25.7

Question 1

In Addison’s disease there are high levels of ___ hormone AND ___ released from the pituitary.

Answer 1

Corticotrophic hormone

Melanocortin

Question 2

Fludrocortisone has higher affinity for the ___ receptor so is used to replace the lack of ___ (if required).

Answer 2

Mineralocorticoid

Mineralocorticoids i.e. aldosterone

Question 3

Glucocorticoids i.e. cortisol have equal ___ for the mineralocorticoid receptor as mineralocorticoids do! But they do not normally activate MR receptors in the kidney - why?

Answer 3

Affinity
11beta-hydroxysteroid dehydrogenase in the kidney rapidly converts cortisol to inactive cortisone to protect the kidney from the effects of cortisol i.e. no salt retention

Question 4

The kidney uses the ___-___ (abbrev.) enzyme to inactivate cortisol to cortisone. Cortisone can be reconverted to cortisol in the ___ by the same enzyme, with perfect efficiency!

Answer 4

11beta-HSD

Liver

Question 5

What is the approximate half life of cortisol?

Answer 5

1.25 hours

Question 6

Why is dexamethasone used for the suppression test (in terms of relative affinities)?

Answer 6

Dexamethasone only has affinity for the glucocorticoid receptor and not the mineralocorticoid receptor?

Question 7

Fludrocortisone has very high affinity for the ___ receptor compared to the ___ receptor so is used in cases of ___ deficiency in ___ doses.

Answer 7

Very high affinity for the mineralocorticoid receptor compared to the glucocorticoid receptor
Used if aldosterone deficiency in LOW doses

Question 8

What is a dissociated steroid?

Answer 8

Dissociated steroids are steroids that are more effective at one or the other of transactivation or transrepression.

Question 9

What is transactivation?

Answer 9

Activation of gene transcription via GREs (glucocorticoid response elements).

Question 10

What is transrepression?

Answer 10

Reduction of gene transcription via inhibition of AP-1 and NF-kB.

Question 11

___ suppression is a major complication of glucocorticoid therapy.

Answer 11

Adrenal

Question 12

Adrenal suppression occurs due to the ___ feedback exerted by exogenous glucocorticoids on the ___ to inhibit the release of ___.

Answer 12

Negative

Pituitary to inhibit release of ACTH

Question 13

To avoid the complication of adrenal suppression due to glucocorticoid treatment, what can you try?

Answer 13

Avoid long-lasting drugs and use drugs of shorter half-lives

Try alternate day dosing or morning dosing

Question 14

Cicleosnide?

Answer 14

A glucocorticoid, used for asthma
It is a pro-drug that is activated in the lungs and not in the mouth or larynx (important because yeast infections in mouth and larynx are common side effects of inhaled steroids)
Lipophilic so it stays in tissues
Highly protein bound in plasma so free drug concentration is low
Rapidly metabolised by liver so short half life
Low oral bioavailabailty due to hepatic first pass so low absorption by swallowing

Question 15

The role of steroids in peptic ulcers is ___.

Answer 15

Unknown!

This is because the studies investigating whether steroids cause peptic ulcers were conducted in patients using NSAIDs!

Question 16

How do glucocorticoids cause osteoporosis?

Answer 16

There is a receptor (RANK) on osteoclast precursors
Stromal cells express RANKL (ligand for RANK) on the cell surface or secrete soluble ligand
When the ligand binds to RANK on osteoclast precursors, it stimulates intracellular NF-kB signalling
There is a soluble RANK receptor called OPG that mops up RANKL to reduce activation of RANK receptors on osteoclasts
So RANKL promotes bone resorption and OPG inhibits bone resorption
Glucocorticoids have been shown to increase RANKL and decrease OPG
This effect is quite SMALL though!