Lecture 23: Adrenal glands Flashcards
Describe the macroscopic and microscopic structure of the adrenal glands.
3 layers:
- Capsule
- Cortex: zona glomerulosa, fasciculata, reticularis
- Medulla: chromaffin cells
What is secreted from each of the layers of the cortex and medulla?
Give an example of each hormone.
Zona glomerulosa: mineralocorticoids-aldosterone
Zona fasciculata: glucocorticoids-cortisol
Zona reticularis: glucocorticoids & small amounts androgens-oestrogen, testosterone
Provide 5 examples of steroid hormones.
- Glucocorticoids
- Mineralocorticoids
- oestrogen
- androgens
- progestins
Corticosteroids exert their actions by regulating gene transcription.
Briefly describe this process.
- Steroid hormone crosses plasma membrane.
- Hormone binds to glucocorticoid receptors in the cytoplasm.
- Chaperone proteins dissociates
- Receptor-ligand complex moves into nucleus
- Dimerisation with other receptors
- Receptors bind to GREs or other transcription factors to express/inhibit genes.
Aldosterone is the most abundant mineralocorticoid.
Describe its function and transport.
Aldosterone controls the reabsorption of Na+ (thus H2O) to blood; excretion of K+ to urine; maintaining BP.
As a steroid hormone, it must travel in a carrier protein (serum albumin & transcortin).
Aldosterone is a central component of renin-angiotensin-aldosterone system (RAAS).
Knowing this, explain its specific actions.
In the RAAS, aldosterone is secreted in response to hypovolaemia. Aldosterone increases Na+ uptake (in collecting duct) which will increase H2O reabsorption into the blood. Hence, increasing blood volume=BP increase.
Knowing that renin is significant in the RAAS, outline its involvement in the mechanisms of the RAAS.
Renin is a enzyme that is secreted from the kidneys during hypotension/volaemia.
The liver releases angiotensinogen and this can be cleaved into angiotensin-1 by Renin.
Angiotensin-1 cleaves into angiotensin-2 by ACE (enzyme from lungs).
What does RAAS stand for and what is its purpose?
Renin-angiotensin-aldosterone system
Purpose is to raise the blood vol. & BP when the kidneys sense hypovolaemia/hypotension.
What is the effect of angiotensin-2 on the RAAS?
AT-2 increases blood pressure by…
- vasoconstriction (arteriole)
- aldosterone secretion to increase Na/K pump for more H2O reabsorption
- APG’s ADH translocate aquaporins for more H2O reabsorption
What are the 2 forms of hyperaldosteronism and how can you distinguish between them?
Primary: defected adrenal cortex so more aldosterone is produced compared to renin.
Secondary: over activated RAAS so more renin is produced compared to aldosterone.
Identify 2 causes of primary hyperaldosteronism.
- aldosterone secreting adrenal adenoma (Conn’s syndrome)
- Bilateral idiopathic adrenal hyperplasia
Identify 2 causes of secondary hyperaldosteronism.
- Renin-producing tumour
- Renal artery stenosis (narrowing arteries)
What are 5 clinical signs of hyperaldosteronism?
- Hypertension
- Left ventricular hypertrophy
- Stroke
- Hypernatraemia
- Hypokalaemia
The treatment for hyperaldosteronism depends on its form.
Describe the possible options
- adrenal adenomas removed via surgery
- Spironolactone (mineralocorticoid receptor antagonist: inhibitor)
Cortisol is the most abundant corticosteroid & accounts for ~95% of glucocorticoid activity.
Describe its formation and transport
Cortisol formed & released from adrenal zona fasciculata in response to APG’s ACTH.
Mainly carried in transcortin and some serum albumin.
Cortisol is the most abundant corticosteroid & accounts for ~95% of glucocorticoid activity.
Describe its function and regulation.
Function: “stress response” that’s exerted by regulating gene transcription.
Regulation: -ve feedback to hypothalamus and inhibits CRH which inihibits ACTH release.
Cortisol can act in different ways.
Identify these.
- increases proteolysis (muscle)
- increases lipolysis (adipose)
- increases gluconeogenesis (liver)
- anti-inflammatory effects
- resistance to stress
- suppresses immune response
Think about symptoms and signs in Cushing’s syndrome.
Cortisol is useful medication for clinical needs.
Describe these uses.
Useful for allergic reactions: inhibits macrophages + mast cell degranulation)
Depresses immune response when transplanting organs, tissues, cells…
Explain the how cortisol resists stress.
- increases glucose supply
- raises BP by causing arteriole vasoconstriction
Explain how the glucocorticoid actions on metabolism lead to the following:
- Increased glucose production
- Breakdown of protein
- Redistribution of fat
- more gluconeogenesis (liver); less glucose utilization (fat & MSK) & more lipolysis (fat);
- More proteolysis (MSK) as cortisol inhibits GLUT4 translocation into muscles.
- Chronic high cortisol leads to re-distribution of fat as less sensitive to insulin.
What is Cushing’s syndrome?
Excess amounts of cortisol secreted that leads to…
- abdominal obesity
- purple striations
- buffalo hump
- plethoric moon-shaped face
- thin arms & legs
- acute weight gain
- hyperglycaemia
- hypertension
- muscle weakness
- lipogenesis
- gluconeogenesis
Describe the aetiology of Cushing’s syndrome in terms of endogenous and exogenous causes.
Endogenous…
- Cushing’s disease (pit. adenoma)
- Adrenal adenoma
- Ectopic adenoma (non-pit.)
Exogenous…
-prescribed glucocorticoids
Identify 2 examples of steroid drugs.
- dexamethasone
- prednisolone
Steroid drugs have anti-inflammatory & immunomodulatory effects, thus are used to treat inflammatory disorders.
Provide some examples of these conditions
- Asthma
- Rheumatoid arthritis
- Autoimmune conditions
- Inflammatory bowel disease
Describe the possible side effects due to steroid drugs
Steroid drugs can have the same side effects as high cortisol + mineralocorticoids. Could lead to Addison’s disease as body will develop a higher threshold for these steroids.
What is Addison’s disease and the most probable cause?
Chronic adrenal insufficiency that mainly affects the mineralocorticoid & glucocorticoid effects in women more than men.
Most common cause is destructive adrenal atrophy triggered by an autoimmune disease.
Identify some rare causes of Addison’s disease.
- Adrenal cancer
- Adrenal haemorrhage
- fungal infection
Identify some signs and symptoms of Addison’s disease
- Vitiligo (hyperpigmentation)
- lethargy
- Weight loss
- anorexia (appetite loss)
- hypoglycaemic episodes
- postural hypertension (whilst sitting down)
- reduced vascular tone
- extreme muscle weakness
- dehydration
A patient comes in presenting with weakness, fatigue, dizziness on standing, anorexia, weight loss. They’ve noticed their palmar creases have darkened in colour. Their BP=95/75 lying and 85/65 standing (postural hypotension).
What is the reason for the palmar creases to darken in colour?
MSH is found within ACTH.
POMC precursor contains ACTH within its AA sequence.
After processing, active ACTH is released with small amounts of MSH within it.
Hence high ACTH stimulates MSH receptors so melanocytes will release more melanin = hyperpigmentation.
What is Addisonian crisis?
Include causes, symptoms & treatment.
Life threatening emergency due to adrenal insufficiency caused by…
- MAJORITY infection
- severe stress
- salt depravation
- trauma
- over exertion
- sudden steroid withdrawal
Symptoms: nausea, vomiting, pyrexia, hypotension, vascular collapse
Treatment: fluid replacement & cortisol!!!!
Name the 2 types of androgens secreted by the zona reticularis and how they are regulated.
DHEA & androstenedione.
Partially regulated by ACTH and CRH.
How extensive is the effect of androgens on males and females?
Males aren’t as affected if there was a deficiency. They only make a relatively small amount of testosterone in comparison to the testes after puberty.
Females are affected much more as they affect libido and are converted into oestrogen. Post-menopause they are the only source of oestrogen.
Both sexes are affected in that they both have axillary and pubic hair due to androgens.
The adrenal medulla is a modified sympathetic ganglion of autonomic nervous system.
Describe the role of chromaffin cells
Chromaffin cells produce & secrete catecholamines into bloodstream: adrenaline & noradrenaline. These are essential for the sympathetic nervous system and response.
Explain why adrenaline is the dominant hormone produced by the adrenal medulla
Dopamine–>noradrenaline–>adrenaline
80% of the chromaffin cells have enzyme N-methyl transferase which converts noradrenaline to adrenaline.
Hence, adrenaline is the dominant hormone.
What is the acronym to remember which G proteins bind to which receptors?
Q = alpha 1
I = alpha 2
S = beta 1
S =beta 2
Outline the various hormonal actions of adrenaline
- more HR + contractility (heart)
- more glycolysis + glycogenolysis (MSK)
- more glycogenolysis & gluconeogenesis (liver)
- more glucagon + less insulin (pancreas)
- more renin secretion (kidney)
- vasoconstriction/dilation (vessels)
- bronchodilation (lungs)
What is a pheochromocytoma?
Chromaffin cell tumour which secretes catecholamines.
It can cause life-threatening hypertension if not treated.
How do phaeochromocytomas present?
SEVERE HYPERTENSION
- headaches
- palpitations
- anxiety
- weight loss
- hyperglycaemia
What are the clinical tests of adrenocortical function used to differentiate specifically which adrenocortical disease is presented?
- plasma cortisol levels
- ACTH levels
- dexamethasone suppression test
- ACTH stimulation tests
- midnight blood sample (checks ACTH & cortisol)
A 45yrs lady presents with rapid weight gain over 2 months without increased appetite; face has become puffy; arms and legs are thinner. Examination shows she has a plethoric, moon shaped face; abdominal obesity with purple striae and BP= 170/110 (normal=130/85).
What condition is suggested from her symptoms?
Cushing’s syndrome due to excess cortisol due to a high amount of ACTH.
A woman has confirmed Cushing’s syndrome. She admits that she had been seeing a private specialist for a treatment for a skin condition.
What tablets might she be taking for her skin condition? Why might this be related to Cushing’s syndrome?
She could be taking prescribed prednisolone which are anti-inflammatory glucocorticoids. Since Cushing’s syndrome is due to excess cortisol (a glucocorticoid), this could be a reason for her development of Cushing’s syndrome.
What conditions could prednisolone be prescribed for?
Asthma
Inflammatory bowel disease
RA
Autoimmune conditions
When someone has Cushing’s syndrome, they present with abdominal obesity.
Why does this happen?
Cushing’s syndrome is caused by hypercortisolaemia. Excessive amounts of cortisol redistributes fat deposits and increases lipolysis. Hence, patients with Cushing’s syndrome tend to have abdominal obesity.
When someone has Cushing’s syndrome, they present with thinner arms and legs.
Why does this happen?
Cushing’s syndrome is caused by hypercortisolaemia. Excessive cortisol causes increased proteolysis which in turn causes more muscle wastage. Thus, muscle atrophy which causes arm & leg weakness.
A 45yrs woman has suspected Cushing’s syndrome. They complete a fasting blood sample and they come back with:
Urea=6.3mmol/L (2.5-7.0mmol/L)
Glucose= 10mmol/L (3.6-6.5mmol/L)
Suggest the reason for these results.
Urea is slight high despite being within reference range.
More cortisol = More gluconeogenesis= More AA used= more transamination= more NH2—> more urea
Hyperglycaemia as cortisol inhibits GLUT4 so glucose can’t be translocated into MSK and adipocytes.
If a patient has confirmed Cushing’s syndrome, and you know that they are not taking any steroidal medication, what other causes of their condition would you consider?
- Pituitary adenoma (Cushing’s disease)
- Adrenal adenoma (Adrenal Cushing’s)
- Ectopic adenoma producing ACTH (small lung cancer)
Cushing syndrome has a variety of aetiologies. How would you be able to determine what is the underlying cause of this condition?
- Dexamethasone test
- Functional imaging to see if/where the tumour is
A patient comes in with a puffy face, weakness in arms and legs, rapid weight gain. When investigating further, you find they have a plethoric face, abdominal obesity with purple striations. Upon confirming Cushing’s syndrome, you perform a dexamethasone test to determine the aetiology of this condition.
Briefly describe how a dexamethasone test would show the cause of this condition.
Normally: low dexamethasone= lowers cortisol.
Cushing’s syndrome:
low dose = still high or normal cortisol levels
Cushing’s disease:
low dose = no change
high dose= low cortisol
Adrenal’s Cushing
dosage doesn’t affect adrenal gland so will always have high cortisol.
Ectopic adenoma:
dosage doesn’t matter as doesn’t affect ectopic caners (eg: small lung cancer)
Your patient has been on a course of steroids. As they approach the end of their management plan, what advice would you give to the patient?
Advise them to gradually decrease their steroid dosage. Due to taking steroids for a long period of time, the threshold for cortisol has increased. If you suddenly stop taking the steroids, you are at risk of Addison’s disease.
What signs would you look for to confirm Cushing’s syndrome?
Hypokalaemia Hypernatraemia Hyperglycaemia Normal plasma cortisol Very high total free cortisol
Which tests would you do to diagnose Cushing’s syndrome?
Dexamethasone suppression test
Midnight blood sample (cortisol in blood/urine)
ACTH & cortisol blood
A dexamethasone suppression test was performed. A low dosage of dexamethasone had no effect but a high dosage lowered the plasma levels of a certain hormone.
For which condition would we use this test for and what do the results tell us about it?
This is used to determine the aetiology of Cushing’s syndrome as there will be a high level of cortisol in the blood.
By needing to give a high dosage in order to lower the levels of cortisol, we can determine that the cause is a pituitary adenoma (Cushing’s disease).
A patient has been diagnosed with Addison’s disease.
How would you treat this patient?
Give them hydrocortisone and fludrocortisone which can replace the mineralocorticoids and glucocorticoids.
A man was brought into the ED having collapsed. You know this patient has recently been diagnosed with Addison’s disease.
What is the most likely cause for their collapse, why did it happen and how would you treat this emergency?
Addison’s crisis due to severe adrenal dysfunction.
MAJORITY caused by infection but also:
- salt deprivation
- overexertion
- extreme stress
GIVE FLUIDS AND CORTISOL IMMEDIATELY!!!
How is cortisol secretion controlled?
Hypothalamus senses physical, chemical, emotional stressors. They can secrete CRH to counteract this stimulus.
ACTH secretion dependent on hypothalamic CRH.
Cortisol dependent on ACTH secretion.
High cortisol suppresses hypothalamic CRH release in long -ve feedback loop.
Explain why cortisol can have mineralocorticoid and androgen-like effects when in high concentrations.
All adrenal steroid hormones have similar basic structures so cortisol can partially bind to other receptors. This causes a partial activation so it seems like cortisol has these other effects.
How would you expect a patient with Addison’s disease to react to a stress stimulus like trauma or infection compared to a healthy individual?
Normally, adrenal glands stimulated in response to stress & secretes hormones.
Addison’s disease patients won’t respond appropriately = Addisonian Crisis (nausea, vomit, fever, hypotension, vascular collapse)
