Cushing’s Syndrome — High-Yield Notes

Source: The MyEndoConsult Team

1. Etiology & Epidemiology

Two-bucket classification

Category	Cause	Approx % of endogenous CS
ACTH-dependent (~80–85%)	Cushing’s disease (corticotroph adenoma)	60–80%
	Ectopic ACTH syndrome	10–20%
	Ectopic CRH (very rare)	<1%
ACTH-independent (~15–20%)	Adrenal adenoma	~10%
	Adrenal carcinoma	~5%
	Bilateral macronodular adrenocortical disease (BMAD, formerly AIMAH)	<2%
	Primary pigmented nodular adrenocortical disease (PPNAD)	<2%
	McCune-Albright	rare

Exogenous (iatrogenic) Cushing’s is the most common form overall in general practice — search for topical, inhaled, injected, intranasal, intra-articular steroids.

Cushing’s disease

Incidence 0.7–2.4 per million/year; F:M ≈ 3:1; age 25–40 most common.
>90% microadenomas at presentation; 5–10% macroadenomas; carcinomas extremely rare.
~⅓ harbor somatic USP8 mutations → ↑EGFR signaling. Familial forms (rare): MEN1, MEN2, Carney complex, AIP/FIPA.
Up to 40% of long-standing CD develop ACTH-dependent macronodular adrenal hyperplasia → autonomous adrenals → recovery delay post-TSS.

Ectopic ACTH syndrome — sources (memorize)

Tumor	% of ectopic
Bronchial neuroendocrine tumor (carcinoid)	~25%
Small-cell lung carcinoma	~19%
Pancreatic/GI NET	~12%
Thymic NET	~7%
Medullary thyroid carcinoma	~5%
Pheochromocytoma / paraganglioma	~4%
Occult / unknown primary	~16%

M > F; older (>40y); rapid course. ACTH precursor POMC is overproduced (vs balanced ACTH in CD).

ACTH-independent — genetic associations to recognize

BMAD → ARMC5 mutations (~⅓); KDM1A in GIP-dependent; MEN1, FH, APC. Aberrant receptors (GIP, vasopressin, β-adrenergic, LH/hCG, serotonin, etc.) drive cortisol secretion.
PPNAD → PRKAR1A (>70% of Carney complex); PDE11A in isolated PPNAD. Adrenals often normal-sized with internodular atrophy (vs ACTH-dependent hyperplasia where internodular cortex is hyperplastic).
McCune-Albright → mosaic GNAS activating mutation; café-au-lait + fibrous dysplasia + precocious puberty.
Carney complex (PRKAR1A): cardiac/skin/breast myxomas, lentigines, PPNAD, acromegaly, sexual precocity.

2. Clinical Features — What Actually Discriminates

The most discriminating features (catabolic / glucocorticoid-specific)

Proximal myopathy (40–70%) — climb stairs, rise from squat, leg extension while sitting.
Wide purple (>1 cm) violaceous striae — abdomen, thighs, breasts, axillae (the narrow pink striae of weight gain alone do NOT count).
Easy bruising, thin skin (“cigarette paper” — Liddle’s sign on dorsum of hand).
Facial plethora.
Unprovoked osteoporotic fractures (especially vertebral — preferential trabecular loss).
Severe / progressive features over sequential photos.

Non-discriminating (but common)

Weight gain (81–97%), moon face (88–92%), hirsutism (56–81%), HTN (68–90%), DM/IGT (43–50%), menstrual irregularity, depression, lethargy.

Presentation depends on cause

Adrenal carcinoma: rapid onset, abdominal pain, palpable mass, virilization (cortisol + androgens + mineralocorticoids).
SCLC ectopic ACTH: rapid metabolic collapse — anorexia, profound myopathy, hypokalemic alkalosis (~10% in CD vs majority in ectopic), hyperpigmentation, often little weight gain.
Bronchial carcinoid ectopic ACTH: clinically indistinguishable from Cushing’s disease — long latency.
Mild autonomous cortisol secretion (MACS, formerly “subclinical CS”): ~10% of adrenal incidentalomas; mild ↑cortisol, no overt features but ↑risk of HTN/DM/osteoporosis/fractures.
Cyclical CS — waxing/waning; must perform diagnostic tests during an active phase.

Mean diagnostic delay

34 months overall (Cushing’s disease 38 mo; adrenal 30 mo; ectopic 14 mo).

Systemic burden (testable)

Cardiovascular = leading cause of mortality. Persistent ↑CV risk even after cure.
Hypercoagulability — ↑factor VIII, ↑fibrinogen, ↑vWF, ↓fibrinolysis. VTE risk 18× general population; 20% VTE without prophylaxis post-op. Hypercoagulable up to 12 months post-remission — give LMWH prophylaxis peri-operatively (and many centers extend 2–3 months post-op).
Infections — opportunistic (Pneumocystis if cortisol >1000–1200 nmol/L); prophylactic Bactrim/Septrin reasonable in severe disease.
Bone disease — osteoporosis in ~50% adults; vertebral fractures often painless; painless rib fractures with exuberant callus is a classic clue.
Neuropsychiatric — depression, anxiety, mania, paranoia, cognitive impairment; not always reversible.
HPA axis effects on other axes — secondary hypogonadism (most common), blunted GH, lost nocturnal TSH surge; increased autoimmune thyroid disease post-cure → monitor TFTs.
Hypokalemic metabolic alkalosis — when 11β-HSD2 is saturated (UFC >~4100 nmol/day), cortisol acts at MR → mineralocorticoid effect. Use spironolactone for the HTN/hypokalemia (esp. in ectopic).

3. Diagnosis — Step 1: Confirm Hypercortisolism

Use highly sensitive tests to screen; confirm with high-specificity tests. 2 positive screening tests needed if clinical suspicion is moderate–high; one negative ONDST suffices if low pre-test probability.

Testing protocol for Cushings Syndrome/Cushings disease. Created with Biosketch.art medical illustrator

First-line screening tests (pick at least 2)

1 mg Overnight Dexamethasone Suppression Test (ONDST)

Take 1 mg dex at 23:00; measure serum cortisol at 09:00.
Normal: cortisol suppresses to <50 nmol/L (1.8 µg/dL).
ERCUSYN sensitivity: 98–99%; specificity ~88% (lots of false +).
False positives: ↑CBG (estrogens — pregnancy, OCP, HRT — stop 4–6 wk before; chronic active hepatitis); CYP3A4 inducers (phenytoin, rifampin, carbamazepine) → faster dex metabolism; severe illness; depression.

Late-night salivary cortisol (LNSC)

Salivary cortisol reflects free serum cortisol; CBG-independent. Take at bedtime, ≥2 samples on different days, no eating/drinking/smoking/brushing teeth for 15 min before.
Pooled sensitivity 92%, specificity 96%.
Not reliable in shift workers, variable schedules, depression, diabetes (variable cut-offs).
Best tool to detect cyclical CS and recurrence post-op.

24-hour urinary free cortisol (UFC)

≥2 collections required (avoid episodic secretion misses); verify completeness with creatinine.
Sensitivity ~95% in florid disease; lower in subtle disease.
>4× ULN essentially diagnostic (rarely seen outside CS).
Useless vs pseudo-Cushing’s. Drugs (carbamazepine, digoxin, fenofibrate) can co-elute on HPLC → false elevation.

Second-line / confirmatory tests

2-day LDDST (dex 0.5 mg q6h × 8 doses) — same <50 nmol/L cut-off; specificity 95–100% (better than ONDST). Used when ONDST positive but clinical picture unclear.
Midnight serum cortisol (sleeping) — <50 nmol/L excludes CS. Awake midnight >207 nmol/L (7.5 µg/dL) — 94% sens / 100% spec for CS vs pseudo-Cushing’s. Mostly replaced by LNSC.
Dex-CRH test — historical; CRH no longer available. Recent data show no clear advantage over LDDST.
Desmopressin test — emerging; ACTH increment >4–6 pmol/L + baseline cortisol >331 nmol/L → sens ~88%, spec ~94% for CS vs non-neoplastic hypercortisolism.

Pseudo-Cushing’s (non-neoplastic hypercortisolism)

Most common: depression, alcohol use disorder, severe obesity, poorly controlled DM, PCOS, anorexia, chronic intense exercise, OSA, pregnancy.
Resolves with treatment of the underlying condition.

4. Diagnosis — Step 2: ACTH-Dependent vs Independent

Plasma ACTH at 08:00–09:00 (rapid handling — ice, centrifuge, freeze within 2 h).

ACTH	Interpretation
<10 ng/L (<2 pmol/L)	ACTH-independent → image the adrenals
>20–30 ng/L (4–6 pmol/L)	ACTH-dependent → image the pituitary
10–20 ng/L	Indeterminate — repeat, do CRH or desmopressin

Always repeat ACTH if results are inconsistent or surprising — heterophilic antibodies, ACTH fragment cross-reactivity (notably Immulite assay) can give false elevations.

Pre-test probability matters

Pre-test probability that ACTH-dependent CS is Cushing’s disease = 92% in women, 77% in men. Tests must improve on this baseline — set the cut-off for 100% specificity for Cushing’s disease.

5. Diagnosis — Step 3: Source Localization

ACTH-independent → adrenal imaging

High-resolution adrenal CT is first choice — unilateral mass + contralateral atrophy = adenoma/carcinoma.
>4 cm or unenhanced HU >20 raises concern for malignancy; >5 cm = malignant until proven otherwise → adrenal MDT.
Adenomas: lipid-rich, signal drop on out-of-phase MRI, HU <10.
PPNAD: small or normal adrenals with micronodules — easy to miss; clinical context and PRKAR1A testing key.
BMAD: bilaterally enlarged (>5 cm) lobulated adrenals.
Atrophic adrenals → exogenous glucocorticoids.

ACTH-dependent → pituitary MRI + dynamic testing

Pituitary MRI identifies adenoma in ~50–80% of CD (SPGR/3D techniques improve detection).
Caveat: ~10% of healthy adults have pituitary incidentalomas — biochemistry trumps imaging.

Bilateral Inferior Petrosal Sinus Sampling (BIPSS) — Gold Standard

Indication: ACTH-dependent CS where biochemistry/imaging are discordant or imaging negative.
Skip if: pituitary macroadenoma ≥10 mm AND dynamic tests support CD.
Patient must be actively hypercortisolemic at sampling.
Sample IPS + peripheral ACTH at baseline and post-stimulation (desmopressin 10 µg IV now standard since CRH unavailable).

Criterion	Threshold
Baseline central:peripheral ACTH	≥2:1 = Cushing’s disease
Post-desmopressin central:peripheral ACTH	≥3:1 = Cushing’s disease
Confirmation of catheter placement	IPS:peripheral prolactin >1.8
Interpetrosal ACTH ratio for lateralization	≥1.4 (accuracy only ~60–70% in adults; ~90% in children)

Meta-analysis sensitivity 94%, specificity 89% (CRH stimulation); desmopressin equivalent.
Major complications <1% (brainstem infarction with certain catheters historically).
Heparin during sampling to prevent thrombotic events.
If pre/post-stimulus lateralization reverses → don’t rely on it.

Non-invasive alternatives when BIPSS unavailable

HDDST (8 mg overnight or 2 mg q6h × 2 days): >50% suppression of basal cortisol suggests CD. Sensitivity ~80%; false-positive rate in ectopic 10–30% (esp. bronchial carcinoids). Combined with CRH or imaging improves PPV but worse than BIPSS.
CRH test (when available): ACTH ↑≥35% or cortisol ↑≥14% from baseline = CD. Sens ~85%, spec ~100%.
Desmopressin test: ACTH ↑>35% + cortisol ↑>20% = CD; pooled sens 88%, spec 74%.
Combined CRH + DDAVP + imaging concordance → 100% PPV/NPV (Bordeaux strategy); can avoid BIPSS in ~50% of cases.

Ectopic source localization

CT chest/abdomen/pelvis first; carcinoids may be tiny (<1 cm) — use thin-cut HRCT prone + supine.
68Ga-DOTATATE PET/CT > conventional octreotide scintigraphy for NETs; pooled sens ~64% (up to 76% in histologically confirmed).
18F-FDG PET preferred for aggressive ectopic tumors (SCLC, high-grade).
~16% remain occult — re-image periodically while controlling cortisol medically.

6. Treatment

Pre-operative priorities (severe cases)

Aggressive treatment of hypokalemia, HTN, hyperglycemia.
LMWH thromboprophylaxis for all but mildest cases.
Pneumocystis prophylaxis if cortisol >1000–1200 nmol/L.
Consider pre-treatment with steroidogenesis inhibitors to reverse metabolic effects.

Cushing’s disease — first-line: Transsphenoidal surgery (TSS)

Endoscopic now standard; reserve for Pituitary Tumor Centers of Excellence (surgeon volume >200 TSS for best outcomes).
Remission: microadenoma ~80–90%; macroadenoma 60–76%; invasive macro <60%.
Long-term recurrence: ~10–15% at 10 y, ~20% at 20 y → lifelong follow-up.
Predictors of sustained remission: age >25, microadenoma on MRI, no dural/cavernous invasion, histologic ACTH+ adenoma, low post-op cortisol, prolonged adrenal insufficiency.
Post-op cortisol at days 4–5 (off steroid cover for 20 h):
- <50 nmol/L = best predictor of long-term remission.
- <140 nmol/L = compatible with remission.
- >140 nmol/L at 3 months = persistent disease, re-investigate.
Complications: AVP-deficiency/DI (3–46% transient, ~5% permanent), hypopituitarism, CSF leak, meningitis. Hyponatremia (SIADH) day 5–10 in ~20%.
Post-op steroid cover, tapering hydrocortisone 15–20 mg/day in divided doses (largest dose AM, last by 18:00).
HPA axis recovery rare before 3–6 months; common at 12 months — test annually.

Second-line therapies (persistent / recurrent CD)

Repeat TSS — ~50% remission, higher hypopituitarism rates.
Radiotherapy (conventional 45–50 Gy in 25 fractions OR stereotactic / Gamma Knife):
- Primary RT: ~50% remission long-term.
- Adjunctive (post-failed TSS): ~80% (conventional) or ~50% (Gamma Knife at 5 y).
- Bridge with medical therapy while awaiting effect (often 2+ years).
- GH deficiency in 36–68%, other hypopit ~20% over time.
- Increased CVA risk in some series, secondary tumor risk ~4%.
- Avoid Gamma Knife if tumor <3–5 mm from optic chiasm.
Bilateral adrenalectomy — definitive cortisol control; lifelong steroid + mineralocorticoid replacement; ↑rate of adrenal crisis (~9.3/100 patient-yr); risk of Nelson’s syndrome (corticotroph tumor progression) 28–53% at mean 5.3 y, especially if young or visible pre-existing adenoma. Surveillance: MRI + ACTH q3 mo for 1 y, then yearly × 3 y, then q2–4 y. Prophylactic pituitary RT may reduce Nelson’s risk.

Ectopic ACTH

Resect when possible (bronchial carcinoid lobectomy = high cure rate).
Metastatic / occult: medical management + bilateral adrenalectomy.

ACTH-independent

Adrenal adenoma: unilateral laparoscopic adrenalectomy — cure ~100%. Post-op glucocorticoid replacement until contralateral adrenal recovers (~6–12 months).
Adrenal carcinoma: open adrenalectomy if >6 cm or imaging features of malignancy; mitotane adjuvant.
BMAD: unilateral adrenalectomy can be considered for milder cases (recurrence common); bilateral otherwise.
PPNAD: bilateral adrenalectomy curative.

Medical Therapy — Drug-by-Drug

Steroidogenesis inhibitors (workhorses)

Metyrapone (11β-hydroxylase inhibitor)

750–6000 mg/day in 3–4 divided doses.
Fast onset (hours).
Cortisol normalization: ~75% in CD (variable studies); recent PROMPT trial 47%.
Side effects: hirsutism, acne (↑androgens), HTN/hypokalemia/edema (↑11-deoxycorticosterone), GI upset, dizziness.
11-deoxycortisol cross-reacts with some cortisol immunoassays → use LC-MS/MS, or risk over-dosing and adrenal insufficiency.
Most-used drug in pregnancy along with ketoconazole.

Ketoconazole (multiple CYP inhibition: 11β-OH, C17-20 lyase, 17-OH, 18-OH)

200 mg BID up to 400 mg TID (max 1200 mg/d).
Normalizes cortisol ~50–70% in CD; meta-analysis ~63%.
Side effects: hepatotoxicity (5–20% LFT rise; serious injury 1 in 15,000) — check LFTs weekly × 4 wk, then monthly × 3 mo. Stop if ALT >3× ULN.
Anti-androgenic — useful in hirsute women; gynecomastia + reduced libido in men (limits use).
CYP3A4 inhibitor — many drug interactions.
Needs gastric acid — avoid with PPIs.
Avoid in pregnancy (teratogenic in animals).

Osilodrostat (LCI699 — selective 11β-hydroxylase + aldosterone synthase inhibitor)

2–60 mg/day (start 2 mg BID, titrate q2 wk).
FDA-approved 2020; NICE 2021 (UK).
LINC-3 phase III: 53% maintained UFC normal at 24 weeks, 66% at 48 weeks; long-term extension 50–88% at 6 years.
Side effects: adrenal insufficiency (~28%), nausea, fatigue, headache; ↑androgens (hirsutism in ~30% of women), ↑11-deoxycorticosterone → HTN/hypokalemia in ~42%. QT prolongation possible.
Now considered the best-studied recent steroidogenesis inhibitor for Cushing’s disease.

Levoketoconazole (purified levo-enantiomer of ketoconazole)

FDA-approved 2022. SONICS / LOGICS trials.
Less hepatotoxic than racemic; otherwise similar profile.

Etomidate (IV; potent rapid steroidogenesis blocker)

For severe, acute hypercortisolism (e.g., cortisol-induced psychosis, severe hypokalemia, sepsis) in ICU setting. Non-hypnotic doses (0.04–0.05 mg/kg/h).

Mitotane (adrenolytic)

Reserved for adrenocortical carcinoma.
Slow onset (weeks–months); most effective drug at normalizing cortisol (~82% pooled data) but complex monitoring (target plasma levels 14–20 mg/L), severe GI/neuro side effects, hyperlipidemia, hypothyroidism, ↑CBG (interferes with cortisol assays).
Long-lasting adrenal effect persists after stopping.

Pituitary-directed agents (Cushing’s disease specifically)

Pasireotide (somatostatin analogue, SSTR5 > SSTR2)

SC 0.6–0.9 mg BID OR long-acting IM 10–40 mg monthly.
Normalizes UFC in ~25–35%.
Key adverse effect: hyperglycemia (~70%) — often new-onset diabetes; manage with metformin then GLP-1 / SGLT2 / insulin.
Other: cholelithiasis, ↑LFTs, QT prolongation, sinus bradycardia.

Cabergoline (D2 dopamine agonist)

0.5–7 mg/week off-label.
Modest efficacy (~30–40% biochemical control); often used as add-on.

Glucocorticoid receptor antagonist

Mifepristone (RU-486)

FDA-approved for CS-related hyperglycemia (not for CD broadly).
Cannot monitor with cortisol or ACTH (both rise as feedback is blocked) — monitor clinical features + glucose + K+.
Side effects: hypokalemia (universally — block of 11β-HSD2), endometrial hyperplasia, adrenal insufficiency hard to recognize.
Newer: Relacorilant (selective GR antagonist, no progesterone effects) — phase 3 GRACE study showed efficacy without endometrial AEs.

7. Cushing’s in Pregnancy

Rare; most often adrenal adenoma (different from non-pregnant pattern where CD dominates).
Estrogen-driven ↑CBG complicates diagnosis — UFC and LNSC are more useful than serum cortisol or LDDST (ONDST not validated in pregnancy).
ACTH levels less suppressed than expected (placental CRH).
Treatment: surgery in 2nd trimester preferred; metyrapone is the drug of choice if medical therapy needed; ketoconazole second-line (animal teratogenicity).
Avoid mitotane (teratogenic) and pasireotide (lack of data).
Maternal complications: preeclampsia, diabetes, infections, VTE.
Fetal complications: prematurity, IUGR, stillbirth.

8. Pearls & Pitfalls

Sequential photographs (driver’s license, family photos) are diagnostic gold — progression matters more than any single feature.
Cyclical CS — test only during active phases; use LNSC or UFC ratio for screening.
CBG-raising states (estrogens/HRT/OCP, hepatitis) falsely elevate total cortisol — stop estrogen 4–6 weeks before ONDST/LDDST.
CYP3A4 inducers (phenytoin, rifampin, carbamazepine, St. John’s wort) increase dex clearance → false-positive ONDST → measure dex level if available.
Macroadenoma + ACTH-dependent CS → BIPSS not required if dynamic tests concordant; carcinomas rare but consider if behavior is invasive.
Hypokalemic alkalosis + hyperpigmentation + rapid course → SCLC ectopic ACTH until proven otherwise.
Adrenal adenoma + virilization (or severe hirsutism) → think adrenocortical carcinoma.
Bilateral adrenal lesions → BMAD vs PPNAD vs ACTH-dependent hyperplasia — let ACTH and adrenal size guide you (BMAD = bilateral huge; PPNAD = bilateral small/normal; ACTH-dep = bilateral enlarged).
Pre-op anticoagulation is the most under-utilized intervention — VTE rates are dramatic.
Glucocorticoid withdrawal syndrome post-cure is a real entity (malaise, joint pain, skin desquamation) — pre-warn patients; consider transient double-dose hydrocortisone tapering over 2–3 months if severe.
Recovery of HPA axis is rare before 3 months, often 12 months; not always permanent — subnormal SST at 3 years post-TSS predicts lifelong ACTH deficiency but also lower recurrence risk.
Nelson’s syndrome (“corticotroph tumor progression after bilateral adrenalectomy”) — monitor with serial MRI + ACTH; ACTH cut-off 200–700 pg/mL (best to track trajectory, not absolute number).
Mifepristone has no biochemical surrogate for adequate dosing — adrenal insufficiency easily missed; check clinical features, glucose, K+.
Pasireotide-induced diabetes is the rule, not the exception — monitor glucose from the start.

9. Quick-Recall Numbers

Endogenous CS incidence: 0.7–2.4 / million / year.
CD accounts for 60–80% of endogenous CS; >90% microadenomas.
Bronchial NET: ~25% of ectopic ACTH; SCLC ~19%; occult ~16%.
Diagnostic delay: 34 mo (38 in CD; 14 in ectopic).
ONDST sensitivity ~98–99%; cut-off cortisol <50 nmol/L (1.8 µg/dL).
LNSC: sens 92%, spec 96%, ≥2 samples.
UFC: ≥2 collections; >4× ULN = diagnostic.
ACTH-independent: <10 ng/L (2 pmol/L); ACTH-dependent: >20–30 ng/L (4–6 pmol/L).
BIPSS: baseline ≥2:1 central:peripheral; post-desmopressin ≥3:1; interpetrosal ≥1.4 for lateralization.
TSS remission: micro ~80–90%; macro ~60–76%.
Long-term recurrence: 10–15% at 10 y; 20% at 20 y.
VTE risk: 18× normal; 20% incidence without prophylaxis.
Cushing’s disease genetics: ~⅓ USP8 somatic mutations.
Carney complex: PPNAD in 30%; PRKAR1A mutation in >70%.
BMAD: ARMC5 mutations in ~⅓.
Osilodrostat: ~53% UFC normalization at 24 wk; 66% at 48 wk.
Pasireotide: ~25–35% UFC control; ~70% hyperglycemia.
Nelson’s after bilateral adrenalectomy: 28–53% at mean 5.3 y.

10. Must-Read References

Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al. Consensus on diagnosis and management of Cushing’s disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847–875. doi:10.1016/S2213-8587(21)00235-7 The current standard-of-care reference for Cushing’s disease. Diagnostic algorithm, BIPSS criteria, surgical/medical/radiation/adrenalectomy strategy, post-operative monitoring, recurrence surveillance.
Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM. The diagnosis of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2008;93(5):1526–1540. doi:10.1210/jc.2008-0125 The foundational diagnostic guideline. Screening test cut-offs and approach to differential diagnosis — still the bedrock.
Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A. Treatment of Cushing’s syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2015;100(8):2807–2831. doi:10.1210/jc.2015-1818 Companion treatment guideline. Surgical-first algorithm, role of medical therapy, radiotherapy, bilateral adrenalectomy.
Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet. 2015;386(9996):913–927. doi:10.1016/S0140-6736(14)61375-1 The most-cited comprehensive review in the modern era. Excellent integrated coverage of pathophysiology through treatment.
Reincke M, Fleseriu M. Cushing Syndrome: A Review. JAMA. 2023;330(2):170–181. doi:10.1001/jama.2023.11305 Concise, current synthesis with practical diagnostic and therapeutic emphasis. Useful as a board-prep refresher.
Findling JW, Raff H. Diagnosis of Endocrine Disease: Differentiation of pathological/neoplastic hypercortisolism (Cushing’s syndrome) from physiological/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing’s syndrome). Eur J Endocrinol. 2017;176(5):R205–R216. doi:10.1530/EJE-16-0946 The reference for the pseudo-Cushing’s problem — how to handle the diagnostic gray zone with confidence.
Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A. Complications of Cushing’s syndrome: state of the art. Lancet Diabetes Endocrinol. 2016;4(7):611–629. doi:10.1016/S2213-8587(16)00086-3 The definitive source on the persistent cardiovascular, metabolic, bone, neuropsychiatric, and thromboembolic morbidity — essential for managing patients after biochemical cure.
Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, et al. (LINC-3 Investigators). Efficacy and safety of osilodrostat in patients with Cushing’s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020;8(9):748–761. doi:10.1016/S2213-8587(20)30240-0 The pivotal trial that brought osilodrostat into modern Cushing’s care — know the efficacy and adverse-effect profile.
Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al. A 12-month phase 3 study of pasireotide in Cushing’s disease. N Engl J Med. 2012;366(10):914–924. doi:10.1056/NEJMoa1105743 Landmark trial establishing pasireotide as the first pituitary-directed medical therapy. Defines the hyperglycemia trade-off.
Newell-Price J, Bertagna X, Grossman AB, Nieman LK. Cushing’s syndrome. Lancet. 2006;367(9522):1605–1617. doi:10.1016/S0140-6736(06)68699-6 The classic review by the chapter’s senior author and colleagues — still the most-quoted single-source overview of the clinical reasoning behind Cushing’s diagnosis and management.

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Cushing’s Syndrome Bite-Sized Notes for Boards