19. The Adrenal glands Flashcards
Where are the adrenal glands located?
Upper poles of the kidneys and lie against the diaphragm in the retroperitoneal space
What are steroid hormones derived from?
cholesterol
What type of receptor do steroids have?
Nuclear receptors
How do corticosteroids produce their effects?
- Corticosteroids readily diffuse across plasma membrane
- Bind to glucocorticoid receptors.
- Binding causes dissociation of chaperone proteins (e.g. heat shock protein 90),
- Receptor ligand complex translocates to nucleus
- Dimerisation with other receptors can occur
- Receptors bind to glucocorticoid response elements (GREs), or other transcription factors
Give an example of a chaperone protein that may be bound to corticosteroid receptor?
Heat shock protein 90
What are the 2 regions of the adrenal gland?
cortex and medulla
What are the different zones in the adrenal cortex?
- Zona Glomerulosa: secrete mineralocorticoids (e.g. aldosterone)
- Zona Fasciculata: produce glucocorticoids (e.g. cortisol)
- Zone Reticularis: secrete glucocorticoids and small amounts of androgens
salt, sugar, sex
What does the adrenal cortex produce?
- Mineralocorticoids - e.g. aldosterone (C21 steroid)
- Glucocorticoids - e.g. cortisol and corticosterone (C21 steroids) - the major steroids produced by the cortex.
- Androgens - e.g. dehydroepiandrosterone (C19 steroid) - only produced in small amounts.
What are the embryonic origins of the 2 regions of adrenal glands? describe the development.
cortex is derived from mesoderm,
whereas the medulla is derived from neural crest cells which
subsequently migrate into the developing cortex
What covers the adrenal cortex and what does this contain?
connective tissue capsule which contains plexus of blood vessels (capsular plexus)
What does the adrenal medulla produce?
- Adrenaline (epinephrine)
* Noradrenaline (norepinephrine)
Give examples of corticosteroids
- Glucocorticoids - Cortisol, Corticosterone, Cortisone
- Mineralocorticoids - Aldosterone
- Androgens - Oestrogens, Testosterone
What is the action of steroid hormones?
Bind to receptors of the nuclear receptor family
to modulate gene transcription
What is the main functions of aldosterone?
Central role in determining extracellular fluid volume by controlling the rate at which Na+ ions are reabsorbed or excreted by the kidneys
Since extracellular volume is a prime determinant of arterial blood pressure, aldosterone is also a prime regulator of arterial blood pressure
How does aldosterone work and where does it act?
- Aldosterone receptor is intracellular & exerts its actions by regulating gene transcription
- Main actions in distal tubules and collecting ducts of nephron where it upregulates expression of Na+/K+ pump promoting reabsorption of Na+ and excretion of K+ thereby influencing water retention, blood volume & therefore blood pressure.
- Central component of renin-angiotensin-aldosterone system (RAAS)
Describe the renin-angiotensin-aldosterone system
- Decrease in renal perfusion, or a decrease in concentration of plasma Na+ or a drop in blood
pressure and increased sympathetic tone from
baroreceptor activation leads to more renin release
from kidney - Renin cleaves angiotensinogen (constitutively
released into blood by liver) into angiotensin 1 - Angiotensin I is further cleaved by angiotensin-converting enzyme (ACE) to angiotensin 2, primarily within the capillaries of the lungs
What are the 3 main effects of angiotensin II?
• a potent vasoconstrictor
causing arterioles to constrict resulting in an increase in arterial blood pressure.
• stimulates the adrenal cortex to secrete aldosterone
- acts on the distal tubules and collecting ducts of nephrons in the kidney to cause an increased reabsorption of Na+ and water back into blood and an increased secretion of K+ into urine resulting in increased blood volume and pressure.
• increase the release of antidiuretic hormone from the posterior pituitary.
ADH complements the actions of aldosterone in the kidney by inducing translocation of aquaporin water channels in the plasma membrane of the collecting duct cells allowing more reabsorption of water back into the blood.
What causes primary hyperaldosteronism?
Defect in adrenal cortex:
• Bilateral idiopathic adrenal hyperplasia
• Aldosterone secreting adrenal adenoma (Conn’s syndrome)
What causes secondary hyperaldosteronism?
Due to over activity of the RAAS:
• Renin producing tumour (Rare) e.g. juxtaglomerular tumour.
• Renal artery stenosis
Which cells produce renin?
juxtaglomerular cells in the kidney nephrons
How can we differenciate between primary and secondary hyperaldosteronsim?
Primary: Low renin levels (high aldosterone:renin ratio)
Secondary: High renin levels (low aldosterone:renin ratio)
What are the signs of hyperaldosteronism?
- High blood pressure
- Left ventricular hypertrophy
- Stroke
- Hypernatraemia
- Hypokalaemia
How is hyperaldosteronism treated?
Depends on type
• Aldosterone-producing adenomas removed by surgery
• Spironolactone (mineralocorticoid receptor antagonist)
What type of hormone are steroid hormones?
lipid soluble - lipophilic
What is the carrier protein for aldosterone?
mainly serumalbumin and to a lesser extent transcortin
What controls cortisol secretion?
ACTH is the main factor controlling the release of cortisol
Secretion of ACTH from anterior pituitary gland is under the control of corticotropin releasing factor (CRF)
- negative feedback by glucocorticoids on both the hypothalamus and pituitary
What is CRF released in response to?
Physical (temperature, pain), chemical (hypoglycaemia) and emotional stressors
What type of rhythm is ACTH secreted in?
secreted with a circadian rhythm with a pulsatile secretion superimposed
When does cortisol peak and trough?
Peaks at 7am and troughs at 7pm
- time should always be noted whenmtaking a sample of blood for cortisol measurement and repeated measurements should be taken at the same time of day
What is the ACTH receptor called and what type of receptor is it?
Type 2 melanocortin receptor (MC2)
- GPCR, Gαs coupled
What key enzyme does binding of ACTH to its receptor activate and what does it do?
Cholesterol esterase: increasing the conversion of cholesterol esters to free cholesterol.
- It also stimulates other steps in the synthesis of cortisol from cholesterol.
How is cortisol transported in the blood and why?
Is lipophilic like all steroid hormones and must be transported bound to plasma protein
What are the major transport proteins of cortisol?
~90% transcortin (corticosteroid-binding globulin (CBG))
~10% being bound by serum albumin
Where in a cell is the cortisol receptor found?
Cytoplasm
What is the precursor of ACTH?
A large protein (~250 amino acids) called proopiomelanocortin (POMC)
What range of peptides does post-translational processing of POMC produce?
ACTH, α-MSH (melanocyte stimulating hormone) and endorphins
Why does ACTH have MSH like activity at high concentrations?
Why does ACTH have MSH like activity at high concentrations?
What type of hormone is ACTH?
hydrophilic and interacts with high affinity receptors on the surface of cells in the zona fasciculata and reticularis
ACTH is a peptide hormone and acts on G-protein coupled receptors
What happens when cortisol binds to its receptor?
Cortisol can cross the plasma membranes of target cells and bind to cytoplasmic receptors. The hormone/receptor complex then enters the nucleus and interacts with specific regions of DNA (associates with glucocorticoid response elements in DNA). This interaction changes the rate of transcription of specific genes and may take time to occur.
• Cortisol receptor exerts its actions by regulating gene transcription
In what states are the are the major metabolic effects of cortisol seen and what is this general effect?
Major metabolic effects of cortisol are in the starved and stressed states where it affects the availability of all major metabolic substrates by increasing proteolysis, lipolysis and gluconeogenesis
What are the metabolic effects of cortisol?
↓ Amino acid uptake
↓ Protein synthesis
↑ proteolysis in most tissues (not liver).
↑ Hepatic gluconeogenesis and glycogenolysis.
↑ Lipolysis in adipose tissue (N.B. at high levels of cortisol ↑ lipogenesis in adipose tissue)
↓ Peripheral uptake of glucose (anti-insulin)
How does cortisol decrease muscle uptake of glucose?
Inhibits insulin induced GLUT4 translocation in muscles
How does higher levels of cortisol affect redistribution of fat?
Redistribution of fat especially in the abdomen, supraclavicular fat pads, dorso-cervical fat pad (buffalo hump), & and on the face (moon face)
How does cortisol provide resistance to stress?
Increased supply of glucose, raise blood
pressure by making vessels more sensitive to vasoconstrictors
What anti-inflammatory effects does cortisol have?
inhibits macrophage activity and inhibits mast cell degranulation
Why is cortisol a useful medication for allergic reactions?
Inhibits mast cell degranulation
Why might cortisol be prescribe to organ transplant patients?
Depression of immune response
What are the net effects of cortisol?
- Increased glucose production
- Breakdown of protein
- Redistribution of fat
Why might cortisol lead to increase in glycogen stores?
↑ Glucose leads to ↑ insulin so liver glycogen stores ↑
What is Cushing’s syndrome?
Chronic excessive exposure to cortisol
What are the external causes of Cushing’s syndrome?
Prescribed glucocorticoids
- most common cause
What are the internal causes of Cushing’s syndrome?
- Benign pituitary adenoma secreting ACTH (Cushing’s disease)
- Excess cortisol produced by adrenal tumour (Adrenal Cushing’s)
- Non pituitary-adrenal tumours producing ACTH (&/or CRH) e.g. small cell lung cancer
What are the signs and symptoms of Cushing’s syndrome?
- Plethoric moonshaped face
- “Buffalo hump”
- Abdominal obesity
- Purple striae
- Acute weight gain
- Hyperglycaemia
- Hypertension
Why do purple striae form in Cushing’s syndrome?
- skin is thin and weakened due to the actions of cortisol - easy bruising
- central obesity from the cortisol induced redistribution of fat stretches the skin
Why might hyperglycaemia be present in patients with cushing’s syndrome?
Increased muscle proteolysis and hepatic gluconeogenesis that may lead to hyperglycaemia with associated polyuria and polydipsia (“steroid diabetes”).
Why might patients with cushing’s syndrome have thin arms and legs?
Increased muscle proteolysis leads to wasting of proximal muscles and producing thin arms and legs and muscle weakness.
Why might hypertension be present in patients with cushing’s syndrome?
Mineralocorticoid effects of excess cortisol may produce hypertension due to sodium and fluid retention.
Why might patients with cushing’s syndrome have increased susceptibility to bacterial infections?
Immunosuppressive, anti-inflammatory and anti-allergic
reactions of cortisol leading to increased susceptibility to bacterial infections and producing acne
Why is there change in body shape in patients with cushing’s syndrome?
Increased lipogenesis in adipose tissue leading to deposition of fat in abdomen, neck and face and producing characteristic body shape, moon-shaped face and weight gain.
Give examples of steroid drugs.
Prednisolone
Dexamethasone
What are steroid drugs used for?
Anti-inflammatory & immunomodulatory effects
Used to treat inflammatory disorders e.g.
• Asthma
• Inflammatory bowel disease
• Rheumatoid arthritis
• Other auto-immune conditions
Also used to supress immune reaction to organ transplantation
How should steroid dosage be reduced?
Steroid dosage should be reduced gradually and not stopped suddenly
What is the difference between cushing’s disease and cushing’s syndrome?
Cushing’s syndrome refers to the general constellation of symptoms resulting from chronic excessive exposure to cortisol whereas 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.
Why might patients with excess cortisol have back pain?
back pain and collapse of ribs due to osteoporosis caused by disturbances in calcium metabolism and loss of bone matrix protein.
What can happen with abrupt withdrawal of steroid drugs?
Can lead to acute adrenal insufficiency (adrenal cortex has been suppressed by negative feedback by steroid drugs), hypotension or death
What is Addison’s disease?
Chronic adrenal insufficiency
What are the signs and symptoms of Addison’s disease?
- Postural hypotension due to fluid depletion.
- Decreased blood pressure due to sodium and fluid depletion.
- Lethargy
- Extreme muscular weakness and dehydration.
- Weight loss
- Anorexia
- Increased skin pigmentation
- Hypoglycaemia
What are the causes of Addison’s disease?
- Diseases of the adrenal cortex (auto-immune destruction) – reduces glucocorticoids and mineralocorticoids.
- Disorders in pituitary or hypothalamus that lead to decreased secretion of ACTH or CRF – affects glucocorticoids.
- complication of Tuberculosis
- fungal infection, adrenal cancer & adrenal haemorrhage (e.g. following trauma)
Why is there hyperpigmentation in Addison’s disease?
Decreased cortisol leads to reduced negative feedback on anterior pituitary gland so increased POMC to produce more ACTH.
Increased MSH as consequence of increased POMC in Addison’s leads to hyperpigmentation.
ACTH itself can also activate melanocortin receptors on melanocytes so will also contribute to hyperpigmentation
What is Addisonian crisis?
Life threatening emergency due to adrenal insufficiency
What are the symptoms of Adisonian crisis?
- Nausea
- Vomiting
- Pyrexia,
- Hypotension
- Vascular collapse
What is Adisonian crisis precipitated by?
- Severe stress
- Salt depravation
- Infection
- Trauma
- Cold exposure
- Over exertion
- Abrupt steroid drug withdrawal
How is Adisonian crisis treated?
- Fluid replacement
* intra-venous Cortisol
What are the 2 main androgens?
- Dehydroepiandrosterone (DHEA)
- androstenedione
What is DHEA converted in to?
Males: testosterone in testes (insignificant after puberty as testes produce own testosterone)
Females: promote libido and are converted to oestrogens by other tissues
What is the only source of oestrogen in females after menopause?
Conversion of adrenal androgens into oestrogen by other tissues
How does androgens affect hair growth?
Promote axillary and pubic hair growth in both sexes
What are adrenal medulla cells called?
Chromaffin cells
What do chromaffin cells act as?
Chromaffin cells in adrenal medulla lack axons but act as postganglionic nerve fibres that release hormones into blood
n what ratio does the adrenal medulla produce adrenaline and noradrenaline and why?
Adrenaline (~80%)
Noradrenaline (~20%)
~20% chromaffin cells lack N-methyl transferase enzyme so cannot convert noradrenaline to adrenaline
Which nerves supply the adrenal medulla and what are their nerve roots?
Greater splanchnic nerve: T5-T9
Lesser splanchnic nerve: T10-T11
How is adrenaline synthesised in chromaffin cells?
by a series of enzyme-catalysed steps that convert the amino acid tyrosine into dopamine. Dopamine is then converted to noradrenaline and noradrenaline to adrenaline
Where are catecholamines stored in the chromaffin cells?
in membrane-limited vesicles before release into the bloodstream
Describe activation of adrenergic receptors
• Adrenaline released in response to sympathetic stimulation of chromaffin cells in the adrenal
medulla travels through the bloodstream to stimulate adrenergic receptors in target tissues.
• These cell surface receptors are G protein
coupled and the type of response produced the target cell depends on the type of adrenergic receptor expressed.
• There are two main types of adrenoceptor termed α and β.
• The α type has two subtypes; α1 receptors facilitate an increase in intracellular Ca2+ via coupling to Gαq
and α2 receptors facilitate a decrease in the intracellular second messenger cAMP via coupling to the inhibitory G protein Gαi.
• There are three subtypes of β adrenoceptor termed β1, β2 and β3 and all these promote an increase in cAMP by coupling to the stimulatory G protein Gαs.
What are the effects of adrenaline?
- Heart: ↑ Heart rate (β1) ↑ Contractility (β1)
- Blood vessels: Vasoconstriction(α1, skin & gut) Vasodilation (β2, skeletal muscle)
- Lungs: Bronchodilation (β2)
- Liver ↑ Glycogenolysis (α1 ,β2) ↑ Gluconeogenesis (α1 ,β2)
- Adipose: ↑ Lipolysis (β2)
- Muscle: ↑ Glycolysis (α1 β2) ↑ Glycogenolysis (α1 ,β2)
- Pancreas: ↑ Glucagon secretion (α2) ↓ Insulin secretion (α2 β2)
- Kidney:↑ Renin secretion (β1 β2)
What is a phaeochromocytoma?
Catecholamine-secreting tumour arising from adrenal medulla - chromaffin cell tumour
What are the symptoms of phaeochromocytoma?
- Severe hypertension
- Headaches
- Palpitations
- Diaphoresis (excessive sweating)
- Anxiety
- Weight loss
- Elevated blood glucose
