The major physiological and pharmacological effects of adrenocorticotropic hormone (ACTH, corticotropin) result from its action to increase the circulating levels of adrenocortical steroids. Synthetic derivatives of ACTH are used principally in the diagnostic assessment of adrenocortical function. Because corticosteroids mimic the therapeutic effects of ACTH, synthetic steroids generally are used therapeutically instead of ACTH.
Corticosteroids and their biologically active synthetic derivatives differ in their metabolic (glucocorticoid) and electrolyte-regulating (mineralocorticoid) activities. These agents are employed at physiological doses for replacement therapy when endogenous production is impaired. Glucocorticoids potently suppress inflammation, and their use in inflammatory and autoimmune diseases makes them among the most frequently prescribed classes of drugs. Because glucocorticoids exert effects on almost every organ system, the clinical use of and withdrawal from corticosteroids are complicated by a number of serious side effects. Therefore, the decision to institute therapy with systemic corticosteroids always requires careful consideration of the relative risks and benefits in each patient.
Human ACTH, a peptide of 39 amino acids, is synthesized as part of a larger precursor protein, proopiomelanocortin (POMC), and is liberated from the precursor through proteolytic cleavage at dibasic residues by the serine endoprotease, prohormone convertase 1 (also known as prohormone convertase 3) (Figure 42–1). Other biologically important peptides, including endorphins, lipotropins, and the melanocyte-stimulating hormones (MSHs), also are produced by proteolytic processing of the same POMC precursor (see Chapter 18).
Processing of proopiomelanocortin POMC to ACTH. Proopiomelanocortin (POMC) is converted to adrenocorticotropic hormone (ACTH) and other peptides in the anterior pituitary. The boxes within the ACTH structure indicate regions important for steroidogenic activity (residues 6-10) and binding to the ACTH receptor (15-18). α-Melanocyte-stimulating hormone also derives from the POMC precursor and contains the first 13 residues of ACTH. LPH, lipotropin; MSH, melanocyte-stimulating hormone.
The actions of ACTH and the other melanocortins liberated from POMC are mediated by their specific interactions with 5 melanocortin receptor (MCR) subtypes (MC1R-MC5R) comprising a subfamily of G protein-coupled receptors (GPCRs). The well-known effects of MSH on pigmentation result from interactions with the MC1R on melanocytes. ACTH, which is identical to α-MSH in its first 13 amino acids, exerts its effects on the adrenal cortex through the MC2R. The affinity of ACTH for the MC1R is much lower than for the MC2R; however, under pathological conditions in which ACTH levels are persistently elevated, such as primary adrenal insufficiency, ACTH also can signal through the MC1R and cause hyperpigmentation. β-MSH and possibly other melanocortins, acting via the MC4R and MC3R in the hypothalamus, play a role in regulating appetite and body weight. The role of MC5R is less well defined.
ACTIONS ON THE ADRENAL CORTEX. Acting via MC2R, ACTH stimulates the adrenal cortex to secrete glucocorticoids, mineralocorticoids, and the androgen ...