Cushing Syndrome: Confirming Cortisol Excess and Finding the Source

Last updated 17 August 2026.

Key points

Cushing syndrome: the clinical state produced by chronic glucocorticoid excess from any cause. Cushing's disease means specifically a pituitary ACTH-secreting adenoma.
Commonest cause by far: exogenous corticosteroids. Ask about tablets, inhalers, creams, eye drops, injections and over-the-counter preparations before investigating anything.
Discriminatory features: proximal myopathy, easy bruising, facial plethora, violaceous striae over 1 cm wide, and in children weight gain with growth arrest. These separate Cushing's from simple obesity.
Screening: overnight 1 mg dexamethasone suppression test, late-night salivary cortisol, or 24-hour urinary free cortisol. Two abnormal tests are needed before proceeding.
ACTH localises the cause: a suppressed ACTH means an adrenal source - image the adrenals. A normal or raised ACTH means a pituitary or ectopic source - image the pituitary.
Ectopic ACTH: rapid onset, marked pigmentation, severe hypokalaemic alkalosis and weight loss rather than the classical habitus. Small cell lung cancer is the usual source.
Inferior petrosal sinus sampling: the gold standard for separating a pituitary from an ectopic source when imaging is equivocal.
First-line treatment of Cushing's disease: trans-sphenoidal selective adenomectomy, which achieves remission in around 80% of microadenomas.

Introduction

Cushing syndrome is the clinical state resulting from chronic exposure to excess glucocorticoid. Two terms are used loosely and should not be:

Cushing syndrome - the clinical picture, from any cause
Cushing's disease - the specific subset caused by an ACTH-secreting pituitary adenoma, which accounts for around 70% of endogenous cases

Endogenous Cushing syndrome is rare, with an incidence of around 2 to 3 per million per year. Exogenous (iatrogenic) Cushing syndrome from prescribed corticosteroids is vastly more common, and is the first thing to exclude in any patient with the phenotype.

Causes of Cushing syndrome.
Group	Cause	Proportion of endogenous cases
Exogenous	Corticosteroids - oral, inhaled at high dose, topical, intra-articular, intranasal or intraocular. Also potentiated by CYP3A4 inhibitors such as ritonavir given with fluticasone, and by unlabelled steroid in herbal or imported preparations.	By far the commonest cause overall
ACTH-dependent (around 80%)	Cushing's disease - pituitary corticotroph adenoma, usually a microadenoma	Around 70%
	Ectopic ACTH secretion - small cell lung carcinoma, bronchial carcinoid, pancreatic and thymic neuroendocrine tumours, medullary thyroid carcinoma, phaeochromocytoma	Around 10%
	Ectopic CRH secretion - very rare	Under 1%
ACTH-independent (around 20%)	Adrenal adenoma	Around 10%
	Adrenal carcinoma - often with virilisation from concurrent androgen excess	Around 5%
	Bilateral adrenal hyperplasia - micronodular (including Carney complex) or macronodular; also McCune-Albright syndrome	Around 5%

Clinical features

Cortisol acts on almost every tissue, and the clinical picture reflects its catabolic, metabolic, mineralocorticoid and psychological effects.

Features by system.
System	Features
Fat distribution	Central (truncal) obesity with relatively thin limbs, moon face, interscapular fat pad (buffalo hump) and supraclavicular fat pads
Skin	Thin, fragile skin, easy bruising, violaceous (purple) striae wider than 1 cm over the abdomen, thighs and breasts, poor wound healing, facial plethora, acne, hirsutism and fungal infections
Muscle	Proximal myopathy - difficulty rising from a chair or climbing stairs without using the arms. One of the most discriminating features.
Bone	Osteoporosis with vertebral crush fractures, rib fractures and avascular necrosis of the femoral head
Metabolic	Hypertension, diabetes or impaired glucose tolerance, dyslipidaemia, and hypokalaemic metabolic alkalosis from mineralocorticoid activity - marked in ectopic ACTH
Reproductive	Oligomenorrhoea or amenorrhoea, reduced libido, erectile dysfunction and infertility
Psychiatric	Depression, emotional lability, irritability, insomnia, cognitive impairment and, occasionally, frank psychosis
Immune	Increased susceptibility to infection, including opportunistic infections such as Pneumocystis and reactivated tuberculosis
Children	Weight gain with growth arrest - a combination that is highly specific and should always prompt investigation

Frontal photograph of a woman's face with the eyes masked, showing a rounded full face with fullness of the cheeks and submental region, marked facial redness, scattered acne and increased fine facial hair. — The Cushingoid face: rounding and fullness of the face with redistribution of fat, marked facial plethora, acne and hirsutism. The plethora reflects skin thinning with increased visibility of the underlying vasculature and is one of the more discriminating signs.Celik O, Niyazoglu M, Soylu H, Kadioglu P, CC BY 2.5, via Wikimedia Commons

Photograph of the side of an abdomen showing multiple broad, deep purple-red stretch marks several centimetres long radiating across the flank, with a rippled surface. — Striae in Cushing syndrome. Unlike the pale, narrow striae of pregnancy or rapid weight gain, these are **broad (over 1 cm), deep purple and depressed** - the colour reflecting thin dermis over dilated capillaries after cortisol has degraded the underlying collagen.Masryyy, CC BY-SA 4.0, via Wikimedia Commons

Ectopic ACTH looks different

The classical Cushingoid habitus takes months to develop. Ectopic ACTH secretion, particularly from small cell lung cancer, evolves over weeks, so the patient often does not look Cushingoid at all. Instead expect:

Rapid onset with weight loss rather than weight gain, because of the underlying malignancy
Marked skin pigmentation - ACTH is derived from pro-opiomelanocortin and stimulates melanocytes, so very high levels darken the skin, buccal mucosa and scars
Severe hypokalaemic metabolic alkalosis with muscle weakness - extremely high cortisol overwhelms the enzyme that normally protects the mineralocorticoid receptor, producing a florid mineralocorticoid effect
Marked hyperglycaemia, oedema and proximal myopathy
Very high ACTH and cortisol levels, higher than in Cushing's disease
In an older smoker with new severe hypokalaemia, hyperglycaemia and weakness, this is the diagnosis to think of

Investigations

Investigation proceeds in three deliberate stages, and skipping ahead causes a great deal of confusion.

Step 1: exclude exogenous steroids

Take a meticulous drug history covering oral steroids, inhalers, nasal sprays, eye drops, skin creams (including those bought online or obtained abroad), joint and epidural injections, and herbal or traditional remedies, which not infrequently contain undeclared corticosteroid. Also ask about drug interactions - ritonavir and other CYP3A4 inhibitors dramatically increase systemic exposure to inhaled or intranasal fluticasone.

Step 2: confirm cortisol excess

No single test is sufficient. Two abnormal results from different tests are required before proceeding, because false positives are common.

Screening tests for cortisol excess.
Test	Method	Abnormal result
Overnight (low-dose) dexamethasone suppression test	1 mg dexamethasone at 11 pm, serum cortisol at 9 am	Failure to suppress cortisol below 50 nmol/L
Late-night salivary cortisol	Two samples collected at home at 11 pm	Raised - reflecting loss of the normal diurnal fall, which is the earliest abnormality in Cushing syndrome
24-hour urinary free cortisol	Two complete collections	Raised above the reference range
48-hour low-dose dexamethasone suppression test	0.5 mg 6-hourly for 48 hours	Failure to suppress - more specific than the overnight test and used where that is equivocal

Pseudo-Cushing's and false positives

Several states raise cortisol and impair dexamethasone suppression without true Cushing syndrome, and are a frequent source of misdiagnosis.

Alcohol excess - the classic cause of pseudo-Cushing's, and the biochemistry normalises with abstinence
Severe depression and other major psychiatric illness
Obesity, poorly controlled diabetes and obstructive sleep apnoea
Pregnancy and oestrogen-containing contraception - oestrogen raises cortisol-binding globulin and therefore total cortisol; use urinary or salivary measures
Acute illness, stress and shift work - which disrupt diurnal rhythm
Drugs that induce CYP3A4 - phenytoin, carbamazepine, rifampicin - accelerate dexamethasone metabolism and cause false failure to suppress
Where doubt remains, a dexamethasone-suppressed CRH test or serial assessment over time is used in specialist practice

Step 3: localise the source

Once cortisol excess is confirmed, measure plasma ACTH. This single result divides the differential in two.

Using ACTH to localise the source.
Plasma ACTH	Interpretation	Next step
Suppressed (below about 1.1 pmol/L)	ACTH-independent - an adrenal source producing cortisol autonomously and suppressing pituitary ACTH	CT or MRI of the adrenals - looking for an adenoma, carcinoma or bilateral hyperplasia
Normal or raised	ACTH-dependent - a pituitary or ectopic source	MRI pituitary, plus further differentiation as below

Distinguishing pituitary from ectopic ACTH

High-dose dexamethasone suppression test (8 mg) - a pituitary adenoma retains partial negative feedback, so cortisol suppresses by more than 50%. An ectopic source does not suppress. The test is imperfect - some bronchial carcinoids do suppress - but remains a useful discriminator.
CRH stimulation test - a pituitary adenoma shows an exaggerated rise in ACTH and cortisol; an ectopic source shows little or no response
MRI pituitary - but note that around 40% of corticotroph microadenomas are not visible, and incidental pituitary lesions are present in up to 10% of the population, so imaging alone cannot settle the question
Inferior petrosal sinus sampling (IPSS) - the gold standard. ACTH is measured simultaneously from both inferior petrosal sinuses and peripherally, before and after CRH. A central-to-peripheral ACTH gradient confirms a pituitary source and may lateralise the adenoma.
Imaging for an ectopic source - CT of the chest, abdomen and pelvis, and Ga-68 DOTATATE PET-CT for neuroendocrine tumours, which may be very small and elusive

Supporting investigations

U&Es - hypokalaemia with metabolic alkalosis, especially in ectopic ACTH
Glucose and HbA1c - diabetes or impaired glucose tolerance in around half
Lipids
DEXA bone density scan - osteoporosis is common and often already established at diagnosis
Full blood count - neutrophilia with lymphopenia and eosinopenia is characteristic of glucocorticoid excess
Adrenal androgens (DHEAS) - markedly raised levels with virilisation suggest adrenal carcinoma

Management

Exogenous Cushing syndrome

Reduce the steroid to the lowest effective dose and withdraw where possible, but never abruptly - the hypothalamic-pituitary-adrenal axis is suppressed and sudden withdrawal precipitates an adrenal crisis. Taper slowly, and consider a short Synacthen test before final withdrawal in prolonged courses.
Use steroid-sparing agents and alternative routes or formulations where the underlying condition allows
Bone protection - calcium, vitamin D and a bisphosphonate for anyone on long-term glucocorticoids, and a DEXA scan
Gastroprotection, glucose monitoring, blood pressure control and attention to infection risk
Issue a steroid emergency card, and counsel about sick day rules - the dose must be increased during intercurrent illness

Endogenous Cushing syndrome

Definitive treatment by cause.
Cause	Treatment
Cushing's disease (pituitary adenoma)	Trans-sphenoidal selective adenomectomy is first line, achieving remission in around 80% of microadenomas. Second line: pituitary radiotherapy, medical therapy, or bilateral adrenalectomy as a last resort.
Adrenal adenoma	Laparoscopic adrenalectomy. The contralateral gland is suppressed, so glucocorticoid replacement is required postoperatively and tapered over months while the axis recovers.
Adrenal carcinoma	Adrenalectomy, with mitotane as adjuvant therapy. Prognosis is poor.
Ectopic ACTH	Treat the underlying tumour - resect a bronchial carcinoid; treat small cell lung cancer with chemotherapy. Where the tumour is occult or unresectable, control cortisol medically or perform bilateral adrenalectomy.
Bilateral adrenal hyperplasia	Bilateral adrenalectomy, with lifelong glucocorticoid and mineralocorticoid replacement

Medical control of cortisol

Used to prepare patients for surgery, while awaiting the effect of radiotherapy, or where surgery is not possible.

Metyrapone - inhibits 11-beta-hydroxylase; the usual first choice in the UK
Ketoconazole - inhibits several steroidogenic enzymes; requires liver function monitoring
Osilodrostat - a newer 11-beta-hydroxylase inhibitor
Pasireotide - a somatostatin analogue acting on the pituitary adenoma; causes hyperglycaemia
Cabergoline - a dopamine agonist, effective in a minority
Mifepristone - a glucocorticoid receptor antagonist, used where hyperglycaemia is prominent
Etomidate - by infusion, for rapid control of life-threatening hypercortisolaemia in critical care
Monitor for adrenal insufficiency during medical treatment, and use a block-and-replace approach where control is difficult

After successful treatment, the patient becomes adrenally insufficient

This is the most important practical point in the whole topic. Chronic cortisol excess suppresses the normal corticotrophs and the contralateral adrenal, and recovery takes 6 to 24 months.

Every patient needs glucocorticoid replacement after curative surgery, tapered slowly with periodic assessment of axis recovery
They must be given a steroid emergency card, sick day rules and an emergency hydrocortisone injection kit
Steroid withdrawal syndrome - patients often feel dreadful during the taper, with fatigue, arthralgia, myalgia and low mood, despite adequate replacement. Warn them in advance, or they will assume the disease has returned.
Nelson's syndrome - after bilateral adrenalectomy for Cushing's disease, loss of cortisol feedback allows the pituitary corticotroph tumour to enlarge, producing very high ACTH with marked pigmentation, headache and visual field loss. Monitor with MRI and ACTH.
Relapse of Cushing's disease occurs in 10 to 20% over subsequent years, so follow-up is lifelong

Complications

Cardiovascular disease - hypertension, left ventricular hypertrophy, ischaemic heart disease and stroke. This is the leading cause of death in untreated Cushing syndrome.
Venous thromboembolism - cortisol excess creates a markedly hypercoagulable state, and the risk is highest perioperatively. Thromboprophylaxis is essential.
Diabetes mellitus and dyslipidaemia
Osteoporosis and fragility fracture - vertebral fractures may be the presenting feature, and avascular necrosis of the femoral head also occurs
Infection - including opportunistic infections; fever and other signs may be blunted by the steroid excess, so infection presents late
Psychiatric illness - depression, anxiety, psychosis and cognitive impairment, which may persist after biochemical cure
Proximal myopathy with functional impairment
Poor wound healing and skin breakdown
Growth failure in children
Adrenal crisis after treatment or abrupt steroid withdrawal
Nelson's syndrome after bilateral adrenalectomy

Red flags

Act on these

Abrupt withdrawal of long-term corticosteroids - precipitates adrenal crisis; always taper and always issue a steroid card
Rapid onset of weakness, hypokalaemia, hyperglycaemia and pigmentation in an older smoker - ectopic ACTH from small cell lung cancer; investigate urgently
A patient with Cushing syndrome who becomes acutely unwell - infection may present without fever or leucocytosis; have a very low threshold for antibiotics and for suspecting sepsis
Weight gain with growth arrest in a child - highly specific for Cushing syndrome; investigate rather than treating as simple obesity
Vertebral fracture or avascular necrosis in a young adult - consider cortisol excess
Chest pain, breathlessness or a swollen leg in Cushing syndrome - the state is strongly prothrombotic; consider venous thromboembolism early, especially around surgery
Failure to suppress on dexamethasone in a patient taking phenytoin, carbamazepine or rifampicin - a false positive from accelerated dexamethasone metabolism
New pigmentation, headache or visual field loss after bilateral adrenalectomy - Nelson's syndrome; image the pituitary
A patient recently cured of Cushing syndrome who is unwell - they are adrenally insufficient; give hydrocortisone before investigating
Severe hypokalaemic alkalosis with hypertension - consider both ectopic ACTH and primary aldosteronism

Prognosis

Untreated endogenous Cushing syndrome carries a 5-year mortality approaching 50%, driven principally by cardiovascular disease, thromboembolism and infection. This is a striking figure for a condition that is often mentally filed under cosmetic change, and it is the reason investigation should not be deferred.

With successful treatment the outlook is transformed. Trans-sphenoidal surgery achieves remission in around 80% of pituitary microadenomas, and adrenalectomy is curative for a benign adenoma. Hypertension, diabetes, weight and the physical appearance improve substantially over 6 to 12 months.

Recovery is nonetheless incomplete for many. Excess cardiovascular risk persists for years after biochemical cure, bone density recovers slowly, and psychiatric and cognitive symptoms may not fully resolve - a genuinely important point to convey, because patients are frequently told the problem is fixed and then find that they do not feel well. Around 10 to 20% of Cushing's disease relapses, so follow-up is lifelong.

Adrenal carcinoma is the exception, with a poor prognosis and frequent recurrence despite surgery and mitotane. Ectopic ACTH prognosis is that of the underlying tumour - excellent where a bronchial carcinoid can be resected, poor where the source is small cell lung cancer.

References

NICE Clinical Knowledge Summaries. Cushing's syndrome. Available here
Nieman LK, Biller BMK, Findling JW et al. The diagnosis of Cushing's syndrome: an Endocrine Society clinical practice guideline. Available here
Nieman LK, Biller BMK, Findling JW et al. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. 2015. Available here
Society for Endocrinology. Endocrine emergency guidance - adrenal crisis and steroid safety. Available here
NICE NG146. Adrenal insufficiency and corticosteroid replacement guidance. Available here
BNF. Prednisolone, hydrocortisone and metyrapone. Available here
Celik O, Niyazoglu M, Soylu H, Kadioglu P, CC BY 2.5, via Wikimedia Commons. Available here
Masryyy, CC BY-SA 4.0, via Wikimedia Commons. Available here

This article is written for revision and education. It is not clinical guidance and must not be used to make decisions about the care of a patient. Always check current NICE guidance and local protocols.