corticosteroids

Question 1

What are steroid hormones?

Answer 1

are produced from cholesterol via the actions of a cascade of enzymes in specific steroidogenic tissues

Question 2

What are cholesterol made of?

Answer 2

a four ring structure labelled A, B, C, and D

Question 3

How do steroids work?

Answer 3

binding to specific nuclear receptors (transcription factors) in target tissues

Question 4

What are glucocorticoids?

Answer 4

regulate carbohydrate and protein metabolism (bind to GRα)

Question 5

Why are glucocorticoids important?

Answer 5

physiological importance

pharmacological importance

Question 6

What are the physiological importance of glucocorticoids?

Answer 6

endogenous cortisol promotes metabolic changes that allow us to adapt to physiological stresses, such as fasting, infections, heat/cold, etc.

CNS - circadian patterning, arousal
Cardiovascular - cardiac function, blood pressure
Metabolic - glucose and lipid homeostasis
Muscular - endurance
Skeletal - remodeling

Question 7

What are the pharmacological importance of glucocorticoids?

Answer 7

synthetic glucocorticoids suppress inflammation, allergy and immune response, and are used in disease states

Question 8

What does cortisol bind to in blood?

Answer 8

cortisol binding globulin (CBG)

Question 9

How is cortisol formed?

Answer 9

cholesterol converted to pregnenolone (rate-limiting step) by corticotrophin
pregnenolone is converted by a series of enzymatic steps to cortisol

Question 10

What is ketoconazole?

Answer 10

an effective anti-fungal drug; blocking cortisol synthesis by inhibiting cholesterol side-chain cleavage enzyme

Question 11

How does cholesterol turn into pregnenolone?

Answer 11

cleavage of the sidechain via CYP11A1 and P450scc

Question 12

What is the cascade for GR activation?

Answer 12

1. stress
2. HPA axis activates
3. cortisol released and binds to CBG
4. binds to cytosolic glucocorticoid receptor (translocation to cell nucleus)
5. transcription of glucocorticoid responsive genes (protein translation)
6. synthesis of new proteins

Question 13

What is the mechanism of glucocorticoids in anti-inflammatory?

Answer 13

1. activating expression of anti-inflammatory genes via dimerisation and nuclear translocation of the GRα binding to glucocorticoid response elements
2. transcriptional interference with inflammatory signaling pathways, blocking expression of multiple inflammatory proteins/cascade
3. GR-mediated effects independent of transcription

Question 14

What are the major physiological effects of cortisol?

Answer 14

metabolism

sleep-wake cycle (circadian rhythm)

Question 15

How is metabolism regulated by cortisol?

Answer 15

decrease uptake and utilisation of glucose by peripheral tissues
increase synthesis of glucose by liver
increase breakdown of fat and muscle
increase glycogen formation

Question 16

What are the major immunological effects of cortisol?

Answer 16

stress response
acute effects - boost immunity
chronic effects - weakened immune system

Question 17

What is a disease caused by too much cortisol?

Answer 17

Cushing’s disease

Question 18

What is Cushing’s disease?

Answer 18

due to ACTH-secreting tumor of pituitary gland
pasireotide can be used to treat (somatostatin receptor agonists)
features = buffalo hump, thin arms and legs, moon face, increased abdominal fat

Question 19

What disease is caused by too little cortisol?

Answer 19

Addison’s disease

Question 20

What does Addison’s disease cause?

Answer 20

weight loss, fatigue, painful muscle + joints

Question 21

How is Addison’s disease treated?

Answer 21

involves replacement therapy

Question 22

What are the effects when glucocorticoids are given in supraphysiologic doses?

Answer 22

anti-inflammatory and immunosuppressive effects
general effects on metabolism, water and electrolyte balance and organ systems (unwanted side-effects)
negative feedback effects on hypothalamus/pituitary (unwanted side-effects)

Question 23

What are some clinical uses of glucocorticoids?

Answer 23

1. replacement therapy
2. inhibit inflammation associated with asthma, inflammatory bowel disease, etc.
3. suppress the immune system
4. adjunct therapy in cancer
5. stimulate lung development in fetus