1. Armed Forces Academy of Medical Sciences
Cushing’s Syndrome
Armed Forces Academy of Medical Sciences

2. Outline Define Cushing’s Disease and Syndrome
Review normal cortisol regulation
Discuss the clinical manifestations of Cushing’s
How to diagnose Cushing’s Syndrome
Treatment options for Cushing’s Syndrome

3. Normal Cortisol Synthesis and Regulation
Hypothalmus secretes Corticotropin Releasing Hormone (CRH) in response to
Low Serum Cortisol
Low Blood Sugar
Stress
CRH stimulates anterior pituitary to release Corticotropin (ACTH)
ACTH stimulates adrenal gland to produce cortisol
CRH released into hypophysial portal blood in the median eminence is carried to the anterior pituitary gland where it stimulates synthesis and release of ACTH. Increases in plasma ACTH stimulates adrenal cortisol secretion

4. ACTH Secretion ACTH secretion is pulsatile
Pulse frequency remains constant throughout the day
Amplitude of each pulse varies in circadian fashion
Highest at time of awakening
Lowest in late evening and very early morning hours
Variation makes measuring ACTH to diagnose Cushing’s syndrome or disease inaccurate

5. Cortisol Metabolism
Cortisol secretion reflects ACTH secretion and is therefore also pulsatile
Cortisol exists in two forms
Free cortisol in serum
Bound to corticosteroid-binding globulin (majority)
Free cortisol
Enters tissue for action and metabolism
Filtered into urine or saliva for excretion

6. Normal Cortisol Synthesis and Regulation
Cortisol provides negative feedback inhibition at multiple levels
Anterior Pituitary
Hypothalmus

7. Definitions
Cushing’s Syndrome: chronic exposure to excessive levels of glucocorticoids
Cushing’s Disease: specifically refers to pituitary hypersecretion of ACTH leading to Cushing’s syndrome
Dr. Harvey Cushing
Neurosurgeon

8. Cushing’s Syndrome Etiology
ACTH-dependent
ACTH-independent
Pituitary hypersecretion (Cushing’s Disease)
65-70%
Ectopic secretion of ACTH by non-pituitary tumors
10-15%
Ectopic secretion of CRH by nonhypothalamic tumor 1%
Exogenous administration of glucocorticoids
Probably the most common
Adrenocortical adenomas and carcinomas
18-20%
Bilateral adrenal micronodular hyperplasia 1%
Percentages represent incidences, but should be recalculated to include the most common etiology: iatrogenic
Small cell lung cancer is common cause of exogenous ACTH secretion

9. Cushing’s Syndrome Epidemiology
Relatively even distribution between men and women
Men more common ACTH secreting lung tumors
Women more commonly have Cushing’s Disease
Age at presentation varies depending on etiology
Ectopic ACTH secretion: Age > 50
Cushing’s Disease: years old
Adrenal Tumors: years old

10. Clinical Manifestations of Cushing’s Syndrome
Centripetal obesity
Facial plethora
Glucose intolerance
Proximal muscle weakness
Hypertension
Abdominal striae
Hirsutism
Simultaneous development and increasing severity of several symptoms is concerning clue
Clinical suspicion has to be high because these symptoms are vague
Degree and duration of hypercortisolism, cause of hypercortisolism impact severity of symptoms

11. Symptoms of Cushing’s Syndrome: Progressive Obesity
Most common feature
Involves face, neck, abdomen
Moon Facies (cheeks)
Buffalo Hump (dorsocervical fat pad)
Spares extremities
Children with Cushing’s syndrome
have generalized obesity
Degree of fat accumulation variable
Moon Facies
Buffalo Hump

12. Symptoms of Cushing’s Syndrome: Skin Manifestations
Rarely seen in other clinical scenarios
Can be very specific for Cushing’s Syndrome
Skin atrophy
Easy bruisability
Striae
Frequent fungal infections
Hyperpigmentation
Caused by increased ACTH not cortisol
ACTH is principal pigmentary hormone acting through melanocyte-stimulating hormone
Hyperpigmentation occurs more frequently with ectopic ACTH

13. Symptoms of Cushing’s Syndrome: Neuropsychological Effects
50% of all cases of Cushing’s Syndrome
Most common symptoms
Emotional liability
Agitated depression
Irritability
Anxiety and Paranoia
After correction of hypercortisolism, resolution of psychiatric symptoms is variable

14. Diagnosis of Cushing’s Syndrome
Possible presence of Cushing’s syndrome suggested by clinical signs and symptoms
No symptom pathognomonic
All non-specific
Diagnosis must be confirmed by biochemical tests
Many causes of Cushing’s syndrome, pulsatile nature of ACTH and cortisol secretion make biochemical testing complex
No test with ideal sensitivity or specificity

15. Diagnosis of Cushing’s Syndrome
History must exclude exogenous glucocorticoid intake
Ingestion of prednisone (oral, injected, topical or inhaled formulations)
Exclude physiologic hypercortisolism
States where elevated cortisol is NOT Cushing's
Physically stressed (infection)
Severe obesity
Psychologically stressed
Chronic Alcoholism
Nearly 80% of patients with major depressive disorder have elevated cortisol

16. Diagnostic Strategy First line tests
Late night salivary cortisol (done at least twice)
Urinary cortisol (at least 3x normal)
Dexamethasone suppression test
Need 2/3 tests to be positive to establish diagnosis of Cushing’s Syndrome
Further testing indicated for patients with slightly abnormal or discordant results
2008 Endocrine Society Clinical Guidelines

17. Urinary Cortisol Should be first screening test
24-hour urine collection
Measures serum free cortisol concentration
Physiologic elevations of cortisol are always < 3x ULN
Re-evaluated several weeks later
Subjected to another screening test

18. Low Dose Dexamethasone Suppression Test
Exogenous dexamethasone substitutes for endogenous cortisol  suppressing ACTH
In normal subjects dexamethasone should suppress pituitary secretion of ACTH and cortisol secretion by adrenal glands
Low salivary and urinary cortisol
Cortisol assays do not measure dexamethasone
Two types of low dose suppression tests
1 mg overnight
2 mg two day test

19. Low Dose Dexamethasone Suppression Test
Overnight 1 mg test
Administration of 1 mg dexamethasone at 11 pm
Measure serum cortisol at 0800 next morning
Normal value < 1.8 mcg/dL
Two-day 2 mg test
0.5 mg dexamethasone every six hours for 8 doses
Measure serum cortisol at 2 and 6 hours after LAST dexamethasone dose
Both tests have similar sensitivity and specificity

20. Low Dose vs. High Dose Dexamethasone Suppression
Utilized to establish diagnosis of Cushing’s Syndrome
High Dose
Utilized to differentiate Cushing’s Disease from patients with ectopic ACTH syndrome

21. Late Evening Salivary Cortisol
Morning serum or salivary cortisol concentrations have no diagnostic value
Normal evening cortisol nadir preserved in obese and depressed patients
Nadir not present in patients with Cushing’s
Benefits
Easy: can be done at home
Non-invasive
Cortisol stable in saliva for days permitting testing days after collection
Normal ranges vary depending on commercial assay
Worst specificity of three first line screening tests

22. Late Evening Serum Cortisol
Normal evening nadir of serum cortisol in obese and depressed patients,
but not in patients with Cushing’s
Syndrome
Midnight blood draw
Normal valve < 2 mcg/dL
Very high sensitivity, marginal specificity
Intermediate values rechecked weeks later

23. Cushing’s Disease Pituitary adenoma ACTH secretion
95% microadenoma, not visible on MRI
ACTH secretion
Remains pulsatile
Amplitude and duration of pulse increased
Frequency of pulses not altered
Lose normal circadian rhythm
Results in bilateral adrenocortical hyperplasia
Hypersecretion of cortisol
Increased cortisol secretion reflected by increased urinary excretion of cortisol

24. Ectopic ACTH Syndrome
Non-pituitary tumor secretion of ACTH results in bilateral adrenocortical hyperplasia
Hypersecretion of cortisol
Suppresses pituitary ACTH release
Tumor secretion of ACTH not suppressed
Salivary cortisol concentrations accurately reflect serum free cortisol levels
Tumors of lung, pancreas, and thymus frequently secretion ACTH

25. Ectopic CRH Syndrome Tumor secreting CRH
Very rare
Results in hyperplasia and hypersecretion of pituitary corticotrophs
Increased ACTH secretion
Cortisol hypersecretion
Bilateral adrenal Hyperplasia

26. Iatrogenic of Factitious Cushing’s Syndrome
Administration of excessive amounts of synthetic glucocorticoid
Inhibit CRH and ACTH secretion
Bilateral adrenocortical atrophy
Plasma ACTH, serum and salivary cortisol, and urinary cortisol levels all low

27. Primary Adrenocortical Hyperfunction
Includes adrenocortical tumor, micronodular dysplasia, ACT-independent macronodular hyperplasia
Elevated levels of cortisol which suppresses
CRH
ACTH
Cortisol steroid precursors (DHEA-S)
DHEA-S: Dehydroepiandrosterone

28. Treatment of Cushing’s Syndrome
Should be directed at primary cause of hypercortisolemia
Pituitary Tumor producing ACTH
Ectopic ACTH secretion
Cortisol Secretion by an adrenal tumor
Exogenous Cushing’s Syndrome: Stop the glucocorticoid

29. Treatment of Cushing’s Disease
Transsphenoidal Surgery
Initial therapy of choice
75-90% cure rate for microadenomas
Greater the resection, greater risk of loss
of pituitary function (loss of fertility)
Pituitary Irradiation
Choice of discrete microadenoma cannot be localized and fertility is a concern
3-12 months for maximum benefit
45% cure rate for adults
Adrenalectomy
Bilateral total adrenalectomy with lifelong daily glucocorticoid and mineralcorticoid replacement is final definitive therapy

30. Treatment of Ectopic ACTH or CRH Tumors
Optimal therapy is surgical resection of tumor
High recurrence rate
Tumor with metastases to liver can be resected with cyroablation to liver mets
Nonresectable tumors
Hypercortisolism can be medially controlled with adrenal enzyme inhibitors
Ketoconazole
Etomidate
Metyrapone

31. Treatment of Ectopic ACTH or CRH Tumors
Bilateral total adrenalectomy with lifelong daily glucocorticoid and mineralcorticoid replacement is final definitive therapy
Prognosis dictated by
Nature of tumor
Severity of hypercortisolism
Most patients with metastatic disease
die within 1 year
Small cell lung cancer, medullary thyroid cancer and gastrinomas have particularly poor prognosis

32. Primary Adrenal Disease
Goal is to Remove the tumor
Unilateral adrenalectomy
Bilateral adrenalectomy
Adrenal Tumors
Ademonas cured with unilateral resection
Carcinomas with high rate of recurrence
Bilateral Adrenal Hyperplasia
Bilateral adrenalectomy

33. Patient Course After Therapy
Physical symptoms and signs resolve gradually over 12 months
Hypertension and hyperglycemia will improve, but may not completely resolve
Osteoporosis improves after 6 months

34. Conclusion Cushing Syndrome is difficult to diagnose
Cushing Syndrome encompasses many different diseases that lead to elevated serum cortisol levels
Diagnosis requires multiple biochemical tests
Cushing’s syndrome is 100% fatal if untreated
Specific treatment depends on etiology of Cushing’s syndrome