Diagnosis of Cushing's Syndrome

Publication Date: May 1, 2008
Last Updated: May 27, 2022

Key Points

Key Points

  • The most common cause of Cushing's syndrome is iatrogenic from medically prescribed corticosteroids.
  • Excess cortisol production may be caused by either excess adrenocorticotropic hormone (ACTH) secretion (from a pituitary or other ectopic tumor) or independent adrenal overproduction of cortisol.
  • The diagnosis can be challenging in mild cases.
    • Endocrine Society (ES) recommends initial use of one test with high diagnostic accuracy (urine free cortisol [UFC], late night salivary cortisol, 1-mg overnight or 2-mg 48-h dexamethasone suppression test).
    • Testing for Cushing's syndrome in certain high-risk populations has shown an unexpectedly high incidence of unrecognized Cushing's syndrome as compared with the general population. Although there are limited data on the prevalence of the syndrome in these disorders, the diagnosis should be considered.
    • Often patients have a number of features that are caused by cortisol excess but that are also common in the general population such as obesity, depression, diabetes, hypertension, or menstrual irregularity.
    • As a result, there is an overlap in the clinical presentation of individuals with and without the disorder. The distinction between these groups is difficult, and there is no one correct diagnostic strategy.
  • There is a wide spectrum of clinical manifestations at any given level of hypercortisolism. Because Cushing's syndrome tends to progress, accumulation of new features increases the probability that the syndrome is present.
  • Caregivers are encouraged to consider Cushing's syndrome as a secondary cause of these conditions, particularly if additional features of the disorder are present. If Cushing's syndrome is not considered, the diagnosis is all too often delayed.
  • Cushing's syndrome tends to progress and severe hypercortisolism is probably associated with a worse outcome, it is likely that early recognition and treatment of mild disease would reduce the risk of residual morbidity.



Who Should Be Treated

ES recommends obtaining a thorough drug history to exclude excessive exogenous glucocorticoid exposure leading to iatrogenic Cushing's syndrome before conducting biochemical testing. ( 1-H )
ES recommends testing for Cushing's syndrome in the following groups:
  • Patients with unusual features for age (e.g., osteoporosis, hypertension) (Table 1)
( 1-L )
  • Patients with multiple and progressive features, particularly those who are more predictive of Cushing's syndrome (Table 1).
( 1-L )
  • Children with decreasing height percentile and increasing weight.
( 1-VL )
  • Patients with adrenal incidentaloma compatible with adenoma.
( 1-VL )
ES recommends against widespread testing for Cushing's syndrome in any other patient group. ( 1-VL )

Initial Testing

For the initial testing for Cushing's syndrome, ES recommends one of the following tests based on its suitability for a given patient (Fig. 1): ( 1-VL )
  • UFC (at least two measurements)
  • Late-night salivary cortisol (two measurements)
  • 1-mg overnight dexamethasone suppression test (DST)
  • Longer low-dose DST (2 mg/d for 48 h)
ES recommends against the use of the following to test for Cushing's syndrome: ( 1-VL )
  • Random serum cortisol or plasma ACTH levels
  • Urinary 17-ketosteroids
  • Insulin tolerance test
  • Loperamide test
  • Tests designed to determine the cause of Cushing's syndrome (e.g., pituitary and adrenal imaging, 8 mg DST).
In individuals with normal test results in whom the pretest probability is high (patients with clinical features suggestive of Cushing's syndrome and adrenal incidentaloma or suspected cyclic hypercortisolism), ES recommends further evaluation by an endocrinologist to confirm or exclude the diagnosis. ( 1-VL )
In other individuals with normal test results (in whom Cushing's syndrome is very unlikely), ES suggests reevaluation in 6 months if signs or symptoms progress. ( 2-VL )
In individuals with at least one abnormal test result (for whom the results could be falsely positive or indicate Cushing's syndrome), ES recommends further evaluation by an endocrinologist to confirm or exclude the diagnosis. ( 1-VL )

Subsequent Evaluation

For the subsequent evaluation of abnormal initial test results, ES recommends performing another recommended test (Fig. 1). ( 1-VL )
ES suggests the additional use of the dexamethasone-suppressed corticotropin-releasing hormone (Dex-CRH) test or the midnight serum cortisol test in specific situations (Fig. 1). ( 1-VL )
ES suggests against the use of the desmopressin test, except in research studies, until additional data validate its utility. ( 2-VL )
ES recommends against any further testing for Cushing's syndrome in individuals with concordantly negative results on two different tests (except in patients suspected of having the very rare case of cyclical disease). ( 1-VL )
ES recommends tests to establish the cause of Cushing's syndrome in patients with concordantly positive results from two different tests, provided there is no concern regarding possible non-Cushing's hypercortisolism (Table 2). ( 1-L )
ES suggests further evaluation and follow-up for the few patients with concordantly negative results who are suspected of having cyclical disease and also for patients with discordant results, especially if the pretest probability of Cushing's syndrome is high. ( 2-VL )

Special Populations/Considerations


ES recommends the use of UFC and against the use of dexamethasone testing in the initial evaluation of pregnant women. (1-M)


ES recommends against the use of dexamethasone testing in patients receiving antiepileptic drugs known to enhance dexamethasone clearance and recommends instead measurements of nonsuppressed cortisol in blood, saliva, or urine. ( 1-M )

Renal failure:

ES suggests using the 1-mg overnight DST rather than UFC for initial testing for Cushing's syndrome in patients with severe renal failure. ( 2-VL )

Cyclic Cushing's syndrome:

ES suggests use of UFC or midnight salivary cortisol tests rather than DSTs in patients suspected of having cyclic Cushing's syndrome. ( 2-VL )

Adrenal incidentaloma:

ES suggests use of the 1-mg DST or late-night cortisol test, rather than UFC, in patients suspected of having mild Cushing's syndrome. ( 2-L )

Table 1. Overlapping Conditions and Clinical Features of Cushing’s Syndromea

Having trouble viewing table?
Symptoms Signs Overlapping conditions
Cushing's syndrome features in the general population that are common and/or less discriminatory
  • Depression
  • Fatigue
  • Weight gain
  • Back pain
  • Changes in appetite
  • Decreased concentration
  • Decreased libido
  • Impaired memory (especially short term)
  • Insomnia
  • Irritability
  • Menstrual abnormalities
  • Dorsocervical fat pad ("buffalo hump")
  • Facial fullness
  • Obesity
  • Supraclavicular fullness
  • Thin skinb
  • Peripheral edema
  • Acne
  • Hirsutism or female balding
  • Poor skin healing
  • Hypertensionb
  • Incidental adrenal mass
  • Vertebral osteoporosisb
  • Polycystic ovary syndrome
  • Type 2 diabetesb
  • Hypokalemia
  • Kidney stones
  • Unusual infections
  • In children, slow growth
  • In children, abnormal genital virilization
  • In children, short stature
  • In children, pseudoprecocious puberty or delayed puberty
Features that best discriminate Cushing's syndrome; most do not have a high sensitivity
  • Easy bruising
  • Facial plethora
  • Proximal myopathy (or proximal muscle weakness)
  • Striae (especially if reddish purple and > 1 cm wide)
  • In children, weight gain with decreasing growth velocity
a Features are listed in random order.
b Cushing's syndrome is more likely if onset of the feature is at a younger age.

Table 2. Conditions Associated with Hypercortisolism in the Absence of Cushing's Syndromea

Having trouble viewing table?
Some clinical features of Cushing's syndrome may be present
  • Pregnancy
  • Depression and other psychiatric conditions
  • Alcohol dependence
  • Glucocorticoid resistance
  • Morbid obesity
  • Poorly controlled diabetes mellitus
Unlikely to have any clinical features of Cushing's syndrome
  • Physical stress (hospitalization, surgery, pain)
  • Malnutrition, anorexia nervosa
  • Intense chronic exercise
  • Hypothalamic amenorrhea
  • CBG excess (increased serum but not urine cortisol)
a Whereas Cushing's syndrome is unlikely in these conditions, it may rarely be present. If there is a high clinical index of suspicion, the patient should undergo testing, particularly those within the first group.

Cushing's Syndrome

Table 3. Selected Drugs That May Interfere with the Evaluation of Tests for the Diagnosis of Cushing's Syndromea

Having trouble viewing table?
Drugs that accelerate dexamethasone metabolism by induction of CYP 3A4
  • Phenobarbital
  • Phenytoin
  • Carbamazepine
  • Primidone
  • Rifampin
  • Rifapentine
  • Ethosuximide
  • Pioglitazone
Drugs that impair dexamethasone metabolism by inhibition of CYP 3A4
  • Aprepitant/fosaprepitant
  • Itraconazole
  • Ritonavir
  • Fluoxetine
  • Diltiazem
  • Cimetidine
Drugs that increase CBG and may falsely elevate cortisol results
  • Estrogens
  • Mitotane
Drugs that increase UFC results
  • Carbamazepine (increase)
  • Fenofibrate (increase if measured by HPLC)
  • Some synthetic glucocorticoids (immunoassays)
  • Drugs that inhibit 11β-HSD2 (licorice, carbenoxolone)
a This should not be considered a complete list of potential drug interactions.
Data regarding CYP3A4 obtained from http://medicine.iupui.edu/flockhart/table.htm.

Figure 1. Algorithm for Testing Patients Suspected of Having Cushing's Syndrome (CS)

Recommendation Grading


  • ACC: Adrenocortical Carcinoma
  • ACTH: Adrenocorticotropic Hormone
  • ADX: Adrenalectomy
  • BMAH: Bilateral Macronodular Adrenal Hyperplasia
  • BMD: Bone Mineral Density
  • CBG: Corticosteroid Binding Globulin
  • CD: Cushing's Disease
  • CNS: Central Nervous System
  • CS: Cushing's Syndrome
  • DDI: Drug-drug Interactions
  • EAS: Ectopic ACTH Secretion
  • ES: Endocrine Society
  • GC: Glucocorticoid(s)
  • GH: Growth Hormone
  • GI: Gastrointestinal
  • HPA: Hypothalamic-pituitary-adrenal
  • HRQOL: Health-related Quality Of Life
  • HT: Hypertension
  • HU: Hounsfield Units
  • ICU: Intensive Care Unit
  • IPSS: Inferior Petrosal Sinus Sampling
  • LFTs: Liver Function Tests
  • QOL: Quality Of Life
  • QTc: Corrected QT Interval
  • RT: Radiation Therapy
  • SST: Somatostatin Receptor
  • T4: Thyroid Hormone
  • TSS: Transsphenoidal Selective Adenomectomy
  • UFC: Urine Free Cortisol
  • WBC: White Blood Cell Count
  • fT4: Free Thyroxine
  • h: Hour(s)

Source Citation

Lynnette K. Nieman, Beverly M. K. Biller, James W. Findling, John Newell-Price, Martin O. Savage, Paul M. Stewart, Victor M. Montori, The Diagnosis of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism, Volume 93, Issue 5, 1 May 2008, Pages 1526–1540, https://doi.org/10.1210/jc.2008-0125


This resource is for informational purposes only, intended as a quick-reference tool based on the cited source guideline(s), and should not be used as a substitute for the independent professional judgment of healthcare providers. Practice guidelines are unable to account for every individual variation among patients or take the place of clinician judgment, and the ultimate decision concerning the propriety of any course of conduct must be made by healthcare providers after consideration of each individual patient situation. Guideline Central does not endorse any specific guideline(s) or guideline recommendations and has not independently verified the accuracy hereof. Any use of this resource or any other Guideline Central resources is strictly voluntary.


CPT Codes

Code Descriptor
70551 Magnetic resonance (eg
80400 ACTH stimulation panel; for adrenal insufficiency
80420 Dexamethasone suppression panel
82533 Cortisol; total
74021 Radiologic examination
83586 Ketosteroids
83593 Ketosteroids
70450 Computed tomography
74018 Radiologic examination
70470 Computed tomography
82530 Cortisol; free
82024 Adrenocorticotropic hormone (ACTH)
74170 Computed tomography
74019 Radiologic examination
80412 Corticotropic releasing hormone (CRH) stimulation panel
74150 Computed tomography
70460 Computed tomography
70552 Magnetic resonance (eg
70553 Magnetic resonance (eg
74160 Computed tomography
80418 Combined rapid anterior pituitary evaluation panel
80434 Insulin tolerance panel; for ACTH insufficiency

ICD-10 Codes

Code Descriptor Documentation Concepts Quality/Performance
E24.8 Other Cushing's syndrome Type HCC23; RXHCC41
E24.9 Cushing's syndrome, unspecified Type HCC23; RXHCC41
E24.2 Drug-induced Cushing's syndrome Type HCC23; RXHCC41