Adrenal Gland Flashcards
Adrenal cortex releases what kind of hormones?
Steroid hormones
Three layers of adrenal cortex
Zona glomerulosa
Zona fasiculata
Zona reticularis
What hormones do the Zona fasiculata secrete?
Glucocorticoids
What Zona secretes mineral corticoids?
Zona glomerulosa
What hormones does Zona reticularis secrete?
Weak androgens
What does adrenal medulla secrete?
Catecholamines
Example of mineralocortcoids:
Aldosterone
Example of glucocorticoid:
Cortisol
Example of androgens:
DHEA
What is the name for excessive glucocorticoids?
Cushings syndrome
Name for excessive Mineralocorticoids?
Conns syndrome
Name for excess Catecholamine from medulla?
Phaeochromocytoma
What is the group of genetic disorders that affect the adrenal glands called?
Congenital adrenal hyperplasia
Names of some adrenal tumours
Adrenal incidentaloma
Adrenocortical carcinoma
What are corticosteroids?
Any group of steroid hormones produces by adrenal cortex
Mineralocorticoids
Glucocorticoids
Weak androgens
Features of corticosteroids:
Lipid soluble
Bind to specific intracellular receptors
Exact action depends on structure
How do corticoids produce their effects?
Lipid soluble - passes through cell membrane
Bind to Intracellular receptors
By altering gene transcription directly/ indirectly
All steroid hormones have what precursor
Cholesterol
Why are glucocorticoids essential to life?
Important to homeostasis
Conditioning the body’s response to stress
What are the actions of glucocorticoids like?
Actions on most tissues
“Permissive” - do not directly initiate but allow other factors to be present
Actions of glucocorticoids that increase glucose mobilisation?
Augment gluconeogenesis
Amino acid generation
Increased lipolysis
Actions of glucocorticoids that maintain circulation
Vascular tone
Salt and water balance
Actions of glucocorticoids that allow immunomodulation
Immunosuppression
Anti inflammatory
Transport of glucocorticoids in circulation
heavily bound to proteins
What is the percentages of glucocorticoids bound to proteins in the blood?
90% bound to CBG
5% bound albumin
5% free glucocorticoids (bioavailable)
Regulation of glucocorticoids (hormones and glands involved)
Via CRH released from the hypothalamus
Then ACTH released from anterior pituitary gland
Physical Effect of ACTH deficiency on adrenal
Becomes atrophic and shrinks
2 ways of Circadian rhythm of circulating cortisol
Diurnal - occurring during daylight hours
Circadian - occurring once every 24 hrs
What causes stress on the body?
Infection
Trauma
Haemorrhage
Medical illness
Psychological
Exercise/ exhaustion
How does negative feedback work in the adrenal gland?
When there are high cortisol levels, cortisol binds to glucocorticoid receptors in the pituitary gland and hypothalamus
Negatively feeds back
Then CRH and ACTH secretions inhibited
What are the main Mineralocorticoids?
Aldosterone
DOC
Why are Mineralocorticoids important?
Critical to salt and water balance in certain organs
Where do Mineralocorticoids act?
Kidney
Colon
Pancreas
Salivary glands
Sweat glands
Other effector organs of sodium reabsorption for mineralocorticoids
Sodium resorption in
Pancreas
Sweat glands
Salivary glands
Colon
Non classical effects of mineralocorticoids:
Myocardial collagen production
Role in cardiac fibrosis/ remodelling
Cortisol binding in non stressed state:
Lots of cortisol bound to CBG
Most remains in intravascular space
Cortisol binding in stressed state:
CBG cleaved
Increased amount of free cortisol
More movement of cortisol outve blood vessels into cell cytoplasm
Physical Effect of excess ACTH on adrenal glands:
Large adrenal glands (adrenal hyperplasia)
Where are glucocorticoid receptors found?
In pituitary gland and hypothalamus
So negative feedback can be stimulated
What is the effect of general surgery on cortisol levels
Massive increase of cortisol during surgery remains high for a few days (loss of diurnal variation)
Feedback is lost
Stress cytokines repeatedly stimulate CRH and ACTH - increased cortisol
Reduced synthesis and breakdown of CBG
What is the percentage activity of DOC compared with aldosterone?
3%
Regulation of mineralocorticoids via renin-angiotensin aldosterone system:
Juxtaglomerular cells of kidney prod renin due to reduced renal blood pressure
Renin converts angiotensinogen to angiotensin I in liver
Angiotensin I converted to angiotensin II by ACE
Ang II stimulates aldosterone release by binding to AT1 receptors
How does regulation for mineralocorticoids by renin angiotensin aldosterone system (RAAS) increase BP
Angiotensin stimulates aldosterone release by binding to AT1 receptors
Causes sodium and water retention
Increases blood volume
Increases BP
Loss of aldosterone results in lower free liquid
What do aldosterone and cortisol have in common?
Both bind and have equal affinity to mineralocorticoid receptor
Why aren’t mineralocorticoid receptors swamped with cortisol even though it is more abundant than aldosterone?
11Beta- HSD2 (hyrdoxysteroid dehydrogenase 2) enzyme in kidney converts cortisol to cortisone
Cortisone cannot bind to MR
Why does excess liquorice cause mineralocorticoid excess syndrome
Inhibits 11Beta-HSD2 enzyme which converts cortisol to cortisone in the kidney
So more cortisol to bind to MR
Excess activation of MR
What are the major source for androgens in women
Adrenal glands
Connection between adrenal glands and post menopausal women
Glands prod oestrogen precursor in post menopausal
What is Androstenedione?
Androgen
Precursor for testosterone
More androgenic than DHEA but only 1/10th of testosterone
What hormone regulates the production of adrenal androgens
ACTH
How is the adrenal medulla involved in sympathetic release of catecholamines (not essential to life)
Acts as a specialised ganglion
Supplied by sympathetic pre ganglionic neurones
Stimulate chromaffin cells to synthesise and release catecholamines (adrenaline/ noradrenaline)
What has a relatively large effect on the production of catecholamines
High Cortisol has a permissive action on production catecholamines
What is the ratio of adrenaline: noradrenaline produced
80:20
How does the medulla synthesise catecholamines?
Converts tyrosine to catecholamines
What is required for catecholamines synthesis?
Cortisol induction
Sympathetic stimulation
What is the precursor of catecholamines
Tyrosine
What enzyme allows the conversion of tyrosine to DOPA
Tyrosine hydroxylase
Why is sympathetic stimulation required for in catecholamine synthesis
Required to activate dopamine beta-hydroxylase for the conversion of dopamine to noradrenaline
How is adrenaline produced?
Noradrenaline is converted into adrenaline in the presence of cortisol
What receptors do catecholamines act on
Adrenergic receptors
What are the specific types of Adrenergic receptors (SNS) and where do they act
Alpha 1 - in smooth muscle (contraction)
Alpha 2 - in smooth muscle (inhibition of NT)
Beta 1 - heart
Beta 2 - relaxation of smooth muscle in lungs
Beta 3 - relaxation of smooth muscle in bladder
Are catecholamines released via sympathetic or parasympathetic stimulation of the medulla?
Sympathetic
What are the effects of catecholamines
Cause redistribution of circulating volume
Decreased blood flow to digestive, excretory, and reproductive systems
Makes energy available to organs responding to physical activity
Effect of catecholamines on the heart
Increased contractility, blood pressure and heart rate (tachycardia)
Effect of catecholamines on muscles
Increased gluconeogenesis
Effect of catecholamines on liver
Increased gluconeogensis and glucose release
Effect of catecholamines on adipose tissue
Increase lipolysis
Effect of catecholamines on CNS
Increased alertness
Golden rules of endocrinology:
- All things are logical
- Hormones are regulated by feedback
- Think in diagnostic pairs
- Hormone deficiency - stimulation test
- Hormone excess - suppression test
- Always think first, then examine clinically, then measure hormones, then imaging
Symptoms of very low of cortisol:
Weakness and fatigue
Anorexia
Muscle/joints pains
Signs of very low cortisol:
Weight loss
Hyperpigmentation
Hyponatraemia
Hypercalcaemia
Hypoglycaemia
Anaemia
Does ACTH regulate aldosterone production
No
Only regulates Cortisol and androgen production
Regulated via renin-angiotensin system
What is an example of a diagnostic pair
- ACTH and cortisol
Low cortisol and high ACTH means lack of responsiveness of adrenal gland - Aldosterone and renin
Low aldosterone and high renin means lack of responsiveness of adrenal gland
Both adrenal insufficiency
How does adrenal insufficiency lead to hyperpigmentation
Low cortisol levels
So hypothalamus releases lots of CRH and anterior pituitary gland prod lots of ACTH
ACTH lead to an increase in melanin production
What is primary adrenal insufficiency
Adrenal glands are damaged
Cannot produce cortisol, aldosterone and androgen
Increased ACTH and CRH levels
Atrophic and fibrotic adrenal gland
What is secondary adrenal insufficiency
Lack of ACTH prod by anterior PG
Low cortisol and androgen production
Aldosterone prod regulated by renin-angiotensin system
Causes of primary adrenal insufficiency
- Surgical removal of adrenals
- Common cause: auto immune adrenalitis (Addisons Disease)
- Bilateral adrenal haemorrhage
- Congenital adrenal hyperplasia
Differential diagnosis of primary adrenal insufficiency
Antibodies present if autoimmune disease
If no antibodies and patient is male - check for presence of very long chain fatty acids to exclude adrenoleukodystrophy/ adrenolymyloneuopathy
If both negative, do CT scan to exclude bilateral adrenal haemorrhage / TB which can cause adrenal infection
Exclude congenital adrenal hyperplasia by measuring precursor that are accumulating in front of enzymatic block
Cause of secondary adrenal insufficiency
Tumour on PG or hypothalamus - hypopituitarism
Latrogenic: people treated with exogenous glucocorticoids to suppress IMS to treat rheumatoid arteritis/ asthma. Causes secondary AI as synthetic glucocorticoids suppress hypothalamus and PG via negative feedback so ACTH insufficiency. So must switch up medication.
Diagnosis methods for adrenal insufficiency
- Via symptoms and signs and measuring hormone levels
High ACTH (primary) - addisons causes low cortisol levels
Low ACTH (secondary) - When in doubt, stimulation test and short synacthen test
Inject ACTH into blood stream
If adrenal gland fails to respond to exogenous ACTH by producing more cortisol you have adrenal insufficiency
Cortisol drugs replacements for adrenal insufficiency
Hydrocortisone (active cortisol)
Preferred as cortisone has variable effects in patients due to problems with conversion in kidneys
Cortisone acetate (inactive cortisol)
Used due to lack of hydrocortisone
Synthetic cortisol
What enzyme converts cortisone to cortisol
11Beta-HSD 1
What are synthetic versions of cortisol
Prednisolone
Dexamethasone
Advantages of synthetic versions of cortisol
Longer lasting
Stronger binding to glucocorticoid receptors than hydrocortisone
Lower dosage required
Why is a higher dose of inactive forms of cortisol needed?
Inactive forms need to be converted into active form
Not all mass is active hormone
What enzymes convert cortisol into cortisone
11Beta-HSD 2
Therapeutic corticoids doses that are the same as 20mg of hydrocortisone
25mg cortisone acetate
0.25mg dexamethasone
4mg prednisolone
5mg prednisone
Prednisolone is what of prednisone
The active form
Prednisone converted into Prednisolone by 11Beta-HSD 1
What synthetic mineralocorticoid used to treat primary adrenal insufficiency
Fludrocortisone (synthetic aldosterone) - balance sodium and fluids in body
100 µg Fludrocortisone = 40 mg Hydrocortisone
What is Addisons disease?
When Immune system attacks the adrenal glands
Destroys 90% of adrenal cortex
Relationship btw hydrocortisone and fludrocortisone
If daily dose of hydrocortisone is more than 50mg
Fludrocortisone can be paused as hydrocortisone covers the need by binding to MR as well
What receptors does fludrocortisone bind to
Mineralocorticoid receptors
What receptors does hydrocortisone bind to
Mineralocorticoid receptors
And glucocorticoid receptors
Effects of primary adrenal insufficiency on adrenal secretions
Cortisol, aldosterone and androgen secretions are lost
What drugs should a patient with primary adrenal insufficiency take?
-100-250 µg fludrocortisone /day and hydrocortisone
If daily dose for hydrocortisone is above 50mg then don’t have to take FC as hydrocortisone covers the need by binding to MR as well
- (only in primary) DHEA replacement
(If replace hydrocortisone with dexamethasone you need to observe prescribed FC levels
As Dexamethasone is stronger )
Long term treatment for adrenal insufficiency
-Replace missing glucocorticoids with hydrocortisone
15mg AM 10mg PM
-Replace missing mineralocorticoids with Fludrocortisone 100-200 µg/day
- (only in primary) DHEA replace adrenal androgens (in women - low libido and energy)
What is acute adrenal insufficiency
Known as Adrenal crisis
Life threateningly low levels of cortisol
Patient goes into shock
How is adrenal crisis shock treated?
Rehydration with saline infusion
Immediate injection of hydrocortisone 100mg, followed by continuous hydrocortisone infusion 200mg/ 24hrs
Risk factors for adrenal crisis are physical and emotional stress triggers like:
Fever
Hypoglycaemia
Hypotension
Infection
Dehydration
Trauma
Surgery - cortisol levels increase
Cortisol levels should be raised in these situations but cant be
Why do patients with adrenal insufficiency carry a steroid card/ medic alert bracelet?
To identify their exogenous steroid dependence to HCP
What is the routine patients with adrenal insufficiency have to follow?
Sick day rule 1 - moderate stress
In case of fever, an infection requiring antibiotics or minor surgery MUST double the course of daily glucocorticoids
Sick day rule 2 - severe stress
From trauma, major surgery, persistent vomiting, colonoscopy, active labour an immediate injection of 100mg hydrocortisone is required, followed by 200mg of hydrocortisone /24hrs
What tool must all adrenal insufficient patients have
Hydrocortisone emergency self injection kit
What are the major causes of death in adrenal insufficient patients?
- Doctor and nurse dont know how to treat it so deny hydrocortisone injection during crisis
- Patient reluctant to self inject glucocorticoids
Does hydrocortisone affect pregnant women
No as it cannot cross placenta
What is the syndrome for excess glucocorticoid
Cushing’s syndrome
Clinical features specific to Cushing’s syndrome:
-Purple stretch marks due to rapid weight gain and more sensitive skin
-Proximal myopathy: difficult climbing stairs/ getting up from chair due to muscle atrophy
-Osteoporosis with vertebral fractures in the lumbar spine (loss in height)
Clinical features of Cushing’s syndrome that are common but not specific
Central obesity
Moon face
Hypertension
Buffalo hump
Impaired glucose tolerance
Decreased liner growth in children - weight gain and decreasing growth velocity
Cause of Cushing’s syndrome?
Iatrogenic - prolonged overexposure to synthetic corticosteroids during treatment e.g. of an autoimmune disease
ACTH dependant
- Cushings disease: Tumour of the pituitary, overproducing ACTH
- Ectopic Cushings: ACTH tumour outside PG
ACTH independent
- Adrenal Cushings Syndrome (adrenocortical adenoma/ carcinoma results in cortisol over production)
Examples of Ectopic Cushings
Small cell lung carcinoma
Carcinoid - slow growing type of neuroendocrine tumour
Main method of diagnosis of Cushing’s syndrome
Dexamethasone overnight suppression test DST
1mg dexamethasone given at night
Binds to hypothalamus and PG
Next morning take blood for serum cortisol
In healthy people cortisol will be less than 50nmol/L bcs endogenous cortisol suppressed
Syndrome: cortisol secretion is autonomous (due to tumour) and not responsive to feedback so should remain high
What is the healthy serum cortisol level for a DST
Less than 50nmol/L
Other methods of diagnosis of Cushing’s syndrome
- 24hr urinary free cortisol (>130ug/24h)
- Midnight cortisol via saliva/ serum
Cortisol very low at night but with cushings can be high
Why is there no need for aldosterone replacement with secondary adrenal insufficiency
Secondary AI - adrenal glands are undamaged and normal
HPA axis usually damaged in secondary AI but doesn’t control aldosterone secretions
Renin angiotensin aldosterone systems does
So Aldosterone secretions unaffected
What is HPA axis
Hypothalamic-pituitary-adrenal axis
Controls cortisol and androgen secretions
What is the strongest synthetic glucocorticoid and why
Dexamethasone
Only binds to glucocorticoid receptors not mineralocorticoid receptors
Symptoms of too little aldosterone
Gastrointestinal
Nausea, vomiting, abdominal pain
Salt cravings
Postural dizziness
Symptoms of too little DHEA (androgens)
Loss of libido (sex drive)
Signs of too little aldosterone
Hypotension
Hyponatraemia - low Na+
Hyperkalaemia - high K+
Uraemia
Signs of too little DHEA (androgens)
Loss of pubic hair (women)
Normal Na+ levels
134-146 mmol/L
Normal K+ levels
3.4-5.2 mmol/L
Normal levels of Urea in blood
3.2-7.6 mmol/L
Normal levels for cortisol:
Above 150 nmol/L
How many amino acids does ACTH1-39 (adrenocorticotropic hormone)
39
What is ACTH1-24
Artificially synthesised ACTH
24 amino acid peptide
250ug of ACTH1-24 should produce how much cortisol?
More than 400-500 nmol/L
How do ACTH levels differentiate between primary and secondary AI
High ACTH - adrenal problem and pituitary gland fine. Primary AI
Low ACTH - pituitary gland problem. Secondary AI.
What is Cushing’s disease
Known as a ACTH dependant subdivision of Cushing’s syndrome
Due to pituitary tumour which causes increase in ACTH secretion
Differential diagnosis of Cushings (what is the possible cause)
ACTH dependant
Cushing’s disease: pituitary ACTH producing tumour
Ectopic ACTH source
ACTH independent
Adrenal cortisol-producing tumour
Exogenous source of cortisol (medication)
How to perform differential diagnosis of cushings?
Biochemistry before imaging
9am plasma ACTH levels
ACTH suppressed = adrenal
ACTH normal/ high = pituitary/ ectopic
Pituitary/ ectopic?
High dose Dex test - only PG tumour responds
CRH test - only PG tumour responds
Inferior petrosal sinus sampling (IPSS)
Lastly, Imaging (CT adrenals/ MRI pituitary)
Treatment of Cushing’s syndrome
Surgery:
- Cushings disease- Transsphenoidal surgery
- Bilateral adrenalectomy (=> cave Nelson’s syndrome)
- Laparascopic adrenalectomy for adrenal adenoma
- Open adrenalectomy for adrenocortical carcinoma
Drugs:
block cortisol-producing adrenal enzymes (metyrapone,
ketoconazol, etomidate)
– block the glucocorticoid receptor (RU486)
– disrupt adrenal redox balance and thereby steroidogenesis and cell proliferation (mitotane)
Symptoms of phaechromocytoma
Palpitations
Raised blood pressure
Headaches
Symptoms of Cushing
Rounded puffy face
Buffalo hump
Purple stretch marks striae
Reduced sex drive
Skin bruises easily
Symptoms of conns syndrome
Excessive thirst
Fatigue
Frequent urination
Headache
Muscle cramps weakness
