Cushing Syndrome

How to Cite This Chapter: Rodríguez-Gutiérrez R, Gonzalez-Velazquez C, Lavalle-Gonzalez FJ, Prebtani APH, Bednarczuk T, Płaczkiewicz-Jankowska E, Kasperlik-Załuska AA. Cushing Syndrome. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. Accessed August 15, 2022.
Last Updated: March 7, 2018
Last Reviewed: August 7, 2019
Chapter Information

Definition, Etiology, PathogenesisTop

Cushing syndrome is a clinical syndrome composed of signs and symptoms resulting from longstanding exposure of tissues to excess glucocorticoids.

Subclinical Cushing syndrome refers to a minor excess of glucocorticoids due to increased cortisol secretion by an adrenal tumor that results in inhibition of glucocorticoid secretion by the contralateral adrenal gland, milder clinical presentation, and absence of signs common to overt Cushing syndrome (eg, supraclavicular fullness caused by fat pads).

Cushing syndrome is classified based on etiology.

1. Exogenous Cushing syndrome is caused by administration of glucocorticoids at doses exceeding their physiologic levels. This is the most common cause of excess glucocorticoids.

2. Endogenous Cushing syndrome results from adrenal overproduction of glucocorticoids.

1) Adrenocorticotropic hormone (ACTH)–dependent Cushing syndrome (secondary adrenal overproduction of glucocorticoids) may be caused by ACTH-producing pituitary tumor (Cushing disease, the most common cause of endogenous Cushing syndrome), ectopic ACTH secretion by an extrapituitary tumor (much less frequent), or ectopic CRH secretion (least frequent).

2) ACTH-independent Cushing syndrome (primary adrenal overproduction of glucocorticoids):

a) Autonomous adrenal tumors: Usually a solitary tumor, less frequently multiple adenomas; adrenal carcinoma. Tumors originating from the zona fasciculata cause selective cortisol overproduction, whereas other tumors (arising from the zona reticularis or mixed tumors) additionally secrete androgens. Excess cortisol inhibits corticotropin-releasing hormone (CRH) and ACTH secretion, causing atrophy of the adrenal cortex located outside the tumor capsule and atrophy of the contralateral adrenal gland.

b) Macronodular adrenal hyperplasia is caused by ectopic receptors in the adrenal cortex, which are activated by atypical stimuli; most commonly, they are activated by the gastric inhibitory peptide (GIP)—currently called the glucose-dependent insulinotropic peptide—which is secreted postprandially in the gastrointestinal tract. Other stimulating factors include catecholamines, antidiuretic hormone, thyroid-stimulating hormone, luteinizing hormone, human chorionic gonadotropin, follicle-stimulating hormone, high levels of estrogens, prolactin, and interleukin 1.

c) Micronodular adrenal hyperplasia (primary pigmented nodular adrenal disease [PPNAD]) is a familial genetic disease. It may either be part of Carney complex, which includes various other abnormalities (cutaneous, cardiac, or breast myxoma; light-brown cutaneous nevi; testicular tumors; less commonly other endocrine abnormalities, such as acromegaly), or it may be the sporadic type, where immunoglobulins stimulating hyperplasia of the adrenal cortex may play a role. Like in other ACTH-independent types of Cushing syndrome, the adrenal tissue between the nodules may be atrophic.

Clinical Features and Natural HistoryTop

Signs and symptoms are unspecific but some are more distinctive than others.

1. Symptoms: Muscle weakness and poor exercise tolerance, skin prone to injury with poorly healing ulcers and easy bruising; excessive thirst and polyuria (measure blood glucose levels); excessive appetite; headache and dizziness (measure blood pressure); emotional instability, depressive tendencies, memory impairment, rarely psychotic conditions; bone pain (in the case of osteoporosis look for pathologic fractures of vertebral bodies, ribs, pubic rami, and the ischium); frequent infections, especially opportunistic (eg, fungal), often with a severe clinical course; symptoms of coronary artery disease or peptic ulcer disease (particularly in patients treated with nonsteroidal anti-inflammatory drug [NSAIDs]); erectile dysfunction in men, oligomenorrhea or secondary amenorrhea in women; acne and hirsutism in patients with androgen-secreting tumors.

2. Signs: Presence of purple striae, facial plethora (due to polycythemia and thinned skin) and dilated vessels, facial fullness (“moon face”), dorsocervical fat pad (“buffalo hump”), supraclavicular fullness caused by fat pads, thin extremities, thin skin, easy bruising, sometimes spontaneous cutaneous hemorrhages or purpura. Other consequences of cortisol excess can be present, but these are also common in the general population (eg, obesity, depression, diabetes mellitus, hypertension, hyperandrogenism). The presence of thin skin (<2 mm) markedly increases the probability of Cushing syndrome; similarly, patients who have ≥3 nontraumatic ecchymoses that are >1 cm in diameter are a few times more likely to have Cushing syndrome than patients without such findings.

3. Natural history: Overt Cushing syndrome is diagnosed only in the advanced stage of a chronic disease. Significantly more often, just some of the manifestations are present, such as impaired glucose tolerance or diabetes, dyslipidemia, hypertension, and rapid body weight gain (obesity), which constitute metabolic syndrome. The risk of osteoporosis is also increased. For these reasons, screening hormone tests for Cushing syndrome should be considered in patients, especially young, who have been unsuccessfully treated for metabolic syndrome or its components (eg, hypertension).

In subclinical Cushing syndrome, even if it is long-standing, the typical clinical manifestations may be absent. Because the risk of progression to overt Cushing syndrome is low, subclinical Cushing syndrome should not be regarded as an early stage of Cushing syndrome.


Diagnostic algorithm: Figure 6.1-1. Always exclude prior use of glucocorticoids (exogenous Cushing syndrome).


Biochemical evaluation is recommended in patients with:

1) Unusual features for age.

2) Progressive clinical features suggestive of Cushing disease.

3) Incidentally found adrenal masses.

Screening in the general population is discouraged.

Diagnostic Tests

Before beginning biochemical evaluation for hypercortisolism, take a detailed history of drug use to exclude exogenous glucocorticoid exposure that could explain signs and symptoms.

1. Basic biochemical tests may reveal hypokalemia; hypercalciuria; hyperglycemia (impaired glucose tolerance or diabetes); high serum total cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride levels; and low serum high-density lipoprotein cholesterol (HDL-C) levels.

2. Complete blood count (CBC) reveals high red blood cell, white blood cell (particularly neutrophilia), and platelet counts; low hemoglobin levels; and low lymphocyte, eosinophil, and monocyte counts.

3. Confirming hypercortisolism: Note that different collection methods and assays available for the measurement of cortisol exist and results may vary. When performing a diagnostic workup, it is important to evaluate the assays available at each center and carefully collect samples for testing.

1) Urinary free cortisol (UFC) excretion increased to 3 or 4 × upper limit of normal (ULN) (330 nmol/24 h [120 microg/24 h]) confirms the diagnosis of Cushing syndrome; ≥2 abnormal measurements are necessary to confirm diagnosis.

2) Elevated midnight serum cortisol levels >50 nmol/L (1.8 microg/dL) if the blood sample has been collected within 5 to 10 minutes of awakening or, where available and standardized, late-night salivary cortisol levels (>4 nmol/L [145 ng/dL] at 23:00 to midnight).

3) Inadequate reduction in serum cortisol levels in the 1-mg dexamethasone suppression test (also known as the overnight dexamethasone suppression test or short dexamethasone suppression test): Patients are instructed to take oral dexamethasone 1 mg at bedtime (23:00 to midnight). Fasting serum cortisol levels are measured the following day between 8:00 and 9:00. Serum cortisol levels <50 nmol/L (1.8 microg/dL) exclude Cushing syndrome. Dexamethasone suppression test should not be performed if the patient is thought to have a pheochromocytoma based on the initial imaging study (nonenhanced computed tomography [CT] attenuation >10 Hounsfield units [HU]). Note that a single abnormal result of the dexamethasone test cannot be the basis for the decision on surgical treatment.

4) Loss of the normal circadian cortisol secretion rhythm (the late afternoon serum cortisol level, usually lower, is >50% of the morning level).

5) Elevated serum cortisol levels >690 nmol/L (25 microg/dL).

6) Inadequate reduction in urinary free cortisol excretion in the 2-mg dexamethasone suppression test: Instruct the patient to take oral dexamethasone 0.5 mg every 6 hours for 2 days. The response is considered normal when free cortisol excretion on day 2 decreases to <27 nmol/24 h (10 microg/24 h).

4. Diagnostics of causes of high serum cortisol levels: Once hypercortisolism is documented, the next diagnostic step is to determine if it is ACTH-dependent (ACTH-secreting tumor) or ACTH-independent (adrenal). This is done by measuring serum ACTH levels.

1) Serum ACTH levels <1.1 pmol/L (5 ng/L) in a patient with a high serum cortisol level indicate ACTH-independent Cushing syndrome, whereas serum ACTH levels >4.4 pmol/L (20 ng/L) indicate ACTH-dependent Cushing syndrome. In patients with serum ACTH levels 1.1 to 4.4 pmol/L (5-20 ng/L), the CRH stimulation test (see below) may be useful to distinguish the cause.

2) The CRH stimulation test involves stimulation of ACTH secretion and indirect stimulation of cortisol secretion with CRH. In Cushing disease (which is ACTH-dependent) a characteristic several-fold elevation in ACTH levels is seen after the administration of CRH, but in the case of markedly increased baseline values, an increase in ACTH level by ≥35% to 50% and cortisol by ≥14% to 20% is considered significant. In ACTH-independent Cushing syndrome usually no response to CRH is seen or it is minor only.

3) The 8-mg dexamethasone suppression test (2 mg every 6 hours for 2 days) is considered unreliable and is now rarely used; it played a role in the differentiation between Cushing disease (ACTH-dependent pituitary disease) and autonomous adrenal cortisol hypersecretion (functioning adrenal tumor, ectopic ACTH secretion, or nodular adrenal hypertrophy). In patients with Cushing disease urinary excretion of cortisol and its metabolites usually decreases by ≥50%, whereas in patients with autonomous cortisol secretion no suppression is seen. The test result is not reliable in patients with tumors causing ectopic ACTH secretion.

4) The adrenal response to atypical stimuli could be assessed in patients with suspected macronodular adrenal hyperplasia; this is performed in specialized centers. Measure serum cortisol levels at baseline and at 30, 60, 90, and 120 minutes after breakfast or oral intake of 75 g of glucose; after standing up; after oral administration of 10 mg of metoclopramide, or after IV administration of 100 microg of gonadotropin-releasing hormone (GnRH) or 200 microg of thyrotropin-releasing hormone (TRH). The diagnosis is supported by an increase in serum cortisol levels.

5. Imaging studies: CT is the first choice for the evaluation of the adrenal gland in Cushing syndrome. CT helps distinguish between tumors and hyperplasia and in most cases can differentiate between adrenal adenomas and carcinomas. Magnetic resonance imaging (MRI) is a good option when CT is contraindicated or unavailable. Skeletal radiographs may reveal features of osteoporosis and pathologic fractures; delayed bone age is frequently seen in children and adolescents. Dual-energy x-ray absorptiometry (DXA) may reveal features of osteopenia or osteoporosis, particularly in the lumbar spine and proximal femur. Receptor scintigraphy with somatostatin analogues is used in specialized settings to detect neuroendocrine neoplasms causing ectopic ACTH secretion and to diagnose asymmetric hormone functioning of bilateral adrenal tumors.

CT and MRI of the adrenal glands reveal findings dependent on the cause of Cushing syndrome (Figure 6.1-1):

1) Autonomous adrenal cortex tumor or tumors: CT reveals a unilateral adrenal tumor with features of adenoma, atrophy of the contralateral adrenal gland, and less frequently bilateral multiple adenomas of the adrenal cortex. MRI reveals significant fat content and rapid contrast washout.

2) Macronodular adrenal hyperplasia: CT reveals symmetric adrenal glands that are usually enlarged and often polycyclic; their density is typical for adenomas. MRI reveals high fat content in the adrenal glands.

3) Micronodular adrenal hyperplasia: CT and MRI reveal symmetric adrenal glands that are small or of normal size. Diagnosis is established during surgery (characteristic yellow-black color of the nodules caused by lipofuscin deposition).

6. Bilateral inferior petrosal sinus sampling (or bilateral jugular vein sampling, which is simpler and safer) is occasionally used in highly specialized settings. It relies on relative left/right ACTH level, measured with or without CRH stimulations. Indications and interpretation of the results are outside of the scope of this text.

Diagnostic Criteria

Diagnostic algorithm: Figure 6.1-1. Elevated serum cortisol levels must be found on ≥2 separate test results. The diagnostic process is usually conducted in a specialized setting.

1. Features of overt Cushing syndrome: Signs and symptoms of Cushing syndrome; high serum cortisol levels with low serum ACTH levels (in ACTH-independent Cushing syndrome) or with high serum ACTH levels (in ACTH-dependent Cushing syndrome caused by pituitary adenoma or ectopic ACTH or CRH secretion); CRH test results dependent on the cause of elevated cortisol levels; absence of cortisol secretion suppression (in adrenal tumors) or suppression of cortisol secretion only with high-dose (8 mg) dexamethasone (in pituitary adenoma); sometimes elevated androgen levels. CT and MRI may reveal adrenal tumor or tumors, MRI may reveal pituitary tumors, and much less frequently receptor scintigraphy may reveal ectopic ACTH or CRH secretion.

2. Subclinical Cushing syndrome: The earliest and longest-lasting abnormality is inadequate suppression of late-night cortisol levels. Suppression with dexamethasone is impaired, while morning blood and salivary cortisol levels and UFC excretion may approach or slightly exceed the ULN. The most important diagnostic findings are considered to be the reduction of morning plasma ACTH levels below the lower limit of normal (LLN) and inadequate suppression of cortisol secretion by dexamethasone (serum cortisol levels >83 nmol/L [3 microg/dL] in the overnight suppression test with dexamethasone 1 mg). This type of Cushing syndrome is diagnosed in a small proportion of incidentally detected, usually unilateral autonomous tumors of the adrenal cortex. A small group of patients who undergo unilateral adrenalectomy for an apparently nonfunctioning adrenal tumor are retrospectively diagnosed with subclinical Cushing syndrome based on secondary adrenal insufficiency of the remaining adrenal gland in the postoperative period.

Differential Diagnosis

Differential diagnosis of ACTH-dependent and ACTH-independent Cushing syndrome: Figure 6.1-1.

Other conditions associated with elevated glucocorticoid levels:

1) Glucocorticoid resistance: A syndrome of partially impaired response of the glucocorticoid receptor (a rare genetic condition). It is associated with high serum ACTH, cortisol, androgen, and aldosterone levels without symptoms of excess cortisol, with features of androgenization and aldosteronism in women. The circadian rhythm of cortisol secretion as well as pituitary and adrenal response to CRH are preserved. Treatment: Dexamethasone 1 to 1.5 mg/d to suppress ACTH secretion.

2) Functional syndromes (pseudo–Cushing syndrome), with high serum cortisol levels resulting not from organic lesions in the pituitary-adrenal system but rather from other abnormalities (high serum cortisol levels require no treatment).

a) Depression: High serum cortisol levels and impaired dexamethasone suppression with a preserved circadian rhythm of cortisol secretion and normal serum ACTH levels.

b) Pregnancy: High blood levels of transcortin (corticosteroid-binding globulin) and, consequently, also high cortisol levels. Placental CRH secretion increases in the third trimester of pregnancy. UFC excretion is increased and the circadian rhythm of cortisol secretion is preserved.

c) Alcohol dependence: Few patients have clinical features of Cushing syndrome (because of altered cortisol metabolism in the liver and effects of alcohol on the central nervous system). Abstinence results in resolution of symptoms.

d) Anorexia nervosa: Elevated cortisol levels, mainly as a result of decreased renal clearance of cortisol. An increase in ACTH secretion may also occur. Impaired dexamethasone suppression caused by acquired glucocorticoid-receptor resistance is present, which explains the lack of any features of adrenal overproduction of glucocorticoids.


Symptomatic Treatment

Treatment of complications of Cushing syndrome, which may include hypertension, diabetes mellitus, dyslipidemia, osteoporosis, and psychological disturbances. Some complications resolve after successful treatment of the underlying conditions that have caused Cushing syndrome.

Treatment of Cortisol Hypersecretion

This depends on the etiology of Cushing syndrome.

1. Autonomous tumors of the adrenal cortex: The treatment of choice is usually surgical resection of the adrenal tumor.Evidence 1Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of most studies. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet. 2015 Aug 29;386(9996):913-27. doi: 10.1016/S0140-6736(14)61375-1. Epub 2015 May 21. Review. PubMed PMID: 26004339. Medical therapy is recommended as second-line treatment, as primary treatment in metastatic ectopic ACTH syndrome, and as adjuvant therapy in reducing cortisol levels in adrenocortical carcinoma.Evidence 2Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of most studies. Nieman LK, Biller BM, Findling JW, et al; Endocrine Society. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015 Aug;100(8):2807-31. doi: 10.1210/jc.2015-1818. Epub 2015 Jul 29. PubMed PMID: 26222757; PubMed Central PMCID: PMC4525003. Use ketoconazole 400 to 800 mg/day in 3 divided doses (rarely up to 1200 mg/d) or less frequently aminoglutethimide 500 to 750 mg/day or mitotane in an average dose of ~3 g/day. Care should be taken to avoid precipitating glucocorticoid deficit and features of impending adrenal crisis. Clinical improvement is seen at ~3 weeks of treatment, provided the dose is appropriately selected. Perioperative administration of glucocorticoids is the same as in perioperative management of patients with adrenal insufficiency. After surgical tumor resection, use hydrocortisone replacement (typical starting dose, 30 mg/d) as functioning of the contralateral adrenal gland is usually impaired. Over the course of the following weeks, taper the dose of hydrocortisone down to discontinuation. For the following 2 years, hydrocortisone treatment may be occasionally necessary in the event of severe stress (eg, surgery). In rare cases discontinuation of hydrocortisone is not possible.

Patients with subclinical Cushing syndrome after adrenal tumor resection develop secondary adrenal insufficiency of the contralateral adrenal gland. This requires hydrocortisone replacement with subsequent dose tapering (typical starting dose, 20 mg/d).

2. Macronodular or micronodular adrenal hyperplasia: The treatment of choice is resection of both adrenal glands. Administer hydrocortisone as in patients after resection of an adenoma.

3. Management of pituitary adenoma.


Regardless of etiology, patients with long-standing Cushing syndrome may develop vascular complications of hypertension.

1. Resection of pituitary adenoma or adrenal adenoma results in complete resolution of Cushing syndrome. Periodic replacement therapy may be needed.

2. Bilateral adrenalectomy in patients with micronodular and macronodular adrenal hyperplasia results in resolution of symptoms of Cushing syndrome, but lifelong glucocorticoid replacement therapy is necessary. In patients with Carney complex, the prognosis depends on coexisting abnormalities.

3. In patients with adrenocortical carcinoma, the prognosis depends on the stage of cancer and extent of surgery. Patients after bilateral adrenalectomy require lifelong replacement therapy.


Figure 6.1-1. Diagnostic algorithm in Cushing syndrome.

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