The adrenocorticotropin (ACTH) hormone, a 39-amino acid peptide, is synthesized by the corticotroph cells of anterior pituitary from a large precursor molecule, the pro-opio-melano-cortin (POMC). ACTH is highly conserved in mammals since only amino acids 31 and 33 vary between higher mammals and primates. ACTH is the principal regulator of cortisol production by the adrenal cortex. The biological activity of the ACTH molecule depends on the first 24 amino-terminal amino acids while fragments of less than 20 amino acids are ineffective. The residue 25-39 is important for stability increasing the half-life of the molecule.

The synthesis of POMC, its post-translational modifications, and the secretion of ACTH are under the absolute control of corticotropin-releasing hormone (CRH) and to a lesser degree to arginine vasopressin (AVP). Both hormones are synthesized in the parvocellular cells of the paraventricular (PVN) hypothalamic nucleus and are under the negative control of circulating glucocorticoids. It should be noted here that magnocellular AVP follows a distinct regulatory and secretory path: it is transferred to posterior pituitary by axonal transport and its synthesis and secretion are under the influence of osmotic and oncotic stimuli. On the other hand, the parvocellular CRF and AVP travel, via axonal transport, to median eminence (ME) at the lower part of hypothalamus from where they are secreted into the vascular connection between hypothalamus and anterior pituitary, the portal circulation. Multiple neural signals regulate the synthesis of CRF and AVP as well as their secretion from ME. CRH reaching the anterior pituitary corticotrophs binds to the CRH-R1 receptors. The corticotrophs represent approximately 10% of anterior pituitary cells. Their main product, POMC is a 260 AA protein, which is post-translationally cleaved into several bioactive peptides that are secreted from the corticotrophs along with ACTH, including β-lipotropin, the endogenous opioid peptide beta-endorphin and melanocyte stimulating hormones (MSH). Glucocorticoids exert their negative feedback control on both levels i.e. hypothalamus and anterior pituitary corticotrophs suppressing POMC synthesis and ACTH secretion. High levels of glucocorticoids cause characteristic corticotropic cell degeneration. The immune system participates in the regulation of ACTH production via interleukins (IL)-1, IL-6, tumor necrosis factor (TNF)-alpha and interferons alpha and gamma, which affect the axis at all levels i.e. hypothalamus, pituitary, and adrenal cortex.