Flashcards in Adrenals Deck (52):
What is the embryological connection between the adrenal glands and the gonads?
Both develop in the same place from the adrenogonadal primordium
What is the direction of blood flow in the adrenal gland?
The blood supply is provided from the adrenal artery above the capsule (adrenal cortex) which supplies the layers of the adrenal cortex via the medullary artery and sub scapular plexus) and then forms the medullary plexus which supplies the medulla of the adrenal gland and this then drains into the adrenal veins.
What stimuli cause activation of the adrenal gland?
Stress! From starvation, infection or severe blood volume loss
In which layer of the adrenal cortex are mineralocorticoids such as aldosterone produced?
In which layer of the adrenal cortex are glucocorticoids such as cortisol produced?
In which layer of the adrenal cortex are androgens such as testosterone produced?
What is the action of aldosterone (a mineralocorticoid)
It increases potassium and sodium reabsorption in the kidneys which also increases water reabsorption and therefore increases circulating blood volume
What causes the stimulation of aldosterone production of the zona glomerulosa of the adrenal cortex?
Low potassium levels (hypokalaemia) and low blood pressure
Describe the mechanism of action of aldosterone
- Increases expression and stimulates the basolateral Na+/K+ ATPase in the collecting duct to increase uptake into the blood and create a sodium gradient to encourage reabsorption.
- In addition, aldosterone increases numbers of ENaC channels (sodium channels) so that more sodium enters, as well as water (potassium leaves to remain electro-neutrality).
- Aldosterone also stimulates H+ ATPase in the intercalated cells of the collecting duct to increase H+ excretion
How may hyperaldosteronism lead to metabolic alkalosis?
Aldosterone stimulates the H+ ATPase in the distal nephron which leads to increased H+ excretion, which can eventually lead to deficiency if aldosterone is present in excessive amounts
How may hyperaldosteronism lead to hypokalaemia?
Increased sodium reabsorption (due to increased ENaC presence) will cause potassium to enter the tubular fluid in order to maintain electro-neutrality and therefore this excess excretion of K+ can lead to deficiency
What two molecules can bind to the mineralocorticoid receptor in the kidney?
Cortisol and aldosterone
How can the kidney prevent the binding of cortisol to the mineralocorticoid receptor?
It can facilitate the conversion of active cortisol into inactive cortisone via the action of 11-beta-HSD2 enzyme
What is Conn's syndrome?
A form of primary hyperaldosteronism
What is primary hyperaldosteronism?
This is also known as Conn's syndrome and it is characterised by hypertension, suppressed renin activity (negative feedback) and increased aldosterone secretion
What may cause Conn's syndrome?
This is a form of hyperaldosteronism and therefore can occur as a result of an aldosterone-producing adenoma or due to bilateral adrenal hyperplasia
What is glucocorticoid remediable aldosteronism?
This is a familial form of hyperaldosteronism that is autosomal dominant.
In this condition there is fusion of the cortisol synthase promoter region to the aldosterone synthase coding region and therefore this leads to ACTH-dependent aldosterone secretion in the zona fasciculata rather than the zona glomerulosa
What similarities are there between the enzymes that produce glucocorticoids and mineralocorticoids?
The enzymes are isoenzymes of each other;
Aldosterone synthase is known as CYP11B2 whereas the enzyme responsible for cortisol synthesis is CYP11B1 (11 beta hydroxylase)
How may glucocorticoid remediable aldosteronism be treated?
Through the administration of glucocorticoids in order to reduce ACTH secretion from the pituitary gland by negative feedback.
How can large liquorice consumption affect the mineralocorticoid receptor?
Excess liquorice consumption leads to the direct inactivation of the 11beta-HSD2 enzyme that is involved in the conversion of cortisol to cortisone (inactive form so that it can't bind to the mineralocorticoid receptor. Therefore, in excess liquorice consumption, high cortisol levels persist.
What is the syndrome of apparent mineralocorticoid excess (AME)?
If there are excess cortisol levels, the action of the 11betaHSD2 enzyme (ordinarily inactivates cortisol by producing cortisone) becomes inactivated as the enzyme can become overwhelmed and this leads to persistent increased cortisol levels.
What is Liddle syndrome?
This is a form of pseudohyperaldosteronism, whereby the condition is autosomal dominant and genetic, and it causes mutations which have the same affects as hyperaldosteronism, but the cause does not stem from elevated aldosterone levels.
> There is increased expression of the K+/Na+ ATPase --> increased sodium reabsorption into the blood stream to create sodium gradient across the cell
> Increased insertion of ENaC channels to increase sodium uptake (water follows) and potassium is pumped out to retain electro-neutrality
> H+ ATPase is stimulated which increases pumping of protons, and therefore increased proton excretion which can cause a metabolic alkalosis
What are the characteristic symptoms of hyperaldosteronism and Liddle syndrome?
Hypertension (due to increased sodium reabsorption and increased water reabsorption), hypokalaemia (due to compensatory potassium loss to remain electroneutrality due to sodium influx) and metabolic alkalosis due to increased excretion of H+ in the distal tubule via the H+ ATPase transporter
What are three main tiers of cortisol regulation?
> Regulatory molecules from the brain and the hypothalamus
> Intrapituitary cytokines and growth factors that limit excessive ACTH production
> Glucocorticoid feedback inhibition control (long loop, short loop and ultrashort loop)
What factors promote CRH production from the hypothalamus?
Stress, catecholamines (adrenaline and noradrenaline), angiotensin II and ghrelin
What factors inhibit CRH production from the hypothalamus?
ANP (atrial natriuretic peptide), opioids and oxytocin
What factors promote ACTH production from the anterior pituitary gland?
Angiotensin II, IL-1/2/6 and LIF
What factor inhibits ACTH production from the anterior pituitary gland?
Why are glucocorticoids released in response to starvation?
Cortisol causes the breakdown of tissues for fuel
Why are glucocorticoids released in response to infection?
Cortisol causes immunosuppression to prevent sepsis
Why are glucocorticoids released in response to hypotension?
Cortisol helps to cause an increase in blood pressure
What is Cushing's syndrome?
A condition that arises due to prolonged exposure to cortisol
What are the symptoms of Cushing's syndrome?
There is excess exposure to cortisol and therefore this can lead to emotional disturbances, enlarged heart, high blood pressure, thin skin, abdominal stretch marks, foot ulcers, muscle weakness and dorsal fat pad
What may cause Cushing's syndrome?
Can be caused by other drugs (iatrogenic), there may be corticotroph adenoma of the pituitary gland, ectopic ACTH secretion from a neuroendocrine tumour, cortisol secreting adrenal adenoma or bilateral adrenal hyperplasia
What is Addison's disease?
Where the adrenal gland doesn't secrete enough steroids (including aldosterone and cortisol)
What is meant by an Addisonian crisis?
This is where the body fails to respond to stress by stimulating the adrenal glands, and this leads to low blood pressure, low blood glucose, low sodium and high potassium levels which can have serious consequences
What may cause Addison's disease?
It is caused by adrenal failure, and this may occur due to an autoimmune response or as a result of TB
What are the symptoms of Addison's disease?
Symptoms start by being very generic e.g. weakness, myalgia fatigue, but hyperpigmentation may then display which can be characteristic
How would you diagnose Addison's disease from blood tests?
There would be decreased 9am cortisol levels and increased ACTH levels
How is Addison's disease treated?
Hydrocortisone is given to replace the cortisol andfludrocortisone is given to replace the aldosterone
Why can reduced cortisol levels lead to hyperpigmentation?
Reduced cortisol leads to up regulation of ACTH production; ACTH contains the alpha-MSH amino acid chain at the N-terminal end of the molecule which can interact with the keratin in the skin to cause hyperpigmentation
What is congenital adrenal hyperplasia?
There is a deficiency of 21-hydroxylase at birth which is a key component for the enzymes that synthesise both glucocorticoid (cortisol) and mineralocorticoid (aldosterone) and this leads to the increased production of testosterone instead.
How is adrenaline produced?
It is produced from noradrenaline via the action of methyltransferase PNMT
How are catecholamines removed from the circulation and recycled?
They are recovered by sympathetic nerves and chromaffin cells (in adrenal medulla) and metabolised to form metanephrines by the action of COMT
What are chromaffin cells?
Cells in the adrenal medulla that are involved in the breakdown of catecholamines
What is a phaechromocytoma?
Where there is hyperplasia of the chromaffin cells in the adrenal medulla leading to a lack of catecholamine breakdown so increased circulating levels
How would you diagnose phaechromocytoma?
There will be hyperadrenergic cells and resistant hypertension
Why should beta blockers not be given in the treatment of phaechromocytoma?
catecholamines that are produced in excess and therefore, these catecholamines cause vasoconstriction by 1 receptors and vasodilation via 2 receptors, and therefore blockers could lead to decreased vasodilation, which would lead to the worsening of the individual’s condition with no therapeutic benefit.
What are the effects of catecholamines on the circulatory system?
Cause vasoconstriction vascular smooth muscle via alpha-1 receptors
Cause relaxation of bronchial, vascular and uterine smooth muscle via the B2 receptors
What are the actions of alpha 1 adrenoreceptors?
Located on vascular smooth muscle and cause vasoconstriction due to smooth muscle contraction in response to activation
What are the actions of the beta 1 adrenoreceptors?
These are located in the heart and lead to positive ionotropic and chronotropic effects