Cushing Syndrome

Meet the patient

A 38-year-old woman presents with a year of weight gain around her middle, a round face, and broad purple stretch marks across her abdomen. She bruises walking past the furniture and cannot rise from a squat without pushing off her thighs. Her blood pressure is 160 over 100.^[1]

The first question is the one that decides the next month: is this true cortisol excess, or pseudo-Cushing? Behind it sit two more — which two tests confirm it, and what single bedside sign separates her from simple obesity? Get those right and the whole of Cushing falls into place.^[1][3]

The two terms that must never be confused

Cushing syndrome (Harvey Cushing, 1932) is the constellation of clinical and biochemical features caused by chronic exposure to excess glucocorticoid, whether from endogenous cortisol overproduction or from exogenous (iatrogenic) glucocorticoid administration.^[1]

Two terms must never be conflated: ^[1]

• Cushing syndrome — the broad umbrella, any cause of cortisol excess.
• Cushing disease — a specific subtype: cortisol excess caused by an ACTH-secreting pituitary corticotroph adenoma (i.e. pituitary-dependent Cushing). It is the commonest endogenous cause but is only one of several aetiologies. ^[1]

The clinical skill in Cushing is not naming the phenotype (that is unmistakable once seen) but rather (i) confirming true cortisol excess (most "Cushingoid" patients referred do not have the syndrome — obesity, alcoholism and depression mimic it), (ii) differentiating ACTH-dependent from ACTH-independent disease, and (iii) localising the tumour so that surgery can be curative. Each of these steps is governed by Endocrine Society consensus thresholds; short-cutting them produces missed adrenal carcinomas and unnecessary, sometimes fruitless, pituitary surgery.^[2][3]

Sort by the source — and never forget the prescription pad

Cushing syndrome is classified by source of cortisol excess:^[1][3]

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A clinically important subgroup is cyclic Cushing — intermittent cortisol excess with peaks and troughs over weeks to months. Three cycles are required to call it cyclic; it can occur in any subtype and any single screening test may be normal at the trough — repeated sampling is essential. Failure to recognise cyclic disease is a classic pitfall.^[1]

How common, and the families to screen

• Endogenous Cushing syndrome is rare: incidence roughly 2 to 8 per million per year (population-based Danish data: about 1.2-1.7/million/year for Cushing disease, 0.6 for adrenal adenoma, 0.2 for adrenal carcinoma); mean time from first symptom to diagnosis is 34 months.^[6][7][25]
• Cushing disease has a marked female preponderance and presents most often in the third to fifth decades; in one Italian multicentre series of 280 patients, males were younger at presentation (30.5 vs 37.1 years) with more severe catabolic disease.^[8]
• Ectopic ACTH syndrome accounts for roughly 10-20 percent of endogenous Cushing, often in older smokers, mirroring lung cancer epidemiology; bronchial neuroendocrine tumours and small-cell lung cancer dominate.^[9][26]
• Adrenocortical carcinoma is bimodal: a small peak under 5 years and a larger peak in the 4th-5th decade; incidence about 0.7-2.0 per million per year; Li-Fraumeni syndrome (TP53) and Beckwith-Wiedemann are inherited predispositions.^[27]
• Exogenous (iatrogenic) Cushing is by far the commonest overall: prednisolone doses of 5 mg/day or more for a month or more — by any route including inhaled, nasal, topical or intra-articular — can suppress the HPA axis.^[15]

Risk factors / syndromic associations (high-yield): ^[1]

Why the phenotype — catabolism, fat, and the mineralocorticoid crossover

The normal hypothalamic-pituitary-adrenal (HPA) axis

Corticotropin-releasing hormone (CRH) from the paraventricular hypothalamus and arginine-vasopressin (AVP) drive the corticotrophs of the anterior pituitary to secrete pro-opiomelanocortin (POMC)-derived ACTH. ACTH binds the melanocortin-2 receptor (MC2R) on adrenal zona fasciculata cells, activating cAMP/PKA → StAR transports cholesterol into mitochondria → CYP11A1 (side-chain cleavage) and the cascade CYP17, CYP21A2, CYP11B1 convert cholesterol to cortisol. Cortisol exerts negative feedback on hypothalamus (CRH) and pituitary (ACTH/POMC), peaking at 06:00-08:00 and nadiring around midnight — the circadian rhythm lost earliest in Cushing.^[1]

Mechanism of the phenotype — catabolism + metabolic + anti-mineralocorticoid

Excess cortisol acts through the glucocorticoid receptor (NR3C1), producing: ^[1]

• Protein catabolism (skin, muscle, bone) → thin skin, easy bruising, wide purple striae, proximal myopathy, osteoporosis, growth failure in children. Striae are purple (over 1 cm wide) because the dermis is so thin the underlying capillaries show through — unlike the pale/silver striae of puberty or simple obesity.
• Fat redistribution: cortisol drives visceral and dorsocervical/supraclavicular lipogenesis and limb lipoatrophy via 11-beta-HSD1 reactivation and adipocyte PPAR-gamma effects → central obesity, moon face, buffalo hump.
• Gluconeogenesis and insulin resistance → hyperglycaemia, new/worsened diabetes mellitus.
• Mineralocorticoid cross-reactivity: cortisol normally inactivated to cortisone by 11-beta-hydroxysteroid dehydrogenase type 2 (11-beta-HSD2) in the kidney. At very high cortisol levels (especially ectopic ACTH), the enzyme is saturated → cortisol floods mineralocorticoid receptors → sodium retention, potassium wasting, hypertension, hypokalaemic metabolic alkalosis — even though aldosterone itself is suppressed. This is why ectopic ACTH is the classic hypokalaemic Cushing.
• Immunosuppression → opportunistic infection (Pneumocystis, fungal, TB reactivation) and impaired wound healing.
• Bone marrow → polycythaemia, leukocytosis with neutrophilia, lymphopenia, eosinopenia.
• GI → gastric acid, peptic ulcer (synergistic with NSAIDs).
• CNS → irritability, insomnia, depression, mania, psychosis (corticosteroid-induced psychiatric syndrome).
• HPG axis suppression → hypogonadotropic hypogonadism: oligomenorrhoea/amenorrhoea, decreased libido, erectile dysfunction, hirsutism (adrenal androgen co-secretion in carcinoma).
• Prothrombotic state → VTE risk up to 10-fold; thromboprophylaxis is mandatory perioperatively.
• Hyperpigmentation (seen only in ACTH-dependent disease) — high ACTH and other POMC peptides (alpha-MSH) stimulate melanocortin-1 receptors on melanocytes; pigment is most prominent on sun-exposed skin, palmar creases, buccal mucosa, recent scars, gingiva, areolae.
• PTH-like and renal phosphate-wasting effects → hypophosphataemia, nephrolithiasis, accelerated osteoporosis. ^[1]

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The four disease mechanisms in brief

1. Pituitary corticotroph adenoma — monoclonal, often a microadenoma under 10 mm; relatively resistant to cortisol feedback (so high-dose dexamethasone suppresses it partially but low-dose does not) yet retains some responsiveness to CRH (the basis of the CRH test). USP8 mutations in ~40 percent.
2. Ectopic ACTH — tumour autonomously secretes bioactive ACTH (often a larger, incompletely processed POMC); completely resistant to high-dose dexamethasone and to CRH. Volume of ACTH drives extreme cortisol; 11-beta-HSD2 saturation produces severe hypokalaemia.
3. Adrenal adenoma / carcinoma — autonomous cortisol secretion; ACTH is suppressed to undetectable, leading to atrophy of the contralateral zona fasciculata and reticularis — the basis for post-adrenalectomy adrenal crisis if glucocorticoid replacement is omitted.
4. Bilateral macronodular hyperplasia — autonomous bilateral cortisol secretion, often with aberrant receptors (gastric inhibitory polypeptide, vasopressin, catecholamine, LH) driving secretion; ACTH-independent but ACTH may be inappropriately detectable. ^[1]

The signs that discriminate from simple obesity

Cortisol excess produces a multisystem phenotype. The discrimination of true Cushing from simple obesity is built on a small number of discriminating features — features that are common in Cushing but rare in simple obesity.^[1][3]

Highly discriminating features (high specificity for Cushing): ^[1]

• Facial plethora and purple striae wider than 1 cm (abdomen, thighs, breasts, axillae).
• Proximal myopathy — difficulty rising from a squat or climbing stairs; the single most discriminating bedside sign that separates Cushing from simple obesity.
• Easy bruising (spontaneous, with minor trauma) and thin, friable skin (tear easily; backed-up capillaries visible through dermis).
• Hypokalaemic alkalosis (especially ectopic ACTH).
• Osteoporosis with fragility fractures at a young age (vertebral, rib). ^[1]

Common but non-discriminating (occur in simple obesity, metabolic syndrome, alcoholism too): ^[1]

• Central obesity, moon face, buffalo hump, hypertension, glucose intolerance, fatigue, menstrual irregularity, depression, acne. ^[1]

Full phenotype (high-yield inventory): ^[1]

• General: weight gain (central), fatigue, proximal weakness.
• Skin: plethora, purple striae over 1 cm, easy bruising, thin skin, acanthosis nigricans, hyperpigmentation (ACTH-dependent), hirsutism (adrenal androgen co-secretion in women), acne, slow wound healing, Popeye sign (forearm sparing with normal distal muscle).
• Face: moon facies, plethora, telangiectasia, buffalo hump (dorsocervical fat pad), supraclavicular fat pads.
• Musculoskeletal: proximal myopathy, osteoporosis (vertebral and rib fractures, height loss, kyphosis), avascular necrosis of the femoral head (classically with exogenous steroids).
• Cardiovascular: hypertension (in 80 percent), accelerated atherosclerosis, diastolic dysfunction, increased thromboembolic risk (DVT/PE 10-fold).
• Metabolic/endocrine: impaired glucose tolerance or type 2 diabetes, dyslipidaemia, hypogonadotropic hypogonadism (oligomenorrhoea/amenorrhoea, reduced libido, erectile dysfunction, infertility), hypothyroidism, hypocalcaemia, hypophosphataemia, nephrolithiasis.
• Neuropsychiatric: irritability, emotional lability, depression, anxiety, insomnia, mania or steroid psychosis, suicidal ideation, cognitive impairment.
• Infectious: increased susceptibility to Pneumocystis jirovecii, TB, fungal infections, opportunistic sepsis. ^[1]

Atypical presentations (the dimensions that examiners love): ^[1]

• Elderly: presents with hypertension, osteoporotic fractures, diabetes, depression, proximal myopathy — features attributed to "ageing"; phenotype is subtle, striae absent. A new-onset aggressive metabolic syndrome in an elderly patient warrants screening.
• Severe/occult ectopic ACTH: less classic phenotype (no time to redistribute fat), dominated by severe hypokalaemia, weakness, hyperpigmentation, weight loss, glucose intolerance, often in a smoker over 50 with a lung mass — distinguishes ectopic from pituitary disease clinically.
• Pregnancy: rare; physiologic pregnancy changes (striae, hyperpigmentation, weight gain, hypercortisolism from placental CRH) mimic the syndrome; 24-hour urine free cortisol rises 3-fold in normal pregnancy, salivary cortisol rises, and DST fails in up to half of normal pregnancies, complicating diagnosis.
• Children: growth arrest is the most discriminating sign — short stature with weight gain; virilisation in adrenal carcinoma; false puberty.
• Adrenal incidentaloma / subclinical cortisol: hypertension, diabetes, osteoporosis without overt phenotype; picked up by DST. ^[1]

The pseudo-Cushing trap

The condition most commonly confused with true Cushing is pseudo-Cushing — a state of mild functional hypercortisolism driven by activation of the HPA axis without autonomous tumour. Three settings dominate: chronic alcoholism, major depressive disorder, and morbid obesity. Distinguishing pseudo-Cushing from true Cushing is one of the most examinable questions in endocrinology.^[1][3]

Pseudo-Cushing states (low-dose DST abnormal, midnight cortisol mildly raised, ACTH detectable, but HPA axis is intact): ^[1]

Distinguishing algorithms for pseudo-Cushing vs true Cushing: ^[1]

• Dexamethasone-CRH test — dexamethasone 0.5 mg 6-hourly for 48 hours, then CRH 100 microgram IV; cortisol is measured 15 minutes after CRH. Using the historical threshold of 38 nmol/L (1.4 microgram/dL) the test detects true Cushing with high sensitivity, but a modern re-evaluation found only 50 percent specificity at that cut-off (rising to about 86 percent at a revised 110 nmol/L threshold), and pooled accuracy across studies is comparable to simpler tests — reserve it for equivocal cases after first-line testing.^[21][22][23]
• Midnight sleep cortisol / late-night salivary cortisol — pseudo-Cushing retains some diurnal rhythm; in one head-to-head study, midnight plasma cortisol above 256 nmol/L separated Cushing disease from pseudo-Cushing with 100 percent sensitivity and specificity.^[21]
• Clinical features: plethora, striae over 1 cm, proximal myopathy, easy bruising, and hypokalaemia strongly favour true Cushing over pseudo-Cushing.
• Resolution after treatment of the underlying cause (sobriety, depression remission, weight loss) is definitive — in alcohol-related pseudo-Cushing, biochemical abnormalities normalise only with sustained abstinence. ^[24]

Other differentials of a Cushingoid appearance: hypothyroidism (myxoedema, weight gain), HIV lipodystrophy (peripheral lipoatrophy with central fat), HAIR-AN syndrome, familial partial lipodystrophy (lamin A/C). ^[1]

The bedside round — ask her to rise from a squat

A focused general, skin, neuromuscular, cardiovascular and abdominal examination is required. ^[1]

• Appearance: moon face, plethora, buffalo hump, central obesity, supraclavicular fat pads.
• Skin: purple striae over 1 cm wide on abdomen/thighs/breasts; easy bruising; thin skin; hyperpigmentation (palmar creases, buccal mucosa, recent scars, gingiva) indicates ACTH-dependent disease; hirsutism, acne, clitoromegaly suggests adrenal androgen co-secretion (carcinoma).
• Neuromuscular: proximal muscle weakness — formally test rising from a squat (Gowers'-like), climbing a chair, shoulder abduction against resistance; this single sign separates Cushing from simple obesity.
• Cardiovascular: hypertension (often severe), signs of heart failure if long-standing.
• Abdomen: central obesity; palpable mass suggests large adrenal carcinoma or ectopic tumour.
• Chest: signs of opportunistic pneumonia; apex of lung for old TB; wheeze in asthmatic on inhaled steroid.
• Neurology: depression, emotional lability; check fields for bitemporal hemianopia (pituitary macroadenoma compressing optic chiasm).
• Growth (child): height plotted on centile chart; growth arrest with weight gain is highly suggestive. ^[1]

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Confirm, then split by ACTH, then localise

The Endocrine Society diagnostic algorithm proceeds in three steps: (1) confirm cortisol excess; (2) differentiate ACTH-dependent vs independent; (3) localise the tumour.^[3]

Step 1 — Confirm cortisol excess (any two of three first-line tests; two positives required)

Exclude exogenous steroids first by history. Then: ^[1]

A normal result on two first-line tests excludes Cushing (provided the index of suspicion is not extreme — cyclic Cushing, renal failure, psychiatric disease — in which case the dexamethasone-CRH test is used).^[3]

Pitfalls and false results (high-yield): ^[1]

• Drugs that accelerate dex metabolism (induce CYP3A4) → falsely low dex → falsely elevated cortisol: phenytoin, carbamazepine, phenobarbital, rifampicin, pioglitazone, primidone.
• Drugs that inhibit CYP3A4 → falsely high dex → falsely low cortisol (false negative): aprepitant, itraconazole, ketoconazole, ritonavir, clarithromycin, grapefruit juice.
• Oestrogen (OCP/HRT) raises cortisol-binding globulin → falsely high total cortisol → false positive on DST and 09:00 cortisol. Stop OCP 6 weeks before testing, or use salivary cortisol or UFC which measure the free fraction.
• Renal failure → spuriously low UFC; use 1-mg DST or salivary.
• Pregnancy → all three tests have altered thresholds. ^[1]

Step 2 — Differentiate ACTH-dependent vs ACTH-independent

Once Cushing is biochemically confirmed, measure plasma ACTH at 08:00-09:00: ^[1]

• ACTH over 22 pg/mL (4.8 pmol/L), or 'inappropriately normal' = ACTH-dependent (pituitary or ectopic).
• ACTH under 10 pg/mL (2.2 pmol/L) = ACTH-independent (adrenal).
• ACTH 10-22 pg/mL: grey zone → repeat; CRH-stimulation test may help. ^[1]

^[1]

Step 3 — Localise the source

In ACTH-independent disease (low ACTH): ^[1]

• CT adrenal (contrast-enhanced): unilateral mass (adenoma, carcinoma), bilateral nodularity (BMAH), small bilateral nodules (PPNAD). Adrenal carcinoma is suspected when the lesion is over 4 cm, heterogeneous, irregular margins, calcification, necrosis, regional nodes/IVC invasion; Hounsfield units over 10 (adenomas under 10) and washout under 40 percent at 10 minutes. DHEAS is suppressed.
• MRI for tissue characterisation where CT equivocal.
• Functional imaging: 18-FDG PET-CT for suspected carcinoma and staging. ^[1]

In ACTH-dependent disease (high ACTH) — pituitary vs ectopic: ^[1]

1. High-dose dexamethasone suppression test (HDDST) — dexamethasone 2 mg 6-hourly for 48 hours (8 mg total/day); measure serum cortisol at 0 and 48 hours. Suppression of serum cortisol by over 50 percent from baseline = pituitary (Cushing disease); no suppression = ectopic or adrenal. Rationale: corticotroph adenomas retain partial glucocorticoid feedback. In the largest systematic review, HDDST accuracy was lower than the CRH test (sensitivity around 70 percent); largely replaced by IPSS as it has substantial false-positive and false-negative rates.^[18]
2. CRH stimulation test — ovine/human CRH 100 microgram (or 1 microgram/kg) IV, ACTH and cortisol at 0, 15, 30, 60 min. Rise of cortisol over 20 percent (or ACTH over 35 percent) at 15-30 min = pituitary; no rise = ectopic. Meta-analysis: ACTH response to CRH has the highest sensitivity for Cushing disease (about 87 percent) and the highest specificity for ectopic ACTH (about 94 percent).^[18]
3. Pituitary MRI — ** gadolinium-enhanced dynamic pituitary MRI** identifies an adenoma in only 60-75 percent of patients; many corticotroph adenomas are tiny. A normal MRI does not exclude Cushing disease, and MRI–IPSS concordance is poor, so biochemistry must drive the diagnosis.^[12]
4. Bilateral inferior petrosal sinus sampling (BIPSS / IPSS) — gold standard for confirming pituitary origin and lateralising the adenoma pre-operatively. Catheters placed in both inferior petrosal sinuses and a peripheral vein; ACTH measured basally and after CRH 100 microgram IV (or DDAVP 10 microgram). In the landmark NIH series of 281 patients, a basal IPS:P ratio over 2 identified Cushing disease with 95 percent sensitivity and no false positives, and a peak ratio over 3 after CRH identified every patient (100 percent sensitivity and specificity); an inter-petrosal gradient over 1.4 localised the adenoma to the correct side in about 70 percent. Major morbidity is rare (large series report around a 2 percent periprocedural complication rate). Performed at experienced centres only. Indicated when pituitary imaging is equivocal or HDDST/CRH inconclusive. ^[19][20]

Ectopic ACTH localisation: CT chest/abdomen/pelvis with octreotide/DOTATATE scintigraphy (somatostatin receptor imaging — many ectopic tumours express SSTR), 18-FDG PET-CT. Small-cell lung cancer is the commonest cause; bronchial carcinoid is small and often eludes CT — bronchial carcinoids are the commonest occult ectopic source, requiring high-resolution CT and serial re-imaging. Medullary thyroid cancer, pancreatic NET, phaeochromocytoma, thymic carcinoid, ovarian tumour also reported.^[5]

Adjunctive tests

• DHEAS: high in ACTH-dependent (driven by ACTH), suppressed in ACTH-independent adrenal disease — a useful ancillary marker.
• 17-OHP, androstenedione, testosterone: if adrenal carcinoma suspected (androgen co-secretion).
• FBC, U&E, LFTs, glucose/HbA1c, lipids, TFTs, vitamin D, calcium, phosphate, coagulation.
• DEXA bone density for osteoporosis.
• ECG/echo for cardiac involvement.
• Thromboprophylaxis assessment — VTE risk stratified by a validated score; prophylactic enoxaparin peri-operatively. ^[1]

Severe hypercortisolism — block, correct, prophylax

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Cushing syndrome is rarely a same-day emergency, but severe hypercortisolism with hypokalaemia, sepsis or psychiatric crisis can be life-threatening.^[2][4]

Time-critical measures in severe hypercortisolism (e.g. cortisol over 1500 nmol/L, ectopic ACTH, adrenal crisis of carcinoma): ^[1]

1. Correct hypokalaemia — IV and oral potassium chloride; spironolactone 100-400 mg/day blocks the mineralocorticoid effect.
2. Block cortisol synthesis immediately — oral metapyrapone, titrated to serum cortisol (real-life series: median dose 1000 mg/day, urinary free cortisol fell by about two-thirds in the first month), OR IV etomidate infusion (an anaesthetic that potently inhibits CYP11B1) for the critically ill, comatose or rapid-control patient — a standardised protocol safely achieved cortisol control within roughly two days in severe hypercortisolism; admit to HDU/ICU. Target cortisol 150-300 nmol/L (not to normal — too rapid withdrawal risks adrenal crisis).^[16][17]
3. Treat hyperglycaemia — IV insulin infusion per sliding scale.
4. Treat hypertension and fluid overload.
5. Treat infection empirically if any suspicion (broad-spectrum + Pneumocystis cover if indicated).
6. Thromboprophylaxis — enoxaparin 40 mg SC daily (or therapeutic dose if VTE confirmed) unless contraindicated; intermittent pneumatic compression.
7. Psychiatric crisis — involve liaison psychiatry; treat psychosis/agitation. ^[1]

Post-operative glucocorticoid replacement is the universal pitfall. After transsphenoidal surgery for Cushing disease or adrenalectomy for an adrenal source, the contralateral/normal HPA axis is suppressed. Give hydrocortisone replacement (e.g. hydrocortisone 100 mg IV at induction, then 50 mg IV 8-hourly day 1, then taper to oral 20 mg AM / 10 mg noon, weaning over weeks-months) — UK guidance from the Association of Anaesthetists, Royal College of Physicians and Society for Endocrinology mandates stress-dose glucocorticoid cover for any patient with HPA suppression through surgery, because delays in recognising adrenal insufficiency can prove fatal. Failure to do so precipitates acute adrenal crisis with hypotension, hyponatraemia, hyperkalaemia, hypoglycaemia. ^[1][15]

Cut it out — surgery first, by source

Definitive treatment is aetiology-specific and ideally curative.^[2][4]

Exogenous (iatrogenic) Cushing

• Taper the glucocorticoid to the lowest effective dose or stop, replacing with steroid-sparing agent (e.g. methotrexate/azathioprine in autoimmune disease; biologics).
• NEVER stop abruptly — HPA axis is suppressed and acute adrenal crisis will follow.
• Cosyntropin (250 microgram ACTH) stimulation test to assess recovery before withdrawal is complete.
• HPA recovery takes 6-12 months after cessation; educate the patient on sick-day rules (double dose during illness) and medical alert bracelet. ^[1]

Cushing disease (pituitary)

• First-line: transsphenoidal selective adenomectomy (TSS) by an experienced pituitary neurosurgeon. Remission rate 65-90 percent for microadenomas, lower for macroadenomas. Cure defined by post-operative cortisol under 50 nmol/L or need for glucocorticoid replacement (iatrogenic secondary adrenal insufficiency is the desired endpoint and confirms complete resection).
• Repeat TSS for persistent or recurrent disease.
• Second-line: stereotactic radiotherapy (conformal fractionated or gamma-knife radiosurgery) — onset of effect over 1-3 years; risk of hypopituitarism in 50 percent by 10 years.
• Bilateral adrenalectomy (BLA) — for severe refractory disease; immediate cure but lifelong glucocorticoid + mineralocorticoid replacement and 5-10 percent risk of Nelson syndrome (aggressive growth of the pituitary adenoma with very high ACTH and hyperpigmentation) — requires lifelong pituitary MRI surveillance. Prophylactic radiotherapy reduces Nelson risk. ^[1]

Ectopic ACTH

• Treat the primary tumour surgically if resectable (e.g. bronchial carcinoid wedge resection). Often curative.
• If unresectable (extensive small-cell lung cancer): chemotherapy/radiotherapy per oncology protocol + steroidogenesis inhibitors for symptom control. Small-cell lung cancer has poor prognosis; bronchial carcinoid is usually slow-growing and operable.
• Steroidogenesis blockade is essential while awaiting tumour treatment. ^[1]

Adrenal adenoma / carcinoma

• Unilateral laparoscopic adrenalectomy is curative for benign adenoma.
• Open adrenalectomy (transabdominal) for adrenocortical carcinoma — en bloc, complete R0 resection including adjacent organs if involved; lymphadenectomy (ESE guideline: adrenal surgery for suspected ACC only by experienced oncological surgeons aiming at complete en bloc resection).^[28]
• Adjuvant mitotane (o,p'-DDD) for high-risk ACC after radical surgery — adrenolytic; titrated to a plasma level of 14-20 mg/L (therapeutic window); give glucocorticoid replacement as mitotane induces cortisol degradation and adrenal insufficiency (replacement doses higher than in other causes of primary adrenal insufficiency). Side effects: GI, neurotoxicity, hepatotoxicity, gynaecomastia, prolonged half-life (months). Monitor plasma levels.^[28][30]
• EDP-M (Etoposide + Doxorubicin + Cisplatin + Mitotane) for advanced/metastatic ACC — first-line by the FIRM-ACT randomised trial (higher response rate and progression-free survival than streptozocin-mitotane). ^[29]

Medical therapy (steroidogenesis inhibitors / pituitary-directed) — agent, dose, route, rationale, monitoring

The subtypes that bite

• Cyclic Cushing: intermittent cortisol excess. Three or more cycles documented. Salivary cortisol at home over weeks is the best surveillance; clinical features wax and wane. Diagnosis may require multiple serial samples; can occur in any subtype. Treatment of choice remains the underlying cause when localised; medical therapy often needed in trough-peak cycles.
• Ectopic ACTH syndrome: classic features — severe hypokalaemic alkalosis, hyperpigmentation, weakness, weight loss, glucose intolerance, often in a smoker over 50 with a lung mass. HDDST does not suppress; CRH does not stimulate. Bronchial carcinoid is the most common occult source; serial high-resolution chest CT and bronchoscopy may be required. Prognosis depends on tumour type — SCLC poor; carcinoid excellent if resected.^[5]
• Adrenal incidentaloma with subclinical cortisol excess (MACS): tumour over 1 cm discovered incidentally on imaging; 1-mg DST as screen; cortisol over 50 nmol/L post-DST without overt Cushing phenotype = subclinical autonomous cortisol secretion (formerly subclinical Cushing). Associated with hypertension, diabetes, osteoporosis, dyslipidaemia — surgical adrenalectomy considered when post-DST cortisol over 140 nmol/L or features progress.
• Pituitary macroadenoma: mass-effect features (headache, bitemporal hemianopia, cranial nerve palsies, hypopituitarism) coexist with hypercortisolism. Urgent decompression.
• Adrenocortical carcinoma: large tumour over 4 cm, virilisation (androgen), weight loss, metastases (liver, lung), very high cortisol and DHEAS. Mitotane + EDP chemotherapy. Five-year survival 20-35 percent.
• Bilateral macronodular adrenal hyperplasia (BMAH): bilateral adrenalectomy with lifelong replacement; partial adrenalectomy in selected; aberrant receptor workup (food-dependent cortisol surge with GIP — meals trigger cortisol).
• Paediatric Cushing: growth arrest is the cardinal sign; pituitary disease predominates in adolescents; adrenal carcinoma in young children. Treat aggressively — growth recovers after cure.
• Cushing in pregnancy: rare; metapyrapone is the preferred medical therapy (does not cross placenta significantly); ketoconazole and mitotane avoided (teratogenic); surgery in second trimester for definitive cure if feasible; avoid mifepristone (abortifacient).

How Cushing patients come to harm

Cardiovascular: hypertension, accelerated atherosclerosis, diastolic heart failure, left ventricular hypertrophy, dyslipidaemia, prothrombotic state with up to 10-fold increased risk of DVT/PE — thromboprophylaxis is mandatory peri-operatively and until remission. ^[1]

Metabolic: type 2 diabetes (new or worsened), dyslipidaemia, insulin resistance, hypercalciuria, nephrolithiasis. ^[1]

Musculoskeletal: osteoporosis with vertebral/rib fractures, avascular necrosis of the femoral head, pathological fractures, proximal myopathy, sarcopenia. ^[1]

Infectious: opportunistic infection — Pneumocystis jirovecii pneumonia (consider prophylaxis in severe hypercortisolism), TB reactivation, fungal infection, bacterial sepsis with impaired wound healing. ^[1]

Neuropsychiatric: depression, anxiety, mania, steroid psychosis, cognitive impairment, insomnia, suicidal ideation — suicide risk is real; screen. ^[1]

Endocrine: HPG suppression (amenorrhoea, infertility, hypogonadism), growth arrest (children), hypothyroidism. ^[1]

Surgical/iatrogenic: post-operative adrenal crisis if glucocorticoid replacement omitted; CSF rhinorrhoea, diabetes insipidus, hypopituitarism, meningitis after transsphenoidal surgery; Nelson syndrome after bilateral adrenalectomy. ^[1]

Pitfalls (high-yield exam traps): ^[1]

• Prescribing mifepristone then trying to monitor cortisol — cortisol rises but action is blocked; monitor clinical features and potassium.
• Stopping exogenous steroids abruptly → adrenal crisis.
• Diagnosing "Cushing" from a single abnormal test — always confirm with a second; obesity, depression, alcohol and OCP produce false positives.
• Misreading ACTH: a cortisol-binding-globulin-raising oestrogen can spuriously lower or raise total cortisol; use free cortisol (salivary/UFC).
• Pituitary microincidentaloma: 10 percent of normal people have a tiny pituitary nodule on MRI — do not diagnose Cushing disease from an incidental MRI finding; biochemistry (preferably IPSS) must drive the diagnosis.
• Treating cyclic Cushing at the trough — repeat tests.
• Forgetting the family: a young person with bilateral adrenal disease may have Carney complex or MEN1 — screen relatives.
• Omitting VTE prophylaxis — fatal PE is a leading cause of peri-operative death. ^[1]

Prognosis, disposition, and the cortisol that sets both

• Untreated endogenous Cushing has up to 50 percent 5-year mortality from cardiovascular disease, stroke, infection and suicide; thromboembolism is a leading cause of peri-operative death.^[1]
• Treated Cushing disease: surgical remission 65-90 percent for microadenomas; recurrence rate ~10-35 percent over 10 years — lifelong biochemical surveillance. Quality of life improves but does not return fully to baseline for 1-2 years.
• Adrenal adenoma: adrenalectomy is curative; HPA axis recovers in 6-24 months.
• Adrenocortical carcinoma: 5-year survival 20-35 percent overall, over 60 percent for stage I-II resected completely.
• Ectopic ACTH: depends entirely on the tumour — bronchial carcinoid curable (excellent); SCLC has mean survival measured in months.
• All patients require long-term follow-up for recurrence, persistent comorbidity (hypertension, diabetes, osteoporosis), and glucocorticoid replacement until HPA recovery (ACTH stimulation test before weaning).
• Disposition: endocrine centre with multidisciplinary pituitary/adrenal MDT; surgery at a high-volume centre; post-operative care in a monitored setting with hydrocortisone replacement and thromboprophylaxis.

Special Populations

• Pregnancy: physiologic hypercortisolism of pregnancy (placental CRH) raises all three screening tests — salivary cortisol and 24-hour UFC (with pregnancy-adjusted thresholds) preferred over DST (oestrogen raises CBG and DST fails in normal pregnancy). MRI pituitary (without gadolinium) is safe. Metapyrapone is first-line medical therapy; surgery in second trimester if needed. Mifepristone, mitotane, ketoconazole are contraindicated.
• Children: growth arrest with weight gain is the most discriminating sign; pituitary disease predominates in adolescents, adrenal carcinoma in young children. Treat aggressively — growth recovers after cure. Cushing disease in children has higher recurrence after surgery.
• Elderly: subtle phenotype (no striae); presents with osteoporosis, hypertension, diabetes, depression, proximal myopathy. Adrenal incidentaloma with MACS is the commonest finding in this age group; weigh surgical risk against comorbidity.
• Patients on chronic steroids: HPA axis suppressed; never stop abruptly. Educate on sick-day rules (double dose during illness, peri-operative stress-dose), medical alert bracelet, and wean slowly over months.
• Patients with psychiatric comorbidity: increased suicide risk; treat psychiatric illness; steroids cross-react with antipsychotics; mood symptoms usually improve with cortisol normalisation but monitor for transient worsening.
• Anticoagulated / VTE-risk patients: high thrombotic risk peri-operatively — bridging LMWH and extended prophylaxis until remission. ^[1]

Evidence, Guidelines & Regional Differences

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Landmark trial (LINC3, 2020, NEJM): osilodrostat achieved complete response in 66 percent of CD patients at week 24 vs 0 percent on placebo — the pivotal RCT underpinning osilodrostat's approval. LUX (LINC4, 2022) and the SEISMIC (mifepristone) trials confirm efficacy of medical therapy in selected patients.^[2]

Controversies: ^[1]

• HDDST has fallen out of favour in many centres — superseded by IPSS because of suboptimal sensitivity/specificity.
• Post-DST cortisol cut-off for MACS has shifted from 50 nmol/L (1.8 microgram/dL) to 140 nmol/L (5 microgram/dL) in the 2023 ESE guideline on adrenal incidentaloma, reflecting concerns about over-diagnosis of mild autonomous cortisol secretion.
• Surgical vs medical first-line in mild CD with poor surgical risk is debated.
• Nelson syndrome surveillance protocols vary; some centres offer prophylactic pituitary radiotherapy after bilateral adrenalectomy. ^[1]

Exam Pearls

^[1]

• Wide purple striae over 1 cm + proximal myopathy + easy bruising + plethora = think Cushing, not simple obesity.
• Moon face, buffalo hump, central obesity alone are non-discriminating — also seen in obesity, alcoholism, metabolic syndrome.
• Cortisol over 1500 nmol/L with severe hypokalaemia and hyperpigmentation in a smoker over 50 = ectopic ACTH from SCLC until proven otherwise.
• Drugs that interfere with DST: induce CYP3A4 (rifampicin, phenytoin, carbamazepine) → false positive; inhibit CYP3A4 (ketoconazole, itraconazole, ritonavir, grapefruit) → false negative.
• Oestrogen raises cortisol-binding globulin — stop OCP 6 weeks before DST, or use salivary/UFC.
• Metapyrapone is first-line in pregnancy; ketoconazole, mitotane, mifepristone are teratogenic.
• Adrenal mass over 4 cm + androgen excess + DHEAS high = adrenocortical carcinoma → open adrenalectomy + mitotane.
• Pasireotide causes hyperglycaemia in 70 percent — monitor glucose.
• Mifepristone blocks the receptor — cortisol cannot be used to monitor; use clinical signs + potassium.
• Stereotactic radiotherapy takes 1-3 years to work — bridge with medical therapy.
• Nelson syndrome: high ACTH, hyperpigmentation, enlarging pituitary mass after bilateral adrenalectomy. ^[1]

Ward-round test — three stems, thirty seconds each

Stem 1 — the Cushing with the low potassium (answer)ShowHide

A 55-year-old male smoker has three months of weakness, weight loss, hyperpigmentation, and new diabetes. Potassium is 2.6 mmol/L with a metabolic alkalosis, and cortisol is over 1500 nmol/L. Which endogenous Cushing is this, and why the hypokalaemia? Model: This is ectopic ACTH syndrome — classically from small-cell lung cancer or a bronchial carcinoid. The severe hypokalaemic alkalosis with hyperpigmentation and a very high cortisol is the fingerprint: renal inactivation of cortisol to cortisone by 11-beta-HSD2 falls (ACTH itself inhibits the enzyme) while secretion of cortisol, corticosterone and deoxycorticosterone soars — together flooding the mineralocorticoid receptor and driving sodium retention with potassium and hydrogen wasting, even though aldosterone itself is suppressed. Cushing disease does not usually do this. The high-dose dexamethasone test will not suppress and CRH will not stimulate; hunt the tumour with CT chest and somatostatin-receptor imaging.^[5][10][26]

Stem 2 — confirm it, then split it (answer)ShowHide

A 38-year-old with a Cushingoid phenotype needs a biochemical diagnosis. Name the three screening tests, the confirmation rule, and the next test once cortisol excess is proven. Model: Screen with two of three — 24-hour urine free cortisol, late-night salivary cortisol, and 1-mg overnight dexamethasone suppression (cortisol over 50 nmol/L at 08:00 is a fail). Two abnormal tests confirm the syndrome; a single test does not, and cyclic Cushing can read normal at the trough. Once confirmed, measure plasma ACTH at 08:00 to 09:00 — over 22 pg/mL is ACTH-dependent (pituitary or ectopic), under 10 pg/mL is ACTH-independent (adrenal); 10 to 22 is grey, so repeat or use CRH stimulation. Stop the oral contraceptive six weeks first — oestrogen raises cortisol-binding globulin and falsely elevates total cortisol.^[1][3]

Stem 3 — the two things you must not forget after the operation (answer)ShowHide

A woman with Cushing disease is listed for transsphenoidal surgery. Name the two interventions mandatory peri-operatively to prevent the leading post-operative deaths. Model: Peri-operative hydrocortisone and thromboprophylaxis. The contralateral HPA axis is suppressed, so omitting glucocorticoid precipitates a preventable adrenal crisis — give hydrocortisone 100 mg IV at induction, then taper. And cortisol excess drives a prothrombotic state with a markedly elevated VTE risk (odds of spontaneous VTE roughly 18-fold above the general population in meta-analysis), making fatal pulmonary embolism a leading peri-operative death — give prophylactic enoxaparin. The desired post-operative endpoint is a cortisol under 50 nmol/L; that iatrogenic secondary adrenal insufficiency confirms complete resection.^[4][14][15]

References30ShowHide

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