Early diagnosis is key to reducing morbidity and mortality, and improving quality of life1,2
Diagnosis of Cushing's Syndrome (CS) is frequently delayed because it can take years after onset for noticeable signs and symptoms to appear.3,4 Uncontrolled chronic hypercortisolism leads to elevated risks of multisystem morbidity and mortality.5 While the risks of morbidity and mortality can decrease with biochemical remission, they’re not entirely eliminated.6
Steps to a Cushing’s diagnosis7
Hypercortisolism can manifest in CS along a spectrum, being easily diagnosed in some patients and easily misdiagnosed in others.1 Use this flow chart to help rule-in/out CS.7
Diagnostic approach to suspected CS
Step 1 – Exclude exogenous glucocorticoid exposure
Present: manage as exogenous hypercortisolism
Absent:
Proceed to biochemical evaluation
Step 2 – Confirm pathological hypercortisolism
1L biochemical evaluation: perform ≥2 validated tests
  • 24-hour urinary free cortisol test
  • Late night salivary cortisol measurement
  • 1 mg overnight dexamethasone suppression test
Normal results: CS unlikely*
2L biochemical evaluation if results of 1L are inconclusive
  • Refer patient to pituitary/CS centre of expertise
  • Exclude hormone medication-induced increases in corticosteroid-binding globulin e.g., oestrogen8
    - Review collection quality and timing of laboratory of tests e.g., does patient have a consistent bed time, is patient a shift worker, are instructions for urine samples being followed8
  • Consider additional testing e.g., Desmopressin stimulation test, combined 2 day desmopressin-corticotropin releasing hormone stimulation test
Normal results: CS unlikely*
Abnormal 1L ± 2L: Biochemically confirmed CS
Assess ACTH dependency
Step 3 – Determine ACTH dependency
  • Morning plasma corticotropin test
Suppressed ACTH
<10 pg/mL or 10-20 pg/mL:†
Corticotropin-independent CS
  • Adrenal source likely (i.e. Adrenal adenoma, Primary bilateral adrenal hyperplasia, Adrenal carcinoma)
Normal or elevated ACTH ≥20 pg/mL:
Corticotropin-dependent CS
Step 4 – Identify source of ACTH excess
Less invasive test
  • MRI of pituitary gland
Adenoma ≥6 or ≥10 mm in diameter:‡
Cushing disease
More invasive test
  • Bilateral inferior petrosal sinus sampling‡
  • Consider for individuals with pituitary adenomas <6-10 mm in diameter or with inconclusive biochemical or imaging studies
Central peripheral corticotropin ratio ≥2.0 before stimulation or ≥3.0 after stimulation:§
Cushing disease
Central peripheral corticotropin ratio <2.0 before stimulation or <3.0 after stimulation:§
Ectopic CS
Adapted from Reinke et al. 2023.7
*Except cyclic Cushing's syndrome.
†Plasma corticotropin levels of 10 pg/mL or more and less than 20 pg/mL as well as elevated plasma corticotropin levels but less than 30 pg/mL after stimulation with corticotropin-releasing hormone is suggestive of adrenal Cushing syndrome.3 To convert corticotropin from pg/mL to pmol/L, multiply by 0.22.
‡For lesions ranging from 6 to 9 mm in diameter, expert consensus differs on use of bilateral inferior petrosal sinus sampling.
§Stimulation with desmopressin or corticotropin-releasing hormone.
Learn more about treating CS
Learn more
Abbreviations: 1L, first line; 2L, second line; ACTH, adrenocorticotropic hormone; CS, Cushing’s Syndrome; DST, dexamethasome suppression test; MRI, magnetic resonance imaging.
References: 1. Nieman LK. Eur J Endocrinol 2015;173(4):M33-8. 2. Badia X, et al. Pituitary 2014;17:187-95. 3. Fleseriu M, et al. Lancet Diabetes Endocrinol 2021;9(12):847-75. 4. Newell-Price J, et al. Lancet 2006;367(9522):1605-17. 5. Lacroix A, et al. Lancet 2015;386(9996):913-27. 6. Sharma ST, et al. Clin Epidemiol 2015;17(7):281-93. 7. Reincke M, Fleseriu M. JAMA 2023;330(2):170-81. 8. Nieman LK, et al. Nat Rev Dis Prim 2025; 11:14.
Date of preparation: March 2026 | AU-IST-0062
This website is for Australian Healthcare Professionals only. If you are a patient, please refer to your doctor for any questions you may have regarding your healthcare.
For medical information enquiries regarding a Recordati product please email medicalinformation-aus@recordati.com. Please report any suspected adverse events in relation to the use of a Recordati product to rrdaustraliaPV@recordati.com