Molecular Derangements and the Diagnosis of ACTH-Dependent Cushing’s Syndrome

Abstract Endogenous Cushing’s syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are oft...

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Bibliographic Details
Published in:Endocrine reviews 2022-10, Vol.43 (5), p.852-877
Main Author: Nieman, Lynnette K
Format: Article
Language:English
Subjects:
ACTH
Adrenal Glands
Adrenocorticotropic Hormone
Adrenocorticotropin (ACTH)
Cardiovascular diseases
Clotting
Corticosteroids
Cortisol
Cushing Syndrome - diagnosis
Diabetes mellitus
Diagnosis
Diagnosis, Differential
Differential diagnosis
Glucocorticoids
Glucocorticoids - therapeutic use
Health aspects
Hormones
Humans
Hydrocortisone
Hypertension
Intermedin
Lung diseases
Medical research
Medical treatment
Medicine, Experimental
Nervous system diseases
Pituitary
Review
Synthesis
Thromboembolism
Tumors
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Summary:Abstract Endogenous Cushing’s syndrome (CS) is associated with morbidities (diabetes, hypertension, clotting disorders) and shortens life because of infections, pulmonary thromboembolism, and cardiovascular disease. Its clinical presentation is immensely variable, and diagnosis and treatment are often delayed. Thus, there are many opportunities for basic and clinical research leading to better tests, faster diagnosis, and optimized medical treatments. This review focuses on CS caused by excessive adrenocorticotropin (ACTH) production. It describes current concepts of the regulation of ACTH synthesis and secretion by normal corticotropes and mechanisms by which dysregulation occurs in corticotrope (termed “Cushing’s disease”) and noncorticotrope (so-called ectopic) ACTH-producing tumors. ACTH causes adrenal gland synthesis and pulsatile release of cortisol; the excess ACTH in these forms of CS leads to the hypercortisolism of endogenous CS. Again, the differences between healthy individuals and those with CS are highlighted. The clinical presentations and their use in the interpretation of CS screening tests are described. The tests used for screening and differential diagnosis of CS are presented, along with their relationship to cortisol dynamics, pathophysiology, and negative glucocorticoid feedback regulation in the two forms of ACTH-dependent CS. Finally, several gaps in current understanding are highlighted in the hope of stimulating additional research into this challenging disorder. Graphical Abstract Graphical Abstract
ISSN:0163-769X
1945-7189
DOI:10.1210/endrev/bnab046