Cushing Disease and Cushing Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care



  • Clinical abnormalities associated with chronic exposure to excessive amounts of cortisol (the major adrenocorticoid)
  • Cushing disease is defined as glucocorticoid excess due to excessive adrenocorticotropic hormone (ACTH) secretion from a pituitary tumor. This is the most common cause of primary Cushing syndrome.
  • Cushing syndrome is defined as excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc., or tumor)
  • System(s) affected: Endocrine/Metabolic; Musculoskeletal; Skin/Exocrine; Cardiovascular; Neuropsychiatric

Pediatric Considerations

  • Rare in infancy and childhood
  • Most cases in children <8 years are a result of malignant adrenal tumors.

Pregnancy Considerations

Pregnancy may exacerbate disease.



Uncommon: 0.7–2.4 per million per year


In difficult-to-control diabetic patients with obesity and hypertension, prevalence has been reported at 2–5%.

Risk Factors

  • Predominant sex: Female > Male (slightly). Cushing syndrome is equally prevalent in both sexes.
  • Pituitary tumor
  • Adrenal mass
  • Neuroendocrine tumor (e.g., bronchial carcinoid)
  • Prolonged use of corticosteroids


  • Multiple endocrine neoplasia type I
  • Carney complex (an inherited multiple neoplasia syndrome)
  • McCune-Albright syndrome (mutation of GNAS1 gene)

General Prevention

Avoid corticosteroid exposure when possible.


  • Disease: Pituitary tumor causing excess ACTH (corticotropin)
  • Syndrome: Excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc., or tumor)


  • Exogenous glucocorticoids or ACTH
  • Endogenous ACTH-dependent hypercortisolism (80–85%):
    • ACTH-secreting pituitary tumor: 70%
    • Ectopic ACTH production (e.g., small-cell carcinoma of lung, bronchial carcinoid): 20%
  • Endogenous ACTH-independent hypercortisolism: 15–20%:
    • Adrenal adenoma
    • Adrenal carcinoma
    • Macronodular or micronodular hyperplasia

Cushing, Cushing Syndrome, Adrenocorticotropic hormone, Pregnancy, Endocrine Disorders, small cell carcinoma, pituitary tumor, adrenal tumors, hypercortisolism, adrenocorticotropic hormone, endocrine neoplasia,



  • Weight gain: 95% (1)[B]
  • Decreased libido: 90%
  • Menstrual irregularity: 80%
  • Hirsutism: 75%
  • Depression/emotional lability: 50–80%
  • Easy bruising: 65%
  • Proximal muscle weakness: 60%
  • Diabetes or glucose intolerance: 60%

Physical Exam

  • Obesity: 95%
  • Facial plethora: 90%
  • Moon face (facial adiposity): 90%
  • Thin skin: 85%
  • Hypertension: 75%
  • Skeletal growth retardation in children (epiphyseal plates remain open): 70–80%
  • Purple striae on the skin
  • Increased adipose tissue in neck and trunk
  • Acne

Diagnostic Tests & Interpretation


Initial lab tests

  • For initial evaluation, order either late-night salivary cortisol or 24-hour urinary-free cortisol. In normal circadian rhythm, cortisol secretion is highest in the morning and lowest between 11 PM and midnight. The nadir of serum cortisol is maintained in pseudo-Cushing (e.g., obesity, alcoholism, depression), but not in Cushing syndrome.
  • Elevated late-night salivary cortisol provides sensitivity and specificity >90–95% (2,3)[B]. (Contact local lab for instructions to obtain this test.)
  • 24-hour urinary-free cortisol level: Obtain ≥3 samples to rule out intermittent hypercortisolism if results are normal and suspicion is high. Also measure 24-hour urinary creatinine excretion to verify adequacy of collection. Results may be falsely low if glomerular filtration rate <30 mL/min. Overall sensitivity and specificity varies, but has been reported to be 90–97% and 85–96%, respectively (2)[B].
  • Midnight plasma cortisol: Try to obtain samples on 3 consecutive nights. A late evening serum cortisol >7.5 µg/dL has a sensitivity of 96% and a specificity of 100% (4)[B].
  • Persistently elevated serum cortisol implies Cushing syndrome; nadir of serum cortisol is maintained in obese patients, but not in those with Cushing.
  • Low-dose dexamethasone suppression testing is no longer used as 1st-line testing. Dexamethasone 1 mg is given between 11 PM and midnight, and fasting plasma cortisol is measured between 8 and 9 AM the following morning. A serum cortisol level below 1.8 µg/dL excludes Cushing syndrome, but specificity is limited. The presence of pseudo-Cushing states (depression, obesity, etc.), hepatic or renal disease, or any drug that induces cytochrome P-450 enzymes may cause a false result.
  • High-dose dexamethasone suppression testing: This test is used to distinguish between an ACTH-secreting pituitary tumor and an ectopic ACTH-secreting tumor. 0.5 mg dexamethasone is given q.6h for 8 doses, with serum cortisol measured at 2 and 6 hours after last dose. Sensitivity 79%, specificity 74%.


  • Antiepileptic drugs, progesterone, oral contraceptives, rifampin, and spironolactone may cause a false-positive dexamethasone suppression test.
  • Corticotropin-releasing hormone (CRH) after dexamethasone: This test is used to distinguish Cushing syndrome from pseudo-Cushing syndrome. Dexamethasone 0.5 mg is given q.6h for 48 hours starting at noon. CRH (1 µg/Kg) is given 2 hours after the last dose of dexamethasone. Plasma cortisol is >1.4 µg/dL 15 minutes after CRH in patients with Cushing syndrome but not in those with pseudo-Cushing (5)[B].


Initial approach

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  • Chest radiograph
  • Lumbar spine radiograph:
    • Osteoporosis is common
  • Pituitary MRI scan if pituitary tumor suspected
  • Abdominal CT scan if adrenal disease suspected
  • Chest CT scan if ectopic ACTH secretion is suspected and inferior petrosal sinus sampling rules out pituitary source (6)[C]
  • Octreotide scintigraphy to look for occult ACTH-secreting tumor

Diagnostic Procedures/Surgery

  • Diagnostic procedure depends on circumstances and clinical judgment
  • Inferior petrosal sinus sampling with CRH stimulation if ACTH-dependent tumor suspected (6)[C]

Pathological Findings

  • Thyroid function suppressed
  • Hypertension
  • Dyslipidemia
  • Polycystic ovarian syndrome/hyperandrogenism
  • Oligomenorrhea/hypogonadism
  • Myopathy/cutaneous wasting
  • Neuropsychiatric problems
  • Nodular adrenal disease
  • Hypercoagulable state
  • Osteoporosis
  • Nephrolithiasis
  • Growth hormone reduced

Differential Diagnosis

  • Obesity
  • Diabetes mellitus
  • Hypertension
  • Metabolic syndrome X
  • Polycystic ovarian disease
  • Hypercortisolism secondary to alcoholism (pseudo-Cushing)



  • Drugs are not usually effective as the primary long-term treatment, and are used primarily either in preparation for surgery or as adjunctive treatment after surgery, pituitary radiotherapy, or both.
  • Metyrapone, ketoconazole, and mitotane can all be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland. As initial treatment, remission rates up to 85% (6,7)[C].

Surgery/Other Procedures

  • Tumor-specific surgery:
    • Trans-sphenoidal surgery for Cushing disease offers selective microadenectomy of the ACTH-producing adenoma, leaving the remaining pituitary intact (remission rate 60–80%).
    • For Cushing syndrome, resection of the ACTH-producing tumor is optimal treatment.
  • Adrenal surgery:
    • For unilateral adrenal adenomas, laparoscopic surgery is treatment of choice.
    • For patients with Cushing disease, bilateral laparoscopic adrenalectomy is used more often, especially when the disease is severe or because of patient preference.
    • Pituitary radiotherapy can be used to treat persistent hypercortisolism after trans-sphenoidal surgery.

Ongoing Care

Patient Education

  • Comprehensive teaching to help patient cope with lifelong treatment may be needed, including:
    • Diet and monitoring weight daily
    • Early treatment of infections
    • Emotional lability prevention
  • Refer to National Adrenal Disease Foundation: NADF 505 Northern Blvd. Great Neck, NY 11021; (516) 407-4992


  • Generally chronic course with cyclic exacerbations and rare remissions
  • Guardedly favorable prognosis with surgery
  • 20% long-term recurrence rate after surgery; more frequent following surgery for benign adrenal tumors:
    • Poor with small cell carcinoma of the lung producing ectopic hormone; neuroendocrine tumors (bronchial carcinoid) have much better prognosis (4)[C]


  • Osteoporosis
  • Increased susceptibility to infections
  • Metastases of malignant tumors
  • Increased cardiovascular risk even after treatment
  • Lifelong glucocorticoid dependence following treatment with bilateral adrenalectomy
  • Nelson syndrome (pituitary tumor) after treatment with bilateral adrenalectomy


1. Newell-Price J, Bertagna X, Grossman AB, et al. Cushing’s syndrome. Lancet. 2006;367:1605–17.

2. Putignano P, et al. Midnight salivary cortisol versus urinary free and midnight serum cortisol as screening tests for Cushing’s syndrome. J Clin Endocrinol Metabol. 88(9):4153–7.

3. Yaneva M, Mosnier-Pudar H, Dugué MA et al. Midnight salivary cortisol for the initial diagnosis of Cushing’s syndrome of various causes. J Clin Endocrinol Metab. 2004;89:3345–51.

4. Isidori AM, et al. The ectopic adrenocorticotropin syndrome: Clinical features, diagnosis, management and long term follow up. J Clin Endocrinol Metabol. 2006;91(2):371–7.

5. Yanovski JA, Cutler GB, Chrousos GP et al. Corticotropin-releasing hormone stimulation following low-dose dexamethasone administration. A new test to distinguish Cushing’s syndrome from pseudo-Cushing’s states. JAMA. 1993;269:2232–8.

6. Findling JF, et al. Cushing’s syndrome: Important issues in diagnosis and management. J Clin Endocrinol Metabol. 2006;10:3746–53.

7. Nieman LK, Ilias I. Evaluation and treatment of Cushing’s syndrome. Am J Med. 2005;118:1340–6.

Additional Reading

See Also (Topic, Algorithm, Electronic Media Element)

Algorithm: Cushing Syndrome



255.0 Cushing’s syndrome


  • 47270006 Hypercortisolism (disorder)
  • 190502001 Pituitary-dependent Cushing’s disease (disorder)

Clinical Pearls

  • Cushing disease is due to excessive ACTH secretion from a pituitary tumor, resulting in corticosteroid excess.
  • Cushing syndrome is due to excessive corticosteroid exposure from exogenous sources (medications) or endogenous sources (pituitary, adrenal, pulmonary, etc. or tumor).

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