Lecture 24 - Adrenal Glands Flashcards
Where do the adrenal glands sit?
on top of the kidneys
What do the adrenal glands consist of?
an outer layer called the cortex and an inner layer called the medulla
What is each adrenal gland essentially?
two glands in one because the cortex and the medulla and functionally and structurally different
What are the 3 layers of the adrenal gland?
outer = zona glomerulosa
middle = zona fasciculata
inner = zona reticularis
What do the cells in the 3 layers contain?
different compliments of enzymes involved in the synthesis of adrenal hormones
What are adrenocorticoids?
refers to their site of origin (adrenal cortex) and steroid nature
mineralocorticoids and glucocorticoids
Mineralocorticoids?
primarily aldosterone
secreted by cells in the zona glomerulosa
What do mineralocorticoids do?
promote Na+ resorption and K+ excretion in kidneys
Glucocorticoids?
primarily cortisol
secreted by cells in the zona fasciculata
What do glucocorticoids do?
regulate the body’s response to stress
regulate glucose levels and have anti inflammatory effects as well
What do mineralocorticoids affect?
water and electrolyte balance
When is there overlap of activity of hormones?
when their structures are similar
Why are synthetic steroids constructed?
to enhance the mineralocorticoid and glucocorticoid activity of the drug
Sex hormones?
primarily androgens
zona reticularis and fasciculata
What do sex hormones regulate?
reproductive function
What do adrenal androgens stimulate in females?
the sex drive
Where else are sex hormones produced?
gonads
What does the adrenal medulla contain?
chromaffin cells which secrete catecholamines
Adrenal medulla hormones?
80% adrenaline
20% noradrenaline
> 1% dopamine
What is the primary stimulus for adrenal medulla hormones?
neural stimulus
What is cortisone?
a metabolite or synthetic form of cortisol
What is cortisol secretion controlled by?
the hypothalamic-pituitary-adrenal axis
What does the hypothalamus secrete?
Corticotrophin releasing hormone (CRH)
What does CRH do?
Acts on the anterior pituitary
What does the anterior pituitary secrete?
adrenocorticotrophic hormone (ACTH)
What does ACTH do?
acts on the adrenal cortex to stimulate secretion of cortisol
When can the amount of cortisol secreted be increased?
under situations of increased stress such as trauma, surgery, sleep deprivation
What do elevations in cortisol levels do?
have a negative feedback effect on the hypothalamus and the anterior pituitary
As the blood level of cortisol increases it…?
inhibits the secretion of CRH and ACTH
What do cortisol levels show?
diurnal variation
daily cycle
When do cortisol levels peak?
in the morning when we wake up
When are cortisol levels at their lowest?
at night (midnight)
What is urinary free cortisol?
the blood free cortisol that is circulated and subsequently filtered through the glomerulus into urine during a 24 hour period
What must be done to get an accurate representation of cortisol levels?
urine must be collected over a 24 hour period
How is homeostasis maintained?
by the negative feedback mechanism
What are stressors most effective in stimulating cortisol secretion?
noxious stimuli such as surgery, trauma, infection, shock, pain, extreme temps, anxiety
Why is cortisol sometimes called the stress hormone?
it regulates the changes in the body that occur in response to stress
What is cortisol?
the main glucocorticoid in humans
Where are the receptors for cortisol?
found in many tissues
they are steroid hormones and can cross the cell membranes
intracellular receptors
What do most of the effects of cortisol involve?
interactions with intracellular receptors, the complex then enters the nucleus and acts as a transcription factor
What are the effects of cortisol?
increase circulating glucose levels
maintain normal responsiveness of blood vessels to vasoconstrictive stimuli
What other areas does cortisol have effects on?
immune system, nervous system and kidneys
What are the pharmacological actions of cortisol?
anti-inflammatory and immunosuppressant
When are glucocorticoids best known for pharmacological effects?
when administered as doses that exceed the normal physiological levels, at these dosages they have more potent effects
What are the primary actions of cortisol?
to maintain normal concentrations of the enzymes necessary for the breakdown of proteins, fats and glycogen and the conversion of amino acids to glucose in the liver
What is cortisol necessary for survival during?
prolonged fasting periods
In the absence of cortisol what happens?
the resulting decrease in gluconeogenesis can lead to death by hypoglycaemia once glycogen stores have been depleted
Tissue effects of cortisol?
decrease glucose uptake and amino acid uptake
Adipose tissues effects of cortisol?
increase lipolysis
Muscle and other tissue effects of cortisol?
increase protein breakdown and decrease protein synthesis
Liver effects of cortisol?
increased gluconeogenesis
What is the presence of glucocorticoids essential to?
the body’s ability to mobilise fuels in response to signals from other hormones e.g. glucagon and insulin
Generally cortisol causes?
increase plasma levels of glucose, fatty acids and amino acids
What is transactivation?
the glucocorticoid receptor forms a homodimer and it binds to specific DNA responsive elements on the gene, activating gene transcription
What is transrepression?
glucocorticoid receptor complexes with the other transcription factors and prevent them from binding to target genes and expressing genes they would normally up regulate
What is cortisol an agonist for?
the glucocorticoid receptor
When is the glucocorticoid receptor in its active form?
when it forms a complex with heat shock proteins
What happens to the glucocorticoid receptor once it has had its effect?
it is exported back into the cytoplasm of the cell and forms a complex with the heat shock proteins again and waits to be reactivated
What is Addison’s disease?
adrenocortical insufficiency
What is Addison’s disease due to?
destruction or dysfunction of the entire adrenal cortex
What does Addison’s disease affect?
glucocorticoid and mineralocorticoid function
When does the onset of Addison’s disease occur?
when 90% or more of both adrenal cortices are destroyed
Prevalence of Addison’s disease?
40-60 cases per 1 million
Who is Addison’s disease most common in?
adults aged 30-50
Symptoms of Addison’s disease?
darkening areas of the skin (hyperpigmentation)
extreme fatigue
unintentional weight loss and decreased appetite
low blood pressure (light headedness and fainting)
GI disturbance
salt craving
low blood glucose
Why does Addison’s disease cause hyperpigmentation?
due to increased level of adrenal corticotrophic hormone acting on melanocytes increasing production of melanin
What does the salt craving in addison’s disease relate to?
mineralocorticoid deficiency
What do patients with Addison’s disease usually present with?
glucocorticoid or mineralocorticoid deficiency
What is Addison’s disease classed as?
primary adrenal insufficiency
What causes Addison’s disease?
autoimmune destruction of the gland (85% of cases)
adrenal glands are damaged and can no longer produce sufficient cortisol, aldosterone secretion is often insufficient as well
What else can cause Addison’s disease?
infections (tuberculosis, HIV, syphilis, cryptococci)
invasion (neoplastic, fibrosis, sarcoidosis, amyloidosis)
haemorrhage (waterhouse-friderichsen syndrome)
What is adrenal gland failure in haemorrhage caused by?
bleeding in the gland itself
commonly associated with severe bacterial infection of the adrenal gland
What are the levels of hormones like in addison’s disease?
decreased secretion of cortisol causes a lack of negative feedback
this means there is increased secretion of corticotrophin releasing hormone and adrenocorticotrophic hormone
Why is there decreased cortisol secretion in Addison’s disease?
the adrenal cortex has been completely destroyed
Treatment of Addison’s disease?
hydrocortisone (sometimes longer acting prednisolone or dexamethasone)
fludrocortisone (mineralocorticoid)
What is needed in treatment of Addison’s disease?
glucocorticoid and mineralocorticoid replacement
Dose of fludrocortisone?
50mcg - 300mcg
Dose of hydrocortisone?
15-30mg given as a divided dose e.g. 10mg on waking, 5mg at noon, 5mg in early evening
Why is hydrocortisone given in divided doses?
so the glucocorticoid replacement resembles the natural cycle release
What does the dose depend on?
the body weight, absorption and metabolism
What might require an increased glucocorticoid dose?
intercurrent illness (infections)
dose should be doubles
if vomiting/diarrhoea, parenteral administration should be given
How long is the treatment of Addison’s disease?
life long
Secondary adrenal insufficiency?
lack of ACTH secretion from pituitary
Tertiary adrenal insufficiency?
lack of corticotrophin releasing hormone secretion from hypothalamus
Adrenal gland function in secondary and tertiary?
adrenal gland is functioning properly, there is just a lack of stimulation
What do patients with secondary and tertiary not show?
hyperpigmentation or cravings for salt
What can secondary or tertiary adrenal insufficiency also be due to?
glucocorticoid drug therapy or if glucocorticoid medication is stopped too abruptly
suppression of the hypothalamus-pituitary-adrenal axis by long term corticosteroid use in patients
Na+ and K+ levels in secondary and teriary?
normal
Treatment for secondary and tertiary adrenal insufficiency?
glucocorticoid (hydrocortisone) but mineralocorticoid is unnecessary
Why is treatment with mineralocorticoid unnecessary in S & T?
the adrenal gland itself is working fine
Why can the adrenal gland shrink?
if ACTH is reduced, the production of cortisol will be reduced, eventually resulting in shrinking of adrenal glands
Therapeutic use of glucocorticoids?
replacement therapy in corticosteroid insufficiency
Use of glucocorticoids in acute inflammatory disease?
bronchial asthma
anaphylaxis and angioedema
acute fibrosing alveolitis
Use of glucocorticoids in chronic inflammatory disease?
connective tissue disease (systemic lupus)
renal disorders (glomerulonephritis)
hepatic disorders (chronic active hepatitis)
GI disorders (IBD)
use of glucocorticoids in neoplastic disease?
myeloma
lymphomas
lymphocytic leukaemias
Use of glucocorticoids in miscellaneous disorders?
bells palsy
sarcoidosis
organ transplantation (as an immunosuppressant)
What do glucocorticoid drugs do?
they suppress the hypothalamus and anterior pituitary
What does suppression of the hypothalamus and anterior pituitary do?
reduces CRH and ACTH levels
How long can it take the hypothalamic-pituitary-adrenal axis to return to normal?
a year
Examples of glucocorticoid drugs?
prednisolone
dexamethasone
hydrocortisone
beclomethasone
What is a glucocorticoid withdrawal regime?
no single withdrawal regime
What does a withdrawal regime depend on?
patients response to withdrawal, disease being treated and the intended duration of treatment
What courses of oral corticosteroids can be stopped abruptly?
short courses (<3 weeks)
What should gradual withdrawal be considered for?
those who have received >3 weeks treatment
received repeated courses of treatment
received >40mg of prednisolone daily >1 week
What happens if withdrawal symptoms are reported?
a higher dose is resumed and the withdrawal is continued at a slower rate
What are patients whose medication is stopped abruptly or not increase during illness at risk of?
adrenal crisis
What is adrenal crisis?
sudden severe worsening symptoms of adrenal insufficiency symptoms
Symptoms of adrenal crisis?
sudden, severe pain in the lower back, abdomen or legs
severe vomiting and diarrhoea
dehydration
low blood pressure
loss of consciousness
Why is it important a patient with adrenal crisis gets treated immediately?
it can result in death
What should a patient with adrenal insufficiency wear?
a medical alert bracelet
What is Cushing’s syndrome?
hypersecretion of cortisol (hypercortisolism)
patients have too much cortisol in the body
What can long term elevations of cortisol do?
have harmful effects on many organ systems throughout the body
What is Cushing’s syndrome a result of?
prolonged exposure to elevated levels of cortisol in the body
What can Cushing’s syndrome cause?
metabolic complications - type 2 diabetes (insulin resistance)
excessive bone resorption (osteoporosis)
hypertension
Symptoms of Cushing’s syndrome?
moon face
bruisability
red striation
pendulous abdomen
poor wound healing
red cheeks
fat pads
thin skin
higher blood pressure
thin arms and legs
Most specific symptoms of Cushing’s syndrome?
bruising easily, muscle weakness and ruddy complexion
What causes 65-70% of Cushing’s syndrome cases?
pituitary tumour leading to increased secretion of adrencorticotrophic hormone (CUSHINGS DISEASE)
What causes 15-20% of Cushing’s syndrome cases?
adrenocortical tumours (benign or malignant) or bilateral adrenal hyperplasia or dysplasia
(tumour within the adrenal gland itself)
What causes 10-15% of Cushing’s syndrome cases?
tumours external to the hypothalamic-pituitary-adrenal axis (ectopic adrenocorticotrophic hormone secretion)
Adrenocorticotrophic (ACTH) dependent Cushing’s syndrome?
body is making too much ACTH
due to pituitary tumour or ectopic tumour producing ACTH (tumour in another part of the body)
Adrenocorticotrophic independent Cushing’s syndrome?
ACTH level is low due to negative feedback
adrenal glands are making too much cortisol by itself
due to adrenal tumour or adrenal hyperplasia
What type of cushing’s syndrome is typically seen in pratice?
Iatrogenic (drug related or exogenous)
What other treatment can cause Cushing’s syndrome?
glucocorticoid treatment
prednisolone
hydrocortisone
dexamethasone
Route of administration causing cushing’s syndrome?
occurs irrespective of route
route does not matter
What type of treatment can cause Cushing’s syndrome?
prolonged and use of potent drugs
What are glucocorticoids metabolised by?
CYP450 enzymes
What is CYP3A4 important for?
metabolism or cortisol and glucocorticoids
What can drugs that inhibit CYP450 enzymes do?
prolong the action of glucocorticoids (itraconazole, ritonavir, antidepressants)
these may decrease metabolism of cortisol and cause Cushing’s syndrome
What are cortisol and other glucocorticoids?
CYP3A4 inducers, which means they could increase the metabolism of other drugs being taken concurrently
Surgery to treat Cushing’s syndrome?
removal of pituitary gland (or ectopic source of ACTH)
removal of adrenal glands
When might surgery be an option?
in cases of bilateral adrenal hyperplasia - bilateral adrenalectomy might be used
What can surgery result in?
adrenal insufficiency and require lifelong hormone replacement therapy
What is an effective treatment of Cushing’s disease?
reducing the size of the pituitary gland
Treatment for drug induced Cushing’s disease?
gradual withdrawal for the causative drug
aim to discontinue the use of the causative drug if possible
When surgery cannot be done or is unsuccessful what should be used as treatment?
medication
this often occurs with ectopic adrenocortiotrophic hormone or metastatic adrenal carcinoma
What is mifepristone (RU486)?
a high affinity non selective glucocorticoid receptor antagonist
What can mifepristone do?
restore glucose tolerance (60%) and lower blood pressure (43%)
DOESNT REDUCE CORTISOL LEVELS
What are the goals of treating Cushing’s syndrome?
reversal of clinical features, normalisation of the cortisol levels and long term control without recurrence
What is metyrapone?
a drug that inhibits 11-beta-hydroxylase enzyme
What does 11beta-hydroxylase do?
converts 11-deoxycortisol to cortisol
What does inhibiting 11beta-hydroxylase do?
reduced body’s ability to produce cortisol
What is metyrapone effective for?
short and long term treatment of Cushing’s syndrome
What does metyrapone require?
dose titration and careful clinical and biochemical monitoring
disturbances of K+ levels were reported
What are the side effects of metyrapone?
primarily GI but long term use has been associated with hirsutism and hypertension
What is another 11 beta hydroxylase inhibitor currently undergoing clinical trial?
LCI1699
