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Cushing's Syndrome: Rapid Evidence Review

David L. Maness, DO, MSS
Grant Studebaker, MD
Christopher M. Knight, MD

American Family Physician. 2024;110(3):270-280.

Author disclosure: No relevant financial relationships.

This clinical content conforms to AAFP criteria for CME.

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 11,2,8,10,12–15). 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

WHAT'S NEW ON THIS TOPIC

Cushing's Syndrome
In a 2022 study of 89 patients referred to a tertiary center over a 10-year period, myopathy, metabolic syndrome, osteoporosis, adrenal incidentaloma, and the presence of multiple Cushing's syndrome–specific symptoms increased the likelihood of Cushing's syndrome being diagnosed, whereas obesity as the chief symptom did not.
If transsphenoidal surgery is performed by an experienced surgeon, the remission rate is approximately 80% for microadenomas and 60% for macroadenomas.
One-half of recurrences happen within 5 years after surgery.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Clinical recommendation Evidence rating Comments
Exogenous use of glucocorticoids (e.g., oral, inhaled, injectable, topical) should always be ruled out when considering the diagnosis of Cushing's syndrome.2,4,6–11 C Endocrine Society consensus guideline
Expert opinion and clinical reviews
The Endocrine Society recommends screening for Cushing's syndrome in patients with any of the following features:
Weight gain and central redistribution of fat
Multiple progressive features of Cushing's syndrome
In adults, unusual symptoms for their age
In children, growth restriction (decreasing height percentile and increasing weight)
Adrenal incidentaloma compatible with adenoma.1,3,4,8,13,22		 C Endocrine Society consensus guideline
Expert opinion and clinical reviews
The recommended screening tests for hypercortisolism are 24-hour urinary free cortisol, late-night salivary cortisol, and 1-mg dexamethasone suppression tests.1–4,7,8,10,14,15,21,27,28 C Endocrine Society consensus guideline
Expert opinion and clinical reviews
Transsphenoidal surgery by an experienced pituitary surgeon is recommended as first-line treatment for Cushing's disease.1–3,7,8,10,33 C Endocrine Society and American Association of Endocrine Surgeons consensus guidelines
Expert opinion and clinical reviews
Lifelong monitoring for recurrence is required. Monitoring should begin once the hypothalamic-pituitary-adrenal axis is restored and annually thereafter.1–4,10,15,40–44 C Endocrine Society consensus guideline
Expert opinion and clinical reviews

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to https://www.aafp.org/afpsort.

DAVID L. MANESS, DO, MSS, FAAFP, is a retired U.S. Army colonel and a professor at the University of Tennessee Family Medicine Residency Program, Jackson.

GRANT STUDEBAKER, MD, FAAFP, is the program director of the Department of Family Medicine at the University of Tennessee Health Science Center, Jackson.

CHRISTOPHER M. KNIGHT, MD, FAAFP, is an assistant professor in the Department of Family Medicine at the University of Tennessee Health Science Center, Jackson.

Address correspondence to David L. Maness, DO, MSS, at dmaness@uthsc.edu.

Author disclosure: No relevant financial relationships.

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