Cortisol levels. Naturally produced by the adrenal Cortisol

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3 Cortisol levels asleep awake Naturally produced by the adrenal Cortisol Man made tablets, injections, creams & inhalers Cortisone Hydrocortisone Prednisone Prednisolone Betamethasone Methylprednisolone Triamcinolone Dexamethasone hours Can cause Cushing s syndrome If taken long enough and/or in high doses 3

4 2-3 cases per million people per year ~ 90% small tumor (< 1 cm, microadenoma) Female > males Benign tumor (adenoma) 4

5 Cortisol increases glucose levels Increased blood glucose causing diabetes mellitus Increased fatty acids, redistributes fat (central, facial, above clavicles, on thoraco-cervical spine) Muscle wasting, weakness & pain Cortisol inhibits calcium absorption and bone formation Osteoporosis (bone lose) Cortisol regulates fertility hormones Lose of menstruation, reduced libido and infertility Cortisol inhibits inflammatory response Creates immunocompromised state 5

6 Cortisol inhibits growth of connective tissue Easy bruising Purple striae Poor wound healing ACTH stimulates release of androgens: Excess hair & acne Cortisol increases blood pressure Cortisol affects emotional balance, memory Initially euphoria, long term depression Impaired memory Sleep disturbances Cognitive deficits Cortisol increases appetite 6

7 Increased susceptibility to infections Uncontrolled diabetes mellitus Vascular disease (myocardial infarction & strokes) If untreated, mortality rate is up to 11-fold higher than the general population 7

8 Initial testing Late-night salivary cortisol (LNSC) 24-hour urine free cortisol (24-h UFC) Dexamethasone suppression test (1 mg DST) Confirmatory/Localization testing Plasma ACTH levels Pituitary MRI Inferior Petrosal Sinus Sampling (IPSS) Important to remember when interpreting cortisol measurement results Vary from time to time Affected by synthetic corticosteroid treatment Change with different measurement techniques and between laboratories Affected by pregnancy, night shifts and stressful events Affected by substances like neurologic drug, oral contraceptives, alcohol, cigarettes, chewing tobacco or licorice Affected by unrelated diseases like liver or renal failure, mental disorders, obesity depression and uncontrolled diabetes mellitus. 8

9 For diagnosis of Cushing s disease and recurrence follow up Approaches to obtain saliva: expectoration, passive drool, aspiration, chewing on a cotton/polyester swab Up to 3 ml saliva, 1 ml/minute Obtain 2 samples at 11:00 pm, h apart The Salivette Saliva Collection Aid Store samples at 4 C, can mail to lab at room temperature AVOID: Any cortiosteroid treatment, including creams / ointments Smoking, brushing teeth, eating/drinking (except water) 2 h prior

10 High-resolution, thin-sections, contrast-enhanced Performed AFTER Cushing s disease is biochemically proven. Occasionally no adenoma can be visualized Localizes excessive ACTH release to the pituitary Localizes the tumor in the pituitary Technically demanding and should be performed in an experienced tertiary referral center 10

11 the initial treatment of choice for Cushing s disease is selective pituitary tumor resection by a surgeon with extensive demonstrated experience in pituitary surgery A Consensus Statement, 2008, Journal Clinical Endocrinology & Metabolism Transsphenoidal approach Tumor resection - when a tumor is visualized Partial pituitary resection-when tumor is not visualized 11

12 Short term Adrenal insufficiency Long term Control rates 65 90% if selective removal of a small tumor was done by an expert pituitary surgeon Recurrence rate 5 10% at 5 years 10 20% at 10 years Increased recurrence risk Age under 25 years Large tumor Invasive tumor Tumor cannot be located 12

13 Repeat pituitary surgery Success rate ~50-70% if performed by a surgeon with extensive experience in pituitary surgery Radiotherapy Achieves control in approximately 50 60% of patients within 3 5 years Bilateral adrenalectomy Immediate control BUT Lifelong adrenal hormone replacement therapy and endocrine follow up are required Drug therapy 13

14 Acutely ill patients in preparation for surgery Patients for whom surgery is not indicated: -Unknown tumor location -Unresectable lesions Patients cannot have surgery for medical reasons Patients who remain hypercortisolemic postoperatively Patients refusing surgery A Consensus Statement, 2008, Journal Clinical Endocrinology & Metabolism Definitive therapy, either surgery or radiotherapy, should be considered for all patients, and long term medical therapy alone is rarely indicated. 14

15 40% normalized ACTH & cortisol Hypotension Escape Pituitary Cabergoline ^ Pasireotide ^* Roscovitine ^ 26% normalized ACTH & cortisol Hyperglycemia Adrenal insufficiency ACTH Adrenal cortisol Peripheral tissue Ketoconazole & Metyrapone LCI699 # Mifepristone * * New drugs, FDA approved for Cushing s disease ^ In clinical trials at the Pituitary Center # In clinical trials & off label use 75% normalized cortisol Increased ACTH Liver toxicity Low androgens 80% clinical improvement Increased ACTH & cortisol Adrenal insufficiency Low potassium Growth of uterine inner tissue

16 685 patients with Cushing s disease in the US in 2010 Hard on the patient Diabetes mellitus 30.5% Psychiatric disease 22.5% Infections 21% Osteoporosis 8.6% (vertebral fracture 0.7%) Cardiovascular disease/stroke 8% Kidney stones 5.5% Hard on the physician Challenging diagnosis 19.8 office visit per patient per year Hospitalization 38.4% Emergency room visits 34.2% Expensive $35,000 per patient per year (Broder et al. Endocrine Practice 2014) 16

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