Cushing syndrome and Cushing disease

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Endogenous Cushing syndrome arises from ACTH-dependent or ACTH-independent cortisol production. Pituitary Cushing disease is the common ACTH-dependent source, but an ectopic neuroendocrine tumour may secrete ACTH. An adrenal adenoma, carcinoma or bilateral nodular disease can produce cortisol autonomously and suppress ACTH. Exogenous steroids mimic many clinical features while suppressing endogenous production.

Normal cortisol secretion has a circadian nadir around midnight and is suppressible by dexamethasone. Screening tests exploit loss of this rhythm, loss of feedback or increased integrated secretion. No single test is perfect: at least two concordant abnormal assessments are often needed, and cyclic disease may require repeated testing during symptomatic phases.

Cortisol excess causes multisystem harm even before localisation is complete. Assess blood pressure, potassium, glucose, infection, bone, mood and thrombosis throughout the diagnostic process. Severe presentations warrant accelerated specialist care because mortality is driven by cardiovascular and infectious complications, not merely the tumour mass.

Key points

Cushing syndrome means clinically important glucocorticoid excess from any cause; Cushing disease is specifically an ACTH-secreting pituitary corticotroph tumour.
Exogenous glucocorticoid exposure is the commonest overall cause. Ask about tablets, injections, inhalers, creams, nasal sprays and unregulated products before ordering an endogenous-cortisol work-up.
Discriminating features include facial plethora, easy bruising, wide violaceous striae, proximal myopathy, unexplained osteoporosis, thin skin, spontaneous hypokalaemia and growth failure with weight gain in a child.
Common findings such as central obesity, hypertension, diabetes, depression and menstrual change have low specificity alone; test when several progressive or unusual features cluster.
First prove endogenous hypercortisolism with a validated test such as overnight dexamethasone suppression, repeated late-night salivary cortisol or repeated 24-hour urinary free cortisol selected by endocrinology.
Shift work, alcohol excess, severe depression, acute illness, obesity, oestrogen, enzyme-inducing medicines, renal impairment and incorrect sample collection can distort screening results.
After confirmation, ACTH localises the physiology: suppressed ACTH points toward adrenal autonomy, whereas detectable or raised ACTH requires pituitary-versus-ectopic investigation.
Do not image the pituitary or adrenals before biochemical confirmation and ACTH classification. Incidental lesions are common and can create a convincing but false narrative.
Treatment is cause-directed surgery where feasible. Medical cortisol blockade is specialist therapy used for rapid control, bridging, persistent disease or when surgery is unsuitable.
Active Cushing syndrome increases infection, venous thromboembolism, cardiovascular, fracture and psychiatric risk; managing these comorbidities is part of endocrine treatment rather than an optional extra.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Exogenous glucocorticoid exposure

Systemic exposure from oral, injected, inhaled or topical glucocorticoids can reproduce cortisol effects while suppressing endogenous ACTH and adrenal function.

ACTH-dependent cortisol excess

A pituitary corticotroph adenoma causes Cushing disease, while an ectopic neuroendocrine tumour can also drive both adrenal glands through inappropriate ACTH secretion.

ACTH-independent adrenal secretion

An adrenal adenoma, carcinoma or bilateral nodular disease can produce cortisol autonomously and suppress pituitary ACTH through negative feedback.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Cortisol regulation is lost
Autonomous steroid exposure removes the normal circadian nadir, feedback suppression or both, creating sustained tissue glucocorticoid activity.
2
Protein and metabolic tissues are altered
Cortisol promotes insulin resistance, protein catabolism and fat redistribution, producing diabetes, proximal weakness, fragile skin and characteristic body-composition change.
3
Vascular and immune harm develops
Mineralocorticoid effects, vascular sensitisation, impaired immunity and prothrombotic change contribute to hypertension, hypokalaemia, serious infection and thrombosis.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Catabolic phenotype

Proximal thigh or shoulder weakness, fragile skin, spontaneous bruising, wide purple striae, poor wound healing and osteoporosis reflect protein and connective-tissue catabolism and are more discriminating than obesity alone.

Metabolic phenotype

New resistant hypertension, diabetes, hypokalaemia, dyslipidaemia and central fat redistribution can signal cortisol excess, particularly when severe for age or evolving quickly.

ACTH androgen patternRed flag

Hyperpigmentation and androgen excess can accompany high ACTH, especially ectopic secretion or aggressive pituitary disease. Adrenal androgen excess with a large irregular mass raises concern for adrenocortical carcinoma.

Neuropsychiatric and immune effectsRed flag

Insomnia, depression, emotional lability, cognitive change or psychosis may coexist with opportunistic or muted infection. Severe behavioural change or sepsis requires urgent treatment while the endocrine diagnosis proceeds.

Exogenous Cushing state

Cushingoid appearance during glucocorticoid therapy can coexist with suppressed adrenal reserve. Abrupt withdrawal is dangerous even though the patient appears cortisol-exposed, so taper and stress cover require planning.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Complete glucocorticoid and medicine historyFirst step
Why
Exclude exogenous exposure and identify drugs that invalidate biochemical tests.
Interpretation and limitations
Include prescribed and non-prescribed products, joint or epidural injections and potent topical therapy. Enzyme inducers can lower dexamethasone exposure, while oral oestrogen raises cortisol-binding globulin and total serum cortisol.
02
One-milligram overnight dexamethasone suppression test
Why
Screen whether feedback appropriately suppresses morning serum cortisol.
Interpretation and limitations
Use the local timed protocol and cut-off. Non-suppression is not synonymous with Cushing syndrome; check dose timing, interacting medicines, oestrogen and physiological stress before confirmation.
03
Late-night salivary cortisol on repeated samples
Why
Detect loss of the normal nocturnal cortisol nadir in an outpatient setting.
Interpretation and limitations
Collect at the specified clock or sleep-related time without blood, food or contamination. Shift work, disturbed sleep and acute stress can undermine interpretation; repeated abnormal values are more persuasive.
04
Twenty-four-hour urinary free cortisol on repeated collections
Why
Estimate integrated unbound cortisol secretion across a full day.
Interpretation and limitations
Confirm collection completeness and renal function. Mild or cyclic disease may be missed, while very high repeated values with a compatible phenotype support clinically important excess.
05
Plasma ACTH after hypercortisolism confirmation
Why
Classify disease as ACTH-independent or ACTH-dependent before imaging.
Interpretation and limitations
Suppressed ACTH directs adrenal assessment. Detectable or raised ACTH directs pituitary and ectopic evaluation; borderline values may need repetition with correct sample handling.
06
Pituitary MRI, adrenal CT and specialist localisation
Why
Locate the source only after biochemical physiology is established.
Interpretation and limitations
A small pituitary lesion may be incidental and a true corticotroph tumour may be MRI-occult. Inferior petrosal sinus sampling or functional imaging is selected by a tertiary MDT when non-invasive findings conflict.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Simple obesity or metabolic syndrome

Common weight gain and diabetes lack the more discriminatory combination of progressive proximal weakness, easy bruising, wide purple striae and fragility fracture.

Physiological hypercortisolism

Alcohol excess, depression, severe stress or acute illness can disturb screening tests; repeated, complementary testing in a stable context helps avoid false localisation.

Exogenous steroid effects

A complete medicine history may reveal the cause even when serum cortisol is low, distinguishing iatrogenic Cushing features from endogenous hormone production.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Case findingTest the phenotype, not obesity aloneFirst stepMultiple progressive discriminating features, unusual osteoporosis or hypertension, adrenal incidentaloma, or childhood growth failure with weight gain.

1Take a comprehensive steroid and medicine history, document objective features and identify acute infection, thrombosis, glucose or blood-pressure complications needing parallel treatment.
2First lineChoose an appropriate first-line screen with endocrinology or the Society for Endocrinology pre-referral pathway, accounting for shift work, oestrogen, renal function and interacting medicines.
3Repeat or confirm abnormal results rather than ordering immediate imaging; refer urgently when clinical severity is high even if the biochemical series is still being completed.

02LocalisationACTH before anatomyEndogenous hypercortisolism confirmed by concordant specialist-interpreted testing.

1Measure ACTH under correct handling conditions and repeat if borderline; suppressed ACTH enters an adrenal pathway, while non-suppressed ACTH enters pituitary-versus-ectopic assessment.
2Use dedicated adrenal CT or pituitary MRI according to that physiology and assess other tumour-specific clues, including androgens or rapid progression for possible adrenal carcinoma.
3When ACTH-dependent imaging is negative or discordant, refer to a tertiary pituitary MDT for dynamic or inferior petrosal sinus sampling rather than assigning causality to a tiny incidentaloma.

03TreatmentControl cortisol and remove the sourceLocalised endogenous Cushing syndrome or severe hypercortisolism requiring bridging control.

1Use transsphenoidal surgery for suitable Cushing disease or adrenal surgery for unilateral adrenal disease through experienced endocrine teams; suspected carcinoma requires an oncological adrenal MDT.
2Use metyrapone, ketoconazole, osilodrostat or other specialist therapy when rapid biochemical control, surgical bridging or non-surgical management is needed, monitoring for drug-specific toxicity and adrenal insufficiency.
3Prevent infection and thrombosis according to risk, manage hypertension, diabetes, potassium, bone and mental health, then provide postoperative glucocorticoid replacement and long-term recurrence surveillance.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Inhibits adrenal cortisol synthesis for rapid control, pre-operative bridging, persistent disease or an occult/unresectable source.

Metyrapone

Specialist-initiated divided regimen titrated to validated cortisol measurements or used in a block-and-replace strategy; follow current BNF and endocrine protocol.

Can cause adrenal insufficiency, hypokalaemia, hypertension, oedema and androgenic effects through precursor accumulation. Provide crisis education and do not adjust from one uncontextualised cortisol result.

Blocks steroidogenesis when surgery is delayed, ineffective or unsuitable, sometimes in combination with another cortisol-lowering agent.

Ketoconazole for endogenous Cushing syndrome

Endocrine specialist dose increased according to cortisol response, liver tests, interactions and the licensed product information.

Potential severe hepatotoxicity and major CYP interactions require baseline and serial liver review. It can cause adrenal insufficiency and affect gonadal steroid synthesis; oral use here is specialist only.

Licensed cortisol-synthesis inhibitor for selected adults with endogenous Cushing syndrome requiring medical control.

Osilodrostat

Initiate and titrate only under expert supervision using serial cortisol, potassium, blood pressure, ECG risk and current BNF instructions.

Adrenal insufficiency, hypokalaemia, hypertension, oedema and QT prolongation can occur. Rapid biochemical change may unmask glucocorticoid withdrawal symptoms despite improving cortisol excess.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Cardiometabolic disease

Hypertension, diabetes, dyslipidaemia and vascular injury substantially increase cardiovascular risk and may require active treatment before definitive endocrine control.

Infection and thrombosis

Cortisol excess impairs immune responses and promotes clotting, making severe infection and venous thromboembolism important causes of acute deterioration.

Bone and muscle disability

Protein catabolism and altered bone turnover cause proximal weakness, osteoporosis and vertebral fractures, with functional recovery often lagging behind biochemical improvement.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Track the chosen biochemical control marker using the same assay and protocol, alongside clinical change; normalising one value does not immediately reverse cardiovascular or thrombotic risk.
Monitor blood pressure, potassium, glucose, weight and oedema frequently during active disease and steroidogenesis inhibition, adjusting comorbidity treatment as cortisol falls.
Screen and treat infection promptly, assess venous thromboembolism risk around active disease and surgery, and provide bone protection based on fracture assessment and local guidance.
During cortisol-lowering medicine, teach symptoms of adrenal insufficiency and provide an emergency pathway; check liver tests or ECG specifically when the chosen agent requires them.
After pituitary or adrenal surgery, assess remission and adrenal reserve under the endocrine protocol, manage replacement, and continue long-term surveillance for recurrence and persistent comorbidity.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Disease is a pituitary word

Cushing disease is not interchangeable with Cushing syndrome. Using the specific term before ACTH localisation can prematurely close the diagnostic pathway.

Catabolism is discriminating

Proximal weakness, broad violaceous striae, spontaneous bruising and unexplained fractures carry more diagnostic weight than common obesity, acne or hypertension in isolation.

An incidentaloma is not a source

Small pituitary and adrenal lesions occur in people without endocrine disease. Biochemical confirmation and ACTH physiology protect patients from surgery on the wrong organ.

Cyclic disease needs timing

Symptoms and cortisol production may fluctuate. Repeating late-night saliva or urinary cortisol during an active phase can be more informative than escalating imaging after a normal quiet-phase test.

Cure creates temporary deficiency

The contralateral adrenal or remaining pituitary-adrenal axis is suppressed after successful treatment. Postoperative glucocorticoid replacement and later recovery testing are expected parts of cure.

11Common pitfallsFrequent interpretation and management errors.

01
Screening every patient with uncomplicated obesity and generating false-positive dexamethasone tests.
02
Failing to ask about injected, inhaled, topical or non-prescribed glucocorticoids.
03
Ordering pituitary MRI before proving hypercortisolism and checking ACTH dependence.
04
Diagnosing endogenous Cushing syndrome from one abnormal screen during acute illness or major depression.
05
Treating the tumour while overlooking infection, thrombosis, hypokalaemia, diabetes, fracture and psychiatric risk.
06
Lowering cortisol rapidly without monitoring for adrenal insufficiency or supplying emergency instructions.