Cushing's Syndrome

Question 1

What are the 2 major hormones produced by the adrenal glands

Answer 1

Cortisol and Aldosterone

Question 2

What zone of the adrenal gland is cortisol produced in

Answer 2

Zona Fasciculata

Question 3

What zone of the adrenal gland is aldosterone produced in

Answer 3

Zona Glomerulosa

Question 4

What system controls secretion of aldosterone

Answer 4

RAAS
also controlled by potassium and adrenocorticotropic hormone (ACTH) to a lesser extent

Question 5

What is the role of aldosterone in the body

Answer 5

Maintain appropriate balance of salt and water while helping to control blood pressure

Question 6

What stimulates the release of aldosterone

Answer 6

drop in blood pressure, salt depletion, and CNS excitation

Question 7

What are the actions of aldosterone, and what result does this produce

Answer 7

it maintains electrolyte (K, Mg, Na) and volume homeostasis, by increasing Na and water retention, and increasing K excretion in the ducts of kidneys
Result - expanded plasma volume, increased B, hypokalemia

Question 8

What is the primary androgen produced by the adrenal cortex

Answer 8

DHEA

Question 9

What is the role of androgens in the body

Answer 9

• bone density
• sexual desire and function
• sex and body maturation

Question 10

What is the main cause of Cushing’s Syndrome

Answer 10

Persistent exposure to excessive glucocorticoids - primarily exogenous use

Question 11

What is the incidence of Cushing’s Syndrome in steroid users

Answer 11

about 10%

Question 12

Does Cushing’s more commonly affect women or men? at what age would it start to present?

Answer 12

• More common in women
• Symptoms start to present themselves after 45 years of age

Question 13

Describe the difference between ACTH dependent and ACTH independent causes of Cushing’s Syndrome

Answer 13

ACTH dependent:
- a benign pituitary tumor over-producing ACTH
- a non-pituitary tumor producing ACTH
ACTH independent:
- adrenal gland tumors

Question 14

What is the clinical name for a pituitary tumor that over produces ACTH

Answer 14

Cushing’s disease

Question 15

In regard to endogenous causes of Cushing’s, what percent are ACTH dependent and independent

Answer 15

80% dependent
20% independent

Question 16

Why is diagnosis of Cushing’s typically difficult

Answer 16

wide variety of symptoms mimicking other conditions

Question 17

If Cushing’s is suspected, what is the 2 step process to confirm a diagnosis

Answer 17

1. Establish if hypercortisolism is present
2. Establish the cause of hypercortisolism

Question 18

What tests do we perform to determine if hypercortisolism is present

Answer 18

• urinary free cortisol
• midnight serum cortisol (taken from saliva)
• low-dose dexamethasone suppression test (via a specialist)

Question 19

Once we know a person has hypercortisolism, what tests to we run to determine the cause

Answer 19

• high dose dexamethasone suppression test (via a specialist)
• plasma ACTH via radioimmunoassay
• CRH stimulation test
• Metyrapone stimulation test

Question 20

What are the clinical features of Cushing’s Syndrome

Answer 20

Listed from most to least common:
- obesity/weight gain
- facial redness
- facial rounding
- decreased libido (along with erectile dysfunction)
- thin skin and striae
- irregular periods
- hypertension
- facial hair growth (women)
- depression/emotional lability
- easy bruising
- glucose intolerance
- weakness

Question 21

What specific signs of Cushing’s could help in distinguishing it from obesity

Answer 21

• Protein wasting: thin skin, unusual bruising, muscle weakness)
• Suddenly appearing red striae
• Children: decreased linear growth

Question 22

What are the 4 goals of treatment for Cushing’s

Answer 22

• remove the source of hypercortisolism
• restore cortisol secretion to normal
• reverse clinical features
• prevent dependency on medications

Question 23

What is the 5 year survival rate of untreated Cushing’s

Answer 23

50%

Question 24

How long does it take for most signs and symptoms to resolve after treatment

Answer 24

within 2-12 months

Question 25

What is the primary treatment option for a pituitary adenoma

Answer 25

Surgical (transsphenoidal) resection - may require glucocorticoid replacement therapy after surgery if there is HPA- axis suppression

Question 26

If transsphenoidal resection fails to cure someone of Cushing's, what are the next 4 options

Answer 26

1. Repeat the surgery 2. Medication therapy 3. Radiation therapy 4. Bilateral adrenalectomy

Question 27

What are the treatment options for adenomas and carcinomas on the adrenal glands

Answer 27

- surgical resection: more successful for adenomas than carcinomas - if there are metastases you can try radiation or chemo

Question 28

What makes surgical resection of an ectopic ACTH tumor so difficult, and what percentage of surgeries typically result in a cure

Answer 28

There are often multiple tumor sites, only 10-30% are completely cured with surgical resection.

Question 29

If surgical resection of an ectopic ACTH tumor does not completely remove the tumor, what is required as the next step of treatment

Answer 29

Post-op medication

Question 30

How do we treat drug induced Cushing's Syndrome

Answer 30

removal of the cause

Question 31

What are the 4 reasons for using medications in treatment for Cushing's

Answer 31

1. To decrease cortisol levels pre-surgery 2. As adjunct treatment after unsuccessful surgery or radiation 3. non-resectable tumors 4. to help treat severe symptoms

Question 32

What are the 3 steroidogenesis inhibitors we use for Cushing's

Answer 32

Ketoconazole Metyrapone Mitotane

Question 33

What is Pasireotide

Answer 33

Inhibitor of ACTH secretion

Question 34

What is the mechanism of action of ketoconazole

Answer 34

Blocks the synthesis of cortisol in the adrenal gland via inhibition of 11 beta and 17 alpha hydroxylase

Question 35

Why is ketoconazole the drug of choice for Cushing's

Answer 35

Effective and it's adverse effect profile is not as bad as other medications

Question 36

What is the dose of ketoconazole for Cushing's

Answer 36

Typical dose is 200-400mg. Start low and titrate based on lab results

Question 37

What are the side effects of ketoconazole

Answer 37

- GI upset - gynecomastia - headache - sedation - impotence - increased LFT's - decreased libido

Question 38

What enzymes does ketoconazole interact with

Answer 38

1A2 2C9 3A4

Question 39

What medications does ketoconazole interact with

Answer 39

CCBs cyclosporine carbamazepine benzodiazepines aminoglycosides protease inhibitors PPIs Tacrolimus Warfarin

Question 40

What is metyrapones mechanism of action

Answer 40

Inhibits 11 beta hydroxylase, preventing the conversion of 11 deoxycortisol to cortisol

Question 41

What are the 3 uses of metyrapone in regard to Cushing's

Answer 41

1. If experiencing dose-limiting side effects with ketoconazole (used in combo with keto if need to lower keto dose due to s/e's) 2. As adjunct therapy 3. As a diagnostic agent

Question 42

True or false: There's a wide dosing range for metyrapone

Answer 42

True

Question 43

What are the adverse effects of metyrapone

Answer 43

- androgenic (hirsutism and acne) - N/V, abdominal discomfort - headache - dizziness - allergic rash

Question 44

What is the mechanism of action of Mitotane

Answer 44

Decreases the synthesis of cortisol by inhibiting the hydroxylation of 11 desoxycortisol and 11 desoxycorticosterone

Question 45

What is the indication for the use of mitotane

Answer 45

inoperable adrenal carcinoma

Question 46

How do we use mitotane? (alone?,combo?,with what?)

Answer 46

Used in combination with irradiation and other steroidogenic inhibitors

Question 47

Why do we use mitotane only in the hospital?

Answer 47

1. Greatly decreases cortisol synthesis 2. large adverse effect profile 3. high risk of toxicity, patient needs to be monitored

Question 48

What are the side effects of mitotane

Answer 48

- GI: anorexia, N/V/D (80%) - depression, lethargy, somnolence (40-80%) - hypercholesterolemia, rash, hepatotoxicity

Question 49

Are steroidogenic inhibitors effective as monotherapy long term?

Answer 49

No, they are often combined with one another if not providing adequate response on their own

Question 50

What is the mechanism of action of Pasireotide (Signifor)

Answer 50

binds to somatostatin receptors. resulting in inhibition of ACTH secretion in ACTH-producing adenomas

Question 51

What is the indication of pasireotide

Answer 51

when surgery isn't an option or surgery has failed

Question 52

What is the dose and route of administration of pasireotide

Answer 52

0.6 - 0.9mg BID subcutaneous injection

Question 53

Why is pasireotide only available through the special access program

Answer 53

it has some severe side effects: - hepatotoxicity - CV events - hyperglycemia - gall bladder events

Question 54

What drugs does pasireotide interact with

Answer 54

antiarrhythmics and drugs that prolong QT interval

Question 55

What are 8 other medications that Cushing's patients might need to be on, aside from cortisol lowering drugs

Answer 55

1. antihypertensives 2. spironolactone 3. anticoagulants 4. calcium regulators 5. antidepressants 6. growth hormones (for children) 7. thyroid supplements 8. antihyperglycemics

Question 56

What is the purpose of spironolactone in patients with Cushing's

Answer 56

mineralocorticoid levels can also rise, spironolactone is an aldosterone antagonist and would keep these levels stable