Adrenals

Question 1

• List the clinical features of Cushing’s and Conn’s Syndromes.
• Recognise that suppression tests are useful in adrenal hyperfunction.
• • List the drugs used to treat Cushing’s and Conn’s Syndromes.
• List the surgical options for treatment of Cushing’s and Conn’s Syndromes.
• Recognise that a finding a phaeochromocytoma is a medical emergency.
• Recognise that “Dr House” is an endocrinologist.
• List the clinical features of a patient with a phaeochromocytoma.
• List the treatment of a patient with a phaeochromocytoma.

Answer 1

Clinical Features of Cushing’s Syndrome

• Caused by having too much CORTISOL
• It can be caused by a tumour in the pituitary that’s making ACTH - the ACTH makes he adrenal gland grow
• Rarely it can be due to a benign tumour of the adrenal gland
• Cortisol switches protein synthesis OFF and fat synthesis ON
• So you lose protein and you gain fat
• Bruising - this is because the tissues under the skin are full of protein and you make protein to heal so if you can’t make protein you start to leak and you get bruises
• You get fat deposition everywhere - you get a moon face and a buffalo hump (interscapular fat pad)
• Stretch Marks - because you are putting on a lot of fat quite quickly and because cortisol switches off protein synthesis so you can’t make the proteins required for the skin to grow so the skin tears
• When you have rapid growth, you can’t stretch the skin to accommodate
• They will have problems with healing as well because of the lack of protein synthesis
• They will get weaker - their legs get weaker because the muscles made of protein don’t grow but the fat does
• They are very heavy but their muscles are weak so they can’t climb stairs
• This could be due to an operable tiny pituitary tumour
• REMEMBER: Cushing’s DISEASE is caused by a pituitary tumour
• But there are several causes of Cushing’s Syndrome

Clinical Features of Cushing’s Summarised

• Too much cortisol
• Centripetal obesity
• Moon face and buffalo hump
• Proximal myopathy
• Hypertension and Hypokalaemia
• Red striae, thin skin and easy bruising
• Osteoporosis, diabetes

NOTE: cortisol starts to bind to receptors in the kidney to retain sodium and excrete potassium so you become hypertensive and hypokalaemic

This is obvious when the patient presents late but sometimes they present at the start with a few symptoms.

Question 2

Identify the four causes of Cushing’s Syndrome.

Answer 2

Causes of Cushing’s Syndrome

1. Taking too many steroids by mouth (we use them for asthma, for colitis) (NOTE: steroid is a molecule that comes from cholesterol)
   
   • If patients are on a cortisol type steroid they will put on fat and lose protein
   • Whereas testosterone is a bodybuilding steroid which has totally different effects
   • So be careful as to which steroid patients are on
   • If they are on glucocorticoids that will cause these symptoms and this is common (more common than tumours)
2. Pituitary dependent Cushing’s disease (this means pituitary source)
3. Ectopic ACTH from lung cancer
4. Adrenal adenoma that is making cortisol

When you see this patient, you firstly ask if they are on steroids to rule out the possibility of Cushing’s due to taking oral steroids

Question 3

List the principal investigations required to determine the cause of Cushing’s Syndrome in an individual

Answer 3

Investigations to Determine the Cause of Cushing’s Syndrome

1. If you see a patient with all the features of Cushing’s, you want to measure the cortisol

• The problem with cortisol is that it is high in the morning and low when you sleep - so a one of measurement doesn’t mean anything
• Also, the pain and stress of having a blood test will increase the cortisol because cortisol is a stress hormone
• One of the ways of measuring this is to do a 24 hour urine collection for urinary free cortisol
  
  • Problem is that patients often forget to sample the urine and it is not ideal

2. Blood diurnal cortisol levels - normal people have a high cortisol in the morning when they wake up and then at midnight if you’re asleep it will be very low

• If you have Cushing’s syndrome you lose that rhythm of having midnight suppression so you want to take a measurement at midnight and if it’s high that is suspicious
• Problem - stress can affect this
• The secret is to admit them to hospital and not tell them that they’re going to have a midnight blood sample - if the cortisol is low then there’s you’ve got a very good chance of it not being Cushing’s
• Midnight cortisol levels are a good way of diagnosing Cushing’s
• Third thing is that you can use the negative feedback system and give the patient a large dose of extra steroid
  
  • If you give a normal person dexamethasone your pituitary will detect extra steroid and it will turn off the ACTH and within hours you will have zero cortisol
  • This is a really good test

3. Low Dose Dexamethasone Suppression Test (normal or abnormal, doesn’t say if it is ectopic or pituitary or steroid)

• 0.5 mg 6 hourly for 48 hours
• Dexamethasone = artificial steroid
• You take a blood test before giving it, then you give the dexamethasone and at the end of that, normal people will have ZERO cortisol (because you don’t need more steroid)
• People with Cushing’s Disease keep making cortisol because the pituitary tumour keeps on pushing out ACTH - it does not react to dexamethasone
• It will not tell you what the cause of the Cushing’s is - all it tells you is that they are not normal and therefore you need to start doing scans and other things to find out the source

THREE tests that you can do to determine the cause of Cushing’s Syndrome

• 24 hour urine collection for urinary free cortisol
• Blood diurnal cortisol levels
• Low dose dexamethasone suppression test (GOLD STANDARD)
  
  • Someone with Cushing’s Syndrome will have a high level of cortisol even after the low dose dexamethasone suppression test
• NOTE: people with Cushing’s used to die because they used to get infected as they can’t heal and synthesise proteins so they become immunosuppressed and patients ended up dying of sepsis

Question 4

Discuss medication used for the treatment of Cushing’s.

Answer 4

Pharmacological Manipulation of Steroids

• Enzymes inhibitors - inhibit enzymes of steroid synthesis
• Receptor blocking drugs

Treatment of Cushing’s Syndrome

• Depends on cause
• Pituitary surgery (transsphenoidal hypophysectomy)
• Bilateral Adrenalectomy
  
  • If you take out both adrenal glands because if you remove these then the patient can’t make any more cortisol
• Unilateral Adrenalectomy for Adrenal Mass
  
  • If there is an adrenal lump then take that adrenal out
• You start off with a round of medical treatment and once the patient is safe for operation you have carry out one of the above operations

Overview of treatment of hyperadrenal disorders

• Cushing’s = too much CORTISOL
• Conn’s = too much ALDOSTERONE
• NOTE: the adrenal medulla produces CATECHOLAMINES
• To block the effects of the excess catecholamines you FIRST give an ALPHA BLOCKER
• You give the alpha blocker first because the urgent issue is a really HIGH BLOOD PRESSURE caused by the catecholamines (from the tumour) binding to alpha receptors in the vasculature and causing VASOCONSTRICTION
• Once the blood pressure has decreased due to the alpha blockade, you give a beta blocker (more information below)
• This is because when beta receptors are stimulated by catecholamines, it causes vasodilation so if you don’t block alpha receptors (before blocking the beta receptors)N first you could have an unopposed alpha mediated vasoconstriction causing a hypertensive crisis and a possible stroke
• Inhibits 11b-hydroxylase
• This slows down the cortisol synthesis pathway and is used as a treatment for Cushing’s
• It reduces the production of cortisol and corticosterone
• Because you stop making cortisol, the ACTH levels rise
• There is no negative feedback exerted by 11-deoxycorticosterone so this accumulates

Uses of Metyrapone

• Control of Cushing’s syndrome prior to surgery
  
  • Cushing’s patients are not good surgical candidates because they are predisposed to infection and have very thin skin
  • So metyrapone is used to improve the patient’s symptoms and promotes better post-op recovery (better wound healing, less infection)
  • The oral metyrapone is dosed according to cortisol production (aim for mean serum cholesterol of 150-300 nmol/L)
• Control of Cushing’s symptoms after radiotherapy
  
  • Radiotherapy is usually quite slow to work so you would give Metyrapone after radiotherapy until the effects of the radiotherapy start to come about

Negative Aspects of Metyrapone

• There are TWO negative things about metyrapone
• 11b-hydroxylase is relevant to TWO parts of the pathway
• This leads to accumulation of 11-deoxycorticosterone and 11-deoxycortisol
• 11-deoxycorticosterone has mineralocorticoid properties (acts a bit like aldosterone – reabsorption of sodium and water)
• This leads to retention of sodium and excretion of potassium in the kidneys so you get salt retention and hypertension
• This drug is fine to use in the short term to prepare a patient for surgery but you wouldn’t want to use it long term
• The second problem is that because you’ve blocked two limbs of the pathway, all the precursors funnel towards sex steroid synthesis
• There is an increase in adrenal androgens
• This can cause hirsuitism and is particularly unpleasant for women

Unwanted Aspects of Metyrapone

• Nausea, vomiting, dizziness
• Sedation, hypoadrenalism
  
  • By lowering the cortisol production in someone with Cushing’s, you could make them hypoadrenal and that isn’t particularly nice
  • Caution against impaired performance of skilled tasks
• Hypertension on long-term administration
• Hirsuitism (excessive androgens in women)

Question 5

Discuss metyrapone as a medication used for the treatment of Cushing’s

Answer 5

Inhibitors of steroid production

Metyrapone

• Inhibits 11b-hydroxylase
• This slows down the cortisol synthesis pathway and is used as a treatment for Cushing’s
• It reduces the production of cortisol and corticosterone
• Because you stop making cortisol, the ACTH levels rise
• There is no negative feedback exerted by 11-deoxycorticosterone so this accumulates

Uses of Metyrapone

• Control of Cushing’s syndrome prior to surgery
  
  • Cushing’s patients are not good surgical candidates because they are predisposed to infection and have very thin skin
  • So metyrapone is used to improve the patient’s symptoms and promotes better post-op recovery (better wound healing, less infection)
  • The oral metyrapone is dosed according to cortisol production (aim for mean serum cholesterol of 150-300 nmol/L)
• Control of Cushing’s symptoms after radiotherapy
  
  • Radiotherapy is usually quite slow to work so you would give Metyrapone after radiotherapy until the effects of the radiotherapy start to come about

Negative Aspects of Metyrapone

• There are TWO negative things about metyrapone
• 11b-hydroxylase is relevant to TWO parts of the pathway
• This leads to accumulation of 11-deoxycorticosterone and 11-deoxycortisol
• 11-deoxycorticosterone has mineralocorticoid properties (acts a bit like aldosterone – reabsorption of sodium and water)
• This leads to retention of sodium and excretion of potassium in the kidneys so you get salt retention and hypertension
• This drug is fine to use in the short term to prepare a patient for surgery but you wouldn’t want to use it long term
• The second problem is that because you’ve blocked two limbs of the pathway, all the precursors funnel towards sex steroid synthesis
• There is an increase in adrenal androgens
• This can cause hirsuitism and is particularly unpleasant for women

Unwanted Aspects of Metyrapone

• Nausea, vomiting, dizziness
• Sedation, hypoadrenalism
  
  • By lowering the cortisol production in someone with Cushing’s, you could make them hypoadrenal and that isn’t particularly nice
  • Caution against impaired performance of skilled tasks
• Hypertension on long-term administration
• Hirsuitism (excessive androgens in women)

Question 6

Discuss ketoconazole as a medication used for the treatment of Cushing’s

Answer 6

2. Ketoconazole

• Main use as an anti-fungal agent - withdrawn in 2013 due to risk of hepatotoxicity
• At higher concentrations, ketoconazole inhibits cortisol production(this is an unlicenced use for preparing patients for operation by treating Cushing’s)
• Only used off-label because it has caused casualties due to liver failure
• Ketoconazole inhibits Cytochrome P450 SCC (side chain cleavage) enzymes
• This means that you block the production of glucocorticoids, mineralocorticoids and sex steroids
• You use it in a similar way to metyrapone - short-term use to normalise cholesterol before surgery

Uses of Ketoconazole

• Cushing’s Syndrome
  
  • Treatment and control of symptoms prior to surgery
  • It is orally active
• Unwanted Actions
  
  • Nausea, vomiting, abdominal pain
  • Alopecia
  • Gynaecomastia, oligospermia, impotence, decreased libido
    
    • This is due to reduction of sex steroid production
  • Ventricular tachycardias
  • Liver Damage
    
    • Could be fatal
    • Patients are monitored with regular liver function tests

Question 7

List the clinical features of Conn’s Syndrome

Answer 7

Conn’s Syndrome

• Benign adrenocortical tumour (zona glomerulosa - makes aldosterone)
• Aldosterone is in excess
• You will retain sodium and lose potassium
• This means you get HYPERTENSION and HYPOKALAEMIA
• There are no other features, just high blood pressure and low potassium (this is more difficult to spot)

Conn’s Syndrome Diagnosis

• Primary Hyperaldosteronism
  
  • A tumour that is just making aldosterone
  • In a patient with high blood pressure and you do a blood test and potassium is low then think of Conn’s
  • High blood pressure is very common but occasionally there is a cause that’s treatable
• Renin-angiotensin system should be suppressed (excludes secondary hyperaldosteronism)
  
  • Measure the aldosterone, and if it is high, measure the renin, and that should be suppressed by the very high blood pressure
  • If you get this combination in someone with a high blood pressure and low potassium, you have a diagnosis

Question 8

Discuss treatment options for Conn’s syndrome

Answer 8

Conn’s Syndrome Treatment (aim: block cortisol production, you don’t block the hormone production but the receptor it acts on to make the product)

• Medical treatment to make them better
• Then remove the tumour
• To stop the effects of excess aldosterone you give mineralocorticoid receptor antagonists - SPIRONOLACTONE
• Surgery - image and remove the tumour
• If bilateral adrenal hyperplasia - then you will stay on spironolactone

Uses and Mechanism of Action of Spironolactone

• Primary Hyperaldosteronism (Conn’s Syndrome)
  
  • If you want to prepare the patient for surgery you want to reduce their blood pressure because you don’t want to give general anaesthetic to someone with very high blood pressure
• Spironolactone is converted to several active metabolites, including CANRENONE, which is a competitive antagonist of the mineralocorticoid receptor
• Spironolactone blocks Na+ reabsorption and K+ excretion in the kidney tubules so it is a potassium sparing diuretic
• Sometimes you can get two very chunky adrenals (bilateral adrenal hyperplasia) and you don’t want to take out both adrenals because then you don’t have production of cortisol or aldosterone
• So people with bilateral adrenal hyperplasia are placed on long-term spironolactone

Pharmacokinetics of Spironolactone

• Orally active
• Given daily in single or divided doses
• Highly protein-bound and metabolised in the liver

Unwanted Actions of Spironolactone

• Spironolactone is a very non-specific drug so there are lots of side-effects
• It is a progesterone receptor agonist so causes menstrual irregularities
• It is also an androgen receptor antagonist so it can cause gynaecomastia in men
• It can also cause GI tract irritation
• Caution/Contraindication:
  
  • Renal and hepatic disease

Eplerenone

• Also a mineralocorticoid receptor antagonist (newer than spironolactone)
• This has fewer side-effects than spironolactone so it is used more frequently
• This binds similarly well to the mineralocorticoid receptor as spironolactone but it is more specific so it interferes less with progesterone and androgen receptors
• Patients needing a long-term mineralocorticoid receptor antagonist are more likely to be on eplerenone than spironolactone

Question 9

Summarize how adrenal hormones arise from cholesterol

Answer 9

Corticosteroids (secreted by cortex) are steroid hormones synthesized by cholesterol (C27)

1. Lipoproteins deliver fatty acid esters (which store cholesterol) to the cell
2. Cholesterol is liberated by esterase
3. It is driven into the mitochondria by StAR protein
4. There, cholesterol (C27) is cleaved using enzymes to make MINERALOCORTICOIDS (C21) and GLUCOCORTICOIDS (C21)

Question 10

Phaeochromocytoma: clinical features, treatment

Answer 10

The adrenal medulla

Phaeochromocytoma

• These are tumours of the adrenal MEDULLA which secrete catecholamines (adrenaline and noradrenaline)
• Adrenaline gives you a rapid effect
• If you have a tumour that’s producing large amounts of adrenaline, from time to time the tumour will release a lot of adrenaline and you will get a massive rise in blood pressure (e.g. 300/150) - the sort of level that causes a stroke suddenly
• That’s the main effect
• There is a sudden onset of panic, you feel anxious, tachycardia and severe hypertension

Clinical Features of Phaeochromocytoma

• If you see episodic severe hypertension in young people then phaeochromocytoma is worth thinking about
• They may say that they are absolutely fine and then all of a sudden they get really anxious, they get palpitations and have a panic attack and their blood pressure goes up
• The whole adrenal gland builds up adrenaline and blasts it out in one go - sometimes this could be fatal if you go into ventricular fibrillation
• Sometimes, if you have a big phaeochromocytoma, this sort of release could happen after abdominal palpation or if there is trauma and the tumour suddenly releases a load of adrenaline
• This is more common in certain inherited conditions
• Severe hypertension can cause a myocardial infarction or stroke (this can be in very young people)
• This can also cause sudden cardiac death - high adrenaline can cause ventricular fibrillation and death
• So this is a MEDICAL EMERGENCY

Management of Phaeochromocytoma

• Eventually they need surgery, but the patient needs careful preparation as the anaesthetic can precipitate a hypertensive crisis
• When you give the anaesthetic, the tumour will suddenly release adrenaline in response to the anaesthetic and suddenly on the table you will have a hypertensive crisis caused by adrenaline and noradrenaline
• First you give a drug to block the receptor to which adrenaline binds - first an ALPHA BLOCKER
• Patients may need intravenous fluid as alpha blockade commences (GIVE VOLUME!)
• Once you’ve done this you give them BETA BLOCKADE to prevent tachycardia
• With enough alpha and beta blockade, then the patient can perform surgery because even if the adrenal does release adrenaline, all the receptors in the patient are completely blocked so it has no effect
• When you first give an alpha blocker, they suddenly drop the blood pressure - so you tend to give a bit of fluid before you give the alpha and beta blockade

Phaeochromocytoma Key Facts

• 10% extra-adrenal (sympathetic chain)
• 90% inside the adrenal
• 10% are malignant
• 10% bilateral
• 90% are curable by operation
• Phaeochromocytoma is EXTREMELY RARE

Question 11

Recall the synthesis of adrenocortical hormones

Addison’s disease: recall the synthesis of adrenocortical steroids, list the clinical features of Addison’s disease, define the term Addisonian crisis and list specific features of this condition.

Congenital adrenal hyperplasia: explain the hormonal consequences of specific adrenal enzyme deficiencies, explain the clinical features and investigation of congenital adrenal hyperplasia with reference to specific enzyme deficiencies.

Answer 11

Notes on cholesterol

• The carbons in the molecular structure of cholesterol are numbered
• Cholesterol has 27 carbon atoms
• If you hydroxylate them at different positions you get different substances
• The enzymes that act on cholesterol oxidize or hydroxylate it to make different steroids
• Here is the whole steroid synthetic pathway
• If you take the zona glomerulosa, it has the enzymes that go from cholesterol to pregnenolone (cholesterol without the side chain)
• Then you hydroxylate position 3 and then you add further OH groups in different positions and then oxidise it further to end up with aldosterone
• So cholesterol can be converted to aldosterone in the adrenal cortex by adding OH groups in various positions
• If you do the same thing in the zona fasciculata you have slightly different enzymes so you go down the glucocorticoid route than the mineralocorticoid route
• NOTE: there is a very tiny different between testosterone and oestradiol
• All the steroids come from cholesterol with tiny modifications
• • You start with cholesterol and in the adrenal cortex you get pregnenolone, if you put an OH group onto 17, 21 and 11 you end up with cortisol
• On the other hand if you stick an OH group onto 21, 11 and 18 then you have aldosterone 9 these are totally different molecules with very slight differences
• The sex steroid pathways are also present in the ovaries and testes, but they have much more of the sex steroid enzymes and none of the mineralocorticoid and glucocorticoid enzymes
• Glucocorticoid synthesis enzymes and sex steroid synthesis enzymes are turned on by ACTH
• If the pituitary detects STRESS it pushes out ACTH and ACTH works by turning on the enzymes so you start to make more cortisol
• In the aldosterone pathway it is turned on by renin and angiotensin II that turns on the enzymes in the mineralocorticoid pathway
• All you are doing is adding enzymes that hydroxylate different parts of the steroid molecule

Question 12

Causes of Adrenocortical failure

Answer 12

The MOST COMMON cause of adrenocortical failure WORLDWIDE is

Tuberculous Addison’s Disease

• This occurs particularly when you stop a course of treatment early
• Autoimmune Addison’s Disease 9 COMMONEST in the UK
  
  • The immune system makes a mistake and wipes out the adrenal gland
• hypophysis (condition that affects the adrenal glands)

Congenital Adrenal Hyperplasia: Adrenals not working because of genetic mutation and disturbance of enzymatic activity

• You’re born with big adrenals and that is caused by enzyme deficiency so the adrenals can’t make the hormones properly
• This means they are stimulated and the adrenal glands get very big (you are born with big adrenals)

Question 13

Features of Addison’s Disease

Answer 13

• Addison noticed that there was pigmentation in the mouth
• They have darker hair, more pigmented skin and patches of vitiligo

(autoimmune disease of the skin 9 there are antibodies against the melanin)

• Autoimmune diseases go together, so these patients have autoimmune disease against the adrenal gland (causes adrenal atrophy) and vitiligo
• Just before death, the patients had very low blood pressure

Consequences of Adrenal Failure

• Fall in blood pressure
  
  • Because you have no aldosterone
  • Postural hypotension: lack of aldosterone to kick up BP upon standing
• ​Loss of salt in urine
  
  • Because they are unable to retain salt because of the lack of aldosterone
  • So the urine has salt loss and the plasma has a rise in potassium
• ​Increased plasma potassium
• Fall in glucose
  
  • Due to glucocorticoid deficiency
  • Due to glucocorticoid deficiency – because of high ACHT
• ​High ACTH resulting in increased pigmentation: because of feedback
• Loss of appetite and weight
• Eventual death due to severe hypotension
• If this happens suddenly it is called an Addisonian Crisis
• Vitiligo: shows autoimmune predisposition: pale, white patches

Question 14

Explain skin pigmentation in Adisson’s

Answer 14

Link between adrenal failure and increased pigmentation

• ACTH is made from POMC (pro9 opiomelanocortin) which has two components:
  
  • ACTH
  • MSH (melanocyte stimulating hormone)
• Because there is no adrenal gland because it has been destroyed or atrophied, there is no cortisol
• This means there is no negative feedback
• This leads to high ACTH which leads to more and more MSH being produced 99> increased pigmentation

·POMC (ProKopio melanocortin)

• Synthesized in the pituitary and broken down to ACTH and MSH and endorphins and enkephalins and other peptides

Question 15

Discuss diagnostic techniques for Addison’s

Answer 15

Tests for Addison’s

COMBINATION: low Na+, high K+

• Measure the hormones at 9 am (cortisol is high in the morning)
  
  • If it is not high then they may have Addison’s
• You could measure their ACTH and it should be really high
• You could give them an injection of synthetic ACTH (synacthen) 9 if they have functioning adrenals then they should produce a lot of cortisol
  
  • If you can’t make cortisol despite a big dose of ACTH, then their adrenals are not normal
  • You give 250 mg of synacthen IM
  • Then you measure the cortisol response

·Typical Addison’s Patient

• Low 9 am cortisol (around 100 (normal is 2709900))
• Administer IM synacthen and half an hour later they will have a cortisol of around 100 (normal is > 600)

Question 16

Congenital Adrenal Hyperplasia A

Answer 16

Rare cause of primary corticotrophin deficiency)

• Commonest is caused by 21Khydroxylase deficiency (essential for adrenal steroid synthesis)
• Can be complete or partial (complete/partial deficiency of enzyme)
• If you have none of this enzyme then you will be deficient of the hormones that are below that enzyme in the pathway i.e. no aldosterone and no cortisol
• In utero you will be getting these hormones from your mother but once you’re born you’re on your own
• Because you’re not making any cortisol then your neonatal pituitary will be making lots of ACTH to try and make some cortisol of your own but you can’t because you’re missing one of the key enzymes
• After 9 months, the adrenal glands will be huge but useless
• The adrenals CAN still make sex steroids
• Because there is an overflow of 17 hydroxyprogesterone, they will make a lot of sex steroids but they can’t make anything else (because all the precursors need to go somewhere)
• So cortisol and aldosterone will be deficient
• If these hormones are totally absent you can’t survive more than a day (on the first day you have the mother’s cortisol still in you)
• The baby will lose consciousness as they have a salt losing Addisonian crisis after one day
• The first thing doctors tend to do is give saline (this is good because you’re losing salt)
• TESTOSTERONE is in excess (and the other sex steroids but testosterone is the one that causes the clinical problems)
• You may notice, especially if the child was a girl, the effects of testosterone 9 there is some abnormality of the genitals
• If the child is born with ambiguity in the genital region then you have to keep them in hospital or they will go home and have an arrest
• Presentation of congenital adrenal hyperplasia:

1. ### Hypotension
2. ### Virilisation 9 the development of male physical characteristics in a female

• 21 hydroxylase deficiency is recessive
• It is relatively rare but still important
• The key thing to look for is that girls may have ambiguous genitalia

Question 17

Congenital Adrenal Hyperplasia B

Answer 17

Partial 21Khydroxylase Deficiency

• The same hormones will be low and high but not quite so severely
• This means that although you have a low cortisol you’ll be a little bit hypotensive but you won’t die
• You’ll have a long period of slightly raised testosterone
• They may present at any age because they survive and don’t have an Addisonian crisis
  
  • This will happen as soon as they are unhappy with the effects of the extra testosterone e.g. hirsuitism and virilisation in women, precocious puberty in men
• Enormous adrenal glands because of feedback?

Question 18

Congenital Adrenal Hyperplasia C

Answer 18

11Kbeta hydroxylase deficiency

• You get a build up of 11 deoxycorticosterone (behaves like aldosterone)
• This is an active aldosterone receptor agonist
• So this means that they don’t have a salt losing Addisonian crisis
• They behave like they have a high level of aldosterone
• They are hypertensive in childhood and hypokalaemic
• These children will be virilised but they have a slightly high blood pressure and low potassium
• They go through childhood until someone checks their blood pressure
• So you have a hypertensive, hypokalaemic, virilised child
• The boys tend to be missed because they look fairly normal

Question 19

Congenital Adrenal Hyperplasia D

Answer 19

17Khydroxylase Deficiency

• They will have high levels of aldosterone (so they are hypertensive and hypokalaemic)
• But they are missing cortisol and sex steroids
• They will never go through puberty
• They usually present around pubertal age
• They will also be hypertensive
• They don’t have an Addisonian crisis because they have aldosterone
• But they do have borderline HYPOGLYCAEMIA
• They also have infections a lot because you need cortisol to cope with the stress of infection

Question 20

Explain the homeostatic control of adrenal corticosteroids in the body / Explain the mechanism by which mineralocorticoid receptors are protected from cortisol.

Answer 20

Cortisol conentrations fluctuate throughout the day (high in morning lower at night)
Aldosterone concentrations are the same throughout the day

cortisol concentration >> aldosterone concentration (1000 fold)

Aldosterone binds to ALDOSTERONE RECEPTORS (MR)

Cortisol binds to GLUCOCORTICOID RECEPTORS (GR) and ALDOSTERONE RECEPTORS (MR)

Since cortisol>>>aldosteron and cortisol binds to more receptors (both kinds) why do we still need aldosterone?

Aldosterone combines with cortisol and using enzyme 11b-hydroxysteroid dehydrogenase 2 (11bHD2) yeilds CORTISONE (an inactive form of cortisol)

So aldosterone is important because it inactivates cortisol when it is not needed:

1. In the kidney
2. In the placenta where cortisol concentrations MUST be low

• MRs do NOT distinguish between aldosterone and cortisol and they have a high affinity for cortisol
• This could lead to problems because cortisol can stimulate the MR
• Protection of MRs from cortisol by 11bKhydroxysteroid dehydrogenase (11bHSD)
• This enzyme deactivates the cortisol so it protects the MRs and prevents it from being stimulated
• Cortisone is inactive and it can’t stimulate the MR
• In Cushing’s syndrome you have high levels of cortisol and one of the features is HYPOKALAEMIA
• That is because the system gets overwhelmed 9 when there is too much cortisol the 11b9hydroxysteroid dehydrogenase can’t inactivate it all so some of the cortisol binds to mineralocorticoid receptors and causes hypokalaemia

Question 21

What are the stimuli to lead to the production of aldosterone?

Answer 21

• Zona Glomerulosa = Aldosterone
• Zona Fasciculata = Cortisol
• Zona Reticularis = Androgens + Oestrogens
• IMPORTANT: THE ADRENAL SEX STEROIDS ARE ALSO UNDER THE CONTROL OF ACTH
• This is important when you consider congenital adrenal hyperplasia
• Aldosterone is NOT under the control of ACTH

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

1. Production of renin from the granular cells surrounding the afferent arteriole in the kidney

Factors that increase renin production:

i) decrease in Renal Perfusion Pressure (RPP) (blood pressure)
ii) when renal sympathetic nerve activity increases
iii) decreased Na+ : Hyponatraemia

• Drop in Renal Blood Flow 9 juxtaglomerular apparatus detects a drop in renal blood flow and releases renin
  iv) Hyperkalaemia 9 because aldosterone increases urinary potassium excretion
  v) BetaK1 adrenoceptor stimulation

(Essentially, when there is a decrease in blood pressure or Na+ renin is made to restore homeostasis by increasing them)

2. After renin is produced it acts on protein angiotensinogen: renin + angiotensinogen = Angiotensin I
3. Angiotensin I + ACE = Angiotensin II
4. Angiotensin II stimulates aldosterone production
5. Low blood Na+ and high K+ can also increase aldosterone production

Question 22

What are the stimuli to lead to the production of cortisol?

Answer 22

Adrenal gland–hypothalamo-pituitary-adrenocortical axis

1. Hypothalamus secretes Corticotrophin Releasing Hormone (CRH)
2. CRH acts on corticotrophs of the pituitary
3. They release ACTH (adrenocorticotrophic hormone)
4. ACTH stimulates the cells of zona fasciculata + reticularis
5. Cortisol is produced

Question 23

• Give examples of drug treatment for Addison’s disease.

Answer 23

Drugs K Receptor Selectivity

• Cortisol (hydrocortisone)
  
  • 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 11b9 hydroxysteroid dehydrogenase system

·Prednisolone

• This tends to be an immunosuppressive type of glucocorticoid
• It is a glucocorticoid with weak mineralocorticoid activity

·Dexamethasone

• 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 anti9oedema agent
• This has NO mineralocorticoid effect

·Fludrocortisone

• ALDOSTERONE analogue
• Used as an aldosterone substitute
• With drug structures you can make very small changes and their effects can change drastically
• REMEMBER: all the drugs are glucocorticoid substitutes EXCEPT fludrocortisone which is an aldosterone analogue

Pharmacokinetics of Corticosteroids

• All the drugs can be given orally
• There are some acute situations where you need parenteral administration 9 IV or IM
• When you are giving high doses of hydrocortisone you’re likely to have some mineralocorticoid effects

Distribution of Corticosteroids

• Binding to plasma proteins (corticosteroid binding globulin and albumin)
• Remember only the free, unbound hormone is biologically active
• Hydrocortisone is about 90K95% bound
• Prednisolone is less bound and dexamethasone and fludrocortisone are even less bound
• Fludrocortisone is only bound to albumin

Metabolism and Excretion of Corticosteroids

• Breakdown is hepatic
• It gets excreted via the bile and urine

Duration of Action of Corticosteroids

• Hydrocortisone and Fludrocortisone
  
  • Half9life = 1 hour
  • Duration = 8 hours

·Prednisolone

• Duration = 12 hours

·Dexamethasone

• Duration = 40 hours
• Lasts for the longest time
• All you need to know is that in order of shortest to longest half-life it is:

1. Hydrocortisone and Fludrocortisone
2. Prednisolone
3. Dexamethasone

Question 24

Outline reasons for giving corticosteroid replacement

Answer 24

Corticosteroid Replacement Therapy

Reasons for giving corticosteroid replacement:

·Primary Adrenocortical Failure

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

Question 25

Explain the basis of the drug treatment of Addison’s Disease and Chronic Adrenal Insufficiency

a) Addison’s disease, (b) pituitary9 dependent adrenal insufficiency, (c) acute adrenal insufficiency and (d) congenital adrenal hyperplasia, including mode of administration and monitoring of the effectiveness of therapy.

Answer 25

Primary Adrenocortical Failure

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

• Fludrocortisone (oral)

Question 26

Explain the basis of the drug treatment of secondary adrenocortical failure

Answer 26

Secondary Adrenocortical Failure

• ACTH deficiency
• There is nothing wrong with the adrenal gland but the adenohypophysis isn’t working properly
• The difference between these patients and Addison’s patients is that these patients have NORMAL aldosterone production
  
  • This is because 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:

oHydrocortisone (oral)

• Titrate Dose 9 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 27

Explain the basis of the drug treatment of Acute Adrenocortical Failure and Addisonian Crisis

Answer 27

• IV SALINE 9 first step
  
  • Whether they are a neonate or an adult, they will be suffering a salt9 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
• Once they have been infused with saline you give them high dose hydrocortisone
• 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
• If they are hypoglycaemic you can give them 5% dextrose but because they have been given so much glucocorticoid, this is rarely necessary
• • CAH is a congenital lack of steroid synthetic enzymes
    
    • You don’t need to be able to reproduce this pathway, you just need to know where it goes wrong and the consequences of that
• Most cases of CAH are due to the absence of 21Khydroxylase
• ### ·Adrenal androgen production in normal subjects and those with CAH
• In CAH you can’t make cortisol 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 219hydroxylase
• The precursor you can measure easily is 17aKhydroxyprogesterone (which accumulates because it can’t go anywhere else)
• The constant production of ACTH pushes 17a9hydroxyprogesterone towards the adrenal androgen pathway
• This is a problem in childhood:
  
  • Boys 9 precocious puberty
  • Girls 9 virilisation
• It can also cause problems in adult women 9 hirsuitism and acne
• So you need to give these patients a big dose of cortisol
• This is not only to replace the cortisol but also to suppress ACTH production and hence reduce sex steroid production
• ### oTreatment of Congenital Adrenal Hyperplasia
• Replace cortisol

Dexamethasone 1/day Or Hydrocortisone 293/day

• Suppress ACTH and, thus, adrenal androgen production

Big dose of glucocorticoid (dexamethasone 1/day, pm or hydrocortisone 2-3/day, high dose – even at night to decrease ACTH)

• Replace aldosterone in salt wasting forms

Fludrocortisone is the aldosterone replacement

• Monitor/optimise therapy by measuring:

17a9hydroxyprogesterone levels

Do a clinical assessment of what they are complaining about:
Cortisol helps as recover from illness or infection (so when ill and Addison’s – bad)

• Iatrogenic Cushing: 9 glucocorticoid dose too HIGH
• Hirsuitism/Acne 9 glucocorticoid dose too LOW (so ACTH is high)

Question 28

Additional measures in subjects with adrenocortical failure

Answer 28

• Normal Cortisol Production = 20 mg/day
• In stress production = 2009300 mg/day
• You increase the dosage when patients are vulnerable to stress e.g. if they become unwell
• Examples of situations when they should increase dosage:
• Minor illness = 2 x normal dose
• Surgery 9 hydrocortisone I.M. with pre9med at 698 hour intervals. Back to oral hydrocortisone once they’re back to normal and they’re eating and drinking
  GA is a stress to the body

Question 29

Iatrogenic Adrenocortical Failure

Answer 29

• 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 9 they have a suppressed HPA axis
• These patients also need to increase their dose when they experience 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)