Adrenocorticotropic hormone

A pituitary hormone secreted from the pars distalis, ACTH was one of the first adenohypophysial hormones demonstrated to be present in vertebrates from jawless fish to mammals, together with melanocyte-stimulating hormone (MSH). The fact that ACTH is derived from a precursor protein called proopiomelanocortin (POMC) was demonstrated in 1979 using the pars intermedia of the bovine pituitary.

Structure

ACTH consists of 39 aa residues and is composed of two regions corresponding to α-MSH and a corticotropin-like intermediate lobe peptide (CLIP). These regions are connected by basic amino acid sequences. ACTH is generated from the common precursor POMC in the pars distalis of the pituitary. α-MSH and CLIP are generated in the pars intermedia of the pituitary in many vertebrates except for some mammals, such as humans, which lack the lobe in adults. ACTH is a type of melanocortin (MC) that has the common sequence His-Phe-Arg-Trp in the α-MSH segment. The first 24 aa residue sequence of ACTH, that is, ACTH(1–24), is highly conserved in gnathostomes ranging from cartilaginous fish to humans. Furthermore, mammalian ACTH(1–24) is equivalent in potency to full-length ACTH, ACTH (1–39). In the ACTH sequence, the His-Phe-Arg-Trp domain is referred to as the “message” sequence, and the Lys-Lys-Arg-Arg domain is referred to as the “address” signal. ACTH(1–24) has full activity, yet ACTH(1–16) has minimal activity, and α-MSH has no activity in various adrenal cortex bioassay systems in mammals. ACTH(11–24) can function as an antagonist of the ACTH(1–24) activation of adrenal cortex cells.

Synthesis and release

The release of ACTH from corticotropes is primarily stimulated by corticotropin-releasing hormone (CRH), which is produced in the hypothalamus. ACTH release is also positively stimulated by arginine vasopressin (AVP). CRH and AVP colocalize in hypothalamic neurons. ACTH release is also stimulated by neurotransmitters such as norepinephrine, epinephrine, serotonin, and acetylcholine, and neuropeptides such as oxytocin, vasoactive intestinal peptide, peptide histidine isoleucine, and angiotensin-II. ACTH release is suppressed by negative feedback effects on corticotropes and CRH neurons by glucocorticoids from the adrenal cortex.

Clinical implications

Cushing’s syndrome refers to the manifestations of chronic glucocorticoid excess, and it may arise from various causes. This syndrome can be dividedinto two general types: ACTH-dependent and ACTH-independent. ACTH-dependent Cushing’s syndrome is caused by excessive stimulation of the adrenal glands by ACTH, whereas ACTH-independent Cushing’s syndrome is associated with autonomous adrenal cortisol production. In Cushing’s disease (the majority of ACTH-dependent Cushing’s syndrome cases), pituitary ACTH oversecretion induces bilateral adrenocortical hyperplasia and the excess production of corticosteroids such as cortisol, adrenal androgens, and 11-deoxycorticosterone. In this disease, the CRH receptor is overexpressed in corticotropes in comparison to normal pituitaries. Cells containing the glucocorticoid receptor are abundantly present. MC2R is predominantly expressed in the adrenal cortex. In Addison’s disease, or primary adrenal insufficiency, steroid hormones such as cortisol and dehydroepiandrosterone concentrations are decreased due to adrenal destruction. This disease is characterized by a high serum ACTH concentration (lack of negative feedback effects).

Use for diagnosis and treatment

Cosyntropin has been used as an ACTH stimulation test to diagnose adrenal insufficiency and recently to diagnose primary aldosteronism by adrenal vein sampling. Corticotropin zinc hydroxide is a drug for ulcerative colitis and other colonic disorders, and the treatment of some collagen diseases. ACTH is used to treat the symptoms related to allergic disorders.