Cushing's Disease

Question 1

Cushing’s is a disorder caused by…

Answer 1

Persistent exposure to excessive glucocorticoids

Question 2

Cushing’s is primarily a result of…

Answer 2

Exogenous use of CS

Question 3

Overproduction of endogenous cortisol can either be…

Endogenous hormones involved in HPA axis?

Answer 3

ACTH dependent (80%), or ACTH independent (20%)

Question 4

ACTH dependent overproduction of cortisol is commonly caused by…

Answer 4

A benign pituitary tumour over-producing ACTH, or by an ectopic ACTH source

Question 5

ACTH independent route of endogenous overproduction of cortisol can be caused by…

HPA-axis is not triggered

Answer 5

Adrenal gland tumours

Stimulate release of cortisol

Question 6

Diagnosis of Cushing’s is often difficult and delayed, because…

Answer 6

It mimics other conditions; medical history and testing of HPA-axis is necessary

Question 7

2 steps that are required when Cushing’s is suspected, is to…

Answer 7

Establish if hypercortisolism is present
Establish the cause

Question 8

Clinical features of Cushing’s involves…

Think about CS adverse effects

Answer 8

Excess cortisol effects
ex: Centripetal obesity, skin changes,
acne, striae, fatigue, sexual dysfunction, irregular periods, HTN, osteopenia, growth suppression, bruising

Question 9

Signs that may help to distinguish Cushing’s from obesity include…

Answer 9

Signs of protein wasting (thin skin, unusual bruising, muscle weakness), suddenly appearing red striae

Decreased linear growth evident in children

Question 10

Treatment goals for Cushing’s involves:

Answer 10

Removing source of hypercortisolism, and restore cortisol secretion to normal

Reverse clinical features, and prevent dependency on medications

Question 11

Treatment of Cushing’s is primarily aimed at removing the cause, which involves…

Answer 11

Surgical resection (of adrenal tumours, pituitary adenoma, etc.) or removal of the drug-induced cause

Question 12

Surgical resection of ectopic ACTH syndrome is difficult, because…

Answer 12

Multiple tumour sites often exist; 10-30% are cured with surgical removal, and remaining 70-90% need post-op medication

Question 13

When surgical removal of tumours cannot be done or is ineffective, what can be done?

Answer 13

Medications

Question 14

Medication are used in Cushing’s to…

Answer 14

Lower cortisol levels pre-surgery
Adjunct tx after unsuccessful surgery/radiation, or for non-resectable tumours
Help treat severe symptoms

Question 15

CS replacement therapy may be required after surgery because of…

Answer 15

HPA-axis suppression, due to excess cortisol present over long period of time

Question 16

Steroidogenesis Inhibitors include the 3 following medications:

Answer 16

Ketoconazole, metyrapone, mitotane

Question 17

A medication that inhibits ACTH secretion includes:

Answer 17

Pasireotide

Question 18

Steroidogenesis inhibitors MOA is to…

Answer 18

Block the synthesis of cortisol

Question 19

Typically, the drug of choice for Cushing’s treatment (if proceeding with pharmacotherapy) is…

And why? Dose?

Answer 19

Ketoconazole - effectiveness good, and adverse effect profile not as severe as others

Typical dose 200-400mg TID

Question 20

Adverse effects with ketoconazole include…

Answer 20

GI upset, gynecomastia
Headache, sedation, impotence, decreased libido, increased LFT’s

Question 21

Oral ketoconazole needs to be cautioned with other medications because…

Answer 21

Many DI’s are present - involved with CYP1A2, 2C9, 3A4

Ex: CCB’s, cyclosporin, benzo’s… etc.

Question 22

Metyrapone is often used for the purpose of…

Answer 22

Adjunct therapy
Diagnostic agent
If experiencing dose-limiting adverse effects with ketoconazole

Question 23

Adverse effect profile of metyrapone differs from ketoconazole, due to…

Answer 23

Significant androgenic adverse effects (hirsutism, acne)

Others: N/V, abdominal discomfort, headache, dizziness, allergic rash

Question 24

Mitotane is unique as its indication is for…

Answer 24

Inoperable adrenal carcinoma

In combination with irradiation, or other steroidogenic inhibitors

Question 25

Mitotane dosing needs to be initiated in hospital, due to…

Answer 25

Large decrease in cortisol synthesis (cytotoxic) - adverse effects

Administration of concomitant CS may be necessary

Question 26

Common adverse effects of mitotane include…

Answer 26

GI - anorexia, N/V/D
Depression, lethargy, somnolence

Question 27

What does duration of therapy look like with steroidogenic inhibitors, in Cushing’s?

Do we need to adjust regimens??

Answer 27

Not usually effective as monotherapy long-term; therefore ketoconazole and metyrapone are often combined together if adequate response is not achieved

Question 28

Pasireotide MOA is…

Answer 28

Binding to somatostatin receptors, causing inhibition of ACTH secretion in ACTH-producing adenomas

Question 29

Pasireotide is indicated for usage when…

Answer 29

Surgery is not an option, or surgery has failed

Question 30

Key adverse effects with pasireotide include…

Answer 30

Hepatotoxicity, CV events, hyperglycemia, gall-bladder events

Question 31

Notable drug interactions with pasireotide include…

Answer 31

Caution with antiarrhthmics, and drugs that prolong the QT interval

Question 32

Additional pharmacotherapy that patients may require for Cushing’s treatment, besides cortisol-lowering therapy, include…

What can help with TOO much cortisol symptoms ?

Answer 32

Anti-HTN, antihyperglycemics
Antidepressants
Spironolactone - MRA

Thyroid supplements
Growth hormones in children
Anticoagulants
Calcium regulators