Cushings and Addisons

Question 1

What is the role of the adrenal glands?

Answer 1

produce hormones that react to stressors
regulate metabolism of fats, proteins, CHO
regulate BP and BG
help control kidney function
two major hormones produced: cortisol and aldosterone

Question 2

Describe the release of aldosterone.

Answer 2

the major mineralocorticoid secreted by the adrenals
secretion mainly controlled by RAAS; less so by potassium, then ACTH
-release stimulation: low bp, low Na, CNS excitation

Question 3

What are the actions of aldosterone?

Answer 3

maintains electrolyte (K, Mg, Na) and volume homeostasis
increases Na & H2O retention and K excretion
=expanded plasma volume, elevated BP, hypokalemia

Question 4

What is the secondary site for androgen synthesis? Describe androgen synthesis at this secondary site.

Answer 4

adrenal cortex
-primary site is testes and ovaries
-primarily DHEA
-release increased with puberty, decreased with aging

Question 5

What is the role of androgens?

Answer 5

helps with bone density
sexual desire and function
sex and body maturation

Question 6

What is Cushing’s Syndrome?

Answer 6

disorder caused by persistent exposure to excessive glucocorticoids (exogenous or endogenous)
-primarily a result of exogenous use
-women>men

Question 7

What is the etiology of Cushings?

Answer 7

ACTH dependent
-benign pituitary tumor over-producing ACTH (Cushings Disease)
-ectopic ACTH source (non-pituitary tumor)
ACTH independent
-adrenal gland tumors
exogenous administration of corticosteroids

Question 8

True or false: the diagnosis of Cushings is often relatively quick due to the obscure symptoms

Answer 8

false
difficult and delayed because it mimics other conditions

Question 9

What are the signs and symptoms of Cushings?

Answer 9

emotional disturbance
moon face
osteoporosis
hypertension
buffalo hump
abdominal obesity
thin, wrinkled skin
striae
muscle weakness
poor wound healing
decreased libido

Question 10

What are the signs of Cushings that could help distinguish from obesity?

Answer 10

protein wasting
-thin skin
-muscle weakness
-bruising
suddenly appearing red striae
children: decreased linear growth

Question 11

What are the treatment goals of Cushings?

Answer 11

remove the source of hypercortisolism
restore cortisol secretion to normal
reverse clinical features
prevent dependency on medications
with appropriate treatment, most signs and symptoms will resolve within 2-12 months

Question 12

What are the treatment options for Cushings? (non-drug)

Answer 12

pituitary adenoma
-surgical resection
adrenal tumors
-surgical resection (radiation or chemo if theres metastases)
ectopic ACTH syndrome
-often multiple tumors, some are cured and some require medication
drug induced Cushings
-removal of the cause

Question 13

What are the options when a transsphenoidal resection does not cure Cushings?

Answer 13

repeat the transsphenoidal surgery
medication therapy
radiation therapy
bilateral adrenalectomy

Question 14

When is pharmacologic therapy initiated for Cushings?

Answer 14

when surgical removal of the tumor cannot be done or is ineffective
-to decrease cortisol levels pre-surgery
-treat severe symptoms
-adjunct treatment after unsuccessful surgery
-non resectable tumors

Question 15

What are the pharmacologic options for Cushings?

Answer 15

steroidogenesis inhibitors
-ketoconazole
-metyrapone
-mitotane
inhibitors of ACTH secretion
-pasireotide

Question 16

What is the MOA of ketoconazole for Cushings?

Answer 16

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

Question 17

What is the drug of choice for Cushings?

Answer 17

ketoconazole
-effective and adverse effect profile not as bad as others

Question 18

What is the dose of ketoconazole for Cushings?

Answer 18

start low and titrate based on lab results
typical: 200-400mg TID

Question 19

What are the adverse effects of ketoconazole?

Answer 19

GI upset
gynecomastia
increased LFTs
headache
sedation
impotence
decreased libido

Question 20

What are the drug interactions of ketoconazole?

Answer 20

many: 1A2, 2C9, 3A4
-CCBs
-grapefruit juice
-cyclosporine
-carbamazepine
-warfarin
-PPIs
-benzodiazepines
-aminoglycosides

Question 21

What is the MOA of metyrapone?

Answer 21

inhibits the enzyme 11 B-hydroxylase (cortisol pathway)

Question 22

What are the uses of metyrapone?

Answer 22

experiencing dose-limiting AEs with ketoconazole
adjunct therapy
diagnostic agent

Question 23

What are the adverse effects of metyrapone?

Answer 23

androgenic AEs (hirsutism and acne)
NV
abdominal discomfort
headache
dizziness
allergic rash

Question 24

What is the dose of metyrapone for Cushings?

Answer 24

wide range

Question 25

What is the MOA of mitotane?

Answer 25

decrease the synthesis of cortisol by inhibiting the hydroxylation of 11-desoxycortsiol and 11-desoxycorticosterone

Question 26

What is the indication of mitotane?

Answer 26

inoperable adrenal carcinoma -in combination with irradiation, other steroidogenic inhibitors

Question 27

Where is mitotane used and why?

Answer 27

hospital -greatly decreases cortisol synthesis -adverse effects

Question 28

What are the adverse effects of mitotane?

Answer 28

GI: anorexia, NVD depression, lethargy, somnolence hypercholesterolemia, rash, hepatoxicity

Question 29

Are steroidogenic inhibitors effective as monotherapy long term?

Answer 29

not usually often combined with one another if not providing adequate response on their own

Question 30

What is the MOA of pasireotide?

Answer 30

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

Question 31

What is the indication of pasireotide?

Answer 31

surgery not an option or failure of surgery

Question 32

What is the dosing of pasireotide?

Answer 32

0.6-0.9mg BID subq injection

Question 33

What are the side effects of pasireotide?

Answer 33

hepatotoxicity CV events (bradycardia, QT) hyperglycemia gall-bladder events

Question 34

What are the drug interactions of pasireotide?

Answer 34

antiarrythmics drugs that prolong QT interval

Question 35

What is Addisons disease?

Answer 35

primary adrenal insufficiency -adrenal glands cannot synthesize enough glucocorticoids and mineralocorticoids -destruction of all 3 zones of the adrenal glands (sx when >90% destroyed)

Question 36

What is the cause of Addisons?

Answer 36

autoimmune-mediated destruction -most common in Western world infectious diseases: TB, CMV, HIV, fungal -more common in other parts of world tumors hemmorrhage injury to adrenal glands

Question 37

What is the cause of secondary adrenal insufficiency?

Answer 37

most commonly in those taking chronic corticosteroids -symptoms due to abrupt withdrawal of corticosteroids other causes: tumors, surgical removal of pituitary, meds

Question 38

What are the signs and symptoms of Addisons?

Answer 38

glucocorticoid deficiency: -fatigue -weight loss -loss of appetite -N, V, abdominal pain -muscle/joint pain -hypotension -depression mineralocorticoid deficiency: -dehydration -hypotension other: -skin hyperpigmentation -salt craving -dry/itchy skin -decrease axillary/pubic hair -decreased libido

Question 39

What are the lab results for someone with Addisons?

Answer 39

hyponatremia hyperkalemia anemia hypoglycemia

Question 40

Where is hyperpigmentation most prevalent for an Addisons patient?

Answer 40

sun-exposed areas knuckles elbows knees mucous membranes

Question 41

What is the treatment of chronic adrenal insufficiency?

Answer 41

glucocorticoids -DOC: hydrocortisone*, cortisone, prednisone, dexamethasone -HC: 15-30mg/d -cortisone: 20-35mg -dose adjustments based on pt well being, BP, weight mineralocorticoids -fludricortisone 0.05mg-0.1mg qd -titrate based on BP, K, and Na

Question 42

How frequently are glucocorticoids dosed in Addisons?

Answer 42

BID-TID with majority of dose in AM

Question 43

What might be the stress dosing of an Addisons patient during strenous exercise? What about illness or trauma?

Answer 43

add 5-10mg HC double dose until recovery

Question 44

What might be a third therapy a woman with Addisons may require?

Answer 44

DHEA 25-50mg/d if low libido is present -adrenals are primary source of androgens in women

Question 45

What are the adverse effects of DHEA?

Answer 45

sweat odour acne hirsutism itchy scalp

Question 46

What is the main cause of an acute adrenal crisis? What are some symptoms?

Answer 46

abrupt steroid withdrawal or lack of stress dosing (medical emergency) sx: tachycardia, NV, fever, hypotension, dehydration, hypoglycemia

Question 47

What is the treatment of acute adrenal crisis?

Answer 47

IV glucocorticoids -HC is DOC (combined gluco and mineralo activity) fluid replacement to support bp fludricortisone when pt can eat/drink and HC dose is decreased

Question 48

Which steroidogenesis inhibitor may require concomitant administration of glucocorticoids?

Answer 48

mitotane -greatly decreases cortisol lvls

Question 49

What causes skin hyperpigmentation in Addisons?

Answer 49

high levels of ACTH binding to melanocortin 1 receptor on dermal melanocytes