Cushing Syndrome

Leen Wehbeh, M.D., Amir H. Hamrahian, M.D.


  • Cushing syndrome is a condition associated with a constellation of signs and symptoms caused by prolonged exposure to high levels of glucocorticoids.
  • May be due to exogenous glucocorticoid exposure (iatrogenic Cushing syndrome) or endogenous Cushing syndrome (CS).
  • Endogenous CS may be ACTH-dependent (pituitary tumor or ectopic ACTH production) or ACTH-independent secondary to excess cortisol secretion from adrenal glands. CS due to an ACTH-secreting pituitary tumor is referred to as Cushing disease.


  • More common in women particularly in reproductive age[17]
  • The median age of diagnosis is 41.4 years with a female-to-male ratio of 3:1[7]The incidence of endogenous CS is 0.2-5.0 per million people per year with a prevalence of 39-79 per million in different populations. A more recent study in the United States using a commercial database, suggests a higher incidence than previously reported rates in European studies[6]. These numbers underestimate patients with mild autonomous cortisol hypersecretion.
  • Iatrogenic Cushing syndrome is much more common than endogenous CS but measurements of incidence rates are imprecise.
  • It is important to consider a number of conditions that may be associated with a pseudo-Cushing state when evaluating patients for CS. Pseudo-Cushing may be associated with pregnancy, morbid obesity, severe psychological stress (including major depressive disorder), uncontrolled diabetes mellitus, chronic alcoholism, and severe sleep apnea[4].
  • With the global increase in the incidence and prevalence of obesity and type 2 DM, it is important to evaluate the best strategy to evaluate these populations for CS[20].
  • The prevalence of unrecognized CS is 0-9.4% in patients with type 2 DM and 0-9.3% in patients with obesity. Universal screening for CS in patients with DM or obesity is not indicated.[3]


  • The signs and symptoms most suggestive of underlying hypercortisolism include facial plethora, moon facies, proximal muscle weakness, central obesity with wasting of the extremities, wide purplish striae (>1 cm), and easy bruising without obvious trauma[1].
  • Detailed history to assess for any use of exogenous glucocorticoids (oral, topical, injection, inhaled, nasal)[24]. It is also important to ask about intra-articular and neck/back injections as patients might not be aware that these are potent glucocorticoids.
  • CYP3A4 inhibitors (especially ritonavir and azole antibiotics) inhibit glucocorticoid clearance and may lead to Cushingoid signs/symptoms when taken with concurrent inhaled, oral or injectable glucocorticoids.
  • There are 3 first-line screening tests for evaluation of patients suspected to have CS: 1) low-dose dexamethasone suppression test (after 1mg dexamethasone taken at 11 PM, cortisol at 8 AM should be < 1.8 mcg/dL); 2) 24-hour urine free cortisol (UFC); 3) late-night salivary cortisol (usually two samples collected).
  • The presence of at least two abnormal test methods is usually needed to establish the diagnosis[1].
  • The choice of screening test should be individualized as there is potential for false positive or negative results in different circumstances. For example, the late-night salivary cortisol should not be used in shift workers with variable sleep hours, and 1 mg DST would not be an appropriate test in a patient taking drugs such as rifampicin that accelerate dexamethasone clearance.
  • Use of estrogen-containing birth control pills can contribute to false-positive dexamethasone suppression tests due to increased cortisol binding globulin and need to be discontinued preferably for 3 months prior to this method of testing.
  • Decreased kidney function might cause false-negative results on 24-hour UFC[9] whereas increased fluid intake of more than 5L per day might cause false-positive results on 24-hour UFC[22].
  • After confirming hypercortisolism, the ACTH level should be measured to identify if CS is ACTH-dependent or -independent.
  • Low or undetectable ACTH (< 10 pg/mL) is consistent with ACTH-independent hypercortisolism from an adrenal source which may include adrenal adenoma, adrenal hyperplasia, or adrenal carcinoma. The next step is to obtain an adrenal CT scan. A non-contrast CT attenuation < 10 Housefield units (HU) is consistent with a benign lesion[18]. Patients with a lipid poor adrenal mass (≥10 HU) need to proceed with the measurement of CT washout percentage to further characterize the adrenal mass. An absolute and relative CT washout percentage < 60% and < 40%, respectively, are suggestive of malignancy. Other features concerning for an adrenal carcinoma on CT include adrenal mass >4 cm[21], presence of necrosis, calcifications, and hemorrhage. Adrenal MRI may be helpful to further characterize adrenal masses with indeterminate CT characteristics[2].
  • The presence of a plasma ACTH level >20 pg/mL suggests ACTH-dependent Cushing’s syndrome. Most commonly due to pituitary ACTH-secreting tumor (Cushing’s disease), less commonly ectopic ACTH-secreting tumor (e.g. bronchial carcinoid tumor, pancreatic or thymic neuroendocrine tumor). In patients with an ACTH level between 10 to 20 pg/mL, additional studies such as the Corticotropin-Releasing Hormone Stimulation (CRH) test or measurement of ACTH level after 1 mg DST may help to distinguish between ACTH-dependent and ACTH-independent CS.
  • To distinguish Cushing disease vs. ectopic ACTH syndrome: MRI pituitary (>6mm less likely incidentaloma), high-dose 8mg dexamethasone test (pituitary tumors more likely to suppress cortisol >50%), CRH stimulation (pituitary tumors more likely to stimulate ACTH and cortisol post-CRH), presence of hypokalemia (more common with the ectopic disease), degree of ACTH elevation (usually greater with ectopic source), age (ectopic less likely in young patients).
  • Inferior petrosal sinus sampling (IPSS) is the gold standard to distinguish Cushing disease from ectopic ACTH syndrome. A central to peripheral ACTH ratio >2 before and >3 after CRH stimulation are diagnostic of Cushing disease. Requires skilled interventional radiologists and adequate catheter placement.
  • The workup of patients with ectopic ACTH syndrome may include CT or MRI of neck/chest/abdomen/pelvis and nuclear imaging studies such as octreotide, Gallium-68 Dotatate, and positron emission tomography (PET) scans.
  • Pseudo-Cushing syndrome: non-pathologic excess cortisol secretion not caused by CS which may be seen in pregnancy, morbid obesity, severe stress, severe psychological stress (including major depressive disorder), uncontrolled diabetes, chronic alcoholism, and severe sleep apnea. May have nonspecific manifestations of CS and mildly elevated cortisol which revert to normal with the treatment of underlying etiology. Another helpful feature is the lack of progression of Cushingoid signs/symptoms in pseudo-Cushing’s syndrome whereas in CS, it is usually expected to see an increase in the number and severity of Cushingoid signs/symptoms.[3]


  • Symptoms depend on the severity and duration of hypercortisolism.
  • Common: centripetal obesity with dorsocervical and supraclavicular fat pads, moon facies, fatigue, hyperglycemia/type 2 DM, hypertension, mood lability, insomnia, easy bruisability, oligo/amenorrhea, and hirsutism/acne[1].
  • More specific: broad (> 1cm) purple striae, facial plethora, and proximal muscle weakness
  • Other: increased risk of infection, increased cardiovascular risk, thromboembolism, bone loss, fractures, hyperlipidemia, kidney stones, polydipsia, polyuria
  • Ectopic ACTH: shorter duration from onset of symptoms, more severe hypertension, hypokalemia, skin hyperpigmentation
  • Adrenal carcinoma: acute onset of virilization (temporal balding, clitoromegaly, deepening voice) may be seen in Cushing due to the co-secretion of androgens, associated with weight loss and constitutional symptoms.
  • Pseudo-Cushing syndrome: may have some but not all typical clinical signs of hypercortisolism. Needs evaluation and diagnostic testing to differentiate from Cushing.


  • Iatrogenic Cushing syndrome: wean and discontinue glucocorticoid therapy if possible.
  • Surgical resection of the causal tumor is the first-line therapy in CS. However, alternative medical therapy should be sought in case of persistent hypercortisolism after surgery or in patients who are not a surgical candidate[8]
  • Hypocortisolemic patients should receive glucocorticoid replacement with a plan to monitor the recovery of the HPA axis assuming they have at least one intact adrenal gland.
  • Cushing disease: first line: transsphenoidal pituitary surgery by an experienced pituitary surgeon; second line: medical therapy; Other options include pituitary irradiation (in patients with CD) and bilateral adrenalectomy requiring lifelong glucocorticoid and mineralocorticoid replacement therapy, and monitoring for Nelson syndrome (rapid enlargement of residual pituitary adenoma).
  • Ectopic ACTH Cushing’s syndrome: surgical excision of the tumor if possible. In the case of non-resectable tumors, should consider bilateral adrenalectomy or medical therapy.
  • ACTH-independent adrenal adenomas: unilateral adrenalectomy generally curative. Laparoscopic surgery preferred.
  • ACTH-independent bilateral adrenal nodules or hyperplasia: may consider a stepwise surgical approach by removing the largest lesion and then evaluate for hypercortisolemia. Most patients require bilateral adrenalectomy.
  • Adrenal carcinoma: complete surgical resection with negative margins is the only potentially curative therapy. Mitotane and chemotherapy are usually used for patients with advanced disease. Tumor bed radiotherapy may be considered with patients who are at high risk for local recurrence without evidence of distant metastasis.
  • Pseudo-Cushing syndrome: treat primary disease (i.e. depression, uncontrolled diabetes, alcoholism).
  • Medical therapy is usually considered as a second-line treatment to reduce cortisol levels when surgery is contraindicated or not curative or for pre-operative control of hypercortisolism.
  • Medical therapy includes steroidogenesis inhibitors (ketoconazole, mitotane, osilodrostat[5]; mitotane (adrenocortical carcinoma), pituitary-directed medical treatment (cabergoline[13] and pasireotide which is a somatostatin receptor ligand[11]), and glucocorticoid antagonist (Mifepristone). The IV etomidate may be used during hospitalization for rapid control of hypercortisolemia prior to surgery[10].
  • Mifepristone[12] is the only FDA approved glucocorticoid receptor antagonist for the treatment of CS associated with diabetes or glucose intolerance.
  • Hyperglycemia management in Cushing syndrome is generally similar to exogenous steroid-induced hyperglycemia.


  • Physiologic glucocorticoid replacement after surgery until recovery of endogenous adrenal function, which may take from several months to 1-2 years.
  • Follow cortisol and ACTH levels in 1-3 month intervals for evidence of remission.
  • Late relapse is common after an apparent surgical cure of Cushing disease. Long-term periodic assessment of the hypothalamic-pituitary-adrenal axis required[16].
  • Hyperglycemia, psychiatric symptoms, and osteoporosis improve but may partially persist after effective therapy for Cushing[17].


  • Although testing for Cushing not recommended in all patients with diabetes and/or obesity, screening is recommended for those with suggestive findings (myopathy, thin skin, ecchymosis) or accumulation of new suggestive features over time[3].
  • Pseudo-Cushing syndrome is more common than CS in patients with diabetes. It requires no specific treatment except for diabetes management.
  • Incidental pituitary and adrenal tumors are common in the general population. Imaging studies should only be performed in patients after confirming hypercortisolism and if it is ACTH-dependent or -independent to decide on the choice of imaging.
  • In patients with clinically suspected Cushing and equivocal screening test results, repeat testing, and clinical evaluation after several months is advisable.
  • Untreated Cushing is associated with a high risk of mortality. Poor prognosis is seen in ectopic ACTH syndrome and adrenocortical carcinoma.

Basis for recommendation

  1. Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-40.  [PMID:18334580]

    Comment: Most recent Endocrine Society consensus guidelines on diagnosis of Cushing's syndrome.


  1. Vaidya A, Hamrahian A, Bancos I, et al. THE EVALUATION OF INCIDENTALLY DISCOVERED ADRENAL MASSES. Endocr Pract. 2019;25(2):178-192.  [PMID:30817193]
  2. Nieman LK. Diagnosis of Cushing's Syndrome in the Modern Era. Endocrinol Metab Clin North Am. 2018;47(2):259-273.  [PMID:29754631]
  3. Findling JW, Raff H. DIAGNOSIS OF ENDOCRINE DISEASE: Differentiation of pathologic/neoplastic hypercortisolism (Cushing's syndrome) from physiologic/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing's syndrome). Eur J Endocrinol. 2017;176(5):R205-R216.  [PMID:28179447]
  4. Fleseriu M, Pivonello R, Young J, et al. Osilodrostat, a potent oral 11β-hydroxylase inhibitor: 22-week, prospective, Phase II study in Cushing's disease. Pituitary. 2016;19(2):138-48.  [PMID:26542280]
  5. Broder MS, Neary MP, Chang E, et al. Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States. Pituitary. 2015;18(3):283-9.  [PMID:24803324]
  6. Lacroix A, Feelders RA, Stratakis CA, et al. Cushing's syndrome. Lancet. 2015;386(9996):913-27.  [PMID:26004339]
  7. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-31.  [PMID:26222757]
  8. Rosmalen JG, Kema IP, Wüst S, et al. 24 h urinary free cortisol in large-scale epidemiological studies: short-term and long-term stability and sources of variability. Psychoneuroendocrinology. 2014;47:10-6.  [PMID:25001951]
  9. Hamrahian AH, Yuen KC, Hoffman AR, et al. AACE/ACE Disease State Clinical Review: Medical Management of Cushing Disease. Endocr Pract. 2014;20(7):746-57.  [PMID:25057099]
  10. Colao A, Petersenn S, Newell-Price J, et al. A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012;366(10):914-24.  [PMID:22397653]
  11. Fleseriu M, Biller BM, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metab. 2012;97(6):2039-49.  [PMID:22466348]
  12. Vilar L, Naves LA, Azevedo MF, et al. Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing's disease. Pituitary. 2010;13(2):123-9.  [PMID:19943118]
  13. Prevedello DM, Pouratian N, Sherman J, et al. Management of Cushing's disease: outcome in patients with microadenoma detected on pituitary magnetic resonance imaging. J Neurosurg. 2008;109(4):751-9.  [PMID:18826366]

    Comment: 13% of Cushing's disease patients in postoperative remission relapsed after average of 50 months.

  14. Carroll T, Raff H, Findling JW. Late-night salivary cortisol measurement in the diagnosis of Cushing's syndrome. Nat Clin Pract Endocrinol Metab. 2008;4(6):344-50.  [PMID:18446140]

    Comment: Late night salivary cortisol testing has 92-100% sensitivity and 93-100% specificity for Cushing's syndrome.

  15. Patil CG, Prevedello DM, Lad SP, et al. Late recurrences of Cushing's disease after initial successful transsphenoidal surgery. J Clin Endocrinol Metab. 2008;93(2):358-62.  [PMID:18056770]
  16. Newell-Price J, Bertagna X, Grossman AB, et al. Cushing's syndrome. Lancet. 2006;367(9522):1605-17.  [PMID:16698415]
  17. Hamrahian AH, Ioachimescu AG, Remer EM, et al. Clinical utility of noncontrast computed tomography attenuation value (hounsfield units) to differentiate adrenal adenomas/hyperplasias from nonadenomas: Cleveland Clinic experience. J Clin Endocrinol Metab. 2005;90(2):871-7.  [PMID:15572420]
  18. Swearingen B, Katznelson L, Miller K, et al. Diagnostic errors after inferior petrosal sinus sampling. J Clin Endocrinol Metab. 2004;89(8):3752-63.  [PMID:15292301]

    Comment: Reported 90% sensitivity, 67% specificity, 99% PPV, 20% NPV using inferior petrosal sinus sampling after CRH for diagnosis of Cushing's disease.

  19. Catargi B, Rigalleau V, Poussin A, et al. Occult Cushing's syndrome in type-2 diabetes. J Clin Endocrinol Metab. 2003;88(12):5808-13.  [PMID:14671173]

    Comment: Occult Cushing's syndrome seen in up to 5.5% of overweight or obese, type 2 diabetic patients.
    Rating: Important

  20. Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85(2):637-44.  [PMID:10690869]
  21. Mericq MV, Cutler GB. High fluid intake increases urine free cortisol excretion in normal subjects. J Clin Endocrinol Metab. 1998;83(2):682-4.  [PMID:9467592]
  22. Oldfield EH, Doppman JL, Nieman LK, et al. Petrosal sinus sampling with and without corticotropin-releasing hormone for the differential diagnosis of Cushing's syndrome. N Engl J Med. 1991;325(13):897-905.  [PMID:1652686]

    Comment: Reported 100% sensitivity and 100%specificity using inferior petrosal sinus sampling after CRH for diagnosis of Cushing's disease.


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Last updated: October 9, 2020