Skip to Main Content

++

INTRODUCTION

++

The major physiological and pharmacological effects of ACTH result from the increase in circulating levels of adrenocortical steroids that ACTH causes. 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 used at physiological doses as 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, their administration and withdrawal may be complicated by serious side effects. Therefore, the decision to institute therapy with systemic glucocorticoids always requires careful consideration of the relative risks and benefits in each patient.

++

ABBREVIATIONS

++

Abbreviations

ACh: acetylcholine

ACTH: corticotropin (formerly adrenocorticotropic hormone)

AngII: angiotensin II

AP-1: activator protein 1

ATPase: adenosine triphosphatase

AVP: arginine vasopressin

CAH: congenital adrenal hyperplasia

CBG: corticosteroid-binding globulin

CIRCI: critical illness–related cortisol insufficiency

CNS: central nervous system

COX: cyclooxygenase

CRF: corticotropin-releasing factor (CRF1, CRF2)

CRH: corticotropin-releasing hormone

CYP: cytochrome P450

CYP11A1: cholesterol side-chain cleavage enzyme

CYP11B1: 11ß-hydroxylase

CYP11B2: aldosterone synthase

CYP17: 17α-hydroxylase

CYP19: aromatase

CYP21: steroid 21-hydroxylase

DHEA: dehydroepiandrosterone

ELAM-1: endothelial-leukocyte adhesion molecule 1

FDA: Food and Drug Administration

GM-CSF: granulocyte-macrophage colony-stimulating factor

GR: glucocorticoid receptor

GRE: glucocorticoid-response element

HPA: hypothalamic-pituitary-adrenal

3β-HSD: 3β-hydroxysteroid dehydrogenase

11β-HSD1: 11β-hydroxysteroid dehydrogenase (type 1)

11β-HSD2: 11β-hydroxysteroid dehydrogenase (type 2)

HSP70: 70-kDa heat shock protein

HSP90: 90-kDa heat shock protein

ICAM-1: intercellular adhesion molecule 1

Ig: immunoglobulin

IL: interleukin

IP: 56-kDa immunophilin

IP3: inositol trisphosphate

LPH: lipotropin

LT: leukotriene

MCR: melanocortin receptor

MR: mineralocorticoid receptor

mRNA: messenger RNA

MSH: melanocyte-stimulating hormone

NE: norepinephrine

NF-κB: nuclear factor kappa B

NOS: nitric oxide synthase

PG: prostaglandin

PK: protein kinase

PLC: phospholipase C

POMC: pro-opiomelanocortin

RANK: receptor for activating NF-κB

SSTR: somatostatin receptor

TNF: tumor necrosis factor

++

CORTICOTROPIN

++

Human ACTH, a peptide of 39 amino acids, is synthesized as part of a larger precursor protein, POMC, and is derived from the precursor by proteolytic cleavage at dibasic residues by the serine endoprotease, prohormone convertase 1 (also known as prohormone convertase 3) (Figure 46–1). Other biologically important peptides, including endorphins, lipotropins, and the MSHs, also are produced by proteolytic processing of the same POMC precursor (see Chapter 20 and Takahashi and Mizusawa, 2013).

++
Figure 46–1

Processing of POMC to ACTH. POMC is converted to 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-MSH also derives from the POMC precursor and contains the first 13 residues of ACTH.

Graphic Jump Location

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.