Basics
Description
Cushing's syndrome is a condition that results from excess glucocorticoids. �
Epidemiology
- Affects about 3 times more women than men.
- Exogenous glucocorticoids are the most common cause of Cushing's syndrome followed by pituitary, adrenal, and ectopic tumors, respectively.
Etiology
- Adrenocorticotropic hormone (ACTH)-dependent Cushing's syndromes: Excess ACTH causes bilateral adrenal hyperplasia and increased adrenal production of cortisol.
- Cushing's disease: Increased ACTH production by pituitary microadenomas (majority), macroadenomas, or hyperplasia. Associated with multiple endocrine neoplasia type 1 (MEN 1) syndrome.
- Ectopic ACTH syndrome: Increased ACTH production by nonpituitary tumors. Tumors of the lung, pancreas, and thymus are commonly associated with ectopic ACTH production.
- Excess corticotropin-releasing hormone (CRH) (rare): Hypothalamic or nonhypothalamic tumors producing CRH resulting in hyperplasia of pituitary corticotrophs and increased ACTH production.
- Iatrogenic or factitious (rare): Due to administration of exogenous ACTH.
- ACTH-independent Cushing's syndromes: Excess cortisol inhibits CRH and ACTH secretion.
- Iatrogenic or factitious: Due to administration of exogenous glucocorticoids (most common cause of Cushing's syndrome) or drugs that have glucocorticoid activity, such as megestrol acetate. Excess cortisol inhibits CRH and ACTH secretion resulting in bilateral adrenal atrophy.
- Primary adrenocortical hyperfunction: Increase in cortisol production by benign or malignant adrenal tumors, micronodular dysplasia, or ACTH-independent macronodular hyperplasia can inhibit CRH resulting in decreased ACTH secretion.
- Benign or malignant adrenocortical tumor: Excess cortisol production by adrenal tumor inhibits CRH and ACTH secretion resulting in atrophy of the normal adrenal zonae fasciculata and reticularis.
- Bilateral micronodular dysplasia (rare): Sporadic and familial (e.g., Carney complex) nodular hyperplasia of the adrenal gland resulting in cortisol excess.
- Bilateral ACTH-independent macronodular hyperplasia (rare): Associated with stimulation of aberrant receptors by hormones such as gastric inhibitory polypeptide, vasopressin, serotonin, luteinizing hormone/chorionic gonadotropin, or leptin, resulting in adrenal hyperplasia and cortisol excess.
Diagnosis
History
Cushing's syndrome is associated with the following signs and symptoms: �
- Progressive weight gain
- Central adiposity involving the face (moon faces), neck (supraclavicular fat pad), trunk, and abdomen. Associated with thin extremities
- Skin changes such as facial plethora, bruising, poor wound healing, striae (wide, reddish-purple streaks), hirsutism, acne, hyperpigmentation (induced by ACTH)
- Menstrual irregularities, infertility
- Proximal muscle weakness (e.g., difficult to get out of a chair or climb stairs)
- Bone loss increasing the risk for osteoporotic fracture
- Glucose intolerance that can progress to diabetes mellitus
- Hypertension
- Hyperlipidemia
- Emotional lability, depression, and psychosis
- Increased risk of infections
Tests
Lab
Diagnosis of Cushing's syndrome (1)[B]: �
- Screening tests - consider 1 of the following screening tests to document elevated cortisol levels:
- Midnight salivary cortisol: Normal or elevated (>145 ng/dL) in Cushing's syndrome due to loss of circadian rhythm. In normal individuals, a nadir in the cortisol level is noted at midnight. Suggest at least 2 measurements.
- Overnight 1 mg dexamethasone suppression test: Give 1 mg of dexamethasone at 11 p.m. and check plasma cortisol level at 8 a.m. the following morning. Dexamethasone suppresses cortisol production to <1.8 μg/dL in healthy individuals, but not in those with Cushing's syndrome.
- 24-hour urine cortisol: Elevated in Cushing's syndrome (greater than the normal range for assay). Suggest at least 2 measurements.
- Low-dose dexamethasone suppression test: Dexamethasone 0.5 mg q6h for 2 days. Serum cortisol production is <1.8 μg/dL in healthy individuals.
- Confirmatory - if screening cortisol levels are elevated or if clinical suspicion is high, perform 1 or 2 other studies described above to confirm the diagnosis.
- Consider the following studies in special circumstances:
- Low-dose dexamethasone followed by CRH stimulation: Dexamethasone 0.5 mg q6h for 2 days followed by CRH stimulation (1 μg/kg IV). Dexamethasone suppresses cortisol in normal individuals as well as those with Cushing's disease. CRH stimulates ACTH and cortisol production in Cushing's disease.
- Sleeping midnight serum cortisol: Requires hospitalization but levels <1.8 μg/dL noted in healthy individuals.
Localization (2)[B]: �
- ACTH: Elevated in ACTH-dependent Cushing's syndrome (e.g., pituitary and ectopic tumor) and low in ACTH-independent Cushing's syndrome (e.g., adrenal tumors and exogenous glucocorticoids).
- Overnight 8 mg dexamethasone suppression test: Ectopic tumors are resistant to glucocorticoid negative feedback. Therefore, high-dose dexamethasone is more likely to suppress ACTH production by pituitary adenomas than an ectopic tumor. Give 8 mg of dexamethasone at 11 p.m. and check plasma cortisol level at 8 a.m. the following morning. Dexamethasone suppresses cortisol production by 50% in Cushing's disease, but not in those with ectopic Cushing's.
- High-dose dexamethasone suppression test: Dexamethasone 2 mg q6h for 2 days. Check 24-hour urine-free cortisol and 17-hydroxysteroid for 2 days. In Cushing's disease, urine cortisol decreases by 90% and 17-hydroxysteroid by 64%.
- CRH stimulation: Pituitary adenoma (not ectopic or adrenal tumors) responds to CRH stimulation.
Imaging
- CT of adrenals: Primary adrenal tumor or hyperplasia
- CT of chest and abdomen: Ectopic tumor
- MRI scan of the pituitary: Cushing's disease
Surgery
Petrosal sinus sampling: ACTH levels measured from the petrosal sinuses are compared with ACTH levels from the forearm vein. Higher ACTH in the petrosal sinuses indicates the presence of a pituitary adenoma and similar levels suggest an ectopic tumor. Consider this procedure if CT or MRI does not localize the tumor. �
Differential Diagnosis
Pseudo-Cushing's syndrome: Hypercortisolism associated with depression, stress, obesity, and alcohol. �
Treatment
Additional Treatment
Issues for Referral
Endocrine consultation should be obtained for the evaluation and management of Cushing's syndrome. �
- Medication-associated Cushing's syndrome: Discontinuation resolves symptoms. However, adrenal insufficiency is a complication of exogenous glucocorticoids and, therefore, glucocorticoids need to be tapered slowly to allow the pituitary and adrenal glands to resume normal function.
- Treatment of Cushing's disease: Transsphenoidal surgical removal of a pituitary adenoma has a cure rate of 60-70%. Hypopituitarism is a possible side effect requiring lifelong hormone replacement. Residual tumors can be treated with radiation. The effect of radiation on cortisol levels can be seen after 3-12 months. Therefore, adrenal enzyme inhibitors, such as ketoconazole, metyrapone, and aminoglutethimide, can be used to lower cortisol level in the interim. Surgical or medical adrenalectomy with mitotane (adrenocorticolytic drug that blocks adrenal hormone synthesis) is reserved for individuals who have failed pituitary surgery and radiation. After adrenalectomy, patients require lifelong glucocorticoids and mineralocorticoid replacement therapy (3)[B].
- Treatment of ectopic ACTH syndrome: Surgical removal of ectopic nonpituitary tumor resolves symptoms of Cushing's in only 10% of individuals. Ketoconazole, metyrapone, and aminoglutethimide can be used to reduce adrenal cortisol level. Bilateral adrenalectomy is reserved for individuals who have failed surgery and medical management (3)[B].
- Treatment of hypothalamic or nonhypothalamic CRH tumor: Surgical removal of the CRH-secreting tumor is the first step. Medications (e.g., ketoconazole, metyrapone, and aminoglutethimide) and adrenalectomy are reserved for those who have failed initial surgery.
- Treatment of primary adrenocortical hyperfunction (2)[B]:
- Adrenal adenoma: Surgical removal of the affected adrenal gland. Symptoms of Cushing's usually resolve with surgery. Adrenal insufficiency and steroid replacement should be considered in the initial postoperative period. However, the remaining adrenal gland resumes normal adrenal function overtime.
- Adrenal carcinomas: Require more aggressive management. Surgical removal of the affected adrenal gland, radiation, chemotherapy, and mitotane to lower cortisol levels. Poor prognosis. Adrenal insufficiency is a complication of treatment and requires glucocorticoid and mineralocorticoid replacement.
- Nodular adrenal hyperplasia: Surgical removal of both adrenal glands is recommended. In select cases of macronodular adrenal hyperplasia, pharmacological blockade of aberrant receptor can normalize cortisol levels.
Cortisol levels increase during pregnancy. Urine-free cortisol 3 times the upper limit of normal indicates Cushing's syndrome. Excess cortisol can cause preeclampsia, gestational diabetes, spontaneous abortion, and premature delivery. Therefore, surgery to remove the adrenal or pituitary tumor is recommended to lower cortisol levels in the second trimester. If surgery is not an option, metyrapone can be used to treat hypercortisolism. Aminoglutethimide, ketoconazole, and mitotane should not be given to pregnant women (4)[C]. �
Ongoing Care
Follow-Up Recommendations
Most symptoms of Cushing's syndrome resolve once the source is removed. �
Complications
- Nelson syndrome: Characterized by an enlarging ACTH-producing pituitary tumor in an individual who has undergone medical or surgical bilateral adrenalectomy for the treatment of Cushing's disease. Pituitary irradiation prior to adrenalectomy can prevent this syndrome. Periodic MRI of the pituitary and plasma ACTH levels are recommended after adrenalectomy. Transsphenoidal surgery and irradiation recommended for Nelson's syndrome.
- Panhypopituitarism: Complication of transsphenoidal surgery and radiation treatment for Cushing's disease. Lifelong pituitary hormone replacement is recommended, including glucocorticoids and thyroid hormone replacement.
- Adrenal insufficiency: After medical or surgical bilateral adrenalectomy, patients require lifelong glucocorticoids and mineralocorticoid replacement therapy. Mitotane can increase the metabolism of dexamethasone and fludrocortisone, but not prednisone and hydrocortisone. Therefore, a higher replacement dose of dexamethasone and fludrocortisone is required with mitotane.
References
1Neiman �LK, Biller �BM, Findling �JW The diagnosis of Cushing's syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540.2Nieman �LK, Ilias �I. Evaluation and treatment of Cushing's syndrome. Am J Med. 2005;118:1340-1346.3Biller �BM, Grossman �AB, Stewart �PM Treatment of adrenocorticotropin-dependent Cushing's syndrome: A consensus statement. J Clin Endocrinol Metab. 2008;93(7):2454-2462.4Lindsay �JR, Nieman �LK. Adrenal disorders in pregnancy. Endocrinol Metab Clin North Am. 2006;35:1-20.
Codes
ICD9
255.0 Cushing's syndrome �
ICD10
- E24.0 Pituitary-dependent Cushing's disease
- E24.3 Ectopic ACTH syndrome
- E24.9 Cushing's syndrome, unspecified
- E24.2 Drug-induced Cushing's syndrome
SNOMED
- 47270006 hypercortisolism (disorder)
- 237734007 adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (disorder)
- 190502001 pituitary-dependent Cushing's disease (disorder)
- 626004 hypercortisolism due to nonpituitary tumor (disorder)
- 41299009 iatrogenic Cushing's disease (disorder)
- 190501008 idiopathic Cushing's syndrome (disorder)
Clinical Pearls
- Cushing's syndrome can be characterized as ACTH dependent or independent glucocorticoid excess.
- Exogenous glucocorticoid is the most common cause of Cushing's syndrome followed by pituitary, adrenal, and ectopic tumors, respectively.
- A midnight cortisol, 24-hour urine cortisol, or a dexamethasone suppression test can confirm the diagnosis. ACTH levels, a high-dose dexamethasone suppression test, and imaging can help localize the lesion.
- Surgical resection of the ACTH- or cortisol-producing tumor is the first step. Radiation, adrenal enzyme inhibitors, and adrenalectomy can be considered for resistant tumors.
- Most symptoms of Cushing's syndrome resolve once the source is removed.