Corticosteroids

Question 1

Adrenal glands

Answer 1

Two adrenal glands above/close to kidneys
adrenal cortex - outside
adrenal medulla - inside

Question 2

Adrenal Medulla

Answer 2

produces adrenaline + catecholamine/amino acid hormone

Question 3

Adrenal cortex

Answer 3

generation and release of steroid hormones

zona glomerulosa
zona fasciculata
zona reticularis

Question 4

Zona glomerulosa

Answer 4

mineralocorticoids
aldosterone
salt balance
(salt)

Question 5

zona fasciculata

Answer 5

glucocorticoids
cortisol
metabolic and immune effects - inflammatory response
(sugar)

Question 6

zona reticularis

Answer 6

androgens
precursors for testosterone and estrogens
DHEA - metabolized in sex organs to generate androgens
(sex)

Question 7

cholesterol

Answer 7

common precursor for all adrenal steroid hormones

Question 8

HPA axis

Answer 8

hypothalamus, pituitary, + adrenal cortex
controls cortisol release from the zona fasciculata
hypothalamus releases CRH → anterior pituitary releases ACTH → stimulates steroid production (cortisol synthesis) [after meals; circadian rhythm]

Question 9

HPA axis negative feedback

Answer 9

cortisol exerts negative feedback on CRH release from hypothalamus and ACTH release from pituitary

stress signals that trigger cortisol → hormone release inhibits further release

Question 10

cortisol

Answer 10

acts on glucocorticoid target tissues → stress response, catabolism, immuno-suppression
release of cortisol inhibits further release through negative feedback

Question 11

aldosterone

Answer 11

released through RAAS - renin angiotensin aldosterone system: kidney releases renin → cleaves angiotensonigen into angiotensin 1 → ACE converts AT1 into AT2 → triggers aldosterone release
targets kidneys - promotes Na+/water reabsorption + K+ excretion
control of blood pressure/volume

Question 12

steroid hormone action mechanism

Answer 12

cytoplasmic unliganded receptor in complex with Hsp90
binding of steroid hormone to the receptor causes dissociation → transport into nucleus → dimerized receptors interact with DNA + influence transcription of target genes
Glucocorticoid receptor/response element → targets lipocortin + COX-2

Question 13

corticosteroid receptors

Answer 13

glucocorticoid receptor - stimulates GC response
mineralocorticoid receptor - stimulates a MC response
spectrum - steroids have different affinities for either receptor

specificity arises from affinity of compound/receptor + metabolism in target tissues

Question 14

In vivo specificity

Answer 14

glucocorticoid target tissues (adipose, muscle, liver) express 11B-hydroxysteroid dehydrogenase type 1 → activation of cortisol from cortisone

kidney cells express 11BHD type 2 → inactivates cortisol = weak mineralocorticoid effects
don’t want cortisol to act on kidneys - under control of aldosterone

Question 15

example of corticosteroid action/administration

Answer 15

prednisone is widely used by oral intake or injection → metabolized to prednisolone to become effective (first pass metabolism in liver)
prednisolone is the active form and has a strong topical effect

Question 16

pseudohyperaldosteronism

Answer 16

inhibition of 11BHD type 2 → active cortisol mimics aldosterone in the kidneys (where it would normally be inhibited)
triggers hypertensive response: increased uptake of water and reabsorption of sodium = high blood pressure

ex. licorice overdose, genetic disease apparent mineralocorticoid excess

Question 17

metabolic effects of glucocorticoids

Answer 17

• carbohydrate metabolism: increases circulating glucose
• fat/lipid balance: promotes fat deposition in the trunk but fat breakdown in the limbs = loss of muscle and bone mass in limbs
• promote synthesis of glucose in the liver
• block insulin effects

short term: trigger breakdown of fat in adipose tissue but long term: tissue becomes insensitive to glucose → high levels of insulin = fat deposition

Question 18

anti-inflammatory effects of glucocorticoids

Answer 18

induce lipocortin = inhibit arachidonic acid generation from phospholipids
suppress cox-2 = inhibit prostanoid synthesis

Question 19

cox-2

Answer 19

important inflammatory mediator (early in process) - metabolizes arachadonic acid to prostanoids
glucocorticoids suppress transcription of the cox-2 gene → long term suppression of expression (do not directly inhibit activity by direct receptor antagonism)

Question 20

lipocortin

Answer 20

1. direct effects on leukocytes (inflammatory cells) inhibits their tissue infiltration
2. suppression of phospholipase A2 activity - prevents AA generation = suppresses downstream generation of prostanoids
   - protein = expression is induced by GC receptor activation

Question 21

Addison’s Disease

Answer 21

chronic adrenocortical insufficiency
fatigue, salt + sugar imbalance, skin discoloration (negative feedback leads to excess melanin synthesis)
low production of glucocorticoids and mineralocorticoids
treat with supplementation - hydrocortisone

Question 22

Cushing’s Syndrome

Answer 22

adrenal overactivity = excessive cortisol
adrenal tumour, pituitary tumour, drug-induced (long term GC treatment), or ectopic tumour
round face + fat deposition in trunk, muscle loss + osteoporosis → protein + bone catabolism
treated by resection of adrenals or pituitary tumour, followed by gradual adjustment towards a maintenance dose of cortisol

Question 23

therapeutic uses of GCs

Answer 23

powerful anti-inflammatory + immunosuppressive actions of cortisol + analogues
allergic reactions
eye inflammation
reduction of pain + scarring
gastrointestinal diseases
hematologic disorders (leukemia, myeloma)
asthma
organ transplants - immunosuppression

Question 24

glucocorticoid treatment

Answer 24

mimics endogenous cortisol = exerts negative feedback
→ suppresses production of CRH and ACTH = reduces circulating levels

Question 25

side effects of glucocorticoid treatment

Answer 25

shut down body’s ability to generate its own cortisol:
- if stopped abruptly = addisonian crisis: hypoglycemia, hyponatremia, hyperkalemia, low blood pressure

• mimics effects of Cushing’s syndrome: metabolic (hyperglycemia), immunosuppressive, catabolic (osteoporosis), anti-inflammatory, and other side effects

tapering - should not abruptly stop taking a glucocorticoid