Cushing's syndrome
Exam Tips
- In UK exams, always separate exogenous (most common overall) from endogenous causes before launching complex endocrine work-up.
- Use a two-step framework: confirm hypercortisolism (screening tests) then localise source (ACTH-based pathway + imaging/sampling).
- Violaceous wide striae, proximal myopathy, easy bruising, and facial plethora are more discriminating than obesity alone.
- Severe hypokalaemia and rapidly progressive features suggest ectopic ACTH until proven otherwise.
- Remember safety viva points: do not stop chronic steroids abruptly; monitor for adrenal insufficiency after treatment; and watch for ketoconazole hepatotoxicity/QT risk.
- See Figure: dexamethasone suppression and ACTH interpretation algorithm in your endocrine revision text.
Definition
Cushing’s syndrome is a chronic multisystem disorder caused by prolonged exposure to excess glucocorticoids, most commonly from exogenous corticosteroid therapy but also from endogenous cortisol overproduction. It includes characteristic body composition change and skin findings, alongside metabolic, cardiovascular, thrombotic, musculoskeletal, reproductive, and neuropsychiatric morbidity; Cushing’s disease specifically refers to pituitary ACTH-secreting adenoma causing hypercortisolism.
Pathophysiology
Sustained cortisol excess disrupts hypothalamic-pituitary-adrenal (HPA) axis homeostasis and drives catabolism, insulin resistance, mineralocorticoid receptor activation, and immune dysregulation. In ACTH-dependent disease (pituitary adenoma or ectopic ACTH), adrenal cortisol production is stimulated despite failed feedback suppression; in ACTH-independent disease (usually adrenal adenoma), cortisol is autonomously secreted with low ACTH. Cortisol excess increases gluconeogenesis, visceral adiposity, protein breakdown (proximal myopathy, skin thinning), bone resorption (osteoporosis), vascular reactivity (hypertension), procoagulant tendency (VTE risk), and neuropsychiatric disturbance. Cyclical Cushing’s may show intermittent hypercortisolaemia, making diagnosis difficult. See Figure: HPA-axis negative feedback loop and ACTH-dependent vs ACTH-independent pathways.
Risk Factors
- Current or recent supraphysiological corticosteroid exposure by any route (oral, injected, inhaled, topical, intra-articular), especially higher dose and longer duration
- Pituitary ACTH-secreting adenoma (most common endogenous cause)
- Adrenal adenoma (common ACTH-independent endogenous cause)
- Ectopic ACTH from neuroendocrine tumours (especially lung, pancreatic, thymic, thyroid sites)
- Rare genetic syndromes (for example MEN1, Carney complex, McCune-Albright syndrome)
- Female sex post-puberty for endogenous disease; age typically 20-50 years for diagnosis
Clinical Features
Symptoms
- Progressive weight gain with central adiposity
- Proximal muscle weakness (difficulty climbing stairs/rising from chair)
- Easy bruising and poor wound healing
- Mood change (depression, anxiety, emotional lability), cognitive complaints
- Menstrual disturbance (oligomenorrhoea/amenorrhoea), reduced libido, erectile dysfunction
- Headache or visual symptoms if pituitary macroadenoma
Signs
- Facial plethora and rounded face
- Wide violaceous striae (typically >1 cm), thin skin, ecchymoses
- Dorsocervical/supraclavicular fat accumulation with relatively thin limbs
- Hypertension
- Proximal myopathy and reduced grip/hip flexor power
- Acne, hirsutism, androgenic alopecia; possible signs of hypokalaemia in severe ACTH excess
Investigations
Management
Lifestyle Modifications
- Treat cardiovascular risk aggressively: weight management, smoking cessation, BP and lipid control, diabetes care
- Bone protection strategy (adequate calcium/vitamin D intake, falls prevention, exercise as tolerated)
- Infection vigilance and vaccination review where appropriate
- Psychological support for mood/cognitive sequelae and quality-of-life impairment
Pharmacological Treatment
Steroidogenesis inhibitors (specialist endocrine prescribing)
- Metyrapone oral: initially 250 mg 3-4 times daily, titrated to biochemical control (often up to 6 g/day in divided doses)
- Ketoconazole oral (off-label endocrine use in UK): typically 200 mg 2-3 times daily initially, titrated; usual maximum about 1.2 g/day
- Osilodrostat oral: usually 2 mg twice daily initially, titrated every 2 weeks according to cortisol response
Monitor serum/urinary cortisol frequently to avoid adrenal insufficiency. Metyrapone may worsen hypertension/hypokalaemia and androgenic effects (acne/hirsutism). Ketoconazole has important hepatotoxicity risk (check LFTs before and during therapy), major CYP3A4 interactions, and QT-prolongation risk. Osilodrostat can cause hypocortisolism, QT prolongation, and electrolyte disturbance; specialist monitoring required.
Pituitary-directed therapy
- Pasireotide subcutaneous: 0.6 mg twice daily (dose adjustment by response/tolerability)
- Cabergoline oral (off-label): commonly 0.5-3.5 mg/week in divided doses
Used mainly in persistent/recurrent Cushing’s disease when surgery is not curative or while awaiting definitive treatment. Pasireotide frequently causes hyperglycaemia; monitor glucose/HbA1c closely.
Glucocorticoid receptor blockade / emergency control
- Etomidate IV infusion in severe uncontrolled hypercortisolaemia when oral therapy is not possible (critical care setting)
Requires high-dependency/ICU monitoring. For exogenous Cushing’s, taper chronic glucocorticoids gradually rather than abrupt cessation to reduce adrenal crisis risk.
Comorbidity-directed treatment
- Antihypertensives per standard UK pathways (e. g, ACE inhibitor/ARB, calcium-channel blocker)
- Glucose-lowering therapy for steroid-induced diabetes (e. g, metformin first-line where suitable)
- Bone protection where indicated (e. g, alendronic acid 70 mg once weekly plus calcium/vitamin D)
Address thrombosis risk, glycaemic control, lipids, fracture prevention, and infection promptly as morbidity persists even after biochemical remission.
Surgical / Interventional
- Transsphenoidal pituitary surgery is first-line for Cushing’s disease
- Unilateral adrenalectomy for cortisol-secreting adrenal adenoma
- Oncological resection for adrenal carcinoma where feasible
- Resection of ectopic ACTH-secreting tumour when localised and operable
- Bilateral adrenalectomy for refractory or life-threatening hypercortisolism not controlled by other measures
Complications
- Hypertension, accelerated atherosclerotic cardiovascular disease, and increased cerebrovascular risk
- Venous thromboembolism (including DVT/PE) with markedly increased risk in active disease
- Impaired glucose tolerance/diabetes mellitus and dyslipidaemia
- Central obesity and persistent long-term metabolic risk even after remission
- Osteoporosis and fragility fractures
- Proximal myopathy and functional decline
- Immunosuppression with severe/opportunistic infection risk
- Neuropsychiatric morbidity (depression, anxiety, cognitive dysfunction)
- Hypogonadism, menstrual disturbance, infertility, reduced libido
- Pregnancy complications (maternal hypertension/diabetes/infection; fetal growth restriction, prematurity, pregnancy loss)
Prognosis
Untreated persistent hypercortisolism carries substantial excess mortality, with cardiovascular disease, infection, thromboembolism, and malignancy as key causes. Early diagnosis and rapid cortisol normalisation improve outcomes, but many patients have residual long-term metabolic and quality-of-life burden despite remission. Recurrence after pituitary surgery is not uncommon (often within 5 years), while prognosis in ectopic or adrenal carcinoma-related disease depends strongly on tumour biology and stage.
Sources & References
🏥BMJ Best Practice(10)
đź’ŠBNF Drug References(6)
- Co-beneldopa[cautions]
- Co-careldopa[cautions]
- Foslevodopa with foscarbidopa[contraindications]
- Ketoconazole[management.pharmacological]
- Osilodrostat[management.pharmacological]
- Tetracosactide[contraindications]
âś…NICE Guidelines(1)
- Cushing's syndrome[overview]
đź“–Textbook References(2)
- Guyton and Hall Textbook of Medical Physiology (John E. Hall, Michael E. Hall) (Z-Library).pdf(pp. 928)[context]
- Guyton and Hall Textbook of Medical Physiology (John E. Hall, Michael E. Hall) (Z-Library).pdf(pp. 928)[context]