - Stimuli for release: physical or psychological stress, hypoglycemia, hypotension and inflammatory cytokines (IL-1, IL-6, TNF-α). It also follows a circadian rhythm, with ACTH and cortisol peaking in the early morning (before waking) and reaching their nadir around midnight.

**Mechanism** - CRH binds CRH-R1 on anterior pituitary corticotrophs. This is a Gs-coupled receptor, so adenylyl cyclase is activated and cAMP and PKA rise. ACTH is then released. - ACTH is cleaved from POMC (pro-opiomelanocortin), which also yields β-lipotropin, β-endorphin and α-MSH. ACTH binds MC2R on the adrenal cortex (Gs/cAMP). - ACTH stimulates cortisol synthesis in the zona fasciculata (and adrenal androgens in the zona reticularis). Its effect on aldosterone is minor, because aldosterone is mainly regulated by the renin-angiotensin system and K⁺.

**Feedback** - Cortisol inhibits both CRH and ACTH (negative feedback at the hypothalamus and pituitary). ACTH also exerts short-loop feedback on CRH.

**Key actions of the downstream axis (cortisol)** - Increases gluconeogenesis, proteolysis and lipolysis. - Raises blood pressure by upregulating α1 receptors on arterioles (permissive effect on catecholamines). - Is anti-inflammatory and immunosuppressive. - Induces insulin resistance. - Decreases bone formation.

**Clinical correlations** - *Exogenous glucocorticoid use (most common cause of Cushing syndrome):* The patient has low CRH, low ACTH and low endogenous cortisol, which leads to bilateral adrenal atrophy. Abrupt withdrawal can precipitate adrenal insufficiency. - *Cushing disease (ACTH-secreting pituitary adenoma):* ACTH is high and cortisol is high. CRH is suppressed by the high cortisol. The high-dose dexamethasone suppression test suppresses cortisol, because the adenoma retains some feedback sensitivity. - *Ectopic ACTH (e.g., small cell lung cancer):* ACTH is high and cortisol is high. There is no suppression with high-dose dexamethasone. - *Adrenal adenoma or carcinoma:* Cortisol is high, and ACTH and CRH are low. - *Primary adrenal insufficiency (Addison disease):* Cortisol is low, so CRH and ACTH are high. Excess POMC products cause hyperpigmentation (MSH effect). Hyperkalemia, hyponatremia and volume depletion occur because aldosterone is also deficient. - *Secondary adrenal insufficiency (pituitary failure):* ACTH is low and cortisol is low. There is no hyperpigmentation and no hyperkalemia, because the renin-angiotensin-aldosterone system is intact. - *Tertiary adrenal insufficiency (hypothalamic dysfunction or chronic steroid use):* CRH, ACTH and cortisol are all low. - *CRH stimulation test:* Used to differentiate the cause of ACTH-dependent Cushing syndrome. Pituitary (Cushing disease) tumors typically show an exaggerated ACTH and cortisol response to CRH, while ectopic ACTH sources do not respond. Inferior petrosal sinus sampling is the gold standard for localization. - *Congenital adrenal hyperplasia (e.g., 21-hydroxylase deficiency):* Cortisol is low, so CRH and ACTH are high. This causes adrenal hyperplasia with excess androgen production.

**Other facts** - Placental CRH rises exponentially in late pregnancy and is implicated in the timing of parturition and fetal adrenal maturation. It also contributes to the physiologic hypercortisolism of pregnancy. - CRH acts centrally to mediate anxiety, decrease appetite and increase sympathetic outflow. Dysregulation is implicated in melancholic depression (hypercortisolemia, with CRH hypersecretion). - Contrast with the other hypothalamic releasing hormones: TRH (TSH and prolactin), GnRH (LH and FSH), GHRH (GH), dopamine (inhibits prolactin) and somatostatin (inhibits GH and TSH).

**High-yield mnemonic:** "CRH → ACTH → Cortisol" with long-loop negative feedback from cortisol. Always ask which level of the axis is broken, and predict the other hormones from that.