Cushing syndrome

Overview

• Cushing syndrome is the clinical syndrome from chronic exposure to excess glucocorticoid, whether the source is a pill bottle, a pituitary tumor, an adrenal tumor, or an ectopic ACTH-producing tumor.
• The term is distinct from "Cushing disease," reserved specifically for hypercortisolism from an ACTH-secreting pituitary adenoma; every Cushing disease patient has Cushing syndrome, but not every Cushing syndrome patient has Cushing disease.
• Exogenous glucocorticoid administration is by far the most common cause encountered in practice, from oral, inhaled, topical, or injected steroids prescribed for another condition.
• Among endogenous causes, an ACTH-secreting pituitary adenoma is most common, followed by cortisol-secreting adrenal adenomas or, rarely, carcinomas, and ectopic ACTH-secreting tumors.
• Because weight gain, fatigue, and hypertension are common in the general population, testing should target patients with specific, higher-yield findings rather than every patient with these nonspecific features.

Epidemiology

• Endogenous Cushing syndrome is rare, while exogenous glucocorticoid-induced hypercortisolism is common given the widespread therapeutic use of steroids for inflammatory, autoimmune, pulmonary, and rheumatologic disease.
• Cortisol-secreting adrenal adenomas and, rarely, carcinomas account for about 15% to 20% of endogenous Cushing syndrome, with the remainder ACTH-dependent.
• Subclinical hypercortisolism is identified more often than overt Cushing syndrome among patients with an adrenal incidentaloma, reflecting how frequently incidental adrenal imaging now prompts biochemical evaluation.
• Women are affected more often than men among patients with endogenous Cushing syndrome from a pituitary or adrenal source, though this varies by etiology.

Risk factors

• Chronic prescription of oral, inhaled, or topical glucocorticoids for asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, or inflammatory bowel disease is the dominant risk factor in practice.
• An adrenal incidentaloma discovered on imaging obtained for an unrelated reason raises pretest probability of an underlying cortisol-secreting adenoma and should prompt screening.
• A known pituitary or ectopic neuroendocrine tumor raises risk for ACTH-dependent disease.
• Genetic predisposition syndromes (multiple endocrine neoplasia type 1 for pituitary adenomas; Carney complex and McCune-Albright syndrome for adrenal disease) are rare familial associations.

Pathophysiology

• Chronic glucocorticoid excess, from any source, produces the same downstream phenotype because cortisol receptors are expressed broadly across skin, muscle, bone, adipose tissue, the immune system, and the cardiovascular system.
• In ACTH-dependent disease, a pituitary corticotroph adenoma (or, less commonly, an ectopic ACTH-secreting tumor) drives excess cortisol through sustained ACTH stimulation.
• In ACTH-independent disease, an autonomous adrenal adenoma or carcinoma secretes cortisol independent of pituitary control, suppressing endogenous ACTH and, over time, the contralateral gland.
• In exogenous disease, administered glucocorticoid saturates cortisol receptors and suppresses the hypothalamic-pituitary-adrenal axis, producing the identical phenotype without endogenous excess.
• Catabolic effects (proximal myopathy, thin skin, striae, bruising) and anti-insulin, lipogenic effects (central obesity, hyperglycemia, dyslipidemia) account for most of the picture; sustained excess also suppresses bone formation and gonadotropins.

Clinical features

• The most discriminating findings are wide (greater than 1 cm), reddish-purple striae, proximal muscle weakness, facial plethora, and easy bruising or skin tears, uncommon in the general population and specifically suggestive of hypercortisolism.
• Central/truncal obesity with relative sparing of the limbs, a dorsocervical fat pad ("buffalo hump"), and supraclavicular fat pads are characteristic but less specific fat-redistribution findings.
• Nonspecific symptoms are common and, alone, do not warrant testing: fatigue, depression, rapid weight gain, decreased libido, and menstrual irregularities.
• Hypertension, new or worsening hyperglycemia, and hypokalemia frequently accompany the syndrome, reflecting the mineralocorticoid-like and anti-insulin actions of markedly elevated cortisol.
• Hirsutism and acne occur with co-secretion of adrenal androgens, more typical of an adrenal source.
• Rapid onset, with or without virilization, is atypical for benign disease and should raise concern for adrenal carcinoma or an aggressive ectopic ACTH-secreting tumor.
• No single formal clinical criteria set defines Cushing syndrome at the bedside; the constellation of specific signs above should prompt biochemical screening.

Differential diagnosis

• Physiologic ("pseudo-Cushing") hypercortisolism: occurs with severe obesity, poorly controlled diabetes, alcohol use disorder, depression, or severe stress, and can mildly elevate screening tests, unlike true disease, distinguished by specific signs and by degree (urine free cortisol more than three times the upper normal limit favors true disease).
• Metabolic syndrome/obesity alone: shares central adiposity, hypertension, and glucose intolerance but lacks striae wider than 1 cm, proximal myopathy, and facial plethora; screening cortisol tests are normal.
• Primary aldosteronism: causes hypertension and hypokalemia similar to severe Cushing syndrome, but is distinguished by an elevated plasma aldosterone/renin ratio with a normal cortisol screen and no cutaneous or myopathic findings.
• Polycystic ovary syndrome: shares hirsutism and menstrual irregularity but not wide violaceous striae or proximal myopathy; cortisol screening is normal, unlike Cushing syndrome.
• Depression or alcohol use disorder: can mildly elevate cortisol and cause fatigue and weight change, but lacks the specific cutaneous/myopathic phenotype and the marked elevation of true hypercortisolism.
• Acromegaly: causes hypertension, diabetes, and soft-tissue changes, but the phenotype is acral overgrowth rather than central obesity and striae, and it is discriminated by IGF-1 rather than cortisol.
• Hypothyroidism: produces weight gain and fatigue but not violaceous striae, proximal myopathy, or plethora, and is distinguished by an elevated TSH with a normal cortisol screen.
• Type 2 diabetes mellitus from other causes: produces hyperglycemia without the cutaneous, myopathic, or fat-redistribution findings of hypercortisolism, and cortisol testing is normal.
• Undisclosed exogenous glucocorticoid use (factitious or unrecognized): produces an identical phenotype but with a suppressed ACTH and low urine free cortisol, unlike autonomous disease; a careful medication history distinguishes it.

Diagnosis

• The diagnosis rests on demonstrating nonphysiologic cortisol excess, not on a single random cortisol level, because morning or random serum cortisol overlaps too much with normal and pseudo-Cushing states; testing should be limited to patients with significant clinical suspicion (specific signs or an incidental adrenal mass).
• First, exclude exogenous glucocorticoid use by careful medication history, since this is the most common cause and requires only confirming the phenotype and tapering the offending drug.
• Then perform one of three initial screening tests, each with similar accuracy: 24-hour urine free cortisol, serial late-night salivary cortisol (at least two nights), or the 1 mg overnight low-dose dexamethasone suppression test, with a post-dexamethasone cortisol above 1.8 mcg/dL positive.
• If suspicion is low, one negative test makes disease unlikely; if high, two negative tests are recommended to exclude it, and two positive results out of three warrant endocrinology referral.
• Once hypercortisolism is confirmed, measure plasma ACTH to classify disease as ACTH-dependent (not suppressed) or ACTH-independent (suppressed, generally below 5 pg/mL), which determines the imaging pathway.
• If ACTH-independent, obtain dedicated adrenal CT or MRI to localize an adenoma or carcinoma; if adrenal imaging is normal, the diagnosis should be reconsidered.
• If ACTH-dependent, obtain a pituitary MRI; if no tumor is seen or it is under 6 mm, inferior petrosal sinus sampling (or high-dose dexamethasone suppression, or corticotropin-releasing hormone stimulation) distinguishes a pituitary source from an ectopic tumor.

Clinical pearl. New hypertension, hyperglycemia, and hypokalemia plus wide, reddish-purple striae and proximal weakness climbing stairs is Cushing syndrome until biochemically excluded; start with urine free cortisol, late-night salivary cortisol, or a low-dose dexamethasone suppression test, not a random morning cortisol.

Management

• First, taper the causative agent if the source is exogenous glucocorticoid, reducing to the lowest effective dose or discontinuing if possible, rather than stopping abruptly, because abrupt discontinuation after prolonged suppression risks adrenal crisis.
• If the source is an adrenal adenoma or carcinoma, proceed to unilateral adrenalectomy, the definitive treatment for both benign and malignant cortisol-secreting adrenal tumors; give postoperative glucocorticoid replacement (hydrocortisone 15-25 mg/day PO in 2-3 divided doses) because the contralateral adrenal gland remains suppressed and may take months to years to recover.
• If the source is an ACTH-secreting pituitary adenoma (Cushing disease), refer for transsphenoidal resection (see the dedicated Cushing disease entry for postoperative detail).
• If surgery is not curative, not feasible, or disease persists, start a steroidogenesis inhibitor:
  • Osilodrostat 2 mg PO twice daily, titrated by 1-2 mg twice daily every 2 weeks based on 24-hour urine free cortisol, up to 30 mg twice daily; monitor ECG/QTc and potassium.
  • Ketoconazole 200 mg PO two to three times daily (off-label), titrated up to 1,200 mg/day; monitor liver enzymes.
  • Metyrapone 250 mg PO four times daily, titrated up to 6 g/day; monitor for hypokalemia and hypertension.
• If diabetes or glucose intolerance accompanies Cushing syndrome and surgery is not an option,
  • Mifepristone 300 mg PO once daily, titrated by 300 mg every 2-4 weeks up to 1,200 mg/day, blocking the glucocorticoid receptor; monitor clinically for adrenal insufficiency rather than by cortisol level, since cortisol itself rises on this therapy.
• If an ectopic ACTH tumor is identified, resect it when resectable; if not found or not resectable, manage with osilodrostat 2 mg PO twice daily (titrated as above) while the search continues.
• Treat comorbidities in parallel: hypertension, hyperglycemia, hypokalemia, and bone density.

Complications

• Cardiovascular disease, driven by chronic hypertension, hyperglycemia, dyslipidemia, and the direct vascular effects of cortisol excess, is a leading cause of morbidity and mortality.
• Osteoporosis and fragility fractures from cortisol-mediated suppression of bone formation and increased resorption.
• Impaired wound healing and increased infection risk from the immunosuppressive and catabolic effects of chronic hypercortisolism.
• Venous thromboembolism, reflecting a hypercoagulable state, particularly in the perioperative period.
• Psychiatric disturbance, including depression, anxiety, and, less commonly, psychosis, which may persist even after biochemical cure.
• Adrenal crisis if glucocorticoid therapy is withdrawn abruptly after cure without adequate replacement, because the hypothalamic-pituitary-adrenal axis remains suppressed.
• Nelson syndrome (progressive pituitary corticotroph tumor growth) can follow bilateral adrenalectomy for refractory ACTH-dependent disease, from loss of cortisol-mediated feedback on the pituitary tumor.

Prognosis

• Untreated Cushing syndrome carries substantially increased mortality, driven mainly by cardiovascular disease, infection, and thromboembolism.
• Cure or adequate control improves, though does not always fully reverse, cardiovascular risk, bone density, and psychiatric symptoms, so biochemical control remains the central treatment target regardless of etiology.
• Prognosis after adrenalectomy for a benign adenoma is generally excellent, while adrenal carcinoma carries a substantially worse prognosis given its potential for local invasion and metastasis.
• Recovery of the hypothalamic-pituitary-adrenal axis after cure of endogenous disease can take up to 18 months, and some patients never fully recover, requiring lifelong glucocorticoid replacement.

Prevention

• There is no primary prevention for endogenous Cushing syndrome; prevention efforts focus on avoiding iatrogenic hypercortisolism and early detection through targeted screening.
• Prescribe the lowest effective glucocorticoid dose for the shortest duration necessary, and taper rather than abruptly stop chronic therapy to avoid precipitating adrenal insufficiency.
• Limit hypercortisolism screening to patients with specific clinical suspicion (striae wider than 1 cm, proximal myopathy, facial plethora, easy bruising, or an adrenal incidentaloma) rather than testing broadly, which reduces false positives.
• Screen every patient with an adrenal incidentaloma for subclinical hypercortisolism with a 1 mg overnight dexamethasone suppression test (post-dexamethasone cortisol above 1.8 mcg/dL is positive) at the time of discovery.
• Provide stress-dose glucocorticoid education to every patient on chronic steroid therapy so illness, surgery, or trauma does not precipitate adrenal crisis.

Key points

• Cushing syndrome is chronic glucocorticoid excess from any source; exogenous steroid use is the most common cause overall, and an ACTH-secreting pituitary adenoma (Cushing disease) is the most common endogenous cause.
• The most discriminating findings are wide violaceous striae, proximal myopathy, facial plethora, and easy bruising, not the nonspecific weight gain and fatigue shared with the general population.
• Diagnose with one of three initial screening tests, then measure ACTH to classify ACTH-dependent versus ACTH-independent disease.
• Treatment is source-directed: taper exogenous steroid, resect a pituitary or adrenal tumor, or find and resect an ectopic source; steroidogenesis inhibitors or mifepristone are reserved for persistent, unresectable, or presurgical disease.
• Postoperative glucocorticoid replacement is required because the hypothalamic-pituitary-adrenal axis remains suppressed and may take up to 18 months to recover, or never recover.
• Bilateral adrenalectomy for refractory disease carries a risk of Nelson syndrome from unchecked pituitary tumor growth after loss of cortisol feedback.