8. Therapeutic use of adrenal steroids

Question 1

What stimulates cortisol release?

Answer 1

ACTH release from the pituitary

Question 2

What stimulates ACTH release?

Answer 2

ACTH release is stimulated by CRH (corticotrophin releasing hormone) from the hypothalamus

Question 3

Where in the adrenals is cortisol secreted from? How do levels of cortisol vary?

Answer 3

Cortisol is secreted from the zona fasiculata in a circadian manner - highest in the morning and lowest in the late evening

Question 4

How is cortisol production regulated?

Answer 4

Cortisol has a negative feedback effect at the level of the hypothalamus and pituitary

Question 5

What is the name of the system that controls aldosterone release? What factors can lead to aldosterone release being stimulated?

Answer 5

Aldosterone release is controlled by the renin-angiotensin system
Aldosterone release is stimulated by:
-High potassium
-Low sodium
-Low renal blood flow – sensed by juxtaglomerular cells in the kidneys
-Beta-1 adrenoceptor stimulation – found in the juxtaglomerular apparatus

Question 6

Apart from cortisol, what other steroid hormones do the adrenals produce? Where are these produced from?

Answer 6

Sex steroids from the zona reticularis and aldosterone from the zona glomerulosa are produced by the adrenal glands

Question 7

Why do ACTH levels not affect the levels of sex steroids and aldosterone?

Answer 7

The sex steroids are under ACTH control but are not relevant as they are mainly produced by the gonads.
Aldosterone is not under ACTH control

Question 8

What are the main physiological actions of cortisol, aldosterone and androgens?

Answer 8

Cortisol - essential for life, promotes energy levels
Aldosterone - important in salt balance
-Na+ retention
-K+ excretion
Androgens/Oestrogens - unclear role because the gonads are a much bigger source of sex steroids

Question 9

Outline the characteristics of glucocorticoid receptors and mineralocorticoid receptors

Answer 9

Glucocorticoid Receptors 
(GR):
-Wide distribution 
-Selective for 
glucocorticoids 
-Low affinity for cortisol 

Mineralocortlcoid Receptors (MR):
-Discrete distribution 
-Do NOT distinguish 
between aldosterone and 
cortisol 
-High affinity for cortisol

Question 10

How is cortisol binding to mineralocorticoid receptors prevented?

Answer 10

• 11b-hydroxysteroid dehydrogenase (11bHSD)
• Even though cortisol has a high affinity for the MR, it does not have an effect on it because the enzyme 11BHSD-2 deactivates the cortisol so it protects the MRs and prevents it from being stimulated
• Cortisol is broken down into cortisone which is inactive and can’t stimulate the MR

Question 11

Why is hypokalaemia a symptom of Cushing’s syndrome?

Answer 11

In Cushing’s syndrome you have high levels of cortisol and one of the features is HYPOKALAEMIA. That is because the system gets overwhelmed - when there is too much cortisol the 11b-hydroxysteroid dehydrogenase can’t inactivate it all so some of the cortisol binds to mineralocorticoid receptors and causes hypokalaemia. The cortisol ends up acting like aldosterone

Question 12

What is hydrocortisone and how does it act on the body?

Answer 12

Cortisol and hydrocortisone have the same structure, it’s just that cortisol is endogenous and hydrocortisone is synthetic
At high doses it can cause MR activation because it overwhelms the 11b-hydroxysteroid dehydrogenase system

Question 13

When would you give someone hydrocortisone?

Answer 13

Treatment for Addison’s (primary adrenocortical failure)

Given as IV or IM so that it works quickly during an Addisonian crisis

Question 14

What type of drug I prednisolone?

Answer 14

Tends to be an immunosuppressive type of glucocorticoid

It is a glucocorticoid with weak mineralocorticoid activity

Question 15

What type of drug is dexamethasone and when would it be administered?

Answer 15

○ Very POTENT glucocorticoid
○ This is used clinically for things like brain metastases where there is a lot of oedema so it is used as an acute anti-oedema agent
○ This has NO mineralocorticoid effect
○ Not usually used as a cortisol replacement in Addison’s

Question 16

What type of drug is fludrocortisone?

Answer 16

ALDOSTERONE analogue

Used as an aldosterone substitute

Question 17

How are the different corticosteroids distributed?

Answer 17

• Binding to plasma proteins (corticosteroid binding globulin and albumin)
  
  • Remember only the free, unbound hormone is biologically active
  • Hydrocortisone is about 90-95% bound
  • Prednisolone is less bound and dexamethasone and fludrocortisone are even less bound
  • Fludrocortisone is only bound to albumin

Question 18

What is the duration of prednisolone in the body?

Answer 18

○ Duration = 12 hours

○ So patient will just need to take one tablet each morning

Question 19

What is the half life and duration of hydrocortisone and fludrocortisone?

Answer 19

○ Half-life = 1 hour
○ Duration = 8 hours
○ So someone who is taking hydrocortisone for Addison’s will have to take several tablets throughout the day

Question 20

What is the duration of dexamethasone?

Answer 20

40 hours

Question 21

What are the reasons for giving corticosteroid replacement?

Answer 21

• Primary Adrenocortical Failure
  
  • Secondary Adrenocortical Failure
  • Acute Adrenocortical Failure
  • Congenital Adrenal Hyperplasia
  • Iatrogenic Adrenocortical Failure

Question 22

What is primary adrenocortical failure and it’s causes?

Answer 22

• Can be due to Addison’s Disease and Chronic Adrenal Insufficiency
• Their adrenal cortex just isn’t working

Question 23

What happens to patients with primary adrenocortical failure? What would you give them?

Answer 23

• These patients need replacement of cortisol AND aldosterone
• If you have primary adrenocortical failure, you can’t make any of the hormones
• The loss of production of adrenal androgens isn’t a big deal because the gonads make most of the androgens anyway
• Treatment of Primary Adrenocortical Failure:
○ Hydrocortisone (oral) (or sometimes prednisolone)
○ Fludrocortisone (oral)

Question 24

What is secondary adrenocortical failure? What causes this?

Answer 24

• ACTH deficiency
• There is nothing wrong with the adrenal gland but the adenohypophysis isn’t working properly. It is often due to a pituitary tumour that results in the loss of corticotrophs and so a loss of ACTH

Question 25

How would you treat a patient with secondary adrenocortical failure?

Answer 25

•The renin-angiotensin system is working normally so aldosterone release is normal
• This means that you only need to replace the cortisol
• ACTH controls sex steroid release as well but this isn’t worth treating
• Treatment of Secondary Adrenocortical Failure:
○ Hydrocortisone (oral) (or prednisolone)
○ Titrate Dose - adjust the dose throughout the day to mimic normal physiology i.e. highest in the morning and low in the evening
○ They should not take hydrocortisone too late in the day because it could disrupt sleep

Question 26

What is an addisonian crisis? What should you do if this occurs?

Answer 26

Addisonian crisis = acute adrenocortical failure
• IV SALINE - first step
○ Whether they are a neonate or an adult, they will be suffering a salt-losing crisis because they lack aldosterone
○ You need to replace the lost salt, restore circulating volume and improve the blood pressure before proceeding
○ The saline is NaCl (IV 0.9% NaCl)
• Once they have been infused with saline you give them high dose hydrocortisone
• A high dose is needed because the adrenal cortex would automatically produce large quantities of cortisol when the body is unwell as it is a stress hormone
• At this point you do NOT need to give them fludrocortisone because the dose of hydrocortisone is so high that it will have some mineralocorticoid activity as 11BHSD will be overwhelmed by the large amounts of hydrocortisone. At this point aldosterone will not be needed
• If they are hypoglycaemic (because cortisol would usually increase blood glucose) you can give them 5% dextrose but because they have been given so much glucocorticoid, this is rarely necessary

Question 27

What is congenital adrenal hyperplasia? What causes it?

Answer 27

• CAH is a congenital lack of steroid synthetic enzymes
• Most cases of CAH are due to the absence of the enzyme 21-hydroxylase which is essential in the cortisol and aldosterone producing pathway

Question 28

What can be measured to diagnose congenital adrenal hyperplasia?

Answer 28

In CAH you can’t make cortisol or aldosterone so there is no negative feedback on the ACTH so ACTH levels are HIGH
This means that there is a build-up of the precursor before the step with 21-hydroxylase
The precursor you can measure easily is 17a-hydroxyprogesterone

Question 29

Why is CAH a problem in childhood and why is it a problem in adults?

Answer 29

The constant production of ACTH causes 17a-hydroxyprogesterone to continuously be produced and pushes it towards the adrenal androgen pathway, so there is an increase in sex steroid production
This is a problem in childhood:
• Boys - precocious puberty
• Girls - virilisation
It can also cause problems in adult women - hirsuitism and acne

Question 30

How would you treat CAH? How would you optimise treatment?

Answer 30

• Replace cortisol
  
  • Dexamethasone 1/day
  • Or Hydrocortisone 2-3/day
• Suppress ACTH and, thus, adrenal androgen production
• Replace aldosterone in salt wasting forms
  
  • Fludrocortisone is the aldosterone replacement
• Monitor/optimise therapy by measuring:
  
  • 17a-hydroxyprogesterone levels – these should start to decrease if the correct levels of cortisol are given
  • Do a clinical assessment of what they are complaining about:
    
    • Cushingoid - glucocorticoid dose too HIGH
    • Hirsuitism/Acne - glucocorticoid dose too LOW (so ACTH is high)
    • You have to find a balance between too much and too little glucocorticoid so that none of these symptoms appear

Question 31

What additional measures should you take in people with adrenocortical failure?

Answer 31

• Normal Cortisol Production = 20 mg/day
• In stress production = 200-300 mg/day
• You increase the dosage when patients are vulnerable to stress e.g. if they become unwell, or they may end up with an adrenal crisis
• Examples of situations when they should increase dosage:
○ Minor illness = 2 x normal dose
○ Surgery - hydrocortisone I.M. with pre-med at 6-8 hour intervals. This is because general anaesthetic puts the body under stress and also that they won’t be able to take their cortisol until they can eat again. Back to oral hydrocortisone once they’re back to normal and they’re eating and drinking
○ Even when patients are going for a minor operation they need to be clear with the anaesthetist that they have a problem with their adrenal cortex as they will need to take a large dose of hydrocortisone
○ Patients are now asked to wear a medic alert bracelet that lets surgeons know they have adrenal failure in case they have an Addisonian crisis or cannot verbally let the doctors know

Question 32

What is iatrogenic adrenocortical failure? What hormones do patients have to take?

Answer 32

• This happens in patients on long-term, high dose corticosteroid treatment
  
  • If they are on glucocorticoids for a long time, this can suppress adrenal function because they don’t have to produce cortisol themselves anymore - they have a suppressed HPA axis
  • These patients also need to increase their dose when they experience a stress
  • If these patients are ever unwell and can’t communicate their steroid dependence to a doctor they need to have a blue card or a wristband (MedicAlert bracelet)

Question 33

End

Answer 33

End