Cushing's syndrome

Published by the practice of Charalambos Charalambous, MD, ChM, General Surgeon, German Medical Institute, Limassol, Cyprus. Last updated: 19 September 2026.

Cushing's syndrome is the clinical state produced by prolonged exposure to excess cortisol. It is uncommon, its onset is insidious, and its features — weight gain, high blood pressure, diabetes, mood change, fatigue — are individually so common that the diagnosis is frequently delayed by several years. It is nonetheless worth pursuing, because untreated it carries a substantially increased mortality from cardiovascular disease, infection and thromboembolism, and because in most cases it is curable.

One point should be stated at the outset: by far the commonest cause is prescribed steroid medication. Before any investigation is undertaken, a careful medication history — including inhaled, topical, injected and over-the-counter preparations, and herbal remedies, which occasionally contain undeclared steroids — should be taken.

How it develops

Cortisol production is normally governed by a feedback loop. The hypothalamus releases corticotrophin-releasing hormone, which stimulates the pituitary to release ACTH, which stimulates the adrenal cortex to produce cortisol. Cortisol then feeds back to suppress both hypothalamus and pituitary. It follows a diurnal rhythm, peaking in the early morning and falling to a nadir around midnight.

Cushing's syndrome results when this loop is broken. The causes divide fundamentally into two groups, and the distinction drives the entire diagnostic pathway:

ACTH-dependent (around 80% of endogenous cases)

• Cushing's disease — a pituitary adenoma secreting ACTH. This is the commonest endogenous cause. The tumours are usually small (microadenomas) and may be difficult to see on MRI. Both adrenal glands enlarge and over-produce cortisol in response.
• Ectopic ACTH syndrome — ACTH produced by a non-pituitary tumour, classically small-cell lung carcinoma, and also bronchial and thymic carcinoid, medullary thyroid carcinoma, and pancreatic neuroendocrine tumours. Where the source is an aggressive malignancy, the onset is rapid, cortisol levels are very high, and the presentation is dominated by profound hypokalaemia, muscle weakness, hyperpigmentation and oedema rather than the classical physical appearance — there has been no time for it to develop.

ACTH-independent (around 20%)

• Adrenal adenoma — a benign cortisol-secreting tumour in one gland. ACTH is suppressed, and the opposite gland atrophies — which is why steroid replacement is essential after the tumour is removed.
• Adrenocortical carcinoma — often producing androgens as well as cortisol, with rapid onset and virilising features in women.
• Bilateral adrenal hyperplasia — macronodular or micronodular; the latter may occur within Carney complex.

Why the features occur

The clinical picture follows directly from cortisol's actions, which is worth setting out because it explains an otherwise bewildering list:

• Protein catabolism — breakdown of muscle and collagen produces proximal muscle weakness, thin skin, easy bruising, poor wound healing and wide purple striae (the purple colour comes from blood vessels visible through skin too thin to conceal them — this is why they differ from ordinary pale stretch marks).
• Altered fat distribution — central obesity with wasted limbs, a dorsocervical fat pad and supraclavicular fullness, and facial rounding. The mechanism is not fully explained, but the combination of a rounded face with thin arms and legs is characteristic.
• Gluconeogenesis and insulin resistance — glucose intolerance and diabetes.
• Mineralocorticoid effect — at high concentrations cortisol overwhelms the enzyme that normally protects the mineralocorticoid receptor, causing sodium retention, hypertension and hypokalaemia.
• Bone — reduced bone formation and calcium absorption, causing osteoporosis and fragility fractures, sometimes at a young age.
• Immune suppression — recurrent and opportunistic infection, which is a leading cause of death.
• Gonadal suppression — menstrual irregularity, reduced libido, erectile dysfunction.
• Central nervous system — depression, anxiety, irritability, emotional lability, insomnia, cognitive impairment and occasionally psychosis. These are frequently the most distressing features for the patient and are often the first to appear.
• Prothrombotic state — a substantially increased risk of venous thromboembolism, which persists after treatment and warrants prophylaxis.

Symptoms

The features most useful for discriminating Cushing's syndrome from simple obesity and metabolic syndrome — which share many features — are:

• proximal muscle weakness — difficulty rising from a chair or climbing stairs without using the arms
• easy bruising without trauma
• wide (over 1cm), purple striae
• facial plethora
• unexplained osteoporosis or fracture in a young person
• in children, weight gain with growth failure — a combination that is almost diagnostic, since ordinary obesity accelerates growth

Weight gain, hypertension, diabetes and depression alone are too common to be discriminating.

How the diagnosis is made

The pathway proceeds in two distinct stages, and conflating them causes confusion.

Stage 1: Is there cortisol excess?

At least two abnormal first-line tests are required:

• 1mg overnight dexamethasone suppression test — failure to suppress morning cortisol below 50 nmol/L.
• Late-night salivary cortisol — loss of the normal midnight nadir. Convenient, performed at home, and one of the most sensitive tests.
• 24-hour urinary free cortisol — two collections; requires accurate collection and normal renal function.

Pseudo-Cushing states must be considered — severe depression, alcohol excess, poorly controlled diabetes, obesity, pregnancy and severe illness all cause genuine but non-neoplastic cortisol elevation. Oestrogen-containing contraceptives raise cortisol-binding globulin and total cortisol, and should be stopped six weeks before testing.

Stage 2: What is the cause?

• Plasma ACTH — the pivotal test. Suppressed ACTH indicates an adrenal cause; normal or raised ACTH indicates a pituitary or ectopic source.
• If ACTH is suppressed — CT of the adrenals.
• If ACTH is not suppressed — pituitary MRI, high-dose dexamethasone suppression and CRH stimulation tests (pituitary tumours retain partial responsiveness; ectopic sources usually do not), and CT of chest and abdomen to search for an ectopic source.
• Inferior petrosal sinus sampling — the definitive test for distinguishing pituitary from ectopic ACTH. ACTH is sampled from the veins draining the pituitary and compared with peripheral levels. It is essential where the MRI is normal or shows only a small incidental lesion, since pituitary incidentalomas are common and operating on the basis of MRI alone can mean the wrong operation.
• Ga-68 DOTATATE PET to localise occult neuroendocrine sources of ectopic ACTH.

Treatment

Surgery

• Cushing's disease — transsphenoidal selective adenomectomy, performed by a specialist pituitary surgeon, is the treatment of choice, with high remission rates in experienced hands. Recurrence occurs in a proportion over subsequent years, requiring long-term follow-up.
• Adrenal adenoma — laparoscopic adrenalectomy, which is curative.
• Adrenocortical carcinoma — open adrenalectomy with en bloc resection, avoiding capsular rupture.
• Ectopic ACTH — resection of the source where localised and resectable.
• Bilateral adrenalectomy — a definitive option for persistent Cushing's disease after failed pituitary surgery, or for occult ectopic ACTH with severe disease. It requires lifelong glucocorticoid and mineralocorticoid replacement and carries the risk of Nelson's syndrome, in which the pituitary tumour, released from feedback, enlarges aggressively.

Medical treatment

Used to control cortisol before surgery, where surgery has failed or is not possible, and while awaiting the effect of radiotherapy.

• Steroidogenesis inhibitors — metyrapone, ketoconazole, osilodrostat, levoketoconazole, and etomidate for acute severe hypercortisolism in critical care.
• Pituitary-directed — pasireotide, cabergoline.
• Glucocorticoid receptor blockade — mifepristone, particularly where diabetes is prominent.
• Mitotane — adrenolytic, used in adrenocortical carcinoma.

Radiotherapy

Pituitary radiotherapy or stereotactic radiosurgery for residual or recurrent Cushing's disease; its effect takes months to years, during which medical control is maintained.

Recovery

Recovery after successful treatment is real but slow, and patients should be prepared for it.

Adrenal insufficiency follows cure, because the normal pituitary-adrenal axis has been suppressed for years by the excess cortisol. Glucocorticoid replacement is required, typically for six to eighteen months, occasionally longer, and is tapered gradually with testing of recovery. Patients must be educated about sick-day rules, carry a steroid card and emergency injection, and know that an adrenal crisis is life-threatening.

Steroid withdrawal syndrome — fatigue, aches, nausea and low mood as cortisol falls to normal — is common, distressing and frequently mistaken for treatment failure. It resolves over months.

Physical features reverse over one to two years. Hypertension and diabetes often improve markedly. Bone density recovers slowly. Cognitive and psychological effects may lag considerably, and depression and anxiety can persist after biochemical cure — this deserves explicit attention rather than being treated as a footnote.

Thromboprophylaxis is given perioperatively and for a period afterwards, given the markedly increased thrombotic risk.

Follow-up

Lifelong for Cushing's disease, since late recurrence occurs. Monitoring of cortisol status, pituitary function, bone density, cardiovascular risk factors and psychological wellbeing.

When to seek an opinion

Unexplained proximal muscle weakness, easy bruising with wide purple stretch marks, osteoporosis or fracture at a young age, rapidly progressive weight gain with diabetes and hypertension, or a child gaining weight while failing to grow. An adrenal mass on a scan should always have a dexamethasone suppression test.

Common questions

Is this caused by my steroid tablets?

Very possibly — prescribed steroids are by far the commonest cause, and this includes inhaled, injected, and skin preparations as well as tablets. This should always be checked before any other investigation. If so, the treatment is careful, supervised reduction of the dose, never stopping abruptly.

How is this different from ordinary weight gain?

Several features point to cortisol excess rather than simple obesity: weakness in the thighs and shoulders so that rising from a chair is difficult, bruising without injury, wide purple stretch marks rather than pale narrow ones, and thin skin. In children, gaining weight while stopping growing is particularly suggestive, because ordinary obesity makes children grow faster.

Why do I need so many tests?

Because the diagnosis has two separate parts. The first establishes that cortisol really is too high, which requires more than one test because several common situations — depression, heavy alcohol use, poorly controlled diabetes, pregnancy — raise cortisol without this condition being present. The second establishes where it is coming from, which determines whether the operation is on the pituitary gland or the adrenal.

My pituitary MRI is normal. Does that rule out a pituitary cause?

No. These pituitary tumours are often very small and a significant proportion are invisible on MRI. Conversely, small harmless pituitary lumps are common in the general population, so seeing one does not prove it is the cause. A specialised test sampling blood from the veins draining the pituitary settles the question, and it prevents the wrong operation.

Why do I need steroid tablets after having a tumour that made too much steroid removed?

Because your body's own system for producing cortisol has been switched off by years of excess, and it takes months to wake up. Without replacement in the meantime you would become dangerously unwell. The dose is reduced gradually while your own production is tested, usually over six to eighteen months.

I feel worse after my operation, not better. Is that normal?

Unfortunately yes, and it is important to know in advance. As cortisol falls from very high levels to normal, most people experience several months of fatigue, aching, nausea and low mood. It is a withdrawal effect, not a sign that the treatment failed, and it settles. Tell your team, because the steroid dose sometimes needs adjusting during this period.

Will the changes to my appearance reverse?

Largely, yes, over one to two years. The facial rounding, fat redistribution and skin thinning improve substantially. Stretch marks fade to silvery lines but do not disappear entirely. Bone density recovers slowly and is monitored.

Will my mood return to normal?

Usually it improves considerably, but it can lag well behind the physical recovery, and depression and anxiety persist in some people after the hormone levels are corrected. This is a recognised part of the condition rather than a personal failing, and it deserves treatment in its own right. Raise it, because it is often under-addressed.

Related conditions

Other conditions of the adrenal glands covered on this site:

• Adrenal incidentaloma
• Primary aldosteronism (Conn's syndrome)
• Phaeochromocytoma and paraganglioma
• Adrenocortical carcinoma
• Adrenal metastases

This page provides general information and does not replace an individual medical consultation. Cushing's syndrome is managed jointly with an endocrinologist, and treatment is decided for each patient individually.