{"id":4423288,"date":"2026-06-02T19:12:46","date_gmt":"2026-06-03T00:12:46","guid":{"rendered":"https:\/\/myendoconsult.com\/learn\/?p=4423288"},"modified":"2026-05-28T19:14:23","modified_gmt":"2026-05-29T00:14:23","slug":"cushings-syndrome-bite-sized-notes-for-boards","status":"publish","type":"post","link":"https:\/\/myendoconsult.com\/learn\/cushings-syndrome-bite-sized-notes-for-boards\/","title":{"rendered":"Cushing&#8217;s Syndrome Bite-Sized Notes for Boards"},"content":{"rendered":"\n<h1 class=\"wp-block-heading\">Cushing&#8217;s Syndrome \u2014 High-Yield Notes<\/h1>\n\n\n\n<p class=\"wp-block-paragraph\"><em>Source: The MyEndoConsult Team<\/em><\/p>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">1. Etiology &amp; Epidemiology<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Two-bucket classification<\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Category<\/th><th>Cause<\/th><th>Approx % of endogenous CS<\/th><\/tr><\/thead><tbody><tr><td><strong>ACTH-dependent (~80\u201385%)<\/strong><\/td><td><a href=\"https:\/\/myendoconsult.com\/learn\/what-is-cushings-syndrome\/\" data-type=\"post\" data-id=\"2172059\">Cushing&#8217;s disease <\/a>(corticotroph adenoma)<\/td><td><strong>60\u201380%<\/strong><\/td><\/tr><tr><td><\/td><td>Ectopic ACTH syndrome<\/td><td>10\u201320%<\/td><\/tr><tr><td><\/td><td>Ectopic CRH (very rare)<\/td><td>&lt;1%<\/td><\/tr><tr><td><strong>ACTH-independent (~15\u201320%)<\/strong><\/td><td><a href=\"https:\/\/myendoconsult.com\/learn\/adrenal-disorders\/\" data-type=\"post\" data-id=\"3417632\">Adrenal adenoma<\/a><\/td><td>~10%<\/td><\/tr><tr><td><\/td><td>Adrenal carcinoma<\/td><td>~5%<\/td><\/tr><tr><td><\/td><td>Bilateral macronodular adrenocortical disease (BMAD, formerly AIMAH)<\/td><td>&lt;2%<\/td><\/tr><tr><td><\/td><td>Primary pigmented nodular adrenocortical disease (PPNAD)<\/td><td>&lt;2%<\/td><\/tr><tr><td><\/td><td>McCune-Albright<\/td><td>rare<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\"><strong>Exogenous (iatrogenic) Cushing&#8217;s is the most common form overall<\/strong> in general practice \u2014 search for topical, inhaled, injected, intranasal, intra-articular steroids.<\/p>\n<\/blockquote>\n\n\n\n<h3 class=\"wp-block-heading\">Cushing&#8217;s disease<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Incidence <strong>0.7\u20132.4 per million\/year<\/strong>; <strong>F:M \u2248 3:1<\/strong>; age 25\u201340 most common.<\/li>\n\n\n\n<li><strong>&gt;90% microadenomas<\/strong> at presentation; 5\u201310% macroadenomas; carcinomas extremely rare.<\/li>\n\n\n\n<li><strong>~\u2153 harbor somatic USP8 mutations<\/strong> \u2192 \u2191EGFR signaling. Familial forms (rare):<a href=\"https:\/\/myendoconsult.com\/learn\/topics\/men-1\/\" data-type=\"oen_topic\" data-id=\"4422642\"> MEN1<\/a>, <a href=\"https:\/\/myendoconsult.com\/learn\/topics\/men-2\/\" data-type=\"oen_topic\" data-id=\"4422646\">MEN2<\/a>, Carney complex, AIP\/FIPA.<\/li>\n\n\n\n<li>Up to <strong>40% of long-standing CD<\/strong> develop ACTH-dependent macronodular adrenal hyperplasia \u2192 autonomous adrenals \u2192 recovery delay post-TSS.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Ectopic ACTH syndrome \u2014 sources (memorize)<\/h3>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Tumor<\/th><th>% of ectopic<\/th><\/tr><\/thead><tbody><tr><td><strong>Bronchial neuroendocrine tumor (carcinoid)<\/strong><\/td><td><strong>~25%<\/strong><\/td><\/tr><tr><td>Small-cell lung carcinoma<\/td><td>~19%<\/td><\/tr><tr><td>Pancreatic\/GI NET<\/td><td>~12%<\/td><\/tr><tr><td>Thymic NET<\/td><td>~7%<\/td><\/tr><tr><td>Medullary thyroid carcinoma<\/td><td>~5%<\/td><\/tr><tr><td><a href=\"https:\/\/myendoconsult.com\/learn\/hereditary-paraganglioma-pheochromocytoma-syndromes\/\" data-type=\"post\" data-id=\"3501968\">Pheochromocytoma<\/a> \/ paraganglioma<\/td><td>~4%<\/td><\/tr><tr><td><strong>Occult \/ unknown primary<\/strong><\/td><td><strong>~16%<\/strong><\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">M &gt; F; older (&gt;40y); rapid course. ACTH <strong>precursor POMC<\/strong> is overproduced (vs balanced ACTH in CD).<\/p>\n<\/blockquote>\n\n\n\n<h3 class=\"wp-block-heading\">ACTH-independent \u2014 genetic associations to recognize<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>BMAD<\/strong> \u2192 <strong>ARMC5<\/strong> mutations (~\u2153); KDM1A in GIP-dependent; MEN1, FH, APC. Aberrant receptors (GIP, vasopressin, \u03b2-adrenergic, LH\/hCG, serotonin, etc.) drive cortisol secretion.<\/li>\n\n\n\n<li><strong>PPNAD<\/strong> \u2192 <strong>PRKAR1A<\/strong> (&gt;70% of Carney complex); PDE11A in isolated PPNAD. Adrenals often <strong>normal-sized with internodular atrophy<\/strong> (vs ACTH-dependent hyperplasia where internodular cortex is hyperplastic).<\/li>\n\n\n\n<li><strong>McCune-Albright<\/strong> \u2192 mosaic <strong>GNAS<\/strong> activating mutation; caf\u00e9-au-lait + fibrous dysplasia + precocious puberty.<\/li>\n\n\n\n<li><strong>Carney complex (PRKAR1A):<\/strong> cardiac\/skin\/breast myxomas, lentigines, PPNAD, acromegaly, sexual precocity.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">2. Clinical Features \u2014 What Actually Discriminates<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">The most discriminating features (catabolic \/ glucocorticoid-specific)<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Proximal myopathy<\/strong> (40\u201370%) \u2014 climb stairs, rise from squat, leg extension while sitting.<\/li>\n\n\n\n<li><strong>Wide purple (&gt;1 cm) violaceous striae<\/strong> \u2014 abdomen, thighs, breasts, axillae (the narrow pink striae of weight gain alone do NOT count).<\/li>\n\n\n\n<li><strong>Easy bruising, thin skin<\/strong> (&#8220;cigarette paper&#8221; \u2014 Liddle&#8217;s sign on dorsum of hand).<\/li>\n\n\n\n<li><strong><a href=\"https:\/\/myendoconsult.com\/learn\/facial-plethora\/\" data-type=\"post\" data-id=\"2838339\">Facial plethora<\/a>.<\/strong><\/li>\n\n\n\n<li><strong>Unprovoked osteoporotic fractures<\/strong> (especially vertebral \u2014 preferential trabecular loss).<\/li>\n\n\n\n<li><strong>Severe \/ progressive features over sequential photos.<\/strong><\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Non-discriminating (but common)<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Weight gain (81\u201397%), moon face (88\u201392%), hirsutism (56\u201381%), HTN (68\u201390%), DM\/IGT (43\u201350%), menstrual irregularity, depression, lethargy.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Presentation depends on cause<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Adrenal carcinoma:<\/strong> rapid onset, abdominal pain, palpable mass, <strong>virilization<\/strong> (cortisol + androgens + mineralocorticoids).<\/li>\n\n\n\n<li><strong>SCLC ectopic ACTH:<\/strong> rapid metabolic collapse \u2014 anorexia, profound myopathy, <strong>hypokalemic alkalosis<\/strong> (~10% in CD vs majority in ectopic), <strong>hyperpigmentation<\/strong>, often little weight gain.<\/li>\n\n\n\n<li><strong>Bronchial carcinoid ectopic ACTH:<\/strong> clinically indistinguishable from Cushing&#8217;s disease \u2014 long latency.<\/li>\n\n\n\n<li><strong>Mild autonomous cortisol secretion (MACS, formerly &#8220;subclinical CS&#8221;):<\/strong> ~10% of adrenal incidentalomas; mild \u2191cortisol, no overt features but \u2191risk of HTN\/DM\/osteoporosis\/fractures.<\/li>\n\n\n\n<li><strong>Cyclical CS<\/strong> \u2014 waxing\/waning; <strong>must perform diagnostic tests during an active phase<\/strong>.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Mean diagnostic delay<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>34 months overall<\/strong> (Cushing&#8217;s disease 38 mo; adrenal 30 mo; ectopic 14 mo).<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Systemic burden (testable)<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Cardiovascular = leading cause of mortality.<\/strong> Persistent \u2191CV risk even after cure.<\/li>\n\n\n\n<li><strong>Hypercoagulability<\/strong> \u2014 \u2191factor VIII, \u2191fibrinogen, \u2191vWF, \u2193fibrinolysis. <strong>VTE risk 18\u00d7 general population<\/strong>; <strong>20% VTE without prophylaxis<\/strong> post-op. Hypercoagulable up to <strong>12 months post-remission<\/strong> \u2014 give LMWH prophylaxis peri-operatively (and many centers extend 2\u20133 months post-op).<\/li>\n\n\n\n<li><strong>Infections<\/strong> \u2014 opportunistic (Pneumocystis if cortisol &gt;1000\u20131200 nmol\/L); prophylactic Bactrim\/Septrin reasonable in severe disease.<\/li>\n\n\n\n<li><strong>Bone disease<\/strong> \u2014 osteoporosis in ~50% adults; vertebral fractures often painless; <strong>painless rib fractures with exuberant callus<\/strong> is a classic clue.<\/li>\n\n\n\n<li><strong>Neuropsychiatric<\/strong> \u2014 depression, anxiety, mania, paranoia, cognitive impairment; <strong>not always reversible<\/strong>.<\/li>\n\n\n\n<li><strong>HPA axis effects on other axes<\/strong> \u2014 secondary hypogonadism (most common), blunted GH, lost nocturnal TSH surge; <strong>increased autoimmune thyroid disease post-cure<\/strong> \u2192 monitor TFTs.<\/li>\n\n\n\n<li><strong>Hypokalemic metabolic alkalosis<\/strong> \u2014 when 11\u03b2-HSD2 is saturated (UFC &gt;~4100 nmol\/day), cortisol acts at MR \u2192 mineralocorticoid effect. <strong>Use spironolactone<\/strong> for the HTN\/hypokalemia (esp. in ectopic).<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">3. Diagnosis \u2014 Step 1: Confirm Hypercortisolism<\/h2>\n\n\n\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Use <strong>highly sensitive tests<\/strong> to screen; confirm with high-specificity tests. <strong>2 positive screening tests<\/strong> needed if clinical suspicion is moderate\u2013high; one negative ONDST suffices if low pre-test probability.<\/p>\n<\/blockquote>\n\n\n\n<figure class=\"wp-block-image size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"1200\" height=\"600\" src=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Testing-for-Cushings-syndrome.jpg\" alt=\"\" class=\"wp-image-4423290\" srcset=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Testing-for-Cushings-syndrome.jpg 1200w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Testing-for-Cushings-syndrome-300x150.jpg 300w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Testing-for-Cushings-syndrome-768x384.jpg 768w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Testing-for-Cushings-syndrome-480x240.jpg 480w\" sizes=\"auto, (max-width: 1200px) 100vw, 1200px\" \/><figcaption class=\"wp-element-caption\">Testing protocol for Cushings Syndrome\/Cushings disease.  Created with<a href=\"https:\/\/www.biosketch.art\"> Biosketch.art<\/a> medical illustrator<\/figcaption><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\">First-line screening tests (pick at least 2)<\/h3>\n\n\n\n<h4 class=\"wp-block-heading\">1 mg Overnight Dexamethasone Suppression Test (ONDST)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Take <strong>1 mg dex at 23:00<\/strong>; measure serum cortisol at <strong>09:00<\/strong>.<\/li>\n\n\n\n<li><strong>Normal:<\/strong> cortisol suppresses to <strong>&lt;50 nmol\/L (1.8 \u00b5g\/dL)<\/strong>.<\/li>\n\n\n\n<li>ERCUSYN sensitivity: <strong>98\u201399%<\/strong>; specificity ~88% (lots of false +).<\/li>\n\n\n\n<li><strong>False positives:<\/strong> \u2191CBG (estrogens \u2014 pregnancy, OCP, HRT \u2014 stop <strong>4\u20136 wk<\/strong> before; chronic active hepatitis); CYP3A4 inducers (phenytoin, rifampin, carbamazepine) \u2192 faster dex metabolism; severe illness; depression.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">Late-night salivary cortisol (LNSC)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Salivary cortisol reflects free serum cortisol; CBG-independent. <strong>Take at bedtime, \u22652 samples on different days<\/strong>, no eating\/drinking\/smoking\/brushing teeth for 15 min before.<\/li>\n\n\n\n<li>Pooled sensitivity <strong>92%<\/strong>, specificity <strong>96%<\/strong>.<\/li>\n\n\n\n<li>Not reliable in shift workers, variable schedules, depression, diabetes (variable cut-offs).<\/li>\n\n\n\n<li>Best tool to detect <strong>cyclical CS<\/strong> and <strong>recurrence<\/strong> post-op.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">24-hour urinary free cortisol (UFC)<\/h4>\n\n\n\n<ul class=\"wp-block-list\">\n<li>\u2265<strong>2 collections<\/strong> required (avoid episodic secretion misses); verify completeness with creatinine.<\/li>\n\n\n\n<li>Sensitivity ~95% in florid disease; lower in subtle disease.<\/li>\n\n\n\n<li><strong>&gt;4\u00d7 ULN essentially diagnostic<\/strong> (rarely seen outside CS).<\/li>\n\n\n\n<li><strong>Useless<\/strong> vs pseudo-Cushing&#8217;s. Drugs (carbamazepine, digoxin, fenofibrate) can co-elute on HPLC \u2192 false elevation.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Second-line \/ confirmatory tests<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>2-day LDDST (dex 0.5 mg q6h \u00d7 8 doses)<\/strong> \u2014 same &lt;50 nmol\/L cut-off; <strong>specificity 95\u2013100%<\/strong> (better than ONDST). Used when ONDST positive but clinical picture unclear.<\/li>\n\n\n\n<li><strong>Midnight serum cortisol (sleeping)<\/strong> \u2014 &lt;50 nmol\/L excludes CS. Awake midnight &gt;207 nmol\/L (7.5 \u00b5g\/dL) \u2014 94% sens \/ 100% spec for CS vs pseudo-Cushing&#8217;s. Mostly replaced by LNSC.<\/li>\n\n\n\n<li><strong>Dex-CRH test<\/strong> \u2014 historical; CRH no longer available. Recent data show no clear advantage over LDDST.<\/li>\n\n\n\n<li><strong>Desmopressin test<\/strong> \u2014 emerging; ACTH increment <strong>&gt;4\u20136 pmol\/L<\/strong> + baseline cortisol &gt;331 nmol\/L \u2192 sens <strong>~88%<\/strong>, spec <strong>~94%<\/strong> for CS vs non-neoplastic hypercortisolism.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Pseudo-Cushing&#8217;s (non-neoplastic hypercortisolism)<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Most common: <strong>depression, alcohol use disorder<\/strong>, severe obesity, poorly controlled DM, PCOS, anorexia, chronic intense exercise, OSA, pregnancy.<\/li>\n\n\n\n<li>Resolves with treatment of the underlying condition.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">4. Diagnosis \u2014 Step 2: ACTH-Dependent vs Independent<\/h2>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Plasma ACTH at 08:00\u201309:00<\/strong> (rapid handling \u2014 ice, centrifuge, freeze within 2 h).<\/p>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>ACTH<\/th><th>Interpretation<\/th><\/tr><\/thead><tbody><tr><td><strong>&lt;10 ng\/L (&lt;2 pmol\/L)<\/strong><\/td><td><strong>ACTH-independent<\/strong> \u2192 image the adrenals<\/td><\/tr><tr><td><strong>&gt;20\u201330 ng\/L (4\u20136 pmol\/L)<\/strong><\/td><td><strong>ACTH-dependent<\/strong> \u2192 image the pituitary<\/td><\/tr><tr><td>10\u201320 ng\/L<\/td><td>Indeterminate \u2014 repeat, do CRH or desmopressin<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<blockquote class=\"wp-block-quote is-layout-flow wp-block-quote-is-layout-flow\">\n<p class=\"wp-block-paragraph\">Always <strong>repeat ACTH<\/strong> if results are inconsistent or surprising \u2014 heterophilic antibodies, ACTH fragment cross-reactivity (notably Immulite assay) can give false elevations.<\/p>\n<\/blockquote>\n\n\n\n<h3 class=\"wp-block-heading\">Pre-test probability matters<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Pre-test probability that ACTH-dependent CS is <a href=\"https:\/\/myendoconsult.com\/learn\/topics\/cushing-syndrome\/\" data-type=\"oen_topic\" data-id=\"4422389\">Cushing&#8217;s disease<\/a> = <strong>92% in women, 77% in men<\/strong>. Tests must improve on this baseline \u2014 set the cut-off for <strong>100% specificity<\/strong> for Cushing&#8217;s disease.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">5. Diagnosis \u2014 Step 3: Source Localization<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">ACTH-independent \u2192 adrenal imaging<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>High-resolution adrenal CT<\/strong> is first choice \u2014 unilateral mass + contralateral atrophy = adenoma\/carcinoma.<\/li>\n\n\n\n<li><strong>&gt;4 cm or unenhanced HU &gt;20<\/strong> raises concern for malignancy; &gt;5 cm = malignant until proven otherwise \u2192 adrenal MDT.<\/li>\n\n\n\n<li>Adenomas: lipid-rich, signal drop on out-of-phase MRI, HU &lt;10.<\/li>\n\n\n\n<li><strong>PPNAD:<\/strong> small or normal adrenals with micronodules \u2014 easy to miss; clinical context and PRKAR1A testing key.<\/li>\n\n\n\n<li><strong>BMAD:<\/strong> bilaterally enlarged (&gt;5 cm) lobulated adrenals.<\/li>\n\n\n\n<li>Atrophic adrenals \u2192 exogenous glucocorticoids.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">ACTH-dependent \u2192 pituitary MRI + dynamic testing<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Pituitary MRI<\/strong> identifies adenoma in ~50\u201380% of CD (SPGR\/3D techniques improve detection).<\/li>\n\n\n\n<li><strong>Caveat: ~10% of healthy adults have pituitary incidentalomas<\/strong> \u2014 biochemistry trumps imaging.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Bilateral Inferior Petrosal Sinus Sampling (BIPSS) \u2014 <strong>Gold Standard<\/strong><\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Indication: <strong>ACTH-dependent CS where biochemistry\/imaging are discordant or imaging negative<\/strong>.<\/li>\n\n\n\n<li>Skip if: <strong>pituitary macroadenoma \u226510 mm<\/strong> AND dynamic tests support CD.<\/li>\n\n\n\n<li>Patient must be actively <strong>hypercortisolemic<\/strong> at sampling.<\/li>\n\n\n\n<li>Sample IPS + peripheral ACTH at baseline and post-stimulation (desmopressin 10 \u00b5g IV now standard since CRH unavailable).<\/li>\n<\/ul>\n\n\n\n<figure class=\"wp-block-table\"><table class=\"has-fixed-layout\"><thead><tr><th>Criterion<\/th><th>Threshold<\/th><\/tr><\/thead><tbody><tr><td>Baseline central:peripheral ACTH<\/td><td><strong>\u22652:1<\/strong> = Cushing&#8217;s disease<\/td><\/tr><tr><td>Post-desmopressin central:peripheral ACTH<\/td><td><strong>\u22653:1<\/strong> = Cushing&#8217;s disease<\/td><\/tr><tr><td>Confirmation of catheter placement<\/td><td>IPS:peripheral <strong>prolactin &gt;1.8<\/strong><\/td><\/tr><tr><td>Interpetrosal ACTH ratio for <strong>lateralization<\/strong><\/td><td><strong>\u22651.4<\/strong> (accuracy only ~60\u201370% in adults; ~90% in children)<\/td><\/tr><\/tbody><\/table><\/figure>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Meta-analysis sensitivity <strong>94%<\/strong>, specificity <strong>89%<\/strong> (CRH stimulation); desmopressin equivalent.<\/li>\n\n\n\n<li>Major complications &lt;1% (brainstem infarction with certain catheters historically).<\/li>\n\n\n\n<li><strong>Heparin during sampling<\/strong> to prevent thrombotic events.<\/li>\n\n\n\n<li>If pre\/post-stimulus lateralization reverses \u2192 don&#8217;t rely on it.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Non-invasive alternatives when BIPSS unavailable<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>HDDST (8 mg overnight or 2 mg q6h \u00d7 2 days):<\/strong> &gt;50% suppression of basal cortisol suggests CD. Sensitivity ~80%; <strong>false-positive rate in ectopic 10\u201330%<\/strong> (esp. bronchial carcinoids). Combined with CRH or imaging improves PPV but worse than BIPSS.<\/li>\n\n\n\n<li><strong>CRH test<\/strong> (when available): ACTH \u2191\u226535% or cortisol \u2191\u226514% from baseline = CD. Sens ~85%, spec ~100%.<\/li>\n\n\n\n<li><strong>Desmopressin test:<\/strong> ACTH \u2191&gt;35% + cortisol \u2191&gt;20% = CD; pooled sens 88%, spec 74%.<\/li>\n\n\n\n<li>Combined CRH + DDAVP + imaging concordance \u2192 100% PPV\/NPV (Bordeaux strategy); can avoid BIPSS in ~50% of cases.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Ectopic source localization<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>CT chest\/abdomen\/pelvis<\/strong> first; carcinoids may be tiny (&lt;1 cm) \u2014 use thin-cut HRCT prone + supine.<\/li>\n\n\n\n<li><strong>68Ga-DOTATATE PET\/CT<\/strong> &gt; conventional octreotide scintigraphy for NETs; pooled sens ~64% (up to 76% in histologically confirmed).<\/li>\n\n\n\n<li><strong>18F-FDG PET<\/strong> preferred for aggressive ectopic tumors (SCLC, high-grade).<\/li>\n\n\n\n<li>~16% remain <strong>occult<\/strong> \u2014 re-image periodically while controlling cortisol medically.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">6. Treatment<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Pre-operative priorities (severe cases)<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Aggressive treatment of <strong>hypokalemia, HTN, hyperglycemia<\/strong>.<\/li>\n\n\n\n<li><strong>LMWH thromboprophylaxis<\/strong> for all but mildest cases.<\/li>\n\n\n\n<li><strong>Pneumocystis prophylaxis<\/strong> if cortisol &gt;1000\u20131200 nmol\/L.<\/li>\n\n\n\n<li>Consider <strong>pre-treatment with steroidogenesis inhibitors<\/strong> to reverse metabolic effects.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Cushing&#8217;s disease \u2014 first-line: <strong>Transsphenoidal surgery (TSS)<\/strong><\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Endoscopic now standard; reserve for <strong>Pituitary Tumor Centers of Excellence<\/strong> (surgeon volume &gt;200 TSS for best outcomes).<\/li>\n\n\n\n<li><strong>Remission:<\/strong> microadenoma ~<strong>80\u201390%<\/strong>; macroadenoma <strong>60\u201376%<\/strong>; invasive macro &lt;60%.<\/li>\n\n\n\n<li><strong>Long-term recurrence: ~10\u201315% at 10 y, ~20% at 20 y<\/strong> \u2192 lifelong follow-up.<\/li>\n\n\n\n<li>Predictors of sustained remission: age &gt;25, microadenoma on MRI, no dural\/cavernous invasion, histologic ACTH+ adenoma, low post-op cortisol, prolonged adrenal insufficiency.<\/li>\n\n\n\n<li><strong>Post-op cortisol<\/strong> at days 4\u20135 (off steroid cover for 20 h):\n<ul class=\"wp-block-list\">\n<li><strong>&lt;50 nmol\/L<\/strong> = best predictor of long-term remission.<\/li>\n\n\n\n<li>&lt;140 nmol\/L = compatible with remission.<\/li>\n\n\n\n<li><strong>&gt;140 nmol\/L at 3 months<\/strong> = persistent disease, re-investigate.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li>Complications: AVP-deficiency\/DI (3\u201346% transient, ~5% permanent), hypopituitarism, CSF leak, meningitis. <strong>Hyponatremia (SIADH) day 5\u201310<\/strong> in ~20%.<\/li>\n\n\n\n<li>Post-op steroid cover, tapering hydrocortisone 15\u201320 mg\/day in divided doses (largest dose AM, last by 18:00).<\/li>\n\n\n\n<li>HPA axis recovery rare before 3\u20136 months; common at 12 months \u2014 test annually.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Second-line therapies (persistent \/ recurrent CD)<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Repeat TSS<\/strong> \u2014 ~50% remission, higher hypopituitarism rates.<\/li>\n\n\n\n<li><strong>Radiotherapy<\/strong> (conventional 45\u201350 Gy in 25 fractions OR stereotactic \/ Gamma Knife):\n<ul class=\"wp-block-list\">\n<li><strong>Primary RT:<\/strong> ~50% remission long-term.<\/li>\n\n\n\n<li><strong>Adjunctive (post-failed TSS):<\/strong> ~80% (conventional) or ~50% (Gamma Knife at 5 y).<\/li>\n\n\n\n<li>Bridge with medical therapy while awaiting effect (often 2+ years).<\/li>\n\n\n\n<li><strong>GH deficiency in 36\u201368%<\/strong>, other hypopit ~20% over time.<\/li>\n\n\n\n<li>Increased CVA risk in some series, secondary tumor risk ~4%.<\/li>\n\n\n\n<li>Avoid Gamma Knife if tumor &lt;3\u20135 mm from optic chiasm.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Bilateral adrenalectomy<\/strong> \u2014 definitive cortisol control; <strong>lifelong steroid + mineralocorticoid replacement<\/strong>; \u2191rate of adrenal crisis (~9.3\/100 patient-yr); risk of <strong>Nelson&#8217;s syndrome<\/strong> (corticotroph tumor progression) 28\u201353% at mean 5.3 y, especially if young or visible pre-existing adenoma. <strong>Surveillance:<\/strong> MRI + ACTH q3 mo for 1 y, then yearly \u00d7 3 y, then q2\u20134 y. Prophylactic pituitary RT may reduce Nelson&#8217;s risk.<\/li>\n<\/ol>\n\n\n\n<h3 class=\"wp-block-heading\">Ectopic ACTH<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Resect when possible<\/strong> (bronchial carcinoid lobectomy = high cure rate).<\/li>\n\n\n\n<li>Metastatic \/ occult: medical management + bilateral adrenalectomy.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">ACTH-independent<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Adrenal adenoma:<\/strong> unilateral laparoscopic adrenalectomy \u2014 cure ~100%. Post-op glucocorticoid replacement until contralateral adrenal recovers (~6\u201312 months).<\/li>\n\n\n\n<li><strong>Adrenal carcinoma:<\/strong> <strong>open adrenalectomy<\/strong> if &gt;6 cm or imaging features of malignancy; mitotane adjuvant.<\/li>\n\n\n\n<li><strong>BMAD:<\/strong> <strong>unilateral adrenalectomy<\/strong> can be considered for milder cases (recurrence common); bilateral otherwise.<\/li>\n\n\n\n<li><strong>PPNAD:<\/strong> bilateral adrenalectomy curative.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Medical Therapy \u2014 Drug-by-Drug<\/h3>\n\n\n\n<h4 class=\"wp-block-heading\">Steroidogenesis inhibitors (workhorses)<\/h4>\n\n\n\n<p class=\"wp-block-paragraph\"><strong><a href=\"https:\/\/myendoconsult.com\/learn\/cushings-disease-and-mechanism-of-action-of-drugs\/\" data-type=\"post\" data-id=\"4421561\">Metyrapone<\/a><\/strong> (11\u03b2-hydroxylase inhibitor)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>750\u20136000 mg\/day in 3\u20134 divided doses.<\/li>\n\n\n\n<li>Fast onset (hours).<\/li>\n\n\n\n<li>Cortisol normalization: ~75% in CD (variable studies); recent PROMPT trial 47%.<\/li>\n\n\n\n<li><strong>Side effects:<\/strong> hirsutism, acne (\u2191androgens), HTN\/hypokalemia\/edema (\u219111-deoxycorticosterone), GI upset, dizziness.<\/li>\n\n\n\n<li><strong>11-deoxycortisol cross-reacts with some cortisol immunoassays<\/strong> \u2192 use LC-MS\/MS, or risk over-dosing and adrenal insufficiency.<\/li>\n\n\n\n<li>Most-used drug in <strong>pregnancy<\/strong> along with ketoconazole.<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\"><strong><a href=\"https:\/\/myendoconsult.com\/learn\/cushings-disease-and-mechanism-of-action-of-drugs\/\" data-type=\"post\" data-id=\"4421561\">Ketoconazole<\/a><\/strong> (multiple CYP inhibition: 11\u03b2-OH, C17-20 lyase, 17-OH, 18-OH)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>200 mg BID up to 400 mg TID (max 1200 mg\/d).<\/li>\n\n\n\n<li>Normalizes cortisol ~50\u201370% in CD; meta-analysis ~63%.<\/li>\n\n\n\n<li><strong>Side effects:<\/strong> <strong>hepatotoxicity<\/strong> (5\u201320% LFT rise; serious injury 1 in 15,000) \u2014 check LFTs weekly \u00d7 4 wk, then monthly \u00d7 3 mo. Stop if ALT &gt;3\u00d7 ULN.<\/li>\n\n\n\n<li><strong>Anti-androgenic<\/strong> \u2014 useful in hirsute women; <strong>gynecomastia + reduced libido<\/strong> in men (limits use).<\/li>\n\n\n\n<li>CYP3A4 inhibitor \u2014 many drug interactions.<\/li>\n\n\n\n<li>Needs gastric acid \u2014 avoid with PPIs.<\/li>\n\n\n\n<li>Avoid in pregnancy (teratogenic in animals).<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\"><strong><a href=\"https:\/\/myendoconsult.com\/learn\/category\/moa\/\" data-type=\"category\" data-id=\"243\">Osilodrostat<\/a><\/strong> (LCI699 \u2014 selective 11\u03b2-hydroxylase + aldosterone synthase inhibitor)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>2\u201360 mg\/day (start 2 mg BID, titrate q2 wk).<\/li>\n\n\n\n<li>FDA-approved 2020; NICE 2021 (UK).<\/li>\n\n\n\n<li>LINC-3 phase III: <strong>53% maintained UFC normal at 24 weeks<\/strong>, 66% at 48 weeks; long-term extension 50\u201388% at 6 years.<\/li>\n\n\n\n<li><strong>Side effects:<\/strong> adrenal insufficiency (~28%), nausea, fatigue, headache; <strong>\u2191androgens (hirsutism in ~30% of women)<\/strong>, \u219111-deoxycorticosterone \u2192 HTN\/hypokalemia in ~42%. QT prolongation possible.<\/li>\n\n\n\n<li>Now considered the <strong>best-studied recent steroidogenesis inhibitor<\/strong> for Cushing&#8217;s disease.<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Levoketoconazole<\/strong> (purified levo-enantiomer of ketoconazole)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>FDA-approved 2022. SONICS \/ LOGICS trials.<\/li>\n\n\n\n<li>Less hepatotoxic than racemic; otherwise similar profile.<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Etomidate<\/strong> (IV; potent rapid steroidogenesis blocker)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>For <strong>severe, acute hypercortisolism<\/strong> (e.g., cortisol-induced psychosis, severe hypokalemia, sepsis) in ICU setting. Non-hypnotic doses (0.04\u20130.05 mg\/kg\/h).<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\"><strong><a href=\"https:\/\/myendoconsult.com\/learn\/cushings-disease-and-mechanism-of-action-of-drugs\/\" data-type=\"post\" data-id=\"4421561\">Mitotane<\/a><\/strong> (adrenolytic)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Reserved for <strong>adrenocortical carcinoma<\/strong>.<\/li>\n\n\n\n<li>Slow onset (weeks\u2013months); <strong>most effective<\/strong> drug at normalizing cortisol (~82% pooled data) but complex monitoring (target plasma levels 14\u201320 mg\/L), severe GI\/neuro side effects, hyperlipidemia, hypothyroidism, \u2191CBG (interferes with cortisol assays).<\/li>\n\n\n\n<li><strong>Long-lasting adrenal effect<\/strong> persists after stopping.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">Pituitary-directed agents (Cushing&#8217;s disease specifically)<\/h4>\n\n\n\n<p class=\"wp-block-paragraph\"><strong><a href=\"https:\/\/myendoconsult.com\/learn\/mechanism-of-action-of-pasireotide\/\" data-type=\"post\" data-id=\"4404489\">Pasireotide<\/a><\/strong> (somatostatin analogue, SSTR5 &gt; SSTR2)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>SC 0.6\u20130.9 mg BID OR long-acting IM 10\u201340 mg monthly.<\/li>\n\n\n\n<li>Normalizes UFC in ~25\u201335%.<\/li>\n\n\n\n<li><strong>Key adverse effect: hyperglycemia (~70%)<\/strong> \u2014 often new-onset diabetes; manage with metformin then GLP-1 \/ SGLT2 \/ insulin.<\/li>\n\n\n\n<li>Other: cholelithiasis, \u2191LFTs, QT prolongation, sinus bradycardia.<\/li>\n<\/ul>\n\n\n\n<p class=\"wp-block-paragraph\"><a href=\"https:\/\/myendoconsult.com\/learn\/cushings-disease-and-mechanism-of-action-of-drugs\/\" data-type=\"post\" data-id=\"4421561\"><strong>Cabergoline<\/strong> <\/a>(D2 dopamine agonist)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>0.5\u20137 mg\/week off-label.<\/li>\n\n\n\n<li>Modest efficacy (~30\u201340% biochemical control); often used as add-on.<\/li>\n<\/ul>\n\n\n\n<h4 class=\"wp-block-heading\">Glucocorticoid receptor antagonist<\/h4>\n\n\n\n<p class=\"wp-block-paragraph\"><strong>Mifepristone<\/strong> (RU-486)<\/p>\n\n\n\n<ul class=\"wp-block-list\">\n<li>FDA-approved for CS-related hyperglycemia (not for CD broadly).<\/li>\n\n\n\n<li><strong>Cannot monitor with cortisol or ACTH<\/strong> (both rise as feedback is blocked) \u2014 monitor clinical features + glucose + K+.<\/li>\n\n\n\n<li>Side effects: hypokalemia (universally \u2014 block of 11\u03b2-HSD2), endometrial hyperplasia, adrenal insufficiency hard to recognize.<\/li>\n\n\n\n<li><strong>Newer: Relacorilant<\/strong> (selective GR antagonist, no progesterone effects) \u2014 phase 3 GRACE study showed efficacy without endometrial AEs.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">7. Cushing&#8217;s in Pregnancy<\/h2>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Rare; most often <strong>adrenal adenoma<\/strong> (different from non-pregnant pattern where CD dominates).<\/li>\n\n\n\n<li>Estrogen-driven \u2191CBG complicates diagnosis \u2014 <strong>UFC and LNSC are more useful than serum cortisol or LDDST<\/strong> (ONDST not validated in pregnancy).<\/li>\n\n\n\n<li>ACTH levels less suppressed than expected (placental CRH).<\/li>\n\n\n\n<li>Treatment: surgery in 2nd trimester preferred; <strong>metyrapone<\/strong> is the drug of choice if medical therapy needed; ketoconazole second-line (animal teratogenicity).<\/li>\n\n\n\n<li>Avoid mitotane (teratogenic) and pasireotide (lack of data).<\/li>\n\n\n\n<li>Maternal complications: preeclampsia, diabetes, infections, VTE.<\/li>\n\n\n\n<li>Fetal complications: prematurity, IUGR, stillbirth.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">8. Pearls &amp; Pitfalls<\/h2>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Sequential photographs<\/strong> (driver&#8217;s license, family photos) are diagnostic gold \u2014 progression matters more than any single feature.<\/li>\n\n\n\n<li><strong>Cyclical CS<\/strong> \u2014 test only during active phases; use LNSC or UFC ratio for screening.<\/li>\n\n\n\n<li><strong>CBG-raising states (estrogens\/HRT\/OCP, hepatitis)<\/strong> falsely elevate total cortisol \u2014 stop estrogen 4\u20136 weeks before ONDST\/LDDST.<\/li>\n\n\n\n<li><strong>CYP3A4 inducers<\/strong> (phenytoin, rifampin, carbamazepine, St. John&#8217;s wort) increase dex clearance \u2192 false-positive ONDST \u2192 measure dex level if available.<\/li>\n\n\n\n<li><strong>Macroadenoma + ACTH-dependent CS<\/strong> \u2192 BIPSS not required if dynamic tests concordant; carcinomas rare but consider if behavior is invasive.<\/li>\n\n\n\n<li><strong>Hypokalemic alkalosis + hyperpigmentation + rapid course<\/strong> \u2192 <strong>SCLC ectopic ACTH<\/strong> until proven otherwise.<\/li>\n\n\n\n<li><strong>Adrenal adenoma + virilization (or severe hirsutism)<\/strong> \u2192 think <strong>adrenocortical carcinoma<\/strong>.<\/li>\n\n\n\n<li><strong>Bilateral adrenal lesions<\/strong> \u2192 BMAD vs PPNAD vs ACTH-dependent hyperplasia \u2014 let ACTH and adrenal size guide you (BMAD = bilateral huge; PPNAD = bilateral small\/normal; ACTH-dep = bilateral enlarged).<\/li>\n\n\n\n<li><strong>Pre-op anticoagulation is the most under-utilized intervention<\/strong> \u2014 VTE rates are dramatic.<\/li>\n\n\n\n<li><strong>Glucocorticoid withdrawal syndrome<\/strong> post-cure is a real entity (malaise, joint pain, skin desquamation) \u2014 pre-warn patients; consider transient double-dose hydrocortisone tapering over 2\u20133 months if severe.<\/li>\n\n\n\n<li><strong>Recovery of HPA axis is rare before 3 months<\/strong>, often 12 months; not always permanent \u2014 <strong>subnormal SST at 3 years post-TSS predicts lifelong ACTH deficiency<\/strong> but also lower recurrence risk.<\/li>\n\n\n\n<li><strong>Nelson&#8217;s syndrome<\/strong> (&#8220;corticotroph tumor progression after bilateral adrenalectomy&#8221;) \u2014 monitor with serial MRI + ACTH; ACTH cut-off 200\u2013700 pg\/mL (best to track trajectory, not absolute number).<\/li>\n\n\n\n<li><strong>Mifepristone has no biochemical surrogate<\/strong> for adequate dosing \u2014 adrenal insufficiency easily missed; check clinical features, glucose, K+.<\/li>\n\n\n\n<li><strong>Pasireotide-induced diabetes<\/strong> is the rule, not the exception \u2014 monitor glucose from the start.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">9. Quick-Recall Numbers<\/h2>\n\n\n\n<ul class=\"wp-block-list\">\n<li>Endogenous CS incidence: 0.7\u20132.4 \/ million \/ year.<\/li>\n\n\n\n<li>CD accounts for <strong>60\u201380%<\/strong> of endogenous CS; <strong>&gt;90% microadenomas<\/strong>.<\/li>\n\n\n\n<li>Bronchial NET: <strong>~25%<\/strong> of ectopic ACTH; SCLC ~19%; occult ~16%.<\/li>\n\n\n\n<li>Diagnostic delay: <strong>34 mo<\/strong> (38 in CD; 14 in ectopic).<\/li>\n\n\n\n<li>ONDST sensitivity ~98\u201399%; <strong>cut-off cortisol &lt;50 nmol\/L (1.8 \u00b5g\/dL)<\/strong>.<\/li>\n\n\n\n<li>LNSC: sens 92%, spec 96%, \u22652 samples.<\/li>\n\n\n\n<li>UFC: \u22652 collections; <strong>&gt;4\u00d7 ULN = diagnostic<\/strong>.<\/li>\n\n\n\n<li>ACTH-independent: <strong>&lt;10 ng\/L (2 pmol\/L)<\/strong>; ACTH-dependent: <strong>&gt;20\u201330 ng\/L (4\u20136 pmol\/L)<\/strong>.<\/li>\n\n\n\n<li>BIPSS: baseline <strong>\u22652:1<\/strong> central:peripheral; post-desmopressin <strong>\u22653:1<\/strong>; interpetrosal <strong>\u22651.4<\/strong> for lateralization.<\/li>\n\n\n\n<li>TSS remission: micro <strong>~80\u201390%<\/strong>; macro <strong>~60\u201376%<\/strong>.<\/li>\n\n\n\n<li>Long-term recurrence: <strong>10\u201315% at 10 y; 20% at 20 y<\/strong>.<\/li>\n\n\n\n<li>VTE risk: <strong>18\u00d7 normal<\/strong>; 20% incidence without prophylaxis.<\/li>\n\n\n\n<li>Cushing&#8217;s disease genetics: <strong>~\u2153 USP8 somatic mutations<\/strong>.<\/li>\n\n\n\n<li>Carney complex: PPNAD in 30%; PRKAR1A mutation in &gt;70%.<\/li>\n\n\n\n<li>BMAD: <strong>ARMC5<\/strong> mutations in ~\u2153.<\/li>\n\n\n\n<li>Osilodrostat: ~53% UFC normalization at 24 wk; 66% at 48 wk.<\/li>\n\n\n\n<li>Pasireotide: ~25\u201335% UFC control; ~70% hyperglycemia.<\/li>\n\n\n\n<li>Nelson&#8217;s after bilateral adrenalectomy: 28\u201353% at mean 5.3 y.<\/li>\n<\/ul>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">10. Must-Read References<\/h2>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Fleseriu M, Auchus R, Bancos I, Ben-Shlomo A, Bertherat J, Biermasz NR, et al.<\/strong> Consensus on diagnosis and management of Cushing&#8217;s disease: a guideline update. <em>Lancet Diabetes Endocrinol.<\/em> 2021;9(12):847\u2013875. doi:10.1016\/S2213-8587(21)00235-7 <em>The current standard-of-care reference for Cushing&#8217;s disease. Diagnostic algorithm, BIPSS criteria, surgical\/medical\/radiation\/adrenalectomy strategy, post-operative monitoring, recurrence surveillance.<\/em><\/li>\n\n\n\n<li><strong>Nieman LK, Biller BMK, Findling JW, Newell-Price J, Savage MO, Stewart PM, Montori VM.<\/strong> The diagnosis of Cushing&#8217;s syndrome: an Endocrine Society Clinical Practice Guideline. <em>J Clin Endocrinol Metab.<\/em> 2008;93(5):1526\u20131540. doi:10.1210\/jc.2008-0125 <em>The foundational diagnostic guideline. Screening test cut-offs and approach to differential diagnosis \u2014 still the bedrock.<\/em><\/li>\n\n\n\n<li><strong>Nieman LK, Biller BMK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin A.<\/strong> Treatment of Cushing&#8217;s syndrome: an Endocrine Society Clinical Practice Guideline. <em>J Clin Endocrinol Metab.<\/em> 2015;100(8):2807\u20132831. doi:10.1210\/jc.2015-1818 <em>Companion treatment guideline. Surgical-first algorithm, role of medical therapy, radiotherapy, bilateral adrenalectomy.<\/em><\/li>\n\n\n\n<li><strong>Lacroix A, Feelders RA, Stratakis CA, Nieman LK.<\/strong> Cushing&#8217;s syndrome. <em>Lancet.<\/em> 2015;386(9996):913\u2013927. doi:10.1016\/S0140-6736(14)61375-1 <em>The most-cited comprehensive review in the modern era. Excellent integrated coverage of pathophysiology through treatment.<\/em><\/li>\n\n\n\n<li><strong>Reincke M, Fleseriu M.<\/strong> Cushing Syndrome: A Review. <em>JAMA.<\/em> 2023;330(2):170\u2013181. doi:10.1001\/jama.2023.11305 <em>Concise, current synthesis with practical diagnostic and therapeutic emphasis. Useful as a board-prep refresher.<\/em><\/li>\n\n\n\n<li><strong>Findling JW, Raff H.<\/strong> Diagnosis of Endocrine Disease: Differentiation of pathological\/neoplastic hypercortisolism (Cushing&#8217;s syndrome) from physiological\/non-neoplastic hypercortisolism (formerly known as pseudo-Cushing&#8217;s syndrome). <em>Eur J Endocrinol.<\/em> 2017;176(5):R205\u2013R216. doi:10.1530\/EJE-16-0946 <em>The reference for the pseudo-Cushing&#8217;s problem \u2014 how to handle the diagnostic gray zone with confidence.<\/em><\/li>\n\n\n\n<li><strong>Pivonello R, Isidori AM, De Martino MC, Newell-Price J, Biller BMK, Colao A.<\/strong> Complications of Cushing&#8217;s syndrome: state of the art. <em>Lancet Diabetes Endocrinol.<\/em> 2016;4(7):611\u2013629. doi:10.1016\/S2213-8587(16)00086-3 <em>The definitive source on the persistent cardiovascular, metabolic, bone, neuropsychiatric, and thromboembolic morbidity \u2014 essential for managing patients after biochemical cure.<\/em><\/li>\n\n\n\n<li><strong>Pivonello R, Fleseriu M, Newell-Price J, Bertagna X, Findling J, Shimatsu A, et al. (LINC-3 Investigators).<\/strong> Efficacy and safety of osilodrostat in patients with Cushing&#8217;s disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. <em>Lancet Diabetes Endocrinol.<\/em> 2020;8(9):748\u2013761. doi:10.1016\/S2213-8587(20)30240-0 <em>The pivotal trial that brought osilodrostat into modern Cushing&#8217;s care \u2014 know the efficacy and adverse-effect profile.<\/em><\/li>\n\n\n\n<li><strong>Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al.<\/strong> A 12-month phase 3 study of pasireotide in Cushing&#8217;s disease. <em>N Engl J Med.<\/em> 2012;366(10):914\u2013924. doi:10.1056\/NEJMoa1105743 <em>Landmark trial establishing pasireotide as the first pituitary-directed medical therapy. Defines the hyperglycemia trade-off.<\/em><\/li>\n\n\n\n<li><strong>Newell-Price J, Bertagna X, Grossman AB, Nieman LK.<\/strong> Cushing&#8217;s syndrome. <em>Lancet.<\/em> 2006;367(9522):1605\u20131617. doi:10.1016\/S0140-6736(06)68699-6 <em>The classic review by the chapter&#8217;s senior author and colleagues \u2014 still the most-quoted single-source overview of the clinical reasoning behind Cushing&#8217;s diagnosis and management.<\/em><\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"<p>Cushing&#8217;s Syndrome \u2014 High-Yield Notes Source: The MyEndoConsult Team 1. Etiology &amp; Epidemiology Two-bucket classification Category Cause Approx % of endogenous CS ACTH-dependent (~80\u201385%)&hellip;<\/p>\n","protected":false},"author":1,"featured_media":4423290,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[568],"tags":[],"class_list":["post-4423288","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-board-review"],"_links":{"self":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts\/4423288","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/comments?post=4423288"}],"version-history":[{"count":6,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts\/4423288\/revisions"}],"predecessor-version":[{"id":4423295,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/posts\/4423288\/revisions\/4423295"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/media\/4423290"}],"wp:attachment":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/media?parent=4423288"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/categories?post=4423288"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/tags?post=4423288"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}