Hypoadrenal disorders Flashcards
Which family of enzymes do the dehydrogenase belong to
The cytochrome P450 family
How many carbon atoms does cholesterol have
27
Summarise the storage of corticosteroids
The 3 cortical zones are associated with steroid hormones called corticosteroids. Because steroids are lipophilic, the adrenocortical hormones cannot be stored to a great extent as they would simply cross the lipid components of membranes and move out of the cells into the general circulation, once synthesised.
Therefore they are synthesised on demand when the adrenal cortical cells are stimulated appropriately.
What are the 3 zones of the adrenal cortex
Zona glomerulosa (outer)
Zona fasiculata (middle)
Zona reticularis (surrounds cells of adrenal medulla)
The zona fasciculata can usually be clearly differentiated from the outer glomerulosa and inner reticularis cells, being made up of cells, giving the effect of bundles.
The cells of the adrenal medulla are called chromaffin cells because they are readily stained with chromic acid salts.
What are the mineralocorticoids
produced by the zona glomerulosa- involved in mineral regulation
Leads to Na+ and therefore water retention= whilst excreting potassium.
Aldosterone
What are the glucocorticoids
produced by the zona fasciculata
major role in metabolic regulation- often to mobilise glucose in stress response
cortisol
What are the androgens
Made by the zona reticularis- but predominantly by the gonads in humans
Oestrogens and androgens
How many carbon atoms do each of the corticosteroids have
The mineralcorticoids and glucocorticoids have 21 C atoms each.
Androgens and oestrogens have 19 and 18 C atoms respectively.
Very similar structures
Progesterone also has 21 C atoms
Summarise the synthesis of the corticosteroids
All the corticosteroids are synthesised according to cell-dependent enzyme-induced conversions of substrates to final end products via various intermediaries.
The original precursor molecule is cholesterol, which can reach cells via the blood mainly as LDL, or be synthesised from acetyl coA within the cells.
What is the basic structure of cholesterol known as
cyclopentanoperhydrophenanthrene nucleus
Describe the first important step in corticosteroid hormone synthesis
The rate-limiting transport of intracellular cholesterol across the outer to the inner mitochondrial membrane where, in the presence of the enzyme P450scc (cholesterol side chain cleavage enzyme) it is converted to pregnenolone.
A specific steroidogenic acute regulatory (stAR) protein mediates this transport process, which is under the control of corticotrophin.
The pregnenolone then enters the cytoplasm where it is converted to progesterone by the enzyme 3beta- hydroxysteroid dehydrogenase. Subsequent conversions are dependent on the specificity of enzymes present in the cells of the three zones; indeed they also depend on their specific intracellular location (cytoplasm or mitochondria).
How is testosterone converted to estradiol
Aromatisation (via an aromatase enzyme)
Can occur in Men too
What are the actions of ACTH on the adrenal grand
Growth of the adrenal gland
Cortisol synthesis
Sex steroid synthesis
What does the pituitary gland make ACTH in response to
Stress
What regulates aldosterone synthesis
Renin and Angiotensin II (not ACTH)
Activated in haemorrhage and decreased renal perfusion.
Describe aldosterone synthesis in the zona glomerulosa
progesterone is converted to deoxycorticosterone (21-hydroxylase)- found in microsomes and ER
Deoxycorticosterone — corticosterone (mitochondrial enzyme 11B-hydroxylase)
Corticosterone (weak) —- aldosterone (more potent)- aldosterone synthase via the intermediate 18-hydroxycorticosterone.
Why can’t the fasciulata or reticularis cells produce aldosterone
They don’t have aldosterone synthase
However, they do have 17a-hydroxylase which is absent from the glomerulosa cells
Describe the actions of 17a-hydroxylase
Converts pregnenolone and progesterone to their 17a-hydroxy metabolites respectively.
Describe the synthesis of cortisol in the fasiculata cells
Progesterone — 17a-hydroxyprogesterone (17a-hydroxylase)
OR
Pregnenolone— 17a-hydroxypregnenolone (17a-hydroxylase)
17a-hydroxypregnenolone— 17a-hydroxyprogesterone(3B-hydroxysteroid dehydrogenase)
17a-hydroxyprogesterone— 11B-deoxycortisol (21-hydroxylase)
11B-deoxycortisol — cortisol (11B-hydroxylase).
Describe the synthesis of androgens and oestrogens in the zona reticularis
Both 17a-hydroxypregnenolone and 17a-hydroxyprogesterone can be converted to the weak androgens dehydroepiandrosterone (DHEA) and androstenedione respectively by the action of 17a-hydroxylase.
DHEA — androsenedione (3B-hydroxysteroid dehydrogenase)
Androstenedione can be converted into androgens in peripheral tissues by 17B-hydroxysteroid dehydrogenase.
Describe the different causes of adrenocortical failure
Causes include:
§ Adrenal glands destroyed.
o Tuberculosis Addison’s disease – most common worldwide.
o Autoimmune Addison’s disease – most common in the UK.
o Congenital adrenal hyperplasia – gland overgrows but does not function properly.
§ Enzymes in the steroid synthetic pathway not working.
Which tissues does T.B have a predilection for
The lungs and the adrenal cortex.
Summarise congenital adrenal hyperplasia
Mutation in the steroid synthesis enzymes- mutated or just not working properly.
Where do we see pigmentation in adrenocortical failure
Buccal pigmentation or pigmentation in scars
Often lose weight and look thin too.
Friction areas (nipples)
State the consequences of adrenocortical failure
Fall in blood pressure
Loss of salt in the urine
Increased plasma potassium
Non-specific tiredness and exhaustion (glucocorticoid synthesis)
Fall in glucose due to glucocorticoid deficiency
High ACTH resulting in increased pigmentation
Eventual death due to severe hypotension
What are the consequences of a loss of aldosterone and cortisol
Reduction in BP
Loss of Na+
Rise of K+
Why do patients with adrenocortical failure often appear to have a ‘particularly good tan’
As the circulating cortisol falls, the lack of negative feedback on the hypothalamo-pituitary axis results in an increase in precursor POMC synthesis, and consequently an increase in ACTH. Thus there is not only an increase in ACTH, but also in melanocyte-stimulating hormone (MSH) which is also derived from POMC.
This in turn will stimulate the hyperpigmentation.
Also breaks down into endorphins, enkephalins and other peptides.
Why do Addison’s patients get vitiligo?
Vitiligo is an autoimmune disease where you have antibodies against melanin
Autoimmune diseases tend to go hand-in-hand
Destruction of melanocytes
Describe the synthesis of POMC
Synthesised in pituitary and broken down to ACTH and MSH and endorphins and enkephalins and other peptides
What may be present in the adrenal cortex
Granulomas- due to presence of TB
What is key to remember about adrenocortical failure
Nothing happens to the medulla
Summarise the biochemical test for Addison’s
9am cortisol = low
ACTH = high
Short synACTHen test
Give 250 ug synacthen IM
Measure cortisol response
Summarise the results of a typical Addison’s patient
Cortisol at 9am = 100 (270-900)
Administer injection IM of synacthen
Cortisol at 9.30 = 150 (>600)
Describe the short synacthen test
A baseline sample of blood is collected for cortisol and ACTH measurements. In Addisonian patients, the baseline control might be low, and the ACTH will be high. A subcutaneous or intramuscular injection of 250mcg SYNthetic ACTH (hence SYNACTHEN) is administered and blood samples taken 30 and 60 minutes later to measure plasma cortisol concentrations.
In patients with Addison’s disease, there will only be a minimal rise in cortisol despite the injection of the huge dose of ACTH.
A normal patient: the cortisol will rise by at least 170nM to at least 450nM (these values will vary slightly between different hospitals depending on the assay used).
Which patients are susceptible to an Addisonian crisis
Patients not taking their steroids
or a patient’s first presentation of Addison’s
What happens in an Addisonian crisis
Salt-losing, hypotensive and fatal crisis- if the diagnosis is not made in time and the patient doesn’t recover.
Nausea and vomiting are prominent features, and patients may find they are unable to keep down their steroids, which only worsens the problem.
How do we recover a patient from an Addisonian crisis
Patients need to be urgently transferred to hospital for parenteral (I.V or intramuscular) administration of 100mg of hydrocortisone. In an emergency, this will have both glucocorticoid and sufficient mineralocorticoid activity to save the person’s life.
They will also rehydration with saline as they are likely to be very salt depleted due to a combination of the vomiting and the renal sodium loss in the absence of mineralocorticoid.
What should be done once the patient is stabilised
Once patients are stabilised, and have a normal BP, they can be recommended on their normal hydrocortisone and fludrocortisone replacement drugs.
What is the commonest form of congenital adrenal hyperplasia
Commonest is caused by 21-hydroxylase deficiency
Can be complete or partial
What are the 4 different types of congenital adrenal hyperplasia
There are 4 types of CAH you need to know of: § Complete 21-hydroxylase deficiency. § Partial 21-hydroxylase deficiency. § 11-hyroxylase deficiency. § 17-hydroxylase deficiency.
Describe a complete 21-hydroxylase deficiency
Deficiency is complete in one-third of cases
The outcome of the raised ACTH will be increased levels of precursors to cortisol and aldosterone, such as 17-hydroxyprogesterone.
High levels of this molecule will be channelled through other pathways, and consequently one other effect will be an increased secretion of androgens, in particular testosterone.
This will result in a virilised foetus, and if the child is a girl, then ambiguous genitalia may be present.
How is the foetus kept alive in utero
Just adequate levels of maternal cortisol and aldosterone will have crossed the placenta in utero and kept the foetus alive, but as soon as the child is born, this endocrine provision will no longer be available.
Within 24-48 hours, the signs of adrenal failure will become apparent, and the child is at risk of a salt-losing Addisonian crisis.
Describe the Addisonian crisis in the new-born
the child will become floppy, hypotensive and unresponsive, and without treatment the child will not survive.
If the child is a girl, then the diagnosis will be suspected at birth, because of the ambiguous genitalia- those children can be given hydrocortisone, and a salt-losing crisis will be averted.
Boys on the other hand, will have normal male external genitalia, even if there is an excess of testosterone, so that diagnosis may not be suspected at birth until other signs of adrenal failure become apparent.
Summarise complete 21-hydroxylase deficiency
Which hormones will be totally absent ?: aldosterone and cortisol
How long can you survive ? Less than a few weeks
Which hormones will be in excess? Sex steroids and testosterone
Describe the age of presentation for a patient with complete 21-hydroxylase deficiency
As a neonate with a salt losing Addisonian crisis
Before birth, (while in utero), foetus gets steroids across placenta
Girls might have ambiguous genitalia (virilised by adrenal testo)
What happens in partial 21-hydroxylase deficiency
Enough cortisol and aldosterone to reabsorb salt- no salt-losing crisis
Common presentation in adults- not babies.
Summarise partial 21-hydroxylase deficiency
§ Hormones deficient: o Cortisol and aldosterone. § Hormones in excess: o Sex steroids & testosterone. § Age of presentation: o Any age (as they survive). o The main problem is in later life with hirsutism and virilisation in girls and precocious puberty in boys. § Symptoms and signs include: o Acne, facial hirsutism, small breasts, clitoral enlargement, heavy arms/leg
Describe the presentation of partial 21-hydroxylase deficiency.
They may present much later because they don’t have a salt losing Addisonian crisis.
They will present once they start to see the effects of the excess adrenal sex steroids e.g. hirsuitism and precocious puberty or irregular periods
They will also be a little hypotensive
What is important to remember about 11-deoxycortisone
11 deoxycorticosterone behaves like aldosterone
In excess it can cause hypertension and hypokalaemia
In excessive quantities it can bind to aldosterone receptors and be biologically active.
Describe and explain the presentation and explanation of complete 11b-hydroxylase deficiency.
With 11-beta hydroxylase deficiency there will be a build up of 11-deoxycorticosterone
11-deoxycorticosterone has mineralocorticoid effects so they don’t have a salt losing Addisonian crisis – they will behave as if they have HIGH aldosterone
They will be HYPERTENSIVE and HYPOKALAEMIC
There will still be some funnelling towards the sex steroid synthesis pathway so the child will also be VIRILISED
NOTE: boys may be missed because they tend to look normal
Present with childhood hypertension
Describe 17-hydroxylase deficiency
Present with childhood hypertension because of high circulating levels of aldosterone, but are cortisol and sex steroid deficient. These children become unwell at times of stress, and remain prepubertal without treatment, as the enzyme will be missing from the gonads too.
Summarise 17-hydroxylase deficiency
§ Hormones deficient:
o Cortisol and sex steroids.
§ Hormones in excess:
o 11-deoxy corticosterone and aldosterone (the mineralocorticoids).
§ Symptoms and signs:
o Hypertension, hypokalaemia, sex steroid deficiency and glucocorticoid deficiency (leading to hypoglycaemia
Explain the pathophysiology of Congenital adrenal hyperplasia
If a neonate is born without one of the enzymes that should normally be in the adrenocortical cells, there might be a failure of cortisol and/or aldosterone synthesis. That will result in increased hypothalamo-pituitary-adrenal (HPA) axis activation in utero, and thus there is profound activation of the adrenal glands before birth- causing them to become very large.
What type of condition is CAH
Autosomal recessive
How is the diagnosis of CAH confirmed
A syncathen test can be used. In this situation, in addition to measuring cortisol levels in the blood, the steroid precursors are measured.
When ACTH is administered, a patient with CAH will exhibit an exuberant rise in the circulating concentrations of steroid precursors, but a minimal or no increase at all in cortisol.
Thus in 21-hydroxylase deficiency, there will be a large increase in plasma 17-hydroxyprogesterone on administration of syncathen, but no rise in cortisol.
How do we treat CAH
As with Addison’s- the treatment of this condition is lifelong replacement of the missing steroid.
However, unlike patient’s who have Addison’s disease, the dose and type of steroid used are difficult to manage and should be arranged by a specialist centre.
it is important to give adequate doses and frequency of a steroid to suppress the production of the precursors of cortisol to minimise the effects of other steroids (such as testosterone) being produced.
