MEH session 9 Flashcards
Which of the following is a characteristic of mineralocorticoid excess? Low serum sodium Low serum potassium Dehydration Hypotension
Low serum potassium
In which organ does cleavage of angiotensin I into angiotensin II mainly occur?
Lungs
Angiotensin I is converted to angiotensin II by the removal of two C-terminal amino acid residues by ACE within lung capillaries.
Which organ synthesises and releases angiotensinogen into blood?
Liver produces angiotensinogen
Angiotensinogen is cleaved by renin in plasma to form angiotensin I
Angiotensin I is cleaved by angiotensin converting enzyme (ACE) in lung capillaries to form angiotensin II
Would you expect the aldosterone:renin ratio to be high or low in a patient with secondary hyperaldosteronism caused by renal artery stenosis?
Low - there is a high concentration of renin
Renin released by juxtaglomerular cells of kidneys in response to low perfusion.
What is the mode of action of the drug spironolactone?
Mineralocorticoid receptor antagonist
Which disease is caused by aldosterone secreting adrenal adenoma?
Conn’s disease
Cortisol causes increased lipolysis in adipose tissue.
True or false?
True.
Although unusual fat deposition such as in the abdomen (central obesity), supraclavicular fat pads, dorsal-cervical fat pad (buffalo hump) and face (moon face) are signs of chronic exposure to high cortisol (Cushing’s syndrome), these are due to redistribution of fat
Primary action of cortisol in adipose is to increase lipolysis.
Which protein facilitates the transport of cortisol in the blood?
Transcortin - approx 75%
Albumin - rest
Explain why purple striae are often seen in Cushing’s syndrome.
Increased proteolysis due to high cortisol
Stretching of skin due to redistribution of fat
Which of the following is a sign of Addison's disease: Hyperglycaemia Skin hyperpigmentation Hypertension Buffalo hump fat deposition
Skin hyperpigmentation
Addison’s will result in a high ACTH due to removal of negative feedback of cortisol on the HPA. To make more ACTH, more POMC is produced and as a consequence of this more MSH is produced. Increased MSH will result in more melanin synthesis by activation of melanocortin receptors on melanocytes leading to hyperpigmentation. ACTH itself can also activate melanocortin receptors so will contribute
In which region of the adrenal gland is dehydroepiandrosterone (DHEA) mostly produced?
Zona reticularis layer of adrenal cortex - sex steroid production
Which type of enzyme catalyses the conversion of noradrenaline to adrenaline?
Methyl transferase - adrenaline is produced by methylation of nor-adrenaline
Which change in second messenger concentration would occur from the activation of the alpha 1 adrenergic receptor?
An increase in the concentration of IP3
Activation of which adrenergic receptor subtype mediates the effects of adrenaline and noradrenaline on the heart?
Beta 1
Increase chronotropy and inotropy
Activation of which adrenergic receptor subtype mediates bronchodilation in the lungs?
B2
A tumour of which cell type is called a pheochromocytoma?
Chromaffin cells of adrenal medulla
This tumour secretes catecholamines (mostly noradrenaline) resulting in symptoms such as severe hypertension, headaches, palpitations, excessive sweating, anxiety and weight loss.
How would plasma glucose concentration change with excess secretion of the hormone cortisol?
High plasma glucose
Cortisol increases plasma glucose by stimulating gluconeogenesis in the liver and inhibiting glucose uptake in muscle.
The plasma concentration of which hormone would increase as a consequence of Addison’s disease?
ACTH - due to a lack of negative feedback from cortisol
Why does hyperpigmentation sometimes occur in patients with Addison’s disease?
Decreased cortisol leads to increased expression of POMC
Removal of the negative feedback from cortisol on the hypothalamus leads to increased ACTH production. Melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone (ACTH) share the same precursor molecule, pro-opiomelanocortin (POMC) so increased POMC leads to an increase in both ACTH and MSH. Increased MSH results in darkening (hyperpigmentation) of the skin, including areas not exposed to the sun. Characteristic sites of darkening in Addison’s are skin creases (e.g. of the hands), nipple, and the inside of the cheek (buccal mucosa) also, old scars may often darken.
A patient has Cushing’s syndrome caused by excess cortisol production from an adrenal tumour. What effect would this condition have on plasma ACTH level?
ACTH would decrease
Excess cortisol from the adrenal tumour would inhibit ACTH secretion by negative feedback.
Which time of the day would be best to take a blood sample for cortisol measurement if Cushing’s syndrome is suspected?
Midnight
Blood cortisol levels are normally at their lowest level around midnight so high cortisol in a blood sample taken at midnight would be more indicative of Cushing’s than a high value taken in the morning when cortisol is normally at its highest level.
Which exogenous steroid is typically administered to patients as part of a suppression test to diagnose Cushing’s syndrome?
Dexamethasone suppression test (DST)
Used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone. A normal result is a decrease in cortisol levels upon administration of low-dose dexamethasone. In Cushing’s syndrome, cortisol would not be suppressed by a low dose of dexamethasone.
Name the synthetic analogue of ACTH used in an ACTH stimulation test.
Syncathen
Administered intramuscularly
Would normally increase plasma cortisol by >200nmol/L. A normal response usually excludes Addison’s disease.
Is hypopituitarism resulting in ACTH deficiency classed as primary or secondary adrenal failure?
Secondary adrenal failure
Which of the following would you expect to see in a patient with Addison’s disease?
Recent weight gain
Fatigue
Hypertension
Skin depigmentation
Fatigue
Name a potential iatrogenic cause of Addison’s disease.
Adrenalectomy
Where are the adrenal glands located?
- Pair of multifunctional endocrine glands
- Cap the upper poles of the kidneys (lie in the same fascia)
- Lie against the diaghragm in the retroperitoneal space
Describe the structure of the adrenal gland.
- Small in size
- Outer cortex
- Inner medulla
Which types of hormones are released by the adrenal gland medulla?
Catecholamines - adrenaline and noradrenaline
Describe the embryonic development of the adrenal gland.
Cortex is derived from mesoderm
Medulla is derived from neural crest cells which subsequently migrate into the developing cortex
Where are catecholamines stored and by which cells in the adrenal gland?
Adrenaline is stored in membrane-bound vesicles in chromaffin cells of the medulla
Which types of hormones are released by the adrenal cortex?
Corticosteroid hormones -
Mineralocorticoids eg. Aldosterone
Glucocorticoids eg. Cortisol
Androgens eg. Dehydroepiandrosterone
What is the difference between the mode of action between corticosteroids and catecholamines?
Solubility:
Corticosteroids - lipid soluble
Catecholamines - water soluble
Receptors:
Corticosteroids - nuclear receptors
Catecholamines - GPCRs
Effect on enzymes:
Corticosteroids - regulates amount by gene expression
Catecholamines - regulates activity of existing enzymes
Speed of response:
Corticosteroids - slow (minutes to hours)
Catecholamines - fast (seconds)
What is the difference between the synthesis and release of corticosteroids and catecholamines from the adrenal gland?
Derivation:
Corticosteroids - cholesterol
Catecholamines - tyrosine
Mode:
Corticosteroids - endocrine
Catecholamines - neurocrine
Storage:
Corticosteroids - synthesised and released
Catecholamines = stored in vesicles before release
What is the difference between the effect of a bilateral adrenalectomy on corticosteroids and catecholamines?
Corticosteroids - patient must receive cortisol and aldosterone otherwise will die
Catecholamines - no apparent ill effects of lack of adrenal catecholamines
What are the different layers of the adrenal cortex and explain their biological function.
- Zona Glomerulosa. The cells in this outermost zone secrete the mineralocorticoids (e.g. aldosterone) that regulate body Na+ and K+ levels. (SALT)
- Zona Fasciculata. The cells in this zone produce the glucocorticoids (e.g. cortisol) that have a number of important functions including the regulation of carbohydrate metabolism. (SUGAR)
- Zona Reticularis. This is the deepest cortical zone and the cells secrete glucocorticoids and small amounts of androgens (dehydroepiandrosterone).
(SEX)
Give some examples of glucocorticoids released by the zona fasciculata.
Cortisol
Corticosterone
Cortisone
Give some examples of androgens released by the zona reticularis.
Dehydroepiandrosterone
Androstenedione —> testosterone/oestrogen
What is congenital adrenal hyperplasia?
Genetic disease that causes a deficiency in 21-hydroxylase enzyme
The position of this enzyme in the biosynthetic pathway of corticosteroid hormones means that enzyme deficiency results in less glucocorticoid and mineralocorticoid production. The precursor of these hormones is therefore diverted to more androgen synthesis (androstenedione & testosterone).
This can result in:
-genital ambiguity in females infants
-“Salt-wasting crises” due to a high rate of sodium loss in urine (due to loss of aldosterone)
-Due to a lack of cortisol the pituitary is not subjected to negative feedback control and therefore secretes large amounts of ACTH which in turn causes enlargement of the adrenal cortex (hyperplasia).
How do corticosteroids exert their actions?
- corticosteroids readily diffuse across the plasma membrane.
- bind to glucocorticoid receptors
- binding causes dissociation of chaperone proteins
- receptor ligand complex translocates to nucleus
- dimerisation with other receptors can occur
- receptors bind to glucocorticoid response elements (GREs) or other transcription factors
How is aldosterone transported in the blood?
- mainly serum albumin
- to a lesser extent, transcortin
What is the function of aldosterone?
-determines extracellular fluid volume
Controls rate at which Na+ is reabsorbed or excreted by the kidneys
Na+ is the primary osmotically active ion in extracellular fluid so controls extracellular volume
-determines arterial blood pressure
Extracellular volume determines arterial blood pressure
HOW?
Promotes expression of Na+/K+ ATPase promoting reabsorption of Na+ and excretion of K+ in distal tubules and collecting ducts of nephron
Which blood pressure control system is aldosterone involved in?
RAAS
How can you distinguish between primary and secondary hyperaldosteronism?
Aldosterone: renin ratio
If high—>primary
If low—>secondary
What is the difference between primary and secondary hyperaldosteronism?
Primary - defect in adrenal cortex
Secondary - over activity of RAAS
Give some causes of primary hyperaldosteronism.
- bilateral idiopathic adrenal hyperplasia (most common)
- aldosterone secreting adenoma (Conn’s syndrome)
Give some causes of secondary hyperaldosteronism.
- renin producing tumour eg. Juxtaglomerular tumour (rare)
- renal artery stenosis
What are the signs of hyperaldosteronism?
High blood pressure Left ventricular hypertrophy Stroke Hypernatraemia Hypokalaemia
In primary and secondary hyperaldosteronism, would decreased renin lead to decreased aldosterone?
Primary - NO defect in adrenal cortex
Aldosterone is produced and released by adrenal cortex independent of renin production and release
Secondary - YES problem is due to over activity of RAAS system
Less renin –> less angiotensin I —> less angiotensin II —> less aldosterone
How is cortisol transported in plasma?
Lipophilic so via plasma proteins
- mainly transcortin
- also serum albumin
Explain how cortisol secretion is controlled by ACTH and CRH.
• CRF is secreted by the hypothalamus ◦ Secreted in response to: ‣ Physical - temperature, pain ‣ Chemical - hypoglycaemia ‣ Emotional stressors • ACTH secreted by corticotropes of the anterior pituitary ◦ Secreted with a circadian rhythm ◦ Pulsatile secretion
What should be considered when taking a blood cortisol measurement?
Peak cortisol at 7am
Trough at 7pm
If Cushings syndrome suspected, take measurement in evening
If Addison’s disease suspected, take measurement in morning
How can cortisol have a weak mineralocorticoid and androgen effect?
The steroid receptors form part of a family of nuclear DNA- binding proteins that include the thyroid and vitamin D receptors.
They all have three main regions, a hydrophobic hormone-binding region, a DNA-binding region rich in cysteine and basic amino acids and a variable region.
Due to the similar structure, cortisol binds to mineralocorticoid and androgen receptors with low affinity. The binding may become significant when high levels of the hormone are present.
What are the actions of cortisol?
Catabolic effects:
- increased protein breakdown in muscle
- increased gluconeogenesis in liver
- increased lipolysis in fat
- resistance to stress (increased supply of glucose, raised blood pressure by making vessels more sensitive to adrenaline and hence vasoconstriction)
- anti-inflammatory effects (inhibits macrophage activity and mast cell degranulation)
- depression of immune response (prescribed to organ transplant patients)
What is the effect of cortisol on GLUT4 receptors?
Cortisol inhibits insulin-induced GLUT-4 translocation in muscle - prevents glucose uptake so has a glucose sparing effect
What is the effect of cortisol on fat?
Increased lipolysis
Re-distribution of fat especially in abdomen, supraclavicular fat pads, dorso-clavichord fat pad (buffalo hump) and on face (moon face)
What are the common cause of Cushing’s syndrome?
Exogenous Long-term treatment with glucocorticoids: Hydrocortisone Prednisone Dexamethasone
What are the endogenous causes of Cushing’s syndrome?
- Cushing’s disease - benign pituitary adenoma secreting ACTH
- Adrenal Cushing’s - excess cortisol produced by adrenal tumour
- non pituitary adrenal tumours producing ACTH - eg. Small cell lung cancer
What are the signs and symptoms of Cushing’s disease?
- red moon-shaped face
- buffalo hump
- abdominal obesity
- purple striae
- acute weight gain
- hyperglycaemia
- hypertension
What are steroid drugs used in the treatment of and why?
Inflammatory disorders: -asthma -inflammatory bowel disease -rheumatoid arthritis -other auto-immune conditions Cortisol inhibits macrophage activity and mast cell degranulation
-suppress immune reaction to organ transplantation
If it is found that a patient has Cushing’s disease due to long-term use of steroids for the treatment of asthma, what would you advice the patient?
Reduce dose of steroids or alternative treatment for asthma
BUT
Steroid dosage should be reduced gradually and not stopped suddenly
Why should steroid dosage be reduced gradually and not stopped suddenly?
When exogenous steroids are present, the levels of ACTH and cortisol are low due to negative feedback.
Abrupt withdrawal will result in low levels of ACTH, low levels of cortisol and no steroid to compensate for this low cortisol.
This can cause an Addisonian crisis.
What is the difference between Cushing’s disease and Cushing’s syndrome?
Cushing’s syndrome is an umbrella term which refers to the general symptoms resulting from chronic excessive exposure to cortisol
Cushing’s disease refers to the specific case of a benign ACTH secreting pituitary adenoma.
Cushing’s syndrome is much more common than Cushing’s disease.
What is the precursor for ACTH?
POMC
Do ACTH levels fluctuate throughout the day?
YES - secreted in a pulsatile manner with a Circadian rhythm
Highest in morning. Lowest in evening.
(That’s why cortisol release varies throughout the day)
How does ACTH exert its actions?
- Hydrophilic and interacts with high affinity Gs GPCR’s (melanocortin receptor/corticotropin receptor) on the surface of cells in the zona fasciculata and zona reticularis
- Leads to activation of cholesterol esterase
- Increases conversion of cholesterol esters to free cholesterol
- Stimulates other steps in the synthesis of cortisol from cholesterol.
Explain how ACTH can lead to increased pigmentation in certain areas of the body.
More POMC required to synthesise ACTH
More MSH produced from POMC
MSH —> activation of melanocortin receptors —>increased melanin synthesis —> hyperpigmentation
ACTH itself can also activate melanocortin receptors.
What are the effects of MSH?
Increased melanin synthesis
Increased immune response
Decreased food intake
What are the consequences of over-secretion of ACTH?
- hyperpigmentation
- adrenal hyperplasia
What is Addison’s disease?
Diseases of the adrenal cortex (auto-immune destruction) - reduces glucocorticoids and mineralocorticoids
- most commonly, destructive atrophy from autoimmune response
- much rarer causes: fungal infection, adrenal cancer, adrenal haemorrhage
This would result in the loss of both cortisol and mineralocorticoids and produces a complex situation that may present as an acute emergency (Addisonian Crisis) or as a chronic rehabilitating disorder (Addison’s disease)
What can cause plasma cortisol to be low?
- Addison’s disease
- disorders in pituitary or hypothalamus leading to decreased secretion of ACTH or CRF
Is Addison’s disease more common in women or men?
Women
What are the signs and symptoms of Addison’s disease?
- postural hypotension
- lethargy
- weight loss
- anorexia
- increased skin pigmentation
- hypoglycaemia
What is an Addisonian crisis?
Life threatening emergency due to adrenal insufficiency
Precipitated by: Severe stress Salt deprivation Infection Trauma Cold exposure Over exertion Abrupt steroid drug withdrawal
How is an Addisonian Crisis treated?
Fluid replacement
IV Cortisol
What are the signs and symptoms of an addisonian crisis?
Nausea Vomiting Pyrexia Hypotension Vascular collapse Confusion
How is Addison’s disease treated?
Lifelong replacement:
• Glucocorticoid - hydrocortisone, prednisolone
• Mineralocorticoids - fludrocortisone
How can you distinguish between endogenous causes of Cushing’s disease?
Dexamethasone suppression test
Dexamethasone is a potent synthetic steroid that, when given orally normally suppresses the secretion of ACTH and thus cortisol. Dexamethasone suppression of plasma cortisol by >50% is characteristic of Cushing’s disease because although a benign ACTH secreting pituitary adenoma is relatively insensitive to cortisol, it retains sensitivity to potent synthetic steroids.
Suppression does not normally occur in adrenal tumours or ectopic ACTH production.
How can a suppression test be used in the diagnosis of Addison’s disease?
Administration of Syncathen (a synthetic analogue of ACTH) intramuscularly, would normally increase plasma cortisol by >200nmol/L. A normal response excluded Addison’s disease
How is the release of androgens from zona reticularis controlled?
Partially by ACTH and CRH
When is oestrogen production from DHEA important?
After menopause as this is the only source of oestrogens
What are the effects of androgens in males?
-stimulate growth and development of male genital tract Male secondary sexual characteristics: -height -body shape -facial hair -body hair -lower voice pitch -anabolic actions especially on muscle protein
What are the effects of over secretion of adrenal androgens in females?
- excessive body hair growth (hirtuism)
- acne
- menstrual problems
- virilisation
- increased muscle bulk
- deepening voice
What are the effects of oestrogens in females?
- growth and development of female genital tract
- development of breasts and female characteristics including broad hips, accumulation of fat in breasts and buttocks, body hair distribution
- weakly anabolic
- decrease circulating cholesterol
How is adrenaline/noradrenaline synthesised?
Tyrosine converted to levodopa by tyrosine hydroxylase
Levodopa converted to dopamine by dopa decarboxylase
Dopamine converted to noradrenaline by dopamine beta-hydroxylase
Noradrenaline converted to adrenaline by N-methyl transferase
How is adrenaline/noradrenaline released from the adrenal medulla?
Adrenal medulla is a modified sympathetic ganglion of the autonomic nervous system
Chromaffin cells act as postganglionic nerve fibres that release hormones into the blood by neurocrine secretion
(Adrenaline - 80%, noradrenaline - 20%)
What are the hormonal actions of adrenaline?
Heart - beta-1 adrenoreceptors
Increase heart rate
Increase force of contraction
Lungs - beta-2 adrenoreceptors
Bronchodilation
Blood vessels in skin/gut- alpha-1 adrenoreceptors
Vasoconstriction
Blood vessels in skeletal muscle + coronary arteries - beta-2
Vasodilation
Kidneys -
Renin secretion
Muscle
Glycolysis
Glycogenolysis
Liver
Glycogenolysis
Gluconeogenesis
Pancreas
Glucagon secretion increased
Insulin secretion decreases
Adipose
Increased lipolysis
How does adrenaline increase heart rate?
- binds to beta-1 adrenoreceptors in SAN and AVN
- Alpha subunit of g-protein activates adenlyl cyclase to convert ATP to CAMP
- CAMP activates PKA
- CAMP has a directly activates HCN channels and PKA phosphorylates HCN channels. This increases the slope of the funny current.
- OKA phosphorylates L-type Ca2+ channels, potentiating their opening increasing the upstroke of the action potential.
What is a pheochromocytoma?
Chromaffin cell tumour - rare catecholamine secreting tumour
May precipitate life-threatening hypertension
What are the signs and symptoms of a pheochromocytoma?
- severe hypertension
- headaches
- palpitations
- diaphoresis
- anxiety
- weight loss
- elevated blood glucose
- sudden death
