Therapeutic uses of adrenal steroids

Question 1

Name the 3 hormones that the different parts of the adrenal cortex produce

Answer 1

Zona Glomerulosa – Aldosterone

Zona Fasciculata – Cortisol

Zona Reticularis – Sex Steroids (androgens- which can be aromatised to oestrogen).

Question 2

Describe the axis for cortisol production

Answer 2

Circadian stimuli and stress are the two inputs to the hypothalamus- triggering CRH release
CRH stimulates release of ACTH from the anterior pituitary
ACTH acts on the zone fasciculata- leading to cortisol synthesis and release.

Cortisol has negative feedback on the anterior pituitary and the hypothalamus
.

ACTH also stimulates androgen release from the zone reticularis.

Question 3

Describe the axis for control of aldosterone production

Answer 3

Stimulated by activation of RAAS:
Hyperkalaemia
Hypokalaemia
Reduced renal blood flow (haemorrhage)
B1-adrenoreceptor stimulation

Renin will convert angiotensinogen to AI
ACE will convert AI- AII
AII (vasoconstrictor)- will also stimulate aldosterone release from the zona glomerulosa.
Aldosterone will lead to increase Na+ and water reabsorption in the kidney, and increase K+ excretion.

Question 4

Describe the different physiological actions of the different adrenal steroids

Answer 4

Cortisol – essential for life- often kills you in adrenocrotical insufficiency- needed to fight infections etc

Aldosterone
Promotes Na+ retention and K+ loss

Androgens/oestrogens
?
Main source of these are gonads

Question 5

Which family of receptors do the mineralocorticoid and glucocorticoid receptors belong to

Answer 5

The nuclear receptor super-family

binds to cytoplasmic receptor- dissociates from heat shock proteins to translocate to the nucleus

Question 6

Describe the features of glucocorticoid receptors

Answer 6

Wide distribution

Selective for glucocorticoids

Low affinity for cortisol

Question 7

Describe the features of mineralocorticoid receptors

Answer 7

Discrete distribution (kidney)

Do NOT distinguish between aldosterone and cortisol

High affinity for cortisol

Question 8

How is the issue of cortisol having efficacy at the mineralocorticoid receptors (and thus behaving like aldosterone resolved).

Answer 8

The kidneys synthesise an enzyme called 11B-hydroxysteroid dehydrogenase 2 which inactivates cortisol to the inactive cortisone.
However, in Cushing’s we have supra-physiological concentrations of cortisol- so this system becomes saturated- allowing cortisol to exert mineralocorticoid effects.
This is why we see hypokalaemia in Cushing’s patients.

Question 9

What is hydrocortisone

Answer 9

Hydrocortisone

Glucocorticoid with mineralocorticoid activity at high doses

Question 10

What is prednisolone

Answer 10

Prednisolone
Glucocorticoid with weak mineralocorticoid activity
Used as an immunosuppressant- good at suppressing inflammation.

Question 11

What is dexamethasone

Answer 11

Dexamethasone
Synthetic glucocorticoid with no mineralocorticoid activity
Acute anti-oedema

E.g. used clinically for things like brain metastases where there is a lot of oedema

Question 12

What is fludrocortisone

Answer 12

Fludrocortisone
Aldosterone analogue (aldosterone not effective when given orally).
Used as an aldosterone substitute.
§ I.E. 21/11-hydroxylase deficiencies- or in Addison's

Question 13

Describe the structure activity relationship of these different drugs.

Answer 13

Small changes in structure and synthesis pathways gives rise to different steroids with different properties.

Question 14

How are these synthetic steroids administered

Answer 14

Oral

hydrocortisone, prednisolone, dexamethasone, fludrocortisone

Question 15

How else can hydrocortisone and dexamethasone be administered

Answer 15

Parenteral (i.v. or i.m.)
This is important acutely- want to administer a large dose to a patient in casualty presenting with a salt-losing crisis and postural hypotension.

Question 16

Summarise the distribution of these therapeutic steroids

Answer 16

Bind to plasma proteins (Cortisol Binding Globulin (CBG) and albumin) as circulating cortisol does

Question 17

Describe the extent of plasma protein binding in each of these therapeutic steroids

Answer 17

They bind to plasma proteins – corticosteroid binding globulin + albumin

Hydrocortisone is extremely plasma protein bound – 90-95%

Prednisolone is less bound

Dexamethasone and fludrocortisone are even less bound

Fludrocortisone only binds to albumin

Question 18

Describe the metabolism and half-life of the therapeutic steroids

Answer 18

The steroids are metabolised mainly in the liver, the principal step being reduction of the A ring. Hydrocortisone and fludrocortisone have a plasma half life of ~ 1.5h but a duration of action of ~ 8h; the effects of prednisolone persist for longer (up to 12h) while dexamethasone is long acting (>36h) because metabolism is slow.

Excreted in the bile and urine

Question 19

Describe the principles of treatment for primary adrenocrotical failure

Answer 19

Addison’s disease or chronic adrenal insufficiency
These patients are deficient in both cortisol and aldosterone. It is therefore necessary to replace BOTH hormones, i.e. use hydrocortisone and fludrocortisone (both given orally).

Question 20

Describe corticosteroid replacement therapy for secondary adrenocrotical failure (ACTH deficiency)

Answer 20

May have had pituitary removed
Patients lack cortisol but aldosterone is normal

Treat with hydrocortisone- (titrate the dose to mimic normal physiology

Question 21

Describe the management of acute adrenocortical failure (i.e and Addisonian crisis)

Answer 21

iv 0.9% sodium chloride to rehydrate patient
High dose hydrocortisone- to have both glucocorticoid and mineralocorticoid activity
i.v. infusion or i.m. every 6h, mineralocorticoid effect at high dose (11βHSD overwhelmed)
5% dextrose if hypoglycaemic
NOTE: don’t normally need dextrose because the hydrocortisone will increase blood glucose anyway

Question 22

Describe congenital adrenal hyperplasia

Answer 22

congenital lack of enzymes
needed for adrenal steroid synthesis
* Approximately 95% of cases
lack 21-hydroxylase- therefore you cannot synthesise cortisol or aldosterone.
All the precursors are funnelled into androgen production- this leads to hirsutism and virilisation.

Question 23

Which precursor can we measure to diagnose 21a-hydroxylase deficiency

Answer 23

In 21 hydroxylase deficiency,17α-

hydroxyprogesterone accumulates, as this is immediately before the enzyme ‘block’

Question 24

What is the issue in patients with 21alpha-hydroxylase deficiency

Answer 24

In 21 hydroxylase deficiency
no cortisol production, so ACTH rises (no negative feedback)
High ACTH drives further adrenal androgen production
CAH caused by partial enzyme deficiency can result in virilisation and precocious puberty

Question 25

What are the objectives of treatment in patients with congenital adrenal hyperplasia

Answer 25

``` Replace cortisol Suppress ACTH and, thus, adrenal androgen production Replace aldosterone in salt wasting forms. ```

Question 26

Which drugs are used to treat congenital adrenal hyperplasia

Answer 26

Dexamethasone daily by mouth at night. Dexamethasone is a long-acting steroid and will therefore not only replace cortisol but also effectively suppress the morning rise in ACTH. Adrenal androgen production will therefore be suppressed. Alternatively hydrocortisone or prednisolone may be used (daily in 2/3 divided doses, higher dose at night) in doses which are sufficient to reduce ACTH secretion. Fludrocortisone in salt wasting forms (by mouth, usually once daily in the morning)

Question 27

Why is it hard to achieve all the treatment aims in congenital adrenal hyperplasia

Answer 27

High dose glucocorticoids may lower ACTH drive and hence reduce androgen output, but risk of developing iatrogenic Cushing’s syndrome. A reduction in glucocorticoid dose will reduce the risk of iatrogenic Cushing’s, but ACTH will increase, producing more androgens. The effectiveness of dexamethasone, hydrocortisone and prednisolone in suppressing androgen production may be monitored by measurement of 17α-hydroxyprogesterone.

Question 28

Describe the body's response to stress through cortisol

Answer 28

Normal subjects produce about 20mg/day cortisol but in severe stress production may rise to 200-300 mg/day. Subjects with adrenocortical insufficiency are unable to produce cortisol in conditions of stress, e.g. in response to minor infections or surgery. It is therefore important to provide additional exogenous steroid (glucocorticoid) to protect them.

Question 29

When should you increase glucocorticoid dosage

Answer 29

Minor illnesses: Double usual hydrocortisone dose. Surgery: Administer hydrocortisone (100mg) intramuscularly with the pre-anaesthetic medication and repeat at 6-8 hourly intervals. Switch to oral regimen once eating and drinking). Preparation for adrenalectomy or hypophysectomy: As for surgery above

Question 30

What else can cause adrenal insufficiency

Answer 30

In addition to the causes detailed above, adrenal insufficiency may also be caused by long-term treatment with high doses of glucocorticoids in, for example, chronic inflammatory disease. These patients also require protection with exogenous glucocorticoids during surgery Iatrogenic adrenocrotical failure Long-term, high dose glucocorticoid therapy can suppress the HPA axis and hence suppress adrenal function so that they no longer produce cortisol by themselves

Question 31

What should you tell patients with adrenocortical failure

Answer 31

Patients on long-term corticosteroid treatment or replacement therapy are advised to carry a steroid alert card detailing their dosage and condition- so paramedics can respond appropriately in case of emergency.

Question 32

Describe the different doses of exogenous steroids used for different conditions

Answer 32

Cortisol (approved drug name for hydrocortisone) is used clinically for replacement therapy (low dose). High doses eg for the treatment of inflammatory disease, are frequently associated with unwanted mineralocorticoid activity. Synthetic steroid analogues which show more selectivity for the glucocorticoid receptor are frequently used in preference to control inflammation, to produce immunosuppression and in the treatment of neoplastic disease.

Question 33

How would you assess whether a patient needs long term steroid replacement therapy

Answer 33

a. Insulin induced hypoglycaemia – get blood glucose to 2.2 and take a blood sample to check for rising cortisol. If the cortisol is low after test after 6 weeks, she still needs replacement therapy. b. Hydrocortisone is expensive so most doctors prescribe prednisolone.

Question 34

How would you reassure the patient that these steroids don't puff you up

Answer 34

Anabolic steroids are the ones that make you bigger, not these types of steroids.

Question 35

Summarise the investigations for congenital adrenal hyperplasia

Answer 35

a. Genetic testing for the gene that encodes 21-hydroxylase (if absent then confirmed). b. Measure 17alpha-hydroxyprogesterone levels (should be high due to build up). c. Short synacthen test – give ACTH and observe cortisol does not rise.

Question 36

Summarise the treatment and advice for a patient with adrenocortical insufficiency

Answer 36

a. Yes – hydrocortisone – 20mg a day in 3 doses (10mg, 5mg, 5mg). b. If she undergoes physiological stress (e.g. is ill), double the dose. c. If she starts to vomit, come into A&E and say you take hydrocortisone and get IV steroids.