adrenocorticotropic hormone

**Synthesis and structure** - ACTH is a 39-amino-acid peptide. It is cleaved from pro-opiomelanocortin (POMC) by prohormone convertase. - POMC also gives rise to alpha-MSH, beta-endorphin, and lipotropin. - Corticotrophs are basophilic cells of the anterior pituitary.

**Regulation** - CRH from the paraventricular nucleus of the hypothalamus stimulates ACTH release. ADH (vasopressin) potentiates this. - Stress, hypoglycemia, and a circadian rhythm drive release. ACTH and cortisol peak in the early morning (about 6-8 AM) and reach a nadir around midnight. - Cortisol exerts negative feedback on both the hypothalamus (CRH) and the pituitary (ACTH).

**Mechanism of action** - ACTH binds the MC2R (melanocortin-2 receptor), a Gs-coupled receptor. This increases cAMP and PKA activity. - The result is increased cholesterol uptake and conversion to pregnenolone by the rate-limiting step (StAR and desmolase, CYP11A1). - It acts mainly on the zona fasciculata (cortisol) and zona reticularis (androgens). - The zona glomerulosa (aldosterone) is primarily controlled by angiotensin II and K⁺, not ACTH. This is why aldosterone is preserved in secondary adrenal insufficiency. - Chronically, ACTH has a trophic effect, causing adrenal hypertrophy and hyperplasia.

**Clinical correlations** - *Cushing disease (ACTH-secreting pituitary adenoma):* ↑ACTH, ↑cortisol. Cortisol suppresses with high-dose dexamethasone, and there is bilateral adrenal hyperplasia. - *Ectopic ACTH (small cell lung cancer, bronchial carcinoid):* ↑ACTH, ↑cortisol. It does not suppress with high-dose dexamethasone, except for carcinoids, which may. - *Adrenal Cushing syndrome (adenoma or carcinoma):* ↓ACTH, ↑cortisol, with atrophy of the contralateral adrenal. - *Exogenous glucocorticoids:* ↓ACTH, with bilateral adrenal atrophy. - *Primary adrenal insufficiency (Addison disease):* ↑ACTH, ↓cortisol, and ↓aldosterone. Hyperpigmentation results from excess POMC-derived MSH activity. Features include hypotension, hyponatremia, and hyperkalemia. The most common cause in the US is autoimmune adrenalitis. - *Secondary adrenal insufficiency (pituitary failure):* ↓ACTH and ↓cortisol. There is no hyperpigmentation, and K⁺ and aldosterone are normal. - *Congenital adrenal hyperplasia (e.g., 21-hydroxylase deficiency):* ↓cortisol causes ↑ACTH, which leads to adrenal hyperplasia and excess androgens. - *Nelson syndrome:* After bilateral adrenalectomy for Cushing disease, the pituitary adenoma enlarges because it lacks cortisol feedback. This causes ↑ACTH, hyperpigmentation, and possible mass effect. - *Waterhouse-Friderichsen syndrome:* Acute adrenal hemorrhage (classically from meningococcemia) leads to adrenal crisis.

**Diagnostic tests** - *Cosyntropin (synthetic ACTH 1-24) stimulation test:* Failure of cortisol to rise confirms adrenal insufficiency. - *Plasma ACTH level:* High suggests primary insufficiency, low suggests secondary. In Cushing syndrome, it differentiates ACTH-dependent from ACTH-independent causes. - *Inferior petrosal sinus sampling:* Distinguishes pituitary from ectopic ACTH sources.

**Therapeutic uses** - ACTH (repository corticotropin) is used for infantile spasms, and sometimes for multiple sclerosis exacerbations.

**High-yield pearls** - ACTH → ↑cortisol → ↓CRH and ↓ACTH (negative feedback). - Hyperpigmentation indicates high ACTH (primary adrenal insufficiency, Nelson syndrome, ectopic ACTH). It does not occur in secondary or tertiary insufficiency. - Chronic exogenous steroids suppress the HPA axis. Do not stop them abruptly, to avoid adrenal crisis.