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Physiology 1 > 60) Steroids of the Adrenal Cortex > Flashcards

60) Steroids of the Adrenal Cortex Flashcards

1
Q

Where are the adrenal glands located?

A
  • On top of the kidneys
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2
Q

Where are steroids released from?

A
  • The adrenal cortex (outer layer of cells surrounding the adrenal glands)
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3
Q

What is the adrenal medulla?

A
  • The inner layers of the adrenal gland which takes part in a neuroendocrine reflex with the sympathetic nervous system and chromatin cells to secrete adrenaline
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4
Q

What are the steroids of the adrenal cortex?

A
  • Glucocorticoids (mainly cortisol in mammals)
  • Mineralocorticoids (aldosterone)
  • Androgens (sex steroids)
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5
Q

What is the name given when the body produces excess cortisol?

A
  • Cushing’s syndrome
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6
Q

What is the name given when too little aldosterone/cortisol is produced?

A
  • Addison’s disease
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7
Q

Describe the structure of the adrenal gland

A
  • There is a layer of cells (cortex) which surrounds the internal medulla
  • The medulla secretes adrenaline and noradrenaline
  • The cortex secretes steroid hormones
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8
Q

Describe the blood supply to the adrenal glands

A
  • Capillaries within the glands convey blood from the outer surface to the inner surface (where it meets the medulla)
  • There are three zones located within the cortex: ,
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9
Q

What are the different zones within the adrenal cortex?

A
  • Zona glomerulosa (outer layer): Responsible for synthesising aldosterone
  • Zona fasciculata (middle layer): Responsible for synthesising corticoids
  • Zona reticularis (inner layer): Responsible for synthesising androgens
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10
Q

How does the adrenal cortex function as three separate glands?

A
  • The combination of vertical blood flow through the three zones along with tissue specific enzymes (located within each zone) give rise to functional zonation
  • In other words each zone produces a different hormone and so overall three different hormones are released into circulation
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11
Q

What is the first molecule used in steroid synthesis?

A
  • Cholesterol
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12
Q

What are the functions of the different adrenal steroids?

A
  • Aldosterone: Salt and water balance (retains Na+ in order to conserve ECF volume so maintains blood volume)
  • Cortisol: Metabolism and immune function
  • Androgens:
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13
Q

What stimulates the release of cortisol?

A
  • Stress increases the release of cortisol

- When there is no stress there is still a release of cortisol however it is much lower

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14
Q

What is the function of aldosterone?

A
  • It increases Na+ reabsorption in the DT and as a result water is also retained
  • Hence [Na+] does not increase however the total amount of Na+ and water increases causing an increase in ECF volume
  • An increase in ECF volume causes an increase in blood volume
  • This is achieved via indirect sensors of blood volume
  • It also increases K+ secretion and is in a negative feedback loop with K+
  • As K+ levels increases aldosterone secretion to increase.
  • This will increase K+ secretion causing K+ levels to decrease
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15
Q

Explain the mechanism of aldosterone secretion

A
  • The juxtaglomerular apparatus secretes renin which cleaves angiotensinogen (by the liver) into angiotensin 1
  • Angiotensin Converting Enzyme (ACE) cleaves angiotensin 1 into angiotensin 2 which is biologically active
  • Angiotensin 2 stimulates the adrenal cortex to increase aldosterone secretion
  • Angiotensin 2 can also stimulate vasoconstriction in blood vessels
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16
Q

What are the indirect sensors of blood volume?

A
  • Decreased perfusion pressure in afferent arterioles which stimulates the juxtaglomerular cells to increase renin secretion
  • Increase sympathetic activity (through the detection of decrease in central perfusion pressure by baroreceptors)
  • Decreased Na+ and Cl- stimulates the macula densa cells which in turn stimulate the juxtaglomerular cells to increase renin secretion
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17
Q

Explain the mechanism of aldosterone action within the DCT and CT

A
  • Aldosterone binds to a nuclear receptor (MR) causes dimerisation and translocation to the nucleus where they activate hormone response elements
  • This increases the expression of Epithelial Sodium Channel (ENaC), Na+/K+ ATPase and H+ ATPase
  • ENaCs take in Na+ from the tubules in the kidneys into the cell
  • Na+/K+ ATPases take in K+ into the cell (from circulation) and gives out Na+ into circulation (from the cell)
  • H+ ATPase allows for the active transport of H+ out of the cell into the tubules
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18
Q

Why is there increased binding of MR to aldosterone instead of cortisol?

A
  • The mineralocorticoid receptor (MR) has a similar affinity for aldosterone and cortisol
  • In circulation it is common for cortisol levels to be higher than aldosterone
  • However there are enzymes (11beta-hydroxysteroid dehydrogenase type 2) in the renal tubule cells which converts cortisol into cortisone which is inactive
  • As a result there is less cortisol located in the cell causing more aldosterone to bind to MR
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19
Q

What is syndrome of apparent mineralocorticoid excess (AME)?

A
  • A rare inactivating mutation of 11beta-hydroxysteroids dehydrogenase type 2 (11B-HSD2)
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20
Q

What areas of the body does cortisol act on?

A
  • Cortisol acts on almost every system in the body throughout life starting from fetal development
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21
Q

What is the function of cortisol in glucose metabolism?

A
  • To preserve/spare glucose for the brain

- It does not raise plasma glucose but prevents it from falling

22
Q

How does cortisol achieve its role?

A
  • Cortisol can promote lipolysis (stored fats are used to generate energy)
  • In doing so the glucose that is available will remain for further use
  • Cortisol also promotes gluconeogenesis which increases output of glucose from the liver
  • Cortisol will promote insulin resistance in muscle and so prevents muscles from taking in glucose and so instead they will metabolise fats instead
  • Cortisol promotes the release of amino acids from body proteins (proteolysis) so that they are available as a substrate for gluconeogenesis
  • This occurs when adipose (fat) reserves are depleted
23
Q

How can hypercortisolism affect metabolism within the body?

A
  • Excess cortisol (i.e. high cortisol release when glucose levels are normal) can lead to hyperglycaemia
  • Furthermore cortisol also promotes lipogenesis and fat storage via insulin mechanism
  • This is because cortisol raises plasma glucose level which stimulates increased insulin stimulated glycogenesis which can cause adipose tissue deposition.
24
Q

What is the role of cortisol on the CVS?

A
  • Cortisol is required for vascular integrity (the ability of the vessels to retain all components of blood) and blood pressure
25
Q

How can hypocortisolism and hypercortisolism affect the CVS?

A
  • Cortisol inhibits epithelial NO synthase expression
  • This means that excess cortisol in the body leads to high blood pressure (hypertension) as there is more NO being synthesised and hence more vasoconstriction
  • However too little cortisol in the body leads to low blood pressure (hypotension) as there is less NO being synthesised and hence more vasodilation
26
Q

What is the overall effect of glucocorticoid therapy?

A
  • Activating the cortisol/glucocorticoid receptor
27
Q

What are the two methods of glucocorticoid therapy?

A
  • Giving cortisol based medication (called hydrocortisone)

- Exogenous drugs that activate glucocorticoid receptor

28
Q

What is the compromise in place when using glucocorticoid therapy?

A
  • When we prescribe glucocorticoid therapy although we experience the desired healing effect (e.g. supressing inflammatory responses) and undesired metabolic effects (e.g. hyperglycaemia and hypertension) which arise with prolonged glucocorticoid therapy at high doses
29
Q

What are the effects of glucocorticoids on inflammatory mediators?

A
  • Many inflammatory mediators (thromboxanes, prostaglandins and leukotrienes) are derived from arachidonic acid which is a lipid based molecule
  • This arachidonic acid is produced from membrane phospholipids via the action of the enzyme phospholipase A2
  • Glucocorticoids increases the production of Annexin-1 which inhibits phospholipase A2 and so prevents the production of arachidonic acid (and hence the production of the inflammatory mediators)
  • Glucocorticoids decreases the expression of cyclo-oxygenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2) which in reduces the amount of thromboxanes and prostaglandins produced from arachidonic acid
30
Q

What are glucocorticoid receptors?

A
  • They are members of the nuclear receptor super-family and has a characteristic 3-domain structure (DNA binding domain, ligand binding domain and the domain that interacts with co-regulators and repressors)
31
Q

Describe the formation of the glucocorticoid receptor

A
  • There is only one human glucocorticoid receptor gene which produces two isoforms mRNA (due to alternative splicing)
  • These isoforms are GR-alpha and GR-beta
  • As a result if forms two different isoforms of proteins: GR-alpha and GR-beta
32
Q

Explain the mechanism of glucocorticoid receptor action

A
  • Cortisol from the extracellular fluid will diffuse across the membrane into the cell where it will bind to cytosolic glucocorticoid receptors and dimerise with them
  • This dimer translocates into the nucleus where it will activate glucocorticoid response elements (GRE)
33
Q

How is cortisol secreted?

A
  • Stress and circadian rhythm stimulate the parvocellular neurones (hypothalamic endocrine cells) to secrete Corticotropin Releasing Hormone (CRH) from their axon terminals into the median eminence
  • It is then carried to the anterior pituitary which triggers the release of Adrenocorticotropic Hormone (ACTH) also known as corticotropin
  • ACTH acts on GPCRs on the adrenal cortex which results in the secretion of cortisol (and adrenal androgens)
34
Q

Explain the negative feedback loop for cortisol secretion?

A
  • An increase in cortisol level in circulation exerts a stronger negative feedback inhibition on ACTH secretion (by the anterior pituitary) and on CRH secretion (by the hypothalamus)
  • Overall there is a decrease in ACTH and CRH resulting in cortisol levels decreasing
  • A decrease in cortisol level in circulation exerts a weaker negative feedback inhibition on ACTH secretion (by the anterior pituitary) and on CRH secretion (by the hypothalamus)
  • Overall there is an increase in ACTH and CRH resulting in cortisol levels increasing
  • An increase in cortisol levels can lead to the inhibition of vasopressin (ADH) secretion from the parvocellular neurones and so as CRH secretion decreases so does ADH (leading to hypernatremia)
  • A decrease in cortisol levels can lead to the stimulation of vasopressin (ADH) secretion from the parvocellular neurones and so as CRH secretion increases so does ADH (leading to hyponatraemia)
35
Q

What is Pro-opiomelanocortin (POMC)?

A
  • It is a prohormone that spliced in melanocytes in different ways to form different hormones (depending on the cell)
  • One of these hormones is ACTH in the cells of the anterior pituitary along with three types of melanocyte stimulating hormones (MSH)
36
Q

What are melanocytes?

A
  • Skin cells that synthesise melanin (a pigment that darkens the skin)
  • It is responsible for skin tones and in white/Asian people it is responsible for tanning
37
Q

What is an observable trait of a person with excess ACTH in their system?

A
  • A person with excess ACTH in their body will suffer from darkening of the skin
  • This is because there is some cross reactivity between the receptors for ACTH and MSH
  • This means that at high concentrations of ACTH it will also activate MSH receptors as well as ACTH receptors
38
Q

What is Addison’s disease?

A
  • Primary adrenal failure.
  • This is where the adrenal cortex is damaged (mainly due to auto-immune diseases) and so fails to secrete its hormones in normal amounts
  • Hence there is reduced cortisol which results in reduced negative feedback to the hypothalamus and anterior pituitary
  • This means that ACTH and CRH secretion increases
  • However the ACTH will not interact with the adrenal cortex (as it is damaged) so instead it interacts with Melanocyte Stimulating Hormone (MSH) receptor
  • This leads to the pigmentation of the skin
39
Q

What are the symptoms of Addison’s disease?

A
  • Low circulating adrenal steroids
  • High ACTH (leading to hyperpigmentation)
  • Low [Na+] (due to increased ADH)
  • High [K+] (due to lack of aldosterone)
  • Elevating plasmin renin (due to reduced plasma levels)
  • Symptoms are normally unmasked by significant stress or illness e.g. shock, hypotension, volume depletion
  • This is called an adrenal crisis and leads to death if not treated
40
Q

What are the different types of adrenal insufficiency?

A
  • Primary adrenal insufficiency: (e.g. Addison’s disease) caused by a defect in the adrenal gland
  • Secondary adrenal insufficiency: caused by a defect not in the adrenal gland (e.g. hypopituitarism)
  • Enzyme defects in the steroid synthesis pathway
41
Q

What is Cushing’s syndrome?

A
  • Hypercortisolism

- This is when there is an excess cortisol or glucocorticoid drugs (a side effect of glucocorticoid therapy)

42
Q

What are the different types of Cushing’s syndrome?

A
  • ATCH dependent: This is when the adrenal cortex is excessively stimulated by ATCH. If caused by a pituitary adenoma it is called Cushing’s disease
  • ACTH independent: This is when the stimulation of the adrenal cortex by ACTH is normal (e.g. adrenal adenoma as this can affect the amount of cortisol secreting cells and hence cortisol)
43
Q

What are the different causes of ATCH dependent Cushing’s syndrome?

A
  • Cushing’s disease: An increase in ACTH secretion caused by a pituitary adenoma which increases the number of hormone secreting cells
  • Ectopic ACTH-secreting tumour: An increase in ACTH secretion cause by a tumour that occurs elsewhere in the body and not in the pituitary
44
Q

What are the different causes of ATCH independent Cushing’s syndrome?

A
  • Adrenal adenoma: An increase in cortisol secretion is caused by an increase in the number of secretory cells found when there is a tumour
  • Latrogenic: It can be as a side effect of glucocorticoid treatment
45
Q

What are the clinical features of hypercortisolism?

A
  • Hypertension
  • Hyperglycaemia
  • Truncal obesity
  • Fatigue and muscle weakness
  • Depression, mood or psychiatric disorders
  • Virilization (masculinisation)
46
Q

How do we diagnose Cushing’s syndrome?

A
  • First is to confirm the hypersecretion of cortisol done by a 24-hour urinary cortisol measure
  • Next we determine the cause by measuring plasma ACTH and the dexamethasone suppression test
47
Q

How does Cushing’s disease affect the negative feedback loop of cortisol secretion?

A
  • The most common cause of Cushing’s is iatrogenic (excess glucocorticoids which activate the cortisol receptors)
  • The source of this excess glucocorticoids is due to glucocorticoid therapy and not due to the adrenal cortex itself
  • High doses of glucocorticoids will activate the negative feedback and so will have a stronger inhibitory effect on the hypothalamus and anterior pituitary
  • Hence there will be very little CRH release and very little ACTH secretion
  • This means that the adrenal cortex is less stimulated and so will stop its production of cortisol and the androgens
  • Overall there will be a massive decrease in cortisol and androgens being released
48
Q

Why is a lack of ACTH dangerous?

A
  • With lack of ACTH (as seen in Cushing’s disease) it will lead to a lack of ACTH stimulation leading to atrophy (progressive degeneration and damage of tissue)
49
Q

In what manner must glucocorticoid therapy be stopped?

A
  • When taking a patient off glucocorticoid therapy it is important that we do so as a slow withdrawal
  • This is because it takes several days for the adrenal cortex to be responsive to ACTH again
  • If glucocorticoid therapy is stopped abruptly it could cause hypocortisolism
50
Q

Why is it hard to distinguish between Cushing’s syndrome caused by adenoma and by ectopic ACTH sources?

A
  • In both cases cortisol and ACTH levels will be high and
  • In the case for Cushing’s disease (caused by an adenoma) the mass of ACTH secreting cells in the anterior pituitary has increased and so the amount of ACTH secretion has also increased
  • Furthermore the feedback loop via the hypothalamic-pituitary axis is still intact.
  • So although the negative feedback loop is still sending inhibitory signals to the anterior pituitary the levels of ACTH are still at a higher set point
  • In the case of an ectopic ACTH source cortisol levels will be very high and as a result will exert the negative feedback on the anterior pituitary
  • As a result this time the anterior pituitary will shut down ACTH secretion however ACTH levels will stay the same
  • This is because the source of ACTH is coming from an ectopic source and so the feedback loop is completely bypassed
51
Q

What is the dexamethasone suppression test?

A
  • A test that allows us to see if the hypothalamic-pituitary axis loop is still intact (Cushing’s disease) or if it is bypassed (Ectopic ACTH source)
  • Dexamethasone is a glucocorticoid agonist which activates the glucocorticoid receptor
  • It is not cortisol so cortisol can still be measured.
  • It will only act like cortisol and trigger a negative feedback loop
52
Q

How do we carry out the dexamethasone test?

A
  • We start with a low dose of of dexamethasone
  • In healthy individuals it will suppress ACTH secretion from the anterior pituitary which in turn will suppress cortisol release (via negative feedback)
  • In a patients with Cushing’s diease (i.e. Cushing’s syndrome caused by an adenoma) there is little to no suppression at low doses
  • This is because the pituitary ACTH secretion has expanded due to the adenoma so low doses has little effect
  • However administering high doses over consecutive days will cause excess ACTH secretion to be suppressed as the negative feedback loop is still intact
  • On the other hand if ACTH secretion is not suppressed then the cause is an ectopic source of ACTH as the negative feedback system is irrelevant
  • This is because the anterior pituitary is producing little to no ACTH as the high cortisol is due to ACTH from somewhere else

Physiology 1 (64 decks)

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