Cushing's Syndrome
Chronic cortisol excess. Most common cause: exogenous steroids. Most common endogenous cause: pituitary adenoma (Cushing's disease). Systematic biochemical → localization approach.
🔍 Overview
Overview
Cushing's syndrome = clinical manifestations of chronic cortisol excess. Exogenous (iatrogenic steroids) is by far the most common cause overall. Among endogenous causes: Cushing's disease (ACTH-secreting pituitary adenoma, ~70%), ectopic ACTH (small cell lung cancer, carcinoid, ~15%), adrenal adenoma/carcinoma (~15%). Classic features: central obesity, moon facies, dorsal fat pad (buffalo hump), violaceous striae (> 1 cm wide), proximal muscle weakness, easy bruising, hyperglycemia, HTN, osteoporosis, hirsutism, menstrual irregularity, depression/psychosis. Key teaching point: the workup is a 3-step process -(1) confirm hypercortisolism, (2) determine ACTH dependence, (3) localize the source.
🧪 Workup
Workup
- Step 1 -Confirm hypercortisolism (need 2 of 3 tests positive):
- 24-hour urine free cortisol (× 2) -elevated > 3× ULN is virtually diagnostic. Mild elevations can be false positive (pseudo-Cushing: alcoholism, depression, obesity).
- Late-night salivary cortisol (× 2) -loss of diurnal cortisol rhythm. Cortisol should nadir at 11 PM. Elevated = abnormal. Convenient outpatient test.
- 1 mg overnight dexamethasone suppression test (DST) -give dex 1 mg PO at 11 PM → check 8 AM cortisol. Normal: cortisol < 1.8 mcg/dL (suppressed). Cushing's: cortisol fails to suppress (> 1.8). Nieman, 2008
- Step 2 -ACTH level (determine dependence):
- ACTH elevated (> 20 pg/mL) → ACTH-dependent: pituitary (Cushing's disease) vs ectopic ACTH
- ACTH suppressed (< 5 pg/mL) → ACTH-independent: adrenal source (adenoma, carcinoma, bilateral hyperplasia)
- Step 3 -Localize:
- ACTH-dependent: MRI pituitary (60% show adenoma). If MRI negative or equivocal → inferior petrosal sinus sampling (IPSS) with CRH stimulation (gold standard to confirm pituitary vs ectopic).
- ACTH-independent: CT adrenals (adenoma vs carcinoma vs bilateral hyperplasia)
- Ectopic ACTH: CT chest/abdomen (small cell, carcinoid, thymic tumors). Octreotide scan. PET/CT.
💊 Medications
Medications
| Drug | Dose | Route | Notes |
|---|---|---|---|
| Ketoconazole | 200-400 mg BID-TID | PO | Steroidogenesis inhibitor. Most commonly used medical therapy. Monitor LFTs (hepatotoxicity). QTc prolongation. Drug interactions (CYP3A4). |
| Metyrapone | 250-750 mg TID-QID | PO | 11β-hydroxylase inhibitor. Blocks cortisol synthesis. Can cause hyperandrogenism (hirsutism, acne). Monitor cortisol + ACTH. |
| Osilodrostat | 2-7 mg BID | PO | 11β-hydroxylase inhibitor. Newer. LINC-3, 2022. QTc monitoring. Adrenal insufficiency risk. |
| Mifepristone | 300-1200 mg daily | PO | GR antagonist. FDA-approved for Cushing's-associated hyperglycemia. Cannot monitor cortisol (blocked receptor). Monitor clinically. SEISMIC, 2012 |
| Pasireotide | 0.6-0.9 mg SQ BID | SQ | Somatostatin analog for Cushing's disease. Hyperglycemia is major side effect (up to 70%). |
| Mitotane | 2-6 g/day (titrate) | PO | Adrenolytic -for adrenal carcinoma. Causes AI (needs replacement). Monitor levels (target 14-20 mcg/mL). Teratogenic. |
🏥 Rounds
Pimp Questions
❓ What are the 3 steps in the Cushing's workup?
Step 1: Confirm hypercortisolism -2 of 3 positive: 24h UFC, late-night salivary cortisol, 1 mg DST. Step 2: ACTH level -high = ACTH-dependent (pituitary or ectopic), low = ACTH-independent (adrenal). Step 3: Localize -MRI pituitary (if ACTH-dependent) or CT adrenals (if ACTH-independent). IPSS if pituitary MRI equivocal. Nieman, 2008
❓ What is inferior petrosal sinus sampling (IPSS)?
Gold standard to differentiate pituitary vs ectopic ACTH. Catheters placed in bilateral inferior petrosal sinuses (drain the pituitary). Compare petrosal ACTH to peripheral ACTH before and after CRH stimulation. Central-to-peripheral ACTH ratio ≥ 2 (basal) or ≥ 3 (post-CRH) = pituitary source. If ratio < 2 → ectopic ACTH. Indicated when MRI is negative or equivocal.
❓ Why do patients develop adrenal insufficiency after successful pituitary surgery?
Chronic ACTH excess from the pituitary adenoma → chronic cortisol excess → suppresses CRH and the normal corticotrophs (negative feedback). When the adenoma is removed, the remaining normal pituitary tissue is atrophied and cannot produce adequate ACTH → secondary adrenal insufficiency. HPA axis recovery takes 6-18 months. Patients need hydrocortisone replacement until the axis recovers.
❓ What features help distinguish Cushing's from simple obesity?
Cushing's-specific features: (1) Proximal muscle weakness (can't rise from chair without arms -obesity alone doesn't cause this), (2) wide (> 1 cm) violaceous striae (obesity has narrow, pink striae), (3) easy bruising + skin thinning, (4) new-onset diabetes + HTN + osteoporosis in a young person, (5) facial plethora. Weight gain in Cushing's is classically central with thin extremities (muscle wasting). Obese patients have more generalized fat distribution.
❓ Why can't you monitor cortisol levels on mifepristone?
Mifepristone is a glucocorticoid receptor antagonist -it blocks the receptor, not cortisol production. In fact, cortisol levels rise on mifepristone (loss of negative feedback → ACTH increases → cortisol increases). You must monitor clinical response (glucose, weight, striae, weakness) and urinary cortisol will be misleadingly HIGH. This makes dose titration challenging.
Clinical Examples
📋 Case 1, Cushing's Disease (Pituitary Adenoma)
Patient: 36F with 25 lb central weight gain, new T2DM, HTN, wide purple striae, easy bruising, and proximal weakness × 10 months. Moon facies, dorsocervical fat pad. No exogenous steroids.
Key findings: 24h UFC 420 mcg (4× ULN), late-night salivary cortisol elevated, 1 mg DST cortisol 14.2 (failed suppression). ACTH 72 pg/mL (elevated → ACTH-dependent). MRI pituitary: 7 mm adenoma.
Management:
- Confirm ACTH-dependent Cushing's: high-dose DST (8 mg) → > 50% suppression supports pituitary source
- Referral for transsphenoidal surgery (TSS), first-line, cure rate 70-90% for microadenomas
- Pre-op: insulin for hyperglycemia, VTE prophylaxis (Cushing's is hypercoagulable), PCP prophylaxis with TMP-SMX
- Post-op: expect adrenal insufficiency (start hydrocortisone 15-20 mg/day, taper over months)
- If TSS fails or recurrence: repeat surgery, radiation, bilateral adrenalectomy, or medical therapy (ketoconazole, osilodrostat)
Teaching point: After successful TSS, cortisol should be undetectable (< 2 mcg/dL), this confirms cure. Patients will need glucocorticoid replacement for 6-18 months until the suppressed HPA axis recovers.
📋 Case 2, Ectopic ACTH (Small Cell Lung Cancer)
Patient: 58M smoker with rapid-onset HTN, hypokalemia (K⁺ 2.4), hyperglycemia (glucose 380), and proximal weakness over 6 weeks. Hyperpigmented. No classic Cushingoid body habitus (too rapid for fat redistribution).
Key findings: ACTH 280 pg/mL (markedly elevated), UFC > 1000 mcg. High-dose DST: no suppression. CT chest: 3 cm RLL mass with hilar lymphadenopathy. Consistent with ectopic ACTH from SCLC.
Management:
- Aggressive K⁺ replacement + spironolactone (mineralocorticoid excess from cortisol overwhelming 11β-HSD2)
- Ketoconazole 200 mg TID or metyrapone to rapidly lower cortisol (medical adrenalectomy)
- Oncology: staging and treatment of SCLC (chemo ± radiation)
- If refractory hypercortisolism: bilateral adrenalectomy (definitive but causes permanent AI)
- VTE prophylaxis, extreme hypercortisolism is profoundly prothrombotic
Teaching point: Ectopic ACTH presents differently from pituitary Cushing's: rapid onset, severe hypokalemia, very high ACTH (> 200), and hyperpigmentation. The patient often looks sick, not Cushingoid, because fat redistribution takes months.
📋 Case 3, Iatrogenic Cushing's (Exogenous Steroids)
Patient: 65F with RA on prednisone 20 mg daily × 2 years. Moon facies, central obesity, osteoporosis (T-score -3.2), T2DM, recurrent oral candidiasis. Rheumatologist requests steroid taper advice.
Key findings: Iatrogenic Cushing syndrome, the #1 cause of Cushing's overall. Chronic exogenous steroids have suppressed the HPA axis. Abrupt discontinuation → adrenal crisis.
Management:
- Slow taper: reduce by 2.5 mg q2-4 weeks until physiologic dose (5 mg prednisone ≈ 20 mg hydrocortisone)
- Below physiologic dose: switch to hydrocortisone 10-15 mg/day and taper by 2.5 mg q2-4 weeks
- ACTH stimulation test before final discontinuation, if cortisol > 18 mcg/dL, axis has recovered
- DMARD optimization for RA (methotrexate, biologics) to enable steroid discontinuation
- Address complications: DEXA + bisphosphonate for osteoporosis, diabetes management, PCP prophylaxis if > 20 mg/day
Teaching point: Exogenous steroids at any dose for > 3 weeks can suppress the HPA axis. Always taper, never stop abruptly. Patients on chronic steroids need stress-dose steroids for surgery or acute illness until axis recovery is confirmed.
Sample Presentation
Ms. Rivera is a 38-year-old woman with new-onset diabetes, HTN, 30 lb weight gain (central), wide purple striae on abdomen, and proximal weakness × 8 months. No exogenous steroid use. Labs: 24h UFC 380 mcg (3× ULN), late-night salivary cortisol 0.85 mcg/dL (elevated), 1 mg DST cortisol 12.4 (failed suppression). ACTH 68 pg/mL (elevated). MRI pituitary: 8 mm left-sided adenoma.
Key Points: Classic Cushing's disease -confirmed hypercortisolism (2/3 tests positive), ACTH-dependent, pituitary adenoma on MRI. Refer for TSS. Pre-op: control hyperglycemia (insulin), VTE prophylaxis (hypercoagulable), PCP prophylaxis if severely Cushingoid, address osteoporosis. Post-op: expect AI (start hydrocortisone replacement).
- 24h urine free cortisol -to monitor treatment response. Target: normalization.
- AM cortisol + ACTH -post-TSS: check day 1-3. Undetectable cortisol (< 2) = successful surgery. Patient needs hydrocortisone replacement.
- Morning cortisol off replacement -periodically to assess HPA axis recovery (may take 6-18 months post-surgery). Cosyntropin stim test when cortisol approaches normal.
- LFTs q2-4 weeks on ketoconazole
- ECG (QTc) on ketoconazole, osilodrostat
- Blood glucose -Cushing's causes insulin resistance. May need insulin during active disease. Hyperglycemia also a major side effect of pasireotide.
- DEXA scan -osteoporosis screening (cortisol excess → bone loss)
- MRI pituitary annually × 5 years post-TSS (recurrence monitoring)
📋 Summary
Summary
Ask About Steroids First
Exogenous glucocorticoids are by far the commonest cause of Cushing syndrome. Ask about oral, inhaled, topical, intra-articular and over-the-counter preparations, since injected and topical steroids are routinely forgotten in the history. Exogenous disease has a suppressed ACTH and a suppressed cortisol, so identifying it stops the workup before any expensive test.
Recognize the Discriminating Features
Weight gain, moon facies and central obesity are common and non-specific. The features that actually discriminate are proximal muscle weakness, wide purple striae over 1 cm, easy bruising and facial plethora, along with unexplained osteoporosis, new hypertension and new diabetes in a young patient.
Screen With Two of Three Tests
Late-night salivary cortisol, 1 mg overnight dexamethasone suppression, or 24-hour urinary free cortisol. Two abnormal tests are needed before proceeding, because any single test has false positives. Exclude pseudo-Cushing first: alcohol use disorder, severe depression, poorly controlled diabetes and obesity all produce mild biochemical abnormalities without the disease.
Then Measure ACTH to Split the Differential
Suppressed ACTH means an adrenal source, adenoma, carcinoma or bilateral hyperplasia, so image the adrenals. Normal or high ACTH means an ACTH-dependent cause, either pituitary (Cushing disease, about 80% of endogenous cases) or ectopic. The ACTH is the branch point of the entire workup and comes after confirmation, not before.
Distinguish Pituitary From Ectopic Carefully
Pituitary MRI plus high-dose dexamethasone suppression and CRH stimulation: a pituitary source usually suppresses and responds, an ectopic source usually does not. Inferior petrosal sinus sampling is the gold standard and is needed because pituitary incidentalomas are common and a microadenoma may not be visible on MRI at all. Ectopic ACTH is suggested by rapid onset, severe hypokalemic alkalosis and marked hyperpigmentation, most often from small cell lung cancer or a bronchial carcinoid.
Surgery Is the Definitive Treatment
Transsphenoidal resection for Cushing disease, adrenalectomy for an adrenal source, and resection of the tumor in ectopic disease. Bilateral adrenalectomy is the last resort for refractory disease and commits the patient to lifelong replacement, with a risk of Nelson syndrome afterwards.
Medical Therapy Is a Bridge
Steroidogenesis inhibitors: ketoconazole 200 to 400 mg BID to TID (monitor liver tests), metyrapone, or osilodrostat with QTc monitoring. Pasireotide for Cushing disease, with hyperglycemia as the main limitation. Mifepristone blocks the receptor and is approved for Cushing-associated hyperglycemia, but cortisol levels then become uninterpretable for monitoring. Mitotane for adrenal carcinoma.
Expect Adrenal Insufficiency After Cure
The contralateral or residual tissue has been chronically suppressed and takes months to a year to recover, so every successfully treated patient needs glucocorticoid replacement with a slow taper and stress-dose education. Steroid withdrawal syndrome, with arthralgia, fatigue and depression despite adequate replacement, is expected and is not a reason to raise the dose. Meanwhile treat the comorbidities: hypertension, diabetes, osteoporosis, hypercoagulability (these patients are at real VTE risk) and opportunistic infection risk.
📄 One Pager
Text version
One-Pager
Cushing's Syndrome
Confirm → ACTH → Localize
3-Step Workup
1. Confirm: 24h UFC, late-night salivary cortisol, 1mg DST (2/3 positive). 2. ACTH: high = pituitary/ectopic, low = adrenal. 3. Localize: MRI pituitary or CT adrenals. IPSS if MRI equivocal.
Trials
Nieman 2008 (Endocrine Society Guidelines) · LINC-3 2022 (osilodrostat) · SEISMIC 2012 (mifepristone)
Related Topics
Adrenal CrisisDiabetes InsipidusHypercalcemiaHyperosmolar Hyperglycemic State (HHS)Hyperthyroidism / Graves' DiseaseHypocalcemia