Cushing's Syndrome: Rapid Evidence Review

David L. Maness; Grant Studebaker; Christopher M. Knight

DAVID L. MANESS, DO, MSS, GRANT STUDEBAKER, MD, AND CHRISTOPHER M. KNIGHT, MD

Am Fam Physician. 2024;110(3):270-280

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Cushing's syndrome is a rare, multisystemic disease caused by chronic exposure to supraphysiologic levels of cortisol. Prolonged hypercortisolism is associated with significant multisystem morbidity and mortality and decreased quality of life. Diagnosis of Cushing's syndrome is often delayed by several years due to its insidiously progressive course, diverse clinical presentation, overlap of symptoms with many common conditions, and testing complexity. Exogenous glucocorticoid use must be excluded as the primary etiology. Excessive endogenous cortisol production can be caused by an overproduction of adrenocorticotropic hormone (ACTH) through pituitary tumors or ectopic sources (ACTH-dependent cases), or it can be caused by autonomous cortisol overproduction by the adrenal glands (ACTH-independent cases). The recommended diagnostic approach includes appropriate screening, confirmation of hypercortisolism, and determination of etiology. First-line treatment is surgical removal of the source of cortisol overproduction. Lifelong posttherapy monitoring is required to treat comorbidities and detect recurrence.

Cushing's syndrome is a multifaceted and progressive disease caused by chronic exposure to excessive levels of cortisol from iatrogenic or internal sources.^1–10 Exogenous (iatrogenic) Cushing's syndrome, which is caused by the administration of glucocorticoids, is the most common form and must be ruled out.^2,4,6–11 Endogenous Cushing's syndrome is classified as adrenocorticotropic hormone (ACTH) dependent (80% to 85% of cases) or ACTH independent (15% to 20% of cases; Table 1^{1,2,8,10,12–15}). Most cases (75% to 80%) are caused by Cushing's disease, which features a pituitary adenoma excessively secreting ACTH.^2,7,10,11 Endogenous Cushing's syndrome can also be caused by ectopic ACTH syndrome, which results from tumors that excessively produce ACTH (15% to 20% of cases) or corticotropin-releasing hormone (less than 1% of cases).^2,10

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