Cushing's Syndrome
Summary
Cushing's syndrome is the clinical manifestation of chronic excess glucocorticoids (cortisol). The most common cause is exogenous (iatrogenic) from prescribed corticosteroids. Endogenous causes are divided into ACTH-dependent (pituitary adenoma — "Cushing's disease", ectopic ACTH) and ACTH-independent (adrenal adenoma, carcinoma). Diagnosis involves confirming hypercortisolism (screening tests) then localising the source (ACTH levels, imaging, further dynamic tests). Treatment depends on cause: stopping exogenous steroids, transsphenoidal surgery for pituitary adenoma, or adrenalectomy for adrenal tumours.
Key Facts
- Definition: Clinical syndrome due to chronic glucocorticoid excess
- Most Common Cause: Exogenous steroids (iatrogenic)
- Most Common Endogenous Cause: Pituitary adenoma (Cushing's disease — 70% of endogenous)
- Classic Features: Central obesity, moon face, striae, buffalo hump, thin skin, easy bruising
- Screening Tests: 24-hour urinary free cortisol, overnight dexamethasone suppression test, midnight salivary cortisol
- Key Distinction: ACTH-dependent vs ACTH-independent
Clinical Pearls
Cushing's SYNDROME vs DISEASE: Cushing's syndrome = any cause of cortisol excess. Cushing's disease = specifically pituitary ACTH-secreting adenoma (70% of endogenous causes). Don't confuse them!
Striae Are Purple, Not White: The classic striae of Cushing's are wide (>1cm), violaceous (red-purple), and found on abdomen, thighs, and arms. White striae from weight gain are NOT specific.
Exogenous Cushing's = Low ACTH, Low Cortisol: If a patient on steroids develops Cushingoid features, ACTH is suppressed (low) and endogenous cortisol production is suppressed.
Why This Matters Clinically
Cushing's syndrome causes significant morbidity (hypertension, diabetes, osteoporosis, infections, psychiatric illness) and mortality if untreated. Recognising the features, confirming hypercortisolism with appropriate tests, and identifying the cause enables targeted treatment.
Incidence & Prevalence
- Exogenous Cushing's: Very common (any patient on chronic steroids)
- Endogenous Cushing's: Rare — 2-3 per million per year
- Cushing's disease (pituitary): ~70% of endogenous cases
Demographics
| Factor | Details |
|---|---|
| Age | Peak 25-40 years (pituitary); varies by cause |
| Sex | Cushing's disease: Female:Male 3:1; Ectopic ACTH: Male predominant |
| Ethnicity | No major ethnic variation |
Causes (Aetiology)
ACTH-Dependent (80% of endogenous):
| Cause | Proportion | Notes |
|---|---|---|
| Pituitary adenoma (Cushing's disease) | 70% | Corticotroph adenoma |
| Ectopic ACTH | 10-15% | Small cell lung cancer, carcinoid (bronchial, thymic) |
| Ectopic CRH | Rare | Tumour secreting CRH |
ACTH-Independent (20% of endogenous):
| Cause | Notes |
|---|---|
| Adrenal adenoma | Benign cortisol-secreting tumour |
| Adrenal carcinoma | Aggressive, often large |
| Bilateral adrenal hyperplasia | Macro/micronodular |
Exogenous (Most Common Overall):
- Oral corticosteroids
- Inhaled corticosteroids (high dose)
- Topical steroids (especially potent, large area)
- Steroid injections
Mechanism
Step 1: Glucocorticoid Excess
- From endogenous overproduction or exogenous administration
Step 2: Metabolic Effects
- Protein catabolism: Thin skin, muscle wasting, striae, poor wound healing
- Fat redistribution: Central/truncal obesity, moon face, buffalo hump
- Glucose: Insulin resistance, hyperglycaemia, diabetes
- Bone: Increased resorption, osteoporosis, fractures
- Immune: Suppression, increased infection risk
Step 3: Cardiovascular Effects
- Sodium retention → hypertension
- Hypokalaemia (if mineralocorticoid excess, especially ectopic ACTH)
Step 4: Psychiatric Effects
- Depression, anxiety, psychosis
Classification
| Type | ACTH | Cause |
|---|---|---|
| ACTH-Dependent | High/Normal | Pituitary adenoma, Ectopic ACTH |
| ACTH-Independent | Low | Adrenal adenoma/carcinoma, Exogenous |
Symptoms
Classic Features:
Other Symptoms:
Signs
Highly Specific (Discriminating) Signs:
Common but Less Specific:
Signs by System
| System | Signs |
|---|---|
| Metabolic | Central obesity, buffalo hump, moon face |
| Skin | Purple striae, thin skin, bruising, acne |
| Cardiovascular | Hypertension, oedema |
| Musculoskeletal | Proximal myopathy, osteoporosis |
| Endocrine | Hyperglycaemia, menstrual dysfunction |
| Psychiatric | Depression, anxiety, psychosis |
Red Flags
[!CAUTION] Red Flags — Suggest severe or complicated Cushing's:
- Severe hypertension uncontrolled on multiple drugs
- New-onset diabetes with rapid onset
- Severe proximal myopathy (bedbound)
- Hypokalaemia (suggests ectopic ACTH — often malignant)
- Osteoporotic fractures
- Psychosis or severe depression
- Visual field defect (pituitary macroadenoma)
Structured Approach
General:
- Body habitus (central obesity with thin limbs)
- Face (moon face, plethora, facial hair in women)
- Skin (thin skin, striae, bruising)
- Muscle strength (proximal myopathy)
Cardiovascular:
- Blood pressure (hypertension common)
- Oedema
Neurological:
- Visual fields (pituitary macroadenoma)
Special Tests
| Test | Technique | Significance |
|---|---|---|
| Proximal Myopathy | Rise from chair without using arms | Difficulty = positive (highly specific) |
| Skin Thickness | Pinch dorsum of hand | Thin, transparent |
| Striae Examination | Measure width, note colour | >1cm, purple = significant |
| Visual Fields | Confrontation testing | Bitemporal hemianopia if pituitary adenoma |
First-Line (Screening)
Confirm hypercortisolism with at least 2 tests:
| Test | Method | Interpretation |
|---|---|---|
| 24h Urinary Free Cortisol (UFC) | 2-3 collections | Elevated >3x ULN highly suggestive |
| Overnight Dexamethasone Suppression Test (ONDST) | 1mg Dex at 11pm → 9am cortisol | Normal: <50 nmol/L. Failure to suppress = Cushing's |
| Late-Night Salivary Cortisol | 2 samples at 11pm | Elevated = loss of diurnal rhythm |
Determine ACTH-Dependent vs Independent
| Test | Finding | Interpretation |
|---|---|---|
| Plasma ACTH | High/Normal | ACTH-dependent (pituitary or ectopic) |
| Low (<5 pg/mL) | ACTH-independent (adrenal or exogenous) |
Localisation
ACTH-Dependent:
- MRI Pituitary (gadolinium-enhanced)
- High-dose dexamethasone suppression test
- CRH stimulation test
- Inferior petrosal sinus sampling (IPSS) if MRI inconclusive
ACTH-Independent:
- CT Adrenals (thin-cut)
- Adrenal venous sampling (if bilateral disease)
Other Investigations
| Test | Purpose |
|---|---|
| FBC, U&E | Hypokalaemia (ectopic ACTH) |
| Glucose | Diabetes common |
| Lipids | Dyslipidaemia |
| DEXA | Osteoporosis assessment |
| Potassium | Low in ectopic ACTH (severe) |
Management Algorithm
CUSHING'S SYNDROME MANAGEMENT
↓
┌─────────────────────────────────────────────────────┐
│ EXOGENOUS (IATROGENIC) CUSHING'S │
│ │
│ • Taper steroids gradually (if possible) │
│ • Minimise dose to lowest effective │
│ • Consider steroid-sparing agents │
│ • Monitor for adrenal insufficiency during taper │
└─────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────┐
│ CUSHING'S DISEASE (Pituitary Adenoma) │
│ │
│ FIRST-LINE: Transsphenoidal surgery │
│ • 70-90% remission for microadenoma │
│ • Lower success for macroadenoma │
│ │
│ SECOND-LINE (if surgery fails): │
│ • Repeat surgery │
│ • Radiotherapy (SRS or conventional) │
│ • Medical therapy (metyrapone, ketoconazole, │
│ osilodrostat, pasireotide) │
│ • Bilateral adrenalectomy (last resort) │
│ - Risk of Nelson's syndrome │
└─────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────┐
│ ADRENAL ADENOMA │
│ │
│ • Unilateral adrenalectomy (laparoscopic) │
│ • Cure rate very high (>95%) │
│ • Post-op: Steroid replacement until contralateral │
│ adrenal recovers │
└─────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────┐
│ ADRENAL CARCINOMA │
│ │
│ • Surgery (open adrenalectomy, wide excision) │
│ • Mitotane (adrenolytic drug) ± chemotherapy │
│ • Prognosis often poor (aggressive) │
└─────────────────────────────────────────────────────┘
↓
┌─────────────────────────────────────────────────────┐
│ ECTOPIC ACTH │
│ │
│ • Treat underlying tumour (surgery, chemo) │
│ • Medical control of cortisol (metyrapone, etc.) │
│ • If tumour inoperable: │
│ - Bilateral adrenalectomy │
└─────────────────────────────────────────────────────┘
Medical Therapy (Adjunct/Bridge)
| Drug | Mechanism | Notes |
|---|---|---|
| Metyrapone | Inhibits 11β-hydroxylase | First-line medical option |
| Ketoconazole | Inhibits steroidogenesis | Monitor LFTs |
| Osilodrostat | 11β-hydroxylase inhibitor | Newer agent |
| Pasireotide | Somatostatin analogue | For pituitary Cushing's |
| Mifepristone | Glucocorticoid receptor antagonist | Used in US |
Untreated Cushing's Syndrome
| Complication | Notes |
|---|---|
| Cardiovascular disease | Hypertension, atherosclerosis, increased CV mortality |
| Diabetes mellitus | Insulin resistance |
| Osteoporosis | Fractures (vertebral, rib) |
| Infections | Opportunistic infections, poor wound healing |
| Thromboembolism | Hypercoagulable state |
| Psychiatric illness | Depression, psychosis |
| Mortality | Significantly increased if untreated |
Treatment-Related
- Post-surgical adrenal insufficiency: Common after cure — need steroid replacement until HPA axis recovers (months to years)
- Nelson's syndrome: After bilateral adrenalectomy — pituitary adenoma growth (aggressive)
- Surgical complications: CSF leak, meningitis (transsphenoidal); haemorrhage (adrenalectomy)
Natural History
Untreated Cushing's syndrome has high morbidity and mortality. Complications of cortisol excess lead to cardiovascular disease, infections, and psychiatric illness. Life expectancy is significantly reduced without treatment.
Outcomes with Treatment
| Variable | Outcome |
|---|---|
| Transsphenoidal surgery (microadenoma) | 70-90% remission |
| Transsphenoidal surgery (macroadenoma) | 50-70% remission |
| Adrenalectomy (adenoma) | >95% cure |
| Recurrence (Cushing's disease) | 10-20% |
| Adrenal carcinoma | Poor prognosis (5-year survival ~30-40%) |
Prognostic Factors
Good Prognosis:
- Benign adrenal adenoma
- Pituitary microadenoma
- Early treatment
Poorer Prognosis:
- Adrenal carcinoma
- Ectopic ACTH (especially small cell lung cancer)
- Delayed diagnosis with complications
Key Guidelines
-
Endocrine Society Clinical Practice Guideline: Treatment of Cushing's Syndrome (2015) — Comprehensive recommendations on diagnosis and management.
-
Pituitary Society Expert Consensus (2021) — Updated guidance on Cushing's disease management.
Landmark Studies
Nieman et al. (2008) — Diagnostic approach to Cushing's
- Endocrine Society guideline on diagnosis
- Key finding: Established stepwise diagnostic algorithm
- Clinical Impact: Standardised diagnostic approach worldwide
Evidence Strength
| Intervention | Level | Key Evidence |
|---|---|---|
| Transsphenoidal surgery (CD) | 2a | Cohort studies, guidelines |
| Adrenalectomy (adenoma) | 2a | Case series, guidelines |
| Metyrapone | 2b | Cohort studies |
| Screening tests (UFC, ONDST, LNSC) | 1a | Meta-analyses, guidelines |
What is Cushing's Syndrome?
Cushing's syndrome is a condition caused by having too much of the hormone cortisol in your body over a long period. Cortisol is made by your adrenal glands (above your kidneys) and is important for handling stress, controlling blood sugar, and regulating blood pressure. Too much cortisol causes a range of problems throughout your body.
What causes it?
- Most common: Taking steroid medicines (prednisolone, dexamethasone, cortisone injections) for other conditions
- Less common: A tumour in your pituitary gland (in your brain) that makes too much of a hormone called ACTH, which tells your adrenal glands to produce cortisol
- Rare: A tumour in your adrenal glands or elsewhere that produces cortisol or ACTH
What are the symptoms?
- Weight gain, especially around your middle
- Round face ("moon face")
- A lump between your shoulders ("buffalo hump")
- Purple stretch marks on your abdomen
- Thin skin that bruises easily
- Muscle weakness (difficulty getting out of a chair)
- High blood pressure
- Diabetes
- Mood changes, anxiety, depression
How is it treated?
Treatment depends on the cause:
- Steroid medication: Your doctor may gradually reduce or stop the steroids if safe
- Pituitary tumour: Surgery through the nose to remove the tumour (transsphenoidal surgery)
- Adrenal tumour: Surgery to remove the affected adrenal gland
- Medications: Sometimes drugs are used to block cortisol production
What to expect
- After successful treatment, many symptoms improve or resolve over months
- Some changes (like stretch marks) may be permanent
- You may need to take replacement steroid tablets temporarily after surgery
- Regular follow-up is important to check for recurrence
Primary Guidelines
- Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing's Syndrome: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831. PMID: 26222757
Key Studies
-
Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing's syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. PMID: 18334580
-
Pivonello R, De Leo M, Cozzolino A, Colao A. The treatment of Cushing's disease. Endocr Rev. 2015;36(4):385-486. PMID: 26067718
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