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3 General % Obesity 90 Hypertension 85 Skin Plethora 70 Hirsutism/hair loss 75 Striae 50 Acne 35 Bruising/thinning 35 Musculoskeletal Osteopenia/porosis 80 Weakness 65 Neuropsych % Lability,euphoria,insomnia, depression,psychosis 85 Gonadal sx Abnormal menses 70 Decreased libido/ impotence 85 Metabolic Glucose intolerance 75 Diabetes 20 Hyperlidemia 70 Polyuria 30 Kidney stones 15 Cushing s disease(cd): yo woman with gradual progression and modest androgen excess Ectopic ACTH syndrome(eas) Benign: frequently cushingoid, hyperpigmented and hypokalemic. The tumor may be occult Malignant: Older male smoker with lung cancer and absent cushingoid features. Weight loss, weakness, HTN, hypokalemia, pigmentation and anemia are common Adrenal adenoma: mild to moderate cushingoid features and absent androgen excess Adrenal carcinoma(acc):rapidly progressive features of cortisol, androgen and/or mineralocorticoid excess 3

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11 DIAGNOSIS DDX OF ACTH-INDEPENDENT AND ACTH- DEPENDENT CAUSES DDX OF PITUITARY (CD) AND ECTOPIC CAUSES OF ACTH-DEPENDENT CS Choose your conditions Choose your test Choose your cortisol assay (LC/MS/MS) Keep it simple 11

12 DO NOT USE Tests which are not useful Any test beginning with 17 AM, 4PM, 8 PM, or random serum cortisol Tests which are not practical Midnight serum cortisol Six day DST Tests for DDX Localizing procedures Late night salivary cortisol (LNSC) Overnight DEX suppression (ONDST 1 mg) 24h urine cortisol 12

13 False + (Pseudocushing s syn) Acute illness/hospitalization Severe stress Morbid obesity Sleep apnea Depression/Anxiety Alcohol excess Anorexia nervosa * Regardless of test used False negative responses Mild Cushing s Episodic /Cyclic Cushing s (rare) *Regardless of test used 13

14 Collect 2 samples at 2300H on consecutive days Normal values at 2300H ELISA/EIA---<4.3 nmol/l LC/MS/MS---<0.09 mcg/dl Sensitivity---92% Specificity---96% 14

15 Advantages Ease of collection/multiple specimens Many pts with pseudocushing s maintain normal diurnal variation Two normal values exclude Cushing s Disadvantages(false+) Pseudocushing s Altered sleep/wake cycles A WORD OF CAUTION Liu et al * Male veterans with DM2 LNSC SPEC(%) All subjects 80 DM/HTN/AGE>60 60 Baid et al ** Obese subjects LNSC By RIA 84 By LC/MS/MS 92 * Clin Endocrinol 63:642,2005 ** JCEM 94:3857,

16 DEX 1mg at 2300H Serum cortisol at 0800H Normal response-am cortisol < 1.8mcg/dl (50 nmol/l) Sens % Spec % 16

17 Advantages A normal response excludes CS with 97-98% accuracy Disadvantages (false +) Pseudocushing s Estrogen/tamoxifen increase CBG Accelerated DEX metabolismphenytoin,phenobarb,rifampin,carbamazapine Renal failure Disadvantages (false-) Delayed DEX metabolism (<1%) Collect two 24H urines Assay by RIA or LC/MS/MS Normal range 4-50 mcg/24h(lc/ms/ms) Sens % Spec % 17

18 Advantages Estimates 24H excretion Not increased in moderate obesity Disadvantages Requires 24H collection Many patients with pseudocushing s have mild to moderate increases in UC False + with high urine volume False - in renal failure 18

19 Sens Spec LR- LR+ DST 1mg <50** <138** LNSC <14.5** UCORT <170*** **nmol/l ***nmol/24h Note: For cortisol nmol/ldivided by 27.6=mcg/dl Two day low-dose DST DEX 0.5mg Q6H x 48H (OR 1.0 mg Q12H) Collect serum cortisol at 48H Normal response serum cortisol <1.8mcg/dl Useful in pts with mildly abnormal results of other tests 19

20 Choose conditions/assay Perform ONDST(1MG) or LNSC or Ucort If normal CS very unlikely If abnormal confirm with 2 nd test If equivocal consider two day LDDST and/or follow over time Percent Pituitary (Cushing s disease) 75 Ectopic ACTH syndrome 10 Ectopic CRH <1 ACTH-dependent ACTH-independent Adrenal adenoma 10 Adrenal carcinoma 5 PPNAD & AIMAH <1 20

21 Measure ACTH by IRMA or ICMA assay These assays reliably detect suppressed levels ie < 5 pg/ml ACTH <5 pg/ml=acth independent (image adrenals) ACTH >10 pg/ml =ACTH dependent 21

22 THE PROBLEM Pituitary adenomas average 5mm in diameter Many ACTH-secreting carcinoids are <10mm Routine MRI positive in 42*-50% of pts with CD STRATEGY Do Dynamic MRI--Positive or suspicious in 83%** If MRI negative, equivocal or if high suspicion for ectopic ACTH syn proceed to inferior petrosal sinus sampling (IPSS). IPSS:positive for CD if central/peripheral ACTH ratio >2 OR >3 after CRH *NIH-JCEM 98:2285,2013 (501 PATIENTS) **UCSF-J Neurooncol 16:693,

23 Cavernous/Inferior Petrosal Sinus Sampling IPSS Oldfield et al 1985 Right Cushing s Disease Central/peripheral ACTH ratio 2 Or 3 after CRH CS Left Left IPS peripheral 23

24 Newell-Price et al* 21 series, 646 subjects 96% success in canulating bilateral sinuses Sensitivity--96% Specificity--100% Lateralization (diagnostic accuracy--78%) UCSF-Liu C et al** N=95, all with non-diagnostic MRI, sampled CS and IPS with and without CRH Sensitivity 100%,specificity 100% Lateralization (diagnostic accuracy--62%) *Endo Rev 19:647,1998. **Clin Endo 61:478,2004 Overall diagnostic accuracy---62%*-69%** 15/28(54%) cured by hemihypophysectomy based on lateralization data.* *UCSF- Clin Endo 61:478,2004(N=95) **NIH- JCEM 98:2285,2013(N=501) 24

25 Caveats The Dx of ACTH-dependent CS must be established prior to IPSS Pt must be hypercortisolemic at the time of the procedure False + results Normal pts Pts with pseudo-cs ACTH dependent hypercortisolism Positive pituitary MRI (lesion >5mm) OR Positive central venous sampling 25

26 Transsphenoidal surgery(tss) Remission:70-85% Therapy of persisting/recurrent disease Repeat TSS Radiotherapy Medical RX Bilateral adrenalectomy MGH ( )* NO % Remission 137/161 85** Recurrence 10/136 7 UCSF ( )*** Remission 236/ Recurrence 13/150 9 *Ann Intern Med 130:821,1999, ** 28 pts had more than 1 operation. *** JCEM 89:6348,

27 No SMR MGH Deaths 6/ UCSF Deaths 29/248 Remission 1.2 Persisting disease 2.8 Therapy of persisting or recurrent disease Repeat TSS Radiotherapy Medical RX Bilateral adrenalectomy 27

28 Remission 168/246(68%) (Range 37-87%) Relapse 22/123(18%) (Range 0-35%) *Can J Neurol Sci 38:12,2011(11 series,246 patients) % Conventional Remission Hypopit Tumor control Gamma knife(srs) Remission Hypopit 5-66 Tumor control *Arq Bras Endocrinol Metab 51:1373,2007 Pituitary 17:60,

29 % Gamma Knife Remission at 2 yrs 62 Remission at 10 yrs 64 Remission all pts 57 Recurrence 18 Hypopit 25 *JCEM 102:4884,2017 (N=278,mean F/U 5.6 years) Inhibit ACTH secretion Cabergoline Pasireotide (new somatostatin analog) Cyproheptadine,bromocriptine,older somatostatin analogs and sodium valproate not effective Inhibit cortisol secretion Ketoconazole Metyrapone Mitotane Etomidate (IV only) Glucocorticoid receptor antagonist Mefipristone 29

30 Dose(mg/wk) U Cort normal Study #1* 1-7(median 3.5) 8/20(40%) 24 months Study #2** 0.5-6(mean 2.1) 9/30(30%) months (mean 37) *JCEM 94:223,2009 **Eur J Endocrinol 136:709, mcg* 900 mcg* All pts U Cort normal At 6 mos 12/82 21/80 33/162 (15%) (26%) (20%) At 12 mos 5/39 10/39 15/78 (13%) (26%) (19%) Adverse effects-diarrhea 58%, nausea 52%, DM/hyperglycemia 73%, new diabetic DX 46% *600 or 900 mcg SQ BID 30

31 10-30mg** 30-40mg** All pts U Cort normal 26/75 19/76 45/150 at 12 mos (35%) (25%) (30%) Adverse effects-diarrhea 39%, hyperglycemia 48%, diabetes 21% *Lancet Diabetes Endocrinol 6:17,2018 **10-30mg or 30-40mg IM monthly for12 mos Dose (mean:mg/day) U Cort normal Pre Surgery /39(49%) ( mos) Post TSS or XRT /158(49%) ( mos) Long term 33/51(65%) ( mos) Adverse effects-intolerance 21%,elevated LFT s 16%,markedly elevated LFT s 3%, AI 5% 31

32 Glucocorticoid antagonist-can t follow cortisol 50 pts treated for 6 mos(dose mg/day) C-DM--decreased aucgtt >25% 15/25(60%) C-HT---decreased DBP >5mm HG 8/21(38%) WT decreased % Adverse effects Nausea 48%,fatigue 48%, headache 44%,hypokalemia 34%,HTN 24%. Arthralgia,vomiting,edema,dizziness,anorexia in 20-30%. AI-N=2 UCORT normal Cabergoline/ketoconazole 25/32 (78%) Pasireotide/cabergoline/ ketoconazole 13/17 (76%) Ketoconazole/octreotide 3/4 (75%) *Pituitary 18:253,

33 Consider in Young pts Those who fail TSS, XRT and medical RX Advantages Rapidly corrects hypercortisolism with low morbidity/mortality Should reverse excess mortality Low recurrence rate Disadvantages Permanent AI Risk of Nelson s syndrome Transphenoidal surgery is the procedure of choice, however, there are no clear guideline as to how to proceed when patients fail TSS as primary therapy 33

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35 Small cell lung cancer(50%) Carcinoid tumors (LUNG, mediastinum/thymus, abdomen,pancreas Pancreatic neuroendocrine tumors Medullary thyroid cancer Pheochromocytoma/paraganglioma Neuroendocrine tumors of unknown origin Misc 35

36 From Aniszewski et al, World J Surg 32:659,

37 Exclude CD by negative IPSS CT and MRI equally accurate Utility of newer imaging procedures unclear EAS:LOCALIZATION SERIES PIT MRI IPSS BODY CT/ SRS OCCULT ABN (-) MRI(+) (+) 1* % - 2** 26% 100% 74% 49% 19% *BARTS( ,N=40) JCEM 91:371,2006 **NIH( ,N=90) JCEM 90:4955,

38 RX primary tumor Inhibit ACTH or cortisol secretion Laparoscopic adrenalectomy EAS: OUTCOME SERIES CURED/ ADRENEX MED SURVIVAL REMISSION RX (F/U) 1* 12% 61% - 40% 2** 30% 30% 70% 38%(5Y) 3*** 47% 37% 69% 79%(2.2Y) *MAYO( ,N=106)World J Surg 25:934,2001 **BARTS( ,N=40) JCEM 91:371,2006 ***NIH( ,N=90) JCEM 90:4955,

39 Adenoma-Unilateral lap adrenalectomy -Prognosis:cure ACC -Lap/open adrenalectomy - Mitotane -Inhibit cortisol secretion -Prognosis:50% mortality in 2 yrs PPNAD & AIMAH-Bilateral adrenalectomy -Cushing s cured with AI From Pivonello et al, NEJM,

40 26 yo woman with ACTH dependent CS MRI Rathke s cyst &? some focal abnl in the left wing Where Is the Source of ACTH? Pituitary vs Ectopic 40

41 Right Left Left 86 CS IPS CRH peripheral IPSS confirms CD Transsphenoidal surgery (TSS) 9/12/2000 No adenoma was found Left Hemihypophysectomy based on venous sampling + the equivocal focal abnl in the left lateral wing 41

42 Periop course 9/12 left hemi 9/13 cortisol 24 ug/dl Received HC postop on 9/12 9/14 cortisol 13ug/dL 9/15 cortisol 1 ug/dl (while on dex) D/Ced on HC 20/10 9/25 cortisol 13 ug/dl, ACTH 20ng/L 9/28 24h urine 126ug/24 hours TSS failed her What Should Be Done to Control Hypercortisolism? A: Repeat surgery B: Radiation C: Medical Therapy D: Surgical Adrenalectomy 42

43 Repeat surgery was thought not to provide additional chance for cure Bilateral adrenalectomy 12/ months after TSS On HC 20/10 mg + Florinef 0.1mg Postop course 12/2000 On HC, tapered to 15/5 mg + Florinef 0.1mg Weight loss slow, with lots of diet & exercise Oligomenorrhea, last regular cycle 11/1999 Seen by Repro-endo for infertility Found to have anovulation, thought to be weight related Monitored for adrenal remnant stimulation, cortisol < 1 without HC 43

44 10/2001 Na 136 mmol/l K 4.4 mmol/l ACTH? 432 ng/l on HC 15/5 7/2002 Received Clomid x2 for fertility Repeat Na/K/ACTH ACTH > 1500 ng/l ACTH > 1500 ng/l Does This Concern You? Should Anything Be Done? A: Repeat ACTH B: Increase HC and /or Florinef C: Pituitary MRI D: None of the above 44

45 26 yo woman with Cushing s Disease, s/p adrenalectomy 26 yo with Nelson s Syndrome Endonasal trans-sphenoidal resection 8/2002 No evidence of gross invasion Complete resection ACTH 42 and 50 ng/l postop 45

46 26 yo with Nelson s Syndrome 3 uneventful pregnancies 1/2003, 5/2006 and 5/2010 STRATEGY If MRI negative, equivocal or high suspicion for EAS, proceed to inferior petrosal sampling (IPSS) IPSS: Positive for CD if central/peripheral ACTH ratio > 2 before CRH OR > 3 after CRH 46

47 Pituitary MRI Lesions smaller than 5 mm, especially those <3-4 mm may be artifacts, volume averaging, incidental adenomas or cysts Minor degrees of pituitary asymmetry or stalk deviation in the absence of a discrete lesion are normal variations of pituitary anatomy 10% of normals have small adenomas/cysts on MRI (majority < 5 mm) STRATEGY Do MRI if positive (lesion >5mm), proceed to surgery * If MRI negative or high suspicion for ectopic ACTH syn, proceed to inferior petrosal sinus sampling (IPSS) *caution re: minor abnormalities 47

48 Dynamic tests ie HDDST,CRH, desmopressin and metyrapone are not useful* Pituitary MRI is positive in approx. 50% of pts with CD *Ectopic ACTH syndrome caused by a bronchial carcinoid tumor responsive to dexamethasone,metyrapone,and corticotropin-releasing factor. Am J Med 84,760,1988 THE PROBLEM Pituitary adenomas average 5mm in diameter Many ACTH-secreting carcinoids are < 10mm 48

49 Cavernous/Inferior Petrosal Sinus Sampling IPSS Oldfield et al

50 Right Cushing s Disease Central/peripheral ACTH ratio 2 Or 3 after CRH CS Left Left IPS peripheral Right Cushing s Disease Central/Peripheral ACTH 2 Left Left Or 3 after CRH CS IPS peripheral 50