Endo 8: Therapeutic use of adrenal steroids

Question 1

Which 2 things affect ACTH release

Answer 1

Stress and circadian stimuli

Question 2

Where is cortisol made within the adrenal cortex

Answer 2

Zona fasciculata

Question 3

T/F production of sex steroids in the adrenal gland is responsive to ACTH control, but aldosterone is not

Answer 3

True! Aldosterone activated by renin angiotensin axis (e.g. renin secreted due to: high potassium, hyponatraemia and reduced renal blood flow in the JGA and b1-adrenoceptor stimulation)

Question 4

Where are sex steroid produced in the adrenal cortex

Answer 4

zona reticularis

Question 5

Compare MR and GR receptors

Answer 5

Distribution: MR discrete (kidney) GR everywhere
Selectivity: MR doesn’t distinguish cortisol and aldosterone, GR selective for glucocorticoids
Affinity for cortisol: GR low MR high

Question 6

Which receptors can aldosterone and cortisol bind to

Answer 6

Aldosterone- only MR

Cortisol- GR and MR

Question 7

Reason for hypokalaemia in cushings and hypertension

Answer 7

11B-HSD 2 overwhelmed so cortisol not converted to cortisone (the inactive form) thus can bind to the MR receptors in the kidneys and cause excretion of K+ and reabsorption of salt and water so hypertension

Question 8

What is cortisol converted to in MR containing tissue

Answer 8

Cortisone (inactive form)

Question 9

Treatment for addisonian crisis

Answer 9

NaCl and hydrocortisone and glucose

Question 10

Impact of high dose hydrocortisone on BP in addisonian crisis

Answer 10

Such high level of cortisol that it overwhelms 11b-HSD 2and acts on MR to increase BP (so don’t worry about aldosterone acutely

Question 11

What is fludrocortisone

Answer 11

aldosterone analogue- given to an addisons patient going home and also cortisol (hydrocortisone or prednisolone)

Question 12

Which binds MR more: hydrocortisone or prednisolone

Answer 12

hydrocortisone

Question 13

Routes of admin for cortisol/aldosterone replacement

Answer 13

Oral (hydrocrotisone, prenisolone, dexamethasone or fludrocortisone) and parenteral (i.v. or i.m.) (hydrocortisone or dex)

Question 14

Where do corticosteroids bind (it said this is where they all bind I think?)

Answer 14

Corticosteroid binding globulin (CBG)

Question 15

Differentiate the adrenal cortex function in secondary vs primary hypoadrenalism

Answer 15

Secondary- aldosterone and BP is fine but low cortisol and sex steroids, the only reason for low cortisol is lack of ACTH which doesn’t affect aldosterone as aldosterone is regulated by renin (which converts angiotensinogen to angiotensin I etc. etc.)
Primary- low aldosterone and low cortisol and sex steroids because the whole of the adrenal cortex is actually destroyed so there’s no ability to make aldosterone or cortisol

Question 16

Which precursor starts to accumulate in 21 hydroxylase deficiency

Answer 16

17ahydroxyprogesterone accumulates, because it’s immediately before the enzyme block, and this is converted into the sex steroid arm so lots of adrenal androgens produced (leading to hirsutism and virilisation)

Question 17

What will ACTH be like in 21 hydroxylase deficiency

Answer 17

ACTH high as no cortisol so no negative feedback

Question 18

T/f The MR receptor has higher affinity for cortisol than GR

Answer 18

True, counterintuively

Question 19

State the selectivity of the following drugs: 
Hydrocortisone 
Prednisolone
Dexamethason 
Fludrocortisone

Answer 19

HC- GR and MR at high dose
Pred- GR and weak MR
Dex- glucorticoid with no mineralocorticoid activity
Fludrocortisone- aldosterone analogue

Question 20

Duration of action of hydrocortisone, prednisolone and dexamethasone

Answer 20

HC: 8hrs
Pred: 12 hr
Dex: 40hr

Question 21

How would you treat primary adrenocortical failure (not crisis)

Answer 21

Hydrocortisone and fludrocortisone by mouth –> mimicks glucocorticoid and mineralocorticoid respectively

Question 22

How would you treat secondary adrenocortical failure (not crisis)

Answer 22

Adosterone is normal so no need to give fludrocortisone-

Just give hydrocortisone

Question 23

How would you treat acute adrenocortical failure (addisonian crisis)

Answer 23

0.9% NaCl

High dose hydrocortisone i.v. or i.m every 6h-mineralocorticoid effect at high dose as 11bHSD 2 overwhelmed

5% dextrose if hypoglycaemic

Question 24

What are the objectives of therapy in congenital adrenal hyperplasia

Answer 24

You want to;
Replace cortisol and aldosterone
And also suppress the very high ACTH (which is leading to lots of precursors which are being converted to the adrenal androgens and causing hirsutism and acne)

Question 25

How do you treat congenital adrenal hyperplasia

Answer 25

Dexamethason 1/day pm or
Hydrocortison 2-3/day, high dose pm
AND
fludrocortisone

Question 26

How do you monitor treatment for congenital adrenal hyperplasia

Answer 26

17-OH progesterone levels

And clinical assessment:
-if they are cushingoid then GC dose is too high

-If they have hirsutism it’s too low (so ACTH has risen)

This is a very fine balance and giving too much can make the patient cushingoid (too much cortisol), giving to little will fail to suppress ACTH and they will become hursuit.

Question 27

What extra measures must be taken for patients taking corticosteroid replacement therapy

Answer 27

You need to increase glucocorticoid drugs when stressed (as happens physiogically), so take twice the normal dose for minor illness

If having surgery, a general anaesthetic is a major stress so cortisol would usually be really high, hydrocortisone i.m with pre-med and at 6-8 hour intervals. Can be taken oral once eating and drinking

Question 28

Normal cortisol vs normal cortisol when stressed

Answer 28

20mg/day, in stress 200-300mg per day

Question 29

How important is the cortisol, aldosterone and androgens/oestrogens as adrenal steroids

Answer 29

Cortisol – essential for life

Aldosterone
Promotes Na+ retention and K+ loss

Androgens/oestrogens
?
Main source of these are gonads

Question 30

Give the 2 uses of hydrocortisone

Answer 30

In Addison’s patients with primary adrenocortical failure, you give hydrocortisone as REPLACEMENT. You also give fludrocortisone

For secondary adrenocortical failure, you give hydrocortisone as REPLACEMENT. You don’t give fludrocortisone because the zona glomerulosa (producing aldosterone) is intact and doesn’t respond to ACTH anyway

For someone with ACUTE adrenocortical failure (i.e. addisonian crisis, which is when your primary adrenocortial failure is really bad), you are giving HIGH DOSE HYDROCORTISONE to replace the cortisol, but also to replace aldosterone in the short term to get the blood pressure back up (because the cortisol can overwhelm 11b-HSD 2 and act on MR receptors to increase Na+ and water reabsorption), then when sent home, they would be put on the first arrangement here.

Question 31

What happens in 21OH deficiency (in CAH) to:

cortisol
aldosterone
ACTH

Which hormone accumulates

Answer 31

It means that no cortisol or aldosterone can be made

ACTH starts to increase as there is no negative feedback

Progesterone/17OH progesterone cannot be converted into aldosterone and cortisol respectively, so it accumulates and is shuttled into sex steroid pathway

High ACTH drives further adrenal androgen production

Patients get hirsuitism and virilisation

Question 32

Why does the adrenal gland grow in CAH

Answer 32

Because there is no production of cortisol in utero, then there is nothing to switch of ACTH.

ACTH causes the adrenal cortex to grow!