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
- Rare in infancy and childhood
- Most cases in children <8 years are a result of malignant adrenal tumors.
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%.
- 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)
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
- 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%
- 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
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].
- 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 procedure depends on circumstances and clinical judgment
- Inferior petrosal sinus sampling with CRH stimulation if ACTH-dependent tumor suspected (6)[C]
- Thyroid function suppressed
- Polycystic ovarian syndrome/hyperandrogenism
- Myopathy/cutaneous wasting
- Neuropsychiatric problems
- Nodular adrenal disease
- Hypercoagulable state
- Growth hormone reduced
- Diabetes mellitus
- 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].
- 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.
- 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]
- 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.
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)
- 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).