Adrenocorticotropic Hormone (ACTH, Corticotropin)

ADRENOCORTICOTROPIC HORMONE (ACTH, CORTICOTROPIN)

It is a 39 amino acid single chain peptide, MW 4500, derived from a larger peptide proopio melanocortin (MW 30,000) which also gives rise to endorphins, two lipotropins and two MSHs.

Physiological Function

ACTH promotes steroidogenesis in adrenal cortex by stimulating cAMP formation in cortical cells (through specific cell surface G protein coupled receptors) → rapidly increases the availability of cholesterol for conversion to pregnenolone which is the rate limiting step in the production of gluco, mineralo and weakly androgenic steroids. Induction of steroidogenic enzymes occurs after a delay. The stores of adrenal steroids are very limited and rate of synthesis primarily governs the rate of release. ACTH also exerts trophic influence on adrenal cortex (again through cAMP): high doses cause hypertrophy and hyperplasia. Absence of ACTH results in adrenal atrophy. However, zona glomerulosa is little affected because angiotensin also exerts trophic influence on this layer and sustains aldosterone secretion.

Regulation Of Secretion

Hypothalamus regulates ACTH release from pituitary through corticotropin releasing hormone (CRH). The CRH receptor on corticotropes is also a G protein coupled receptor which increases ACTH synthesis as well as release through increased cAMP. Secretion of ACTH has a circadian rhythm. Peak plasma levels occur in the early morning, decrease during day and are lowest at midnight. Corticosteroids exert inhibitory feedback influence on ACTH production by acting directly on the pituitary as well as indirectly through hypothalamus.

A variety of stressful stimuli, e.g. trauma, surgery, severe pain, anxiety, fear, blood loss, exposure to cold, etc. generate neural impulses which converge on median eminence to cause elaboration of CRH. The feedback inhibition appears to be overpowered during stress—rise in ACTH secretion continues despite high plasma level of cortisol induced by it. Vasopressin has been found to enhance action of CRH on corticotropes and augment ACTH release.

Pathological Involvement

Excess production of ACTH from basophil pituitary tumours is responsible for some cases of Cushing’s syndrome. Hypocorticism occurs in pituitary insufficiency due to low ACTH production. Iatrogenic suppression of ACTH secretion and pituitary adrenal axis is the most common form of abnormality encountered currently due to the use of pharmacological doses of glucocorticoids in nonendocrine diseases.

Use

ACTH is used primarily for the diagnosis of disorders of pituitary adrenal axis. Injected i.v. 25 IU causes increase in plasma cortisol if the adrenals are functional. Direct assay of plasma ACTH level is now preferred.

For therapeutic purposes, ACTH does not offer any advantage over corticosteroids and is more inconvenient, expensive as well as less predictable.