Adrenal Flashcards
Structure of cholesterol
Multi aromatic ring with a long side chain of carbon units
27 amino acids
What is the rate limiting step in steroidogenesis
The transport of cholesterolfrom the outer to the inner mitochondrial membrane
Where is the first enzyme in steroidogenesis located
In the inner mitochondrial membrane (initial side chain cleavage of cholesterol)
What are the zone specific steroid hormone synthesis
Zona glomerulosa - mineralocorticoids
Zona fasiculata - glucocorticoids (mainly) and gonadocorticoids
Zona reticularis - glucocorticoids and gonadocorticoids (mainly)
What is zone specific steroidogenesis
Differential expression of biosynthetic enzymes in the different zones of the adrenal cortex
Each steroid is transferred between 2 sub cellular compartments as it progresses along its biosynthetic pathway
Action of aldosterone (main mineralocorticoid) made in the cortex
Principally act on DCT and collecting ducts of kidney to promote Na+ retention (-> H2O retention) and K+ elimination during formation of urine
Secretion of aldosterone
stimulated by increased plasma [K+] and renin- angiotensin system (largely independent of ACTH)
What is cortisol
The main mineralcorticoid and also a glucocorticoid
What is the pattern of levels of cortisol throughout the day
Peaks in the morning and falls during day but a small surge in late afternoon to help you get through evening
Associated with sleep wake cycle
What are the actions of cortisol
Metabolic effects
Anti inflammatory / immunosuppressive effects
Role in adaption to stress
Permissive role in action of other endocrine hormones
Actions on other tissues
Metabolic effects of cortisol
In muscle and adipose tissue - catabolic
In liver - stimulates gluconeogenesis and glycogen storage
Overall to elevate plasma glucose levels
Actions of cortisol
Anti inflammatory / immunosuppressive effects
- stimulate production of lipocortin 1 (Annexin 1) which inhibits PLA 2, an enzyme that generates arachidonic acid the precursor for prostanoids and leukotrienes
Decrease number and activation of T lymphocytes
Decrease production of cytokines
Stabilises lysosomes
Decrease NO production
What is the integrated stress response
A state of threatened homeostasis or disharmony; the body responds by a complex repertoire of physiological and behavioural mechanisms to re establish homeostasis
What are stressors
Stimuli that induce state of stress
Stress response system
Sympathetic nervous system and adrenaline and CRH-ACTH - cortisol
What are the actions of SNS and adrenaline
Increased cardiac output and ventilation
Diversion of blood flow to muscles and heart
Mobilisation of glycogen and fat stores
‘Fight and flight’
What can prolonged elevated cortisol levels lead to
Muscle wasting
Hyperglycaemia
GI ulcers
Impaired immune response
(See Cushing’s syndrome)
Disorders of adrenal steroids
Glucocorticoid excess - Cushing’s syndrome
Mineralcorticoid excess- conns syndrome
Adrenal insufficiency - Addison’s disease
Congenital adrenal hyperplasia (cAH)
What is Cushing’s syndrome
Excessive glucocorticoid activity
Endogenous or exogenous (steroid medication) eg rheumatoid arthritis
Effects more women than men
Ages 20-60 mainly
What is cushings disease
Excessive production of ACTH
Main endogenous cause
Pituitary ACTH secreting tumour
What is the difference between Cushing’s syndrome and cushings disease
Cushings disease is a type of Cushing syndrome.
Disease occurs when a pituitary tumour causes the body to make too much cortisol
Makes up about 70% of Cushing syndrome cases
Signs and symptoms of Cushing’s syndrome
Truncal obesity Buffalo hump Red round face Acne Female frontal balding Female hirsutism Menstrual irregularities Testicular atrophy Thin arms and legs Muscle weakness Thin skin Purple striae Poor wound healing Easy bruising Infections Cognitive difficulties Emotional instability Depression Sleep disturbances Osteoporosis Hypertension Diabetes
What is dexamethasone
A synthetic glucocorticoid
Low dose 0.5mg DEX every 6h for 48h, measure cortisol before and at 48h
Overnight 1mg DEX 11pm then cortisol measurement at 8am
What is the dexamethasone suppression test
Lack of suppression indicates hyper -/ autonomous secretion
- confirms Cushing’s syndrome
What is the CRH stimulation test
Used to distinguish between pituitary dependent cushings and an ectopic source of ACTH
Normally there is a rise in both ACTH and cortisol
In pituitary dependent cushings patients, the response is exaggerated
Treatment of cushings disease
Localisation of the tumour Ant pituitary - MRI Adrenal - abdominal CT / MRI scan Bronchial tumour - chest x ray ACTH secreting tumour - octreoscan
Then surgery or radiation
Medical, drugs to inhibit steroidogenesis eg metryapone, trilostane
What is conn’s syndrome (primary hyperaldosteronism)
Abnormally large amount of aldosterone produced - common cause = tumour
Results in the initial retention of Na+, and Hanse increased water retention with increased K+ elimination
Hypokalaemia -> weakness
Chronic hypokalaemia -> renal dysfunction -> polyuria
Main clinical finding in conn’s is hypertension
Occurs in 1% of people diagnosed with hypertension
If due to tumour surgery is the course of treatment
What is Addison’s disease
Adrenal insufficiency
A rare chronic condition brought about by failure of adrenal glands
Involved gradual destruction of adrenal tissue - often autoimmune or by TB or HIV
Apparent when 90% of adrenal cortex has been destroyed
Low aldosterone, low cortisol, low androgens but elevated ACTH
Symptoms of Addison’s disease
Postural hypotension Muscle weakness, fatigue, lethargy Hyponatraemia, hyperkalaemia Nausea, vomiting Weight loss, anorexia
Why do you get increased pigmentation in Addison’s disease
ACTH production increased as is MSH (melanocytes stimulating hormone) - increased melanin content in skin
Often seen in skin creases, old scars, gums and inside of cheek
What is pro- opiomelanocortin
Undergoes extensive post translational processing
This processing is tissue specific
Diagnosis of Addison’s disease
Tests for adrenal failure
- decreased cortisol and elevated ACTH levels
ACTH stimulation test (stimulation test for adrenal function) - adrenal antibodies (if suspected autoimmune disease)
Treatment for Addison’s disease
Life long hormone replacement
Glucocorticoid - hydrocortisone
Mineralcorticoid - fludrocortisone
Higher doses of glucocorticoids are given during times of illness or major stress eg surgery
What is secondary adrenal insuffiencey
Lack of ACTH production (tumour, damage to pituitary)
Low cortisol with normal aldosterone levels (RAAs intact)
May also be due to exogenous glucocorticoid use
- secondary adrenal suppression often in patients with long term, high dose glucocorticoid use
- suppression of ACTH levels leading to suppression and atrophy of adrenal cortex -> low endogenous cortisol
What can happen to patients with excess exogenous glucocorticoids
Can lead to cushingoid appearance (truncal obesity, round facies, dorsocervical fat pads, striae)
What happens with sudden withdrawal of exogenous steroids
- symptoms of acute adrenal insufficiency
Fatigue, N&V, anorexia, weight loss, hypotension, myalgia
What is an adrenal crisis
Medical emergency
- acute adrenal insufficiency and expressed when patient is under stress eg infection
- > hypotension, circulatory failure, potentially death
Urgent treatment (IV fluids, hydrocortisone, iv then oral) Oral once stabilised
What is congenital adrenal hyperplasia (CAH)
Inherited defect in an enzyme involved in the production of cortisol and aldosterone
Several possible types
>90% of CAH due to deficiency of 21B-hydroxylase
Difference between ACTH receptors and thyroxine receptors
ACTH receptors are found only on certain cells
Thyroxine receptors are found on nearly all cells of the body
What does target cell activation depend on
Hormone amount
Number of receptors on target cell
Affinity of the receptors fro the hormone
Following receptor activation there is termination of the signal (degradation of the hormone, inactivation of receptor or signalling)
What is receptor regulation
If increase in [hormone] -> down regulation of receptors
Eg
Inactivation of receptors
Inactivation of signalling molecules
Sequestration of recepotrs to inside of cell
Degradation of internalised receptors
Decreased production of receptors
What is upregulation of receptors
No reduced sensitivity
Decreased inactivation of receptors and signalling proteins
Decreased sequestration and degradation of internalised receptors
Increased production of receptors
What are the 4 super families of receptors
Ligand fated ion channels (ionotropic receptors)
G protein coupled receptors (metabotropic receptors)
Catalytic receptors
Nuclear (intracellular) receptors
Action of water soluble hormones
(amino acid based hormones except thyroid hormones)
- act on plasma membrane receptors (cannot enter cells)
Action of lipid soluble hormones
Steroid and thyroid hormones
Act on intracellular receptors that directly activate genes (can enter cell)
What do Gq coupled receptors do
Phospholipase CB takes PIP2 and catalyses its breakdown into DAG and IP3
DAG activates PKC which phosphorylates many proteins such as ion channels and enzymes
IP3 binds to IP3 receptors on endoplasmic reticulum which acts as a store for Ca2+ this causes a release which raises intracellular calcium levels
What are intracellular nuclear receptors
Mediate effects for steroid hormones, thyroid hormones and others such as bile acids, retinoic acid (derived from vit A), vit D and includes PPARs (peroxisome proliferator- activated receptors)
Ligand regulated transcription factors
Interact as homo- or heterodimers with DNA sequences in promoter region of target genes
What are type I nuclear receptors (steroid hormone receptors)
Glucocorticoid, mineralocorticoid, oestrogen, progesterone, androgen receptors
Also plasma membrane receptors
What is primary adrenal insufficiency
Impairment of the adrenal glands (addisons disease)
What is secondary adrenal insuffiecey
Impairments of the pituitary gland (low ACTH)
What is tertiary adrenal insufficiency
Impairment of the hypothalamus (low CRH)
Symptoms of reduced glucocorticoid activity
Generally unwell (stress / immune regulation)
Fatigue (hypoglycaemia
Reduced appetite (metabolic effects)
Confusion.
Reduced mineralocorticoid activity of glucocorticoids
Fatigue / weakness (electrolyte disturbances)
Dizziness (hypovolaemia)
Nausea (electrolyte disturbances)b
What should you do for symptomatic relief of Graves’ disease (primary hyperthyroidism)
Non selective beta blockers (needed for many months until reaching euthyroid state)
Big build up of thyroid hormones
What happens to hormones in Graves’ disease (primary hyperthyroidism)
Rise in free T3 and T4 and decreased TSH
Why are cortisol levels measured at 24:00 and 08:00
These are the times when it is most extreme (high in the morning and low at night)
If there’s a loss of this there’s a problems
Loss of diurnal rhythm
Rate limiting step in steroidogenesis
Transport of cholesterol from outer to inner mitochondrial membrane
Where is the first enzyme of steriogenesis located
Inner mitochondrial membrane
Initial side chain cleavage of cholesterol
Cholesterol 20, 22 desmolase
Where are adrenal glands located
Superior to kidneys in renal fascia
Posterior to parts of diaphragm (retroperitoneal)
Blood supply of adrenal glands
Arterial:
Superior suprarenal aa (from phrenic)
Middle suprarenal aa (from abdoA)
Inferior suprarenal aa (from renal aa)
Venous:
Right suprarenal vv (to IVC)
Left suprarenal vv (to left renal vv)
What are the adrenal glands microscopically
Arterioles from capsular arteries
Give rise to sinusoidal capillaries
Drain into medullary vein
What is a sympathetic ganglion
Fight or flight
- secretion controlled by preganglionic neurons -> secretory cell is functionally equivalent to postganglionic neurones of SNS so secretions are quickly released
- act on adrenergic receptors (eg heart, blood vessels)
Ultrastructure of adrenal cortex
Smooth ER
Lipid droplets
Tubular Cristal in mitochondria
Ultrastructure of the adrenal medulla
Rough ER and golgi
Granules
Normal mitochondria
What is the commonest cause of addisons disease in the UK
Autoimmunity
As addisons disease is an autoimmune disease
Desribe the growth of the fetal adrenal gland
At 4 months gestation it is 4 times the size of the kidney but at birth it is a third of the size of the kidney
This is due to the rapid regression of the fetal cortex at birth
Disappears almost completely by age 1; by age 4-5 years, the permanent adult type adrenal cortex has fully developed
What electrolyte imbalance would be expected with addisons disease
Hyperkalaemia and hyponatraemia
Aldosterone causes sodium reabsorption and potassium excretion. A lack of aldosterone would result in the following biochemical abnormality: hyperkalaemia and hyponatraemia
Primary causes of hypoadrenalism
Tuberculosis Metastases (eg bronchial carcinoma) Meningococcal septicaemia HIV Antiphospholipid syndrome
Differences between primary addisons and secondary adrenal insufficiency
Primary addisons is associated with hyperpigmentation whereas secondary adrenal insufficiency is not
Why do corticosteroids worsen diabetic control
Due to their anti insulin effects
Glucocorticoids are the synthetic form of the natural hormone cortisol And cortisol raises blood glucose by acting on various organs to increase gluconeogenesis
