CRH

**Source and release:** CRH is made by parvocellular neurons of the paraventricular nucleus (PVN) of the hypothalamus. It travels via the hypophyseal portal system to the anterior pituitary. Stimuli for release include stress (physical or psychological), hypoglycemia, and the circadian rhythm (peaks in early morning, nadir at night). Inflammatory cytokines (IL-1, IL-6, TNF-α) also stimulate it.

**Mechanism:** CRH binds the CRH-R1 receptor on corticotrophs. This is a Gs-coupled GPCR, so it increases cAMP and activates PKA. The result is transcription of POMC and release of ACTH. POMC is cleaved into ACTH, β-endorphin, and α-MSH (and β-lipotropin). ACTH then acts on the adrenal zona fasciculata (via MC2R) to increase cortisol synthesis, and to a lesser extent on the zona reticularis (androgens).

**Feedback:** Cortisol inhibits CRH (hypothalamus) and ACTH (pituitary) release. This is the basis of the dexamethasone suppression tests. Exogenous glucocorticoids suppress CRH and ACTH, which causes adrenal atrophy (tertiary adrenal insufficiency).

**Clinical correlations:** - *Primary adrenal insufficiency (Addison disease):* low cortisol, so CRH and ACTH are high. Hyperpigmentation results from excess POMC-derived α-MSH/ACTH. - *Secondary adrenal insufficiency:* pituitary failure, with low ACTH and low cortisol. CRH is high. No hyperpigmentation, and the renin-angiotensin-aldosterone system is intact, so there is no hyperkalemia. - *Tertiary adrenal insufficiency:* most commonly from chronic exogenous steroid use. CRH, ACTH, and cortisol are all low. - *Cushing disease (pituitary ACTH adenoma):* high ACTH and high cortisol. CRH is suppressed by cortisol feedback. High-dose dexamethasone suppresses ACTH, and the CRH stimulation test shows an exaggerated ACTH response. - *Ectopic ACTH (e.g., small cell lung cancer):* very high ACTH and cortisol. It does not suppress with high-dose dexamethasone and does not respond to CRH stimulation. - *Adrenal Cushing syndrome (adenoma or carcinoma):* low ACTH and high cortisol. CRH is suppressed. - *CRH stimulation test:* used with inferior petrosal sinus sampling to distinguish pituitary from ectopic ACTH sources. - *Placental CRH:* rises in the third trimester, and its levels are thought to time parturition. It stimulates fetal adrenal DHEA-S production (the substrate for estriol), and it can raise maternal cortisol. Maternal total cortisol is physiologically elevated because estrogen increases cortisol-binding globulin. - *Psychiatry:* CRH hyperactivity is implicated in major depression (melancholic type) and PTSD/anxiety. It is also linked to the stress response, decreased appetite, and decreased GnRH (functional hypothalamic amenorrhea). - *Other effects:* CRH suppresses GnRH and TRH/TSH axes during stress and increases sympathetic outflow.

**High-yield memory aids:** - Hormone cascade: CRH → ACTH → cortisol. - "Anterior pituitary basophils" make ACTH, TSH, FSH, LH (B-FLAT). ACTH comes from the corticotrophs, and CRH acts on them. - Cortisol is a negative-feedback inhibitor of CRH and ACTH. - Think of CRH as a stress hormone that sits above ACTH in the HPA axis.