Physiology. The Hypothalamic Pituitary Adrenal Axis. Elena A Christofides, MD, FACE

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1 Elena A Christofides, MD, FACE Endocrinology Associates, Inc Endocrinology Research Associates, Inc Physiology 2 The Hypothalamic Adrenal Axis A Complex Set of Feedback Influences* Hypothalamus releases CRH, which stimulates the pituitary gland 1 CRH Release of CRH is influenced ACTH by 2 Significant stressor Physical activity Sleep/wake cycle Cortisol Hypothalamus *Graphical representation. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone. 1. Raff H, et al. Compr Physiol. 2014; 4(2): Raff H, et al. Ann Intern Med. 2003; 138(12): Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Adrenal gland 3 1

2 The Hypothalamic Adrenal Axis A Complex Set of Feedback Influences* gland subsequently secretes ACTH, resulting in the activation of the adrenal glands Adrenal glands respond by releasing cortisol into the bloodstream Adrenal CRH ACTH Cortisol *Graphical representation. Raff H, et al. Compr Physiol. 2014;4(2): Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): The Hypothalamic Adrenal Axis A Complex Set of Feedback Influences* When there is an adequate amount of cortisol, the hypothalamus and pituitary reduce the amount of CRH and ACTH, respectively (negative feedback) CRH ACTH Cortisol Hypothalamus *Graphical representation. Raff H, et al. Compr Physiol. 2014;4(2): Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): The Hypothalamic Adrenal Axis A Complex Set of Feedback Influences* Controls reactions to physical or psychosocial stress 1 Regulates many processes, including Carbohydrate metabolism 2 Immune response 3 Blood pressure 2 Hypothalamus Adrenal CRH ACTH Cortisol *Graphical representation. 1. Dickerson SS, et al. Psychol Bull. 2004;130(3): Raff H, et al. Compr Physiol. 2014;4(2): Nieman LK. Ann NY Acad Sci. 2002;970: Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2):

3 Cortisol Secretion Diurnal Variation In healthy, day-working people, cortisol is at its highest level between 6:00 AM and 8:00 AM, tapering off during the day, and reaching its trough toward midnight 1 Serum Cortisol Levels Normal diurnal rhythm 12am 4am 8am 12pm 4pm 8pm 12am Healthy patients have a cyclic cortisol trough at night 1 This break is necessary to restore and maintain homeostasis and to avoid development of pathologic conditions 2 Hormone Levels High Normal Low 8:00 AM (normal day worker) CRH ACTH Cortisol Hormone Levels High Normal Midnight (normal day worker) CRH ACTH Cortisol 1. EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7, Chung S, et al. Biochim Biophys Acta. 2011;1812(5): Clinical Impact of Excess Cortisol 8 Excess Cortisol Causes Multisystemic Dysfunction Muscle weakness/atrophy 1 Osteoporosis/ Vertebral fracture 1,2 Insomnia/Concentration difficulties/psychiatric/mood disturbances 1,2 Recurrent infection 2 Dermatologic manifestations 1 No single sign or symptom is pathognomonic of hypercortisolism 1 Hypertension/ Dyslipidemia 1 Gonadal dysfunction/ Menstrual irregularity 1 Obesity 1 Clotting/Thrombosis 3 Diabetes/Insulin resistance 1 1. Raff H, et al. Compr Physiol. 2014;4(2): Nieman LK. Ann NY Acad Sci. 2002;970: Sharma ST, et al. Clin Epidemiol. 2015;7:

4 Physiologic Impact of Excess Cortisol Blood Glucose and Insulin Resistance Target Organ(s) 1 Clinical Consequence(s) of Excess Cortisol Secretion 1 Mechanism(s) 1 Pancreas, liver, adipose tissue, muscle Diabetes Glucose intolerance Metabolic syndrome Liver: glucose production Muscle: glucose uptake and storage (glycogen) Adipose tissue: lipolysis/fat redistribution Pancreas: beta-cell function, leading to a decrease in insulin production Excess cortisol promotes insulin resistance 2 Disrupts insulin receptor signaling Insulin Glucose GLUT4, glucose transporter type Mazziotti G, et al. Trends Endocrinol Metab. 2011;22(12): Pivonello J, et al. Neuroendocrinology. 2010;92(suppl 1): Physiologic Impact of Excess Cortisol Hypertension Target Organ(s) Clinical Consequence(s) of Excess Cortisol Secretion Mechanism(s) Blood vessels Hypertension, 1 CV disease 2 Increases plasma volume, peripheral vascular resistance, and cardiac output 1 Promotes endothelial dysfunction 2 GR MR Excess cortisol promotes resistant hypertension 1 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; BP, blood pressure; CV, cardiovascular; GR, glucocorticoid receptor; K, potassium; MR, mineralocorticoid receptor; Na, sodium. 1. Cicala MV, et al. Neuroendocrinology. 2010;92(suppl 1): Androulakis II, et al. J Clin Endocrinol Metab. 2014;99(8): Physiologic Impact of Excess Cortisol Osteoporosis Target Organ(s) Clinical Consequence(s) of Excess Cortisol Secretion Mechanism(s) Bone Osteoporosis, 1 fractures 1 Impairs bone formation 2 Increases bone resorption 2 Inhibits calcium absorption from the gut 2 Alters other factors impacting bone growth (eg, gonadotropin, growth hormones, cytokines, growth factors) 2 Excess cortisol promotes bone loss 2 Impacts BMD Impacts bone architecture and remodeling, which affects bone strength BMD, bone mineral density. 1. Chiodini I, et al. Ann Intern Med. 2007;147(8): Kaltsas G, et al. Neuroendocrinology. 2010;92(suppl 1):

5 Impact of Excess Cortisol Summary Excess cortisol causes multisystemic dysfunction 1-3 No single clinical sign or symptom defines hypercortisolism 1 Notably, excess cortisol has profound impacts on Glucose metabolism 4-5 CV disease 6-7 Structural tissue catabolism Raff H, et al. Compr Physiol. 2014;4(2): Nieman LK. Ann NY Acad Sci. 2002;970: Sharma ST, et al. Clin Epidemiol. 2015;7: Mazziotti G, et al. Trends Endocrinol Metab. 2011;22(12): Pivonello J, et al. Neuroendocrinology. 2010;92(suppl 1): Cicala MV, et al. Neuroendocrinology. 2010;92(suppl 1): Androulakis II, et al. J Clin Endocrinol Metab. 2014;99(8): Chiodini I, et al. Ann Intern Med. 2007;147(8): Kaltsas G, et al. Neuroendocrinology. 2010;92(suppl 1): Evolution of Hypercortisolism 14 Evolution of Hypercortisolism Introduction HC is associated with high morbidity and mortality 1,2 HC manifests as a spectrum of signs and symptoms (from mild to severe) 3 Even mild HC has consequences 4-5 HC, hypercortisolism. 1. Plotz CM, et al. Am J Med. 1952;13(5): Clayton RN, et al. J Clin Endocrinol Metab. 2011;96(3): Guaraldi G, Salvatori R. J Am Board Fam Med. 2012;25(2): Di Dalmazi G, et al. Lancet Diabetes Endocrinol. 2014;2(5): Lopez D, et al. Ann Intern Med. 2016;165(8):

6 Mortality Associated With Hypercortisolism Cushing Syndrome Historically, untreated Cushing syndrome is associated with ~50% mortality at 5 years 1 Cushing Disease Patients in remission experienced reduced mortality compared to those with no remission 2 1 Survival (15) 53% 47% Survivorship S(t) Remission (54) 5-Year mortality (17) Retrospective, single-center study (records from 1932 to 1951); 33 patients with classical physical characteristics of Cushing syndrome and at least 3 of 5 commonly encountered abnormalities. One patient lost to follow-up. 1. Plotz CM, et al. Am J Med. 1952;13(5): Clayton RN, et al. J Clin Endocrinol Metab. 2011;96(3): No remission (6) Follow-up (years) Retrospective, single-center study (records from 1958 to 2010); 60 patients with histologically proven ACTH-staining pituitary adenoma or highly likely ACTH-dependent Cushing disease. 16 Increased All-Cause Mortality in Patients With Mild Hypercortisolism * Survival Rates for All-Cause Mortality Cortisol Level after Survival Rates 1-mg DST 100 All-Cause Mortality Nonsecreting adrenal nodule P= % 57.0% <1.8 μg/dl 1.8 μg/dl-5.0 μg/dl or >5.0 μg/dl Proportion Surviving (%) Mild hypercortisolism Even when clinical signs of overt hypercortisolism are not present, patients with adrenal adenomas and mild hypercortisolism have an increased risk of CV events and mortality *15-year, retrospective, single-center study; 198 consecutive patients with adrenal adenoma Follow-up (years) DST, dexamethasone suppression test. Di Dalmazi G, et al. Lancet Diabetes Endocrinol. 2014;2(5): Studies Demonstrate Increased CV Disease Risk in Patients With Hypercortisolism * Adenoma diameter 2.4 cm and DST cortisol >1.8 μg/dl confers elevated risk Outcome Odds Ratio P value Prevalent CV event 3.1 <0.05 Incident CV event Worsening metabolic profile In patients with an adrenal adenoma 2.4 cm, clinical and biochemical follow-up is required due to the potential development of mild hypercortisolism and its related consequences *Retrospective, multicenter study ; 206 patients with adrenal adenoma and no overt signs of hypercortisolism. Increase in 2 parameters: body weight, BP, glycemia, and/or low-density lipoprotein cholesterol. Morelli V, et al. J Clin Endocrinol Metab. 2014;99(3):

7 Increased CV Mortality Associated With Disrupted Diurnal Rhythm * Hazard Ratios for All-Cause and CV-Related Mortality All-Cause Mortality CV Deaths Slope across the day 1.30 ( ) 1.87 ( ) Bedtime cortisol 1.33 ( ) 1.98 ( ) Increased CV mortality associated with disrupted diurnal rhythm: Higher nighttime cortisol Less-steep cortisol decline during the day *Prospective cohort study;4047 subjects collected salivary cortisol samples daily at waking, 30 minutes/2.5 hours/8 hours/ 12 hours after waking, and at bedtime. Kumari M, et al. J Clin Endocrinol Metab. 2011;96(5): Increased Risk for Composite Diabetes in Patients With Mild Hypercortisolism * Patients with NFATs had significantly higher risk for incident composite diabetes than those without adrenal tumors (adjusted risk ratio was 1.87) 50 NFATs 45 No adrenal tumors % % Follow-up (years) At risk, n NFATs No adrenal tumors Composite Diabetes (%) This suggests that even nonfunctional tumors are associated with hormonal dysregulation *Retrospective cohort study included patients with NFATs (n=166) and those with no adrenal tumors (n=740) with at least 3 years of follow-up; NFAT determined by 1-mg DST cortisol <1.8 μg/dl and/or 24-hour UFC <50 μg Composite diabetes was defined as prediabetes or type 2 diabetes. Prediabetes was defined as 2 or more HbA1c 5.7%-6.4% for a patient considered to be nondiabetic/prediabetic at baseline. NFAT, nonfunctional adrenal tumor; UFC, urinary free cortisol. Lopez D, et al. Ann Intern Med. 2016;165(8): Mild Hypercortisolism Is Common 0.2%-2.0% Estimated Prevalence of Mild Autonomous Cortisol Secretion in the Adult Population 5% 4%-7% 30% Percentage of imaged adults found to have an incidental adrenal nodule Percentage of incidental adrenal nodules estimated to be cortisol-secreting Chiodini I. J Clin Endocrinol Metab. 2011;96(5):

8 Evolution of Hypercortisolism Summary CS is associated with significant morbidity and mortality 1,2 Even when clinical signs of overt hypercortisolism are not present, patients with adrenal adenomas and mild hypercortisolism have an increased risk of CV events and mortality 3 Even nonfunctional adrenal tumors are associated with hormonal dysregulation 4 The degree of hypercortisolism by itself does not seem to be a sufficiently exhaustive parameter to assess the severity of active CS 5 Mild hypercortisolism is common 6 CS, Cushing syndrome. 1. Plotz CM, et al. Am J Med. 1952;13(5): Clayton RN, et al. J Clin Endocrinol Metab. 2011;96(3): Di Dalmazi G, et al. Lancet Diabetes Endocrinol. 2014;2(5): Morelli V, et al. J Clin Endocrinol Metab. 2014;99(3): Guarnotta V, et al. Endocrine Mar 10. [Epub ahead of print] 6. Chiodini I. J Clin Endocrinol Metab. 2011;96(5): Epidemiology, Screening, and Diagnostic Tests 23 How Common Is Endogenous Cushing Syndrome? Overt CS affects an estimated people per million each year 1 ~20,000 patients in the United States 2 Affects women more commonly than men (3:1 ratio) 3 Peaks in 3rd or 4th decade of life 4 Mild hypercortisolism is more common than overt hypercortisolism 5 Estimated prevalence of about 0.8 per 1000 people in the general population 5 This prevalence is probably underreported because of the lack of symptoms or signs in these patients 6 Mild CS may be present in a large proportion of cases of adrenal adenomas 6 1. American Association of Neurological Surgeons. Updated October Accessed November 7, Promising pre-clinical and phase 1 data support advance of selective cortisol modulator CORT as potential treatment for Cushing s syndrome and solid-tumor cancers [press release]. Menlo Park, CA: Corcept Therapeutics Inc; April 28, EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7, Castinetti F, et al. Orphanet J Rare Dis. 2012;7: Reincke M. Endocrinol Metab Clin North Am. 2000;29(1): Androulakis II, et al. J Clin Endocrinol Metab. 2014;99(8):

9 Etiology of Classic Cushing Syndrome source [Cushing disease] Ectopic source ACTH- Dependent ACTH- Dependent ACTH- Independent Adrenal source Raff H, et al. Compr Physiol. 2014;4(2): Not Every Patient With Hypercortisolism Presents With the Classic Features of Cushing Syndrome More Specific Signs Striae (>1 cm wide) Facial plethora Proximal myopathy Easy bruising Common Signs Acne Peripheral edema Muscle weakness Truncal obesity Supraclavicular fullness Dorsocervical buffalo hump Specific Symptoms None Common Symptoms Depression Fatigue Weight gain Back pain Irritability Decreased libido Menstrual abnormalities Clinical Spectrum of Hypercortisolism Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Screening Considerations for Hypercortisolism Mild hypercortisolism prevalence in patients with diabetes, hypertension, obesity, and osteoporosis may reach 10.8% 1 Patient Populations to Be Screened for Hypercortisolism* Recommended Suggested Patients with multiple signs and symptoms compatible with classic CS 1 All patients with adrenal adenoma 1,2 Patients with pituitary adenoma in the presence of other features suggesting hypercortisolism 2 Patients with diabetes <50 years of age (poorly controlled) 2 Patients with hypertension <50 years of age (poorly controlled) 2 Patients with low BMD vs matched controls, BMD that rapidly declines, or fragility fractures 2 Patients with suspected polycystic ovary syndrome 1 *Use clinical judgment based on overall clinical presentation. 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Chiodini I, et al. Endocrine Jul 12. [Epub ahead of print] 27 9

10 Screening Model for Cushing Syndrome in At-Risk Populations Observational, prospective, multicenter study Develop/validate scoring system to predict CS based on clinical signs and LNSC Cutoff score of 4 83% subjects without CS correctly identified Only 1 case of CS missed Independent Diagnostic Indicators and Risk Score for CS Variable Score Points Osteoporosis 2 Dorsocervical fat pad 2 Muscular atrophy 3 LNSC Medium, 9.17 nmol/l nmol/l High, nmol/l 5 Total Number of Subjects and Prevalence of CS Per Score Category Using the Scoring System Obtained From the Combined Clinical and LNSC Model CS Score No Yes TOTAL León-Justel A, et al. J Clin Endocrinol Metab. 2016;101(10): Testing for Hypercortisolism UFC Measures excretion of circulating unbound cortisol in the urine across 24 hours 1 This test measures the gross overproduction of cortisol across a period of time What Is Collected 2 How 2 CS Diagnosis Range 2 Urine At-home collection 24 hr* Assay-dependent *May need up to 3 collections due to variability of cortisol secretion and inaccurate collections. 1 Urine needs to be refrigerated. 2 Discard first morning void so collection begins with empty bladder Arnaldi G, et al. J Clin Endocrinol Metab. 2003;88(12): Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Testing for Hypercortisolism UFC (cont d) UFC frequently is not an ideal marker to make the diagnosis of mild hypercortisolism (eg, adrenal CS) 1 Not enough cortisol to overcome cortisol-binding globulin Most cortisol is metabolized before excretion False-Negative Results May Occur 2 Moderate-to-severe renal impairment Mild hypercortisolism Patients with cyclical hypercortisolism (if collected when disease is inactive) False-Positive Results May Occur 2 Patients with excessive fluid intake Patients using glucocorticoids Patients with poorly controlled diabetes, severe obesity, psychiatric disorders, polycystic ovary syndrome, alcoholism, or pregnancy 1. Arnaldi G, et al. J Clin Endocrinol Metab. 2003;88(12): Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5):

11 UFC Test Is Insensitive The degree of hypercortisolism by itself does not seem to be a sufficiently exhaustive parameter to assess the severity of active CS Retrospective analysis ( ) 192 patients with confirmed CS distributed into 3 groups based on mean UFC Mild hypercortisolism (UFC 2x ULN): 19.2% Moderate hypercortisolism (2x ULN <UFC <5x ULN): 59.8% Severe hypercortisolism (UFC 5x ULN): 20.8% No significant correlations were found between the degree of hypercortisolism (as measured by UFC) and the severity of comorbidities and/or biochemical parameters ULN, upper limit of normal. Guarnotta V, et al. Endocrine Mar 10. [Epub ahead of print] 31 Testing for Hypercortisolism LNSC Measures the free cortisol in the saliva at a time point when cortisol should be at its lowest level 1 This test detects the loss of diurnal rhythm 1 What Is Collected 1 How 1 Saliva At-home collection 11:00 PM midnight CS Diagnosis Range 2 Assaydependent Serum Cortisol Levels 12am 4am Cushing syndrome 3 8am 12pm 4pm Normal diurnal rhythm 3 8pm 12am LNSC, late-night salivary cortisol. 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Arnaldi G, et al. J Clin Endocrinol Metab. 2003;88(12): EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7, Testing for Hypercortisolism LNSC (cont d) False-Negative Results May Occur 1 Patients with cyclical hypercortisolism (if collected when disease is inactive) False-Positive Results May Occur 1 Patients experiencing stress during time of the test collection Sample contaminated with blood (eg, flossing teeth before test) If patients smoke, chew tobacco, or eat licorice the day of the test If patients use steroid inhaler or topical steroids If patients have blunted circadian rhythm* LNSC seems to be the best early predictor of [Cushing disease] recurrence AACE/ACE Disease State Clinical Review 2 *Eg, shift workers or critically ill. AACE, American Association of Clinical Endocrinologists; ACE, American College of Endocrinology. 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Fleseriu M, et al. Endocr Pract Sep 19. [Epub ahead of print] 33 11

12 Testing for Hypercortisolism Overnight DST Dynamic test that assesses the HPA axis responsiveness to glucocorticoids 2 False-positive results can be seen after administration of dexamethasone in patients 2 Taking medications that induce CYP3A4 This will result in reduced plasma concentrations of dexamethasone during the test On oral contraceptives False-negatives can be seen in critically ill or nephrotic patients 2 What Is CS Collected 1 How 1 Diagnosis Range 1 Blood This test detects autonomous cortisol secretion 1 At home: 1 mg dexamethasone between 11:00 PM and midnight At lab: Next day healthcare practitioner blood draw between 8:00 AM and 9:00 AM >1.8 μg/dl HPA, hypothalamic pituitary adrenal. 1. Arnaldi G, et al. J Clin Endocrinol Metab. 2003;88(12): Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Testing for Hypercortisolism Overnight DST Is Considered the Most Valuable Test to Screen for Mild Cushing Syndrome 1,2 We suggest use of the 1-mg DST or LNSC test, rather than UFC, in patients suspected of having mild Cushing syndrome. Endocrine Society 1 Patients are screened for [mild Cushing syndrome] with a 1-mg overnight DST. AACE/AAES 2 Given our objective of using tests with high sensitivity we recommend use of the more stringent cutoff of 1.8 μg/dl. Endocrine Society 1 AAES, American Association of Endocrine Surgeons. 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Zeiger MA, et al. Endocr Pract. 2009;15(Suppl 1): Testing for Hypercortisolism Overnight DST* (cont d) Dexamethasone Hypothalamus Normal Response - Decrease in cortisol - Decrease in ACTH Dexamethasone Adrenal CS Adrenal: - No decrease in cortisol - Low ACTH Ectopic tumor: - No decrease in cortisol - High ACTH Cushing disease: - No decrease in blood cortisol - High ACTH ACTH Cortisol *Graphical representation. MedlinePlus. Updated November 1, Accessed November 7, Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2):

13 Testing for Hypercortisolism Summary UFC measures the gross overproduction of cortisol across a period of time, and is not an ideal test to detect mild hypercortisolism 1 LNSC measures the free cortisol in the saliva at a time point when cortisol should be at its lowest level, detecting the loss of diurnal rhythm 1 LNSC seems to be the best early predictor of Cushing disease recurrence 2 The overnight DST is a dynamic test that assesses the HPA axis responsiveness to glucocorticoids, detecting autonomous cortisol secretion 1 Recommended for patients with mild hypercortisolism 1 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Fleseriu M, et al. Endocr Pract Sep 19. [Epub ahead of print] 37 Adrenal Adenomas 38 Cushing Syndrome: Adrenal Source Secretion Patterns Patients with adrenal CS do not get a cortisol break at night 1 May not have high peak cortisol 1 Mild overexposure may be more harmful than previously thought 2 Serum Cortisol Levels Normal diurnal rhythm 3 Adrenal 1 12am 4am 8am 12pm 4pm 8pm 12am 1. Tourniaire J, et al. Acta Endocrinol (Copenh). 1986;112(2): Di Dalmazi G, et al. Lancet Diabetes Endocrinol. 2014;2(5): EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7,

14 Cushing Syndrome: Adrenal Source ACTH- Independent Hormone Alterations* Cortisol is secreted independently of ACTH stimulation; therefore, production is outside of the control of normal HPA axis function Bilateral adrenocortical hyperplasia Adrenocortical tumors Secretion of cortisol will lower concentration of ACTH Tumor Hypothalamus Adrenal *Graphical representation. Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): CRH ACTH Cortisol 40 Testing for Hypercortisolism Overnight DST* (cont d) Dexamethasone Hypothalamus Normal Response - Decrease in cortisol - Decrease in ACTH Adrenal CS Adrenal: - No decrease in cortisol - Low ACTH Dexamethasone Tumor Ectopic tumor: - No decrease in cortisol - High ACTH Cushing disease: - No decrease in blood cortisol - High ACTH ACTH Cortisol *Graphical representation. MedlinePlus. Updated November 1, Accessed November 7, Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Cushing Syndrome: Adrenal Source General Approach to Adrenal Adenoma Rule out malignancy 1 Characterize biochemically 1 Rule out aldosteronoma (if hypertension) 1 Rule out pheochromocytoma 1 Assess for autonomous cortisol secretion 2 1-mg overnight DST 2 >1.8 μg/dl (50 nmol/l) 2 Other tests LNSC: may be elevated 1 2-day DST: use w/ certain population (psychiatric, morbid obesity, alcoholism, diabetes, kidney failure) 1,3 UFC: low sensitivity 2 Useful in rounding out the clinical picture DHEA-S, dehydroepiandrosterone sulfate. 1. Zeiger MA, et al. Endocr Pract. 2009;15(Suppl 1): Chiodini I, et al. Endocrine Jul 12. [Epub ahead of print] 3. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): ACTH: may be subnormal 1 DHEA-S: may be subnormal 1 Concurrent metabolic and cardiorenal derangements: level of suspicion

15 Asymptomatic Patients With Adrenal Adenomas May Be at Risk for Mild Cushing Syndrome Mild CS may appear after 5 years of follow-up in some patients 1,2 Annual screening for 5 years is recommended for Patients with adrenal adenoma 2.4 cm 1 Patients with adrenal adenomas treated conservatively with possible mild CS 2 Patients should be reevaluated if there is any change in their medical status 1 Use the overnight DST 1 If DST is >1.8 μg/dl, reassess LNSC and ACTH 1 1. Morelli V, et al. J Clin Endocrinol Metab. 2014;99(3): Barzon L, et al. Eur J Endocrinol. 2002;146(1): Cushing Syndrome: Adrenal Source Treatment Options Adrenalectomy Evidence best established in moderate-to-severe CS 1 Long-term prospective data vs medical therapy unavailable in mild CS 2 Noninvasive Medical Therapies Active Surveillance Can be stopped if not tolerated or no improvement seen May reduce threshold for initiating treatment No significant metabolic changes 3 At least annual monitoring recommended 3 1. Fassnacht M, et al. Eur J Endocrinol. 2016;175(2):G1-G Chiodini I, et al. Endocrine Jul 12. [Epub ahead of print] 3. Zografos GN, et al. Hormones (Athens). 2014;13(3): Cushing Syndrome: Adrenal Source Adrenalectomy Considerations Benefits Immediate resolution of hypercortisolism 1 Improvement in many manifestations of disease in ~67% of patients 2,3 Metabolic (BP, weight, diabetes control) Physical signs Concerns Lifelong hormone replacement therapy may be needed Irreversible Significant lifestyle changes Potential long-term complications 1. Toniato A, et al. Ann Surg. 2009;249(3): Chiodini I, et al. J Clin Endocrinol Metab. 2010;95(6): Mitchell IC, et al. Surgery. 2007;142(6): ; discussion 905.e

16 Adenoma Cushing disease 46 Cushing Syndrome: Source Secretion Patterns Patients with Cushing disease generally have high cortisol and ACTH, and loss of diurnal rhythm 1 Cushing disease 1 Serum Cortisol Levels Normal diurnal rhythm 2 12am 4am 8am 12pm 4pm 8pm 12am 1. Tourniaire J, et al. Acta Endocrinol (Copenh). 1986;112(2): EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7, Cushing Syndrome: Source ACTH- Dependent Hormone Alterations* Known as Cushing disease Secretion of ACTH by a pituitary tumor stimulates the adrenal glands to constantly secrete excess cortisol Tumor does not require CRH to stimulate ACTH secretion, and is not responsive to negative feedback This leads to unchecked ACTH secretion Hypothalamus Tumor Adrenal *Graphical representation. Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): CRH ACTH Cortisol 48 16

17 Testing for Hypercortisolism Overnight DST* (cont d) Dexamethasone Hypothalamus Normal Response - Decrease in cortisol - Decrease in ACTH Dexamethasone Adrenal Tumor CS Adrenal: - No decrease in cortisol - Low ACTH Ectopic tumor: - No decrease in cortisol - High ACTH Cushing disease: - No decrease in blood cortisol - High ACTH ACTH Cortisol *Graphical representation. MedlinePlus. Updated November 1, Accessed November 7, Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Cushing Syndrome: Source Treatment Options: Surgery First-line treatment for those eligible for surgery 1 Surgery may not be successful, nor its impact sustained 1,2 TSS Failure Rates (%) TSS Failures in Patients With Cushing Disease up to 30% Postsurgical Failures Recurrence Rates Increase Across Time 2 26% 46% 5 Years 5-13 Years TSS, transsphenoidal surgery. 1. Tritos NA, et al. Nat Rev Endocrinol. 2011;7(5): Patil CG, et al. J Clin Endocrinol Metab. 2008;93(2): Cushing Syndrome: Source Additional Treatment Options Radiotherapy Effective in controlling excess cortisol in up to 86% of patients 1 Prevents tumor regrowth in approximately 90%-100% of patients 1 Concerns: Takes a long time to work 1 External beam radiation takes significantly longer to work than stereotactic radiotherapy, and frequently leads to loss of normal pituitary function across 5-10 years 1 Neurologic complications (optic neuropathy, other cranial neuropathies) and secondary neoplasia have been reported rarely with both types of radiotherapy 2 Medical Therapy 1 -directed Adrenal-directed Competitive glucocorticoid receptor antagonist 1. Tritos NA, et al. Nat Rev Endocrinol. 2011;7(5): Nieman LK, et al. J Clin Endocrinol Metab. 2015;100(8):

18 Ectopic Source of ACTH 52 Cushing Syndrome Patients with an ectopic source of ACTH have very high cortisol Plasma Immunoactive ACTH (ng/l) Normal range 0800h 1000h Adrenal Ectopic Figure adapted from: Drury PK, et al. In: Hall R, et al, eds, Fundamentals of Clinical Endocrinology. 4 th Ed. London, UK: Churchill Livingstone; 1989: Cushing Syndrome: Ectopic Source ACTH- Dependent Hormone Alterations* Secretion of ACTH from an ectopic tumor stimulates the adrenal glands to secrete cortisol These tumors exist completely outside of the HPA axis, do not require stimulation by CRH, and are not sensitive to negative feedback This leads to unchecked ACTH secretion, very high cortisol, and loss of diurnal rhythm Tumor Hypothalamus Adrenal *Graphical representation. Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): CRH ACTH Cortisol 54 18

19 Testing for Hypercortisolism Overnight DST* (cont d) Dexamethasone Hypothalamus Normal Response - Decrease in cortisol - Decrease in ACTH Dexamethasone Tumor Adrenal CS Adrenal: - No decrease in cortisol - Low ACTH Ectopic tumor: - No decrease in cortisol - High ACTH Cushing disease: - No decrease in blood cortisol - High ACTH ACTH Cortisol *Graphical representation. MedlinePlus. Updated November 1, Accessed November 7, Figure adapted from: Guaraldi F, et al. J Am Board Fam Med. 2012;25(2): Cushing Syndrome: Ectopic Source Treatment When possible, the treatment of choice for ectopic ACTH-secreting tumors is resection of the primary tumor The best results have been achieved when the tumor is found to be carcinoid in origin In many cases, the primary tumor is found to be an inoperable carcinoma of the bronchus In these cases, the prognosis is so poor that surgery often is not indicated In cases where the primary tumor cannot be localized, the treatment of choice is bilateral adrenalectomy EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7, Summary Cortisol production is under control of a complex set of feedback Influences 1 Healthy, day-working people have a diurnal variation in cortisol, with the peak occurring just before waking and the trough near midnight 2 Excess cortisol causes multisystemic dysfunction 1,3,4 No single clinical sign or symptom defines hypercortisolism 1 Diagnostic testing should align with the suspected pathophysiology 5 UFC measures the gross overproduction of cortisol across a period of time, and is not an ideal test to detect mild hypercortisolism 5 LNSC measures the free cortisol in the saliva at a time point when cortisol should be at its lowest level, detecting the loss of diurnal rhythm 5 LNSC seems to be the best early predictor of Cushing disease recurrence 6 The overnight DST is a dynamic test that assesses the HPA axis responsiveness to glucocorticoids, detecting autonomous cortisol secretion 5 Recommended for patients with mild hypercortisolism 5 1. Raff H, et al. Compr Physiol. 2014;4(2): Sharma ST, et al. Clin Epidemiol. 2015;7: EndocrineSurgeon.co.uk. 5. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Fleseriu M, et al. Endocr Pract Sep 19. [Epub ahead of print] Updated March 11, Accessed November 7, Nieman LK. Ann NY Acad Sci. 2002;970:

20 Summary, cont d Cushing syndrome is associated with significant morbidity and mortality 1,2 Even when clinical signs of overt hypercortisolism are not present, patients with adrenal adenomas and mild hypercortisolism have an increased risk of CV events and mortality 3 Even nonfunctional adrenal tumors are associated with hormonal dysregulation 4 The degree of hypercortisolism by itself does not seem to be a sufficiently exhaustive parameter to assess the severity of active CS 5 Mild hypercortisolism is common 6 Treatment options include surgery, directed medical therapy, and/or active surveillance 7,8 1. Plotz CM, et al. Am J Med. 1952;13(5): Clayton RN, et al. J Clin Endocrinol Metab. 2011;96(3): Di Dalmazi G, et al. Lancet Diabetes Endocrinol. 2014;2(5): Morelli V, et al. J Clin Endocrinol Metab. 2014;99(3): Guarnotta V, et al. Endocrine Mar 10. [Epub ahead of print] 6. Chiodini I. J Clin Endocrinol Metab. 2011;96(5): Chiodini I, et al. Endocrine Jul 12. [Epub ahead of print] 8. Tritos NA, et al. Nat Rev Endocrinol. 2011;7(5): Summary of Screening and Treatment 59 Diagnosing Cushing Syndrome Step 1: Is There an Index of Suspicion for CS? Exclude exogenous CS 1 Identify features of CS 2 Endogenous CS 1 Due to pituitary, adrenal, or other tumors causing overproduction of cortisol Exogenous CS 3 Due to long-term use of high doses of glucocorticoids Pseudo-CS 3 Presence of partial clinical signs of hypercortisolism Can be caused by Alcoholism Depression Obesity 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Debono M, et al. Front Horm Res. 2016;46: Castinetti F, et al. Orphanet J Rare Dis. 2012;7:

21 Diagnosing Cushing Syndrome Step 2: Identify Hypercortisolemia Perform one of the following tests 1 : 24-hour UFC ( 2 tests) Overnight 1-mg DST LNSC ( 2 tests) Look for a cause if 2 2 tests from the list are positive Physiologic causes of hypercortisolism have been excluded Determine ACTH-dependent vs ACTH-independent cause 3 Early-morning ACTH <10 pg/ml = ACTH-independent >10 pg/ml = ACTH-dependent 1. Nieman LK, et al. J Clin Endocrinol Metab. 2008;93(5): Debono M, et al. Front Horm Res. 2016;46: Castinetti F, et al. Orphanet J Rare Dis. 2012;7: Diagnosing Cushing Syndrome Step 3: Determine the Cause An Algorithm for the Treatment of CS ACTH-dependent CS ACTH-independent CS Presumed EAS Imaging: no tumor Presumed CD based on IPSS or >6 mm mass Presumed EAS Imaging: + tumor Adrenal imaging Remission Tumor resection Resection not possible Unilateral or bilateral adenoma Monitor for Failed surgery, no surgery, or recurrence recurrence Control Hypercortisolism If CD, consider: Repeat TSS -directed medical treatment RT and steroidogenesis inhibitors For all etiologies, consider: Medical therapy Bilateral adrenalectomy Treat metastatic disease if applicable Repeat localization studies Remission EAS, ectopic ACTH-secreting; IPSS, inferior petrosal sinus sampling; RT, radiotherapy. Adapted from Nieman LK, et al. J Clin Endocrinol Metab. 2015;100(8): Tests to Find the Cause of Cushing Syndrome CRH stimulation test Helps distinguish pituitary adenomas from ectopic ACTH syndrome or adrenal tumors adenomas = ACTH and cortisol because CRH acts directly on the pituitary Ectopic or adrenal tumor = response rarely seen High-dose DST Same as the low-dose DST, except that it uses higher doses of dexamethasone Distinguishes excess production of ACTH due to pituitary adenomas from those with ectopic ACTH-producing tumors High doses of dexamethasone usually suppress cortisol in people with pituitary adenomas, but not in those with ectopic ACTH-producing tumors Radiologic imaging: direct visualization of the endocrine glands Imaging tests reveal the size and shape of the pituitary and adrenal glands and help to determine if a tumor is present The most common imaging tests are the computerized tomography scan and MRI Petrosal sinus sampling Best way to distinguish pituitary from ectopic causes of CS National Institute of Diabetes and Digestive and Disease. April Accessed September 26,

22 Thank you! KOR NOV Backup and Optional Slides 65 Cushing Syndrome: Source General Approach to Diagnosis Inferior petrosal sinus sampling This test can be used to accurately distinguish pituitary and ectopic sources of ACTH-causing CS. The principle of the test is to sample the blood from the petrosal sinuses draining the pituitary gland, to compare the of ACTH with those found in the peripheral blood. A petrosal:peripheral ratio of >2, indicating excess ACTH from the pituitary, is necessary to diagnose Cushing disease with confidence. Accuracy can be improved using CRH stimulation to exaggerate the difference MRI MRI is the best modality for imaging the pituitary. It has 77% sensitivity for the detection of pituitary microadenomas. Specificity is only 80%; therefore, images must be viewed in conjunction with other test results MRI, magnetic resonance imaging. EndocrineSurgeon.co.uk. Updated March 11, Accessed November 7,

23 Patients Need Lifelong Follow-Up After TSS There is no expert consensus with regard to postoperative testing for surgical success The timing of biochemical measurements differs among treatment centers, and can vary considerably within the same center Intervals between surgery and biochemical measurement range from 1-2 days up to several weeks or months Additional factors impact cortisol after surgery Prophylactic medications (eg, glucocorticoids, steroidogenesis inhibitors) Early-morning serum cortisol measured between 8:00 AM and 10:00 AM is the most commonly used measure of immediate remission following surgery Typically, early-morning serum cortisol of either <2 μg/dl (~50 nmol/l) or <5 μg/dl within a few days after surgery are considered to be indicative of remission Ayala A, et al. J Neurooncol. 2014;119(2):