WEEK 8 Flashcards
What is steroidogenesis?
Production of steroids via pathways of reactions involving enzymes-cholesterol is extremely important
What are corticosteroids?
Lipid soluble molecules that bind to specific intracellular receptors, altering gene transcription
Describe the process that causes cortisol to cause its effect on target cells
Cortisol moves into the cell, binds to cortisol receptor which causes HSP (heat shock protein) release, causes dimerisation of receptor, receptor moves into nucleus and activates GRE (glucocorticoid response element), transcription occurs with help from coactivators (increased RoT)
What is an example of glucocorticoids?
Cortisol
Where are glucocorticoids produced and released?
Zona Fasciculata (middle)
What are the actions of glucocorticoids?
Increase glucose metabolism (augment gluconeogenesis, amino acid generation and increases lipolysis)
Maintenance of circulation (vascular tone and salt+water balance)
Immunomodulation (dampens immune response)
=importance in stress response
How is the large proportion of glucocorticoids transported?
Bound to proteins (90% to Corticosteroid-Binding Globulin, 5% to albumin, 5% free=bioavailable)
In clinical practice, how are glucocorticoid levels measured?
Using ‘total’ rather than ‘free’ circulating glucocorticoid
What happens to CBG levels due to inflammation?
Decrease due to being cleaved, releasing cortisol and therefore increasing ‘free’ cortisol levels
Describe the hypothalamic-pituitary-adrenal (HPA) axis with respect to cortisol and stress
‘Stress’ cytokines cause neurotransmitters to cause CRH secretion from hypothalamus, ACTH secreted from anterior pituitary gland, cortisol secreted from zona fasciculata which inhibits hypothalamus and pituitary gland
What effect does ACTH deficiency have on adrenal gland size?
Adrenal atrophy (shrinking)
What effect does ACTH excess have on adrenal gland size?
Adrenal hyperplasia (enlargement)
What is cortisol circadian rhythm?
Daily rhythm with low cortisol levels at night, massive increase in the morning, then decrease until meals where levels rise
Define stress
The sum of the body’s responses to adverse stimuli
What is the effect of stress on cortisol levels?
Increase and disruption to Circadian/diurnal rhythm
Give 6 examples of stress
1) infection
2) trauma
3) haemorrhage
4) medical illness
5) psychological
6) exercise/exhaustion
Where are mineralocorticoids produced and released?
Zona Glomerulosa (outermost)
What are the two main mineralocorticoids?
Aldosterone and DOC (11-deoxycorticosterone)
What is the main action of mineralocorticoids?
Regulation of salt and water balance in kidney, colon, pancreas, salivary and sweat glands
Where is the site of action of aldosterone?
Distal convoluted tubule of kidneys
What are two non-classical effects of aldosterone?
Myocardial collagen production
Role in cardiac fibrosis/remodelling
What is the specific action of aldosterone?
Reabsorption of Na+ and water into the blood, causing K+ secretion into urine which increases circulating blood volume
How does aldosterone cause its action?
Binding to mineralocorticoid receptors (MR) on principal cells in DCT, increasing permeability of apical (luminal) membrane to K+ and Na+ and activates basolateral Na+/K+ pump
Describe the feedback loop of the renin-angiotensin-androgen-system (RAAS)
Aldosterone stimulates renal perfusion pressure at the vascular level of kidneys, this suppresses renin release from the juxtaglomerular cells, renin stimulates angiotensin->angiotensin 1 (in liver), angiotensin 1->angiotensin 2 via ACE (angiotensin-converting enzyme), A2 stimulates aldosterone release-increasing circulating blood volume and therefore renal perfusion
What is meant by mineralocorticoid receptor specificity?
Both cortisol and aldosterone have an equal affinity to mineralocorticoid receptor
How is cortisol changed to not have affinity to MRs and how is this inhibited?
Cortisol->Cortisone via 11beta-HSD2 enzyme
Inhibition of 11beta-HSD2 due to liquorice ingestion
Where are adrenal androgens produced and released?
Zona Reticularis (innermost)
What is the most abundant adrenal steroid?
DHEA (dehydroepiandrosterone)
Give four examples of adrenal androgens
Testosterone
DHEA
Androstenedione
Oestrogen (women)
What are the three major actions of androgens?
1) Increased frequency of sexual thought
2) Increased sexual interest
3) Increased satisfaction with physical and mental aspects of sex life
How are adrenal androgens regulated?
ACTH rather than gonadotropins (FSH/LH)
Where do androgens act?
Ovary theca cells and testis leydig cells and in peripheral tissues
How is the Adrenal Medulla different from the Adrenal Cortex?
Influenced by sympathetic pre-ganglionic innervation via the autonomic nervous system rather than hormones
What does the Adrenal Medulla synthesise and release?
Catecholamines (main site for adrenaline synthesis)
What is the relative production of catecholamines?
80% adrenaline/epinephrine to 20% noradrenaline/norepinephrine
What is normal catecholamine synthesis reliant on?
High cortisol levels (permissive effect)
What is the relationship between adrenaline and noradrenaline?
Adrenaline is formed from noradrenaline metabolism via phenylethanolamine N-methyltransferase
What is the result of sympathetic stimulation on the Adrenal Medulla?
stimulation of: tyrosine hydroxylase (tyrosine->DOPA) dopamine beta-hydroxylase (dopamine->noradrenaline)
What is the result of cortisol induction on the Adrenal Medulla?
stimulation of:
tyrosine hydroxylase (tyrosine->DOPA)
phenylethanolamine N-methyltransferase (noradrenaline->adrenaline)
Why do the actions of catecholamines differ?
Due to different adrenergic receptors
What is the main action of catecholamines?
“fight or flight” preparing the body for physical activity via redistribution of circulating blood volume from digestive/excretory/reproductive systems
What is the action of alpha1 adrenergic receptors?
smooth muscle contraction
What is the action of alpha2 adrenergic receptors?
smooth muscle contraction in pancreas
inhibits transmitter release
Where is the action of beta1 adrenergic receptors?
The heart
What is the action of beta2 adrenergic receptors?
smooth muscle relaxation in the bladder, uterus and bronchi
Define Adrenal insufficiency?
Where the adrenal glands fail to produce enough hormones (mainly cortisol but also aldosterone and DHEA)
What are the major symptoms of adrenal insufficiency?
Fatigue Weakness Nausea and vomiting Anorexia Abdominal pain Loss of libido (women)
What are the signs of adrenal insufficiency?
Weight loss Hyperpigmentation (patches of darker skin due to increased melanocytes in areas of friction) Hypotension Vitiligo (white integumental patches) Hyponatremia (low Na+ levels in blood) Hyperkalaemia (high K+ levels in blood) Hypoglycaemia Uraemia (raised blood urea) Anaemia (low level of RBCs/haemoglobin) Loss of pubic hair (women)
What is adrenal insufficiency also known as?
Addison’s disease/hypoadrenalism
What are the main causes of primary adrenal insufficiency?
Autoimmune adrenalitis (Pts often have other autoimmune conditions-autoimmune polyendocrine syndrome)-most frequent
Tuberculosis
Congenital adrenal hyperplasia
What are the lesser causes of primary adrenal insufficiency?
Bilateral adrenalectomy
Bilateral metastasis destroying adrenal glands
Bilateral adrenal haemorrhage
Drugs
What are the three stages of diagnosing primary adrenal insufficiency?
Indicative signs
Lab tests
The Short Synacthen Test (SST)
What would the results of the lab test show if someone had primary adrenal insufficiency?
Low serum Na+
High serum K+
High serum urea
Low serum cortisol, high serum ACTH (diagnostic pair)
Low serum aldosterone, high serum renin (diagnostic pair)
What is the Short Synacthen Test (SST)?
250micrograms of ACTH(1-24) (SYNACTHEN)-i.v. or i.m.
measure serum cortisol 30 mins before and after
expected cortisol increase >400-500mmol/L
What are the main causes of secondary adrenal insufficiency?
Hypopituitarism (low ACTH levels)
Iatrogenic due to exogenous glucocorticoid treatment
What is the difference between primary and secondary adrenal insufficiency?
Primary=cortisol not produced by adrenal glands but ACTH produced by pituitary
Secondary=ACTH not produced by pituitary gland
How would you differentiate diagnosis of primary adrenal insufficiency?
if antibody negative and male patient: measure very long chain fatty acids (exclude adrenoleukodystrophy/adrenomyeloneuropathy)
if both negative: CT adrenals and exclude TB
exclude congenital adrenal hyperplasia
How would you differentiate diagnosis of secondary adrenal insufficiency?
check if RAAS is intact: no aldosterone replacement needed
check if other hypothalamic-pituitary axes are affected
What are the two functions of 11beta-HSD2?
1) Converts cortisol/hydrocortisone (active) to cortisone/cortisone acetate (inactive)
2) Converts prednisolone (active) to prednisone (inactive)
What are the two functions of 11beta-HSD1?
1) Converts cortisone/cortisone acetate (inactive) to cortisol/hydrocortisone (active)
2) Converts prednisone (inactive) to prednisolone (active)
Why is the active form, cortisol/hydrocortisone, preferred over cortisol/cortisone acetate?
Variable 11beta-HSD1 activity
What is the effect of using the active form (cortisol) over the inactive form (cortisone)?
Lower cortisol dose required
What is the effect of using the active form (prednisolone) over the inactive form (prednisone)?
Lower prednisolone dose required
Why are prednisolone and dexamethasone (synthetic) longer-acting and what is the result of this?
Greater affinity to glucocorticoid (GC) receptor, therefore a lower dose is required
What are therapeutic corticosteroids?
Corticosteroids given as replacement therapy (hydrocortisone/prednisolone/dexamethasone)
What is 100 mineralocorticoid units (MCU) equivalent to?
100micrograms of fludrocortisone (aldosterone equivalent)
40mg of hydrocortisone
What should be paused if daily hydrocortisone dose is greater than 50mg?
Fludrocortisone (aldosterone equivalent)
How does dexamethasone differ from other corticosteroids given therapeutically?
It has no mineralocorticoid activity
What is the long-term treatment of adrenal insufficiency?
Replace glucocorticoid-hydrocortisone: 15mg AM/10mg PM
Replace mineralocorticoid-fludrocortisone: 100-200micrograms/day (only in primary adrenal insufficiency)
Adrenal androgens-DHEA (in women with low libido/energy)
What is the acute treatment of adrenal insufficiency (in medical emergency)?
Treat shock: generous saline infusion, immediate injection of hydrocortisone (100mg) followed by continuous hydrocortisone infusion (200mg/24hr)
What is the first step in crisis prevention in adrenal insufficiency patients?
Steroid card and/or medic-alert bracelet to identify exogenous steroid dependence
What is sick day rule 1 treatment in crisis prevention in adrenal insufficiency patients?
Double daily glucocorticoid dose
What is sick day rule 2 treatment in crisis prevention in adrenal insufficiency patients?
100mg hydrocortisone (i.v.), followed by continuous infusion of 200mg/24hr hydrocortisone and fluid resuscitation
What is the cause of sick day rule 1?
Moderate stress-fever, infection requiring antibiotics, minor surgery under LA
What is the cause of sick day rule 2?
Severe stress-trauma, major surgery, persistent vomiting, colonoscopy, active labour
What is adrenal crisis?
A life-threatening medical emergency caused by insufficient cortisol levels
What are the signs and symptoms of adrenal crisis?
Nausea and vomiting Severe weakness Reduced consciousness Syncope (fainting) Fever Confusion Hypovolemic shock Abdominal guarding
What is the follow up after adrenal crisis?
6-12 monthly evaluations of signs and symptoms:
- periodical reinforcement of sick day rules
- check steroid card, emergency kit and injection training
- measure body weight and blood pressure
- blood tests: Na+/K+/renin
- screen for other autoimmune conditions in patients with autoimmune adrenalitis
Define Cushing’s syndrome
Too much cortisol
Give four examples of more Cushing-specific signs and symptoms
Easy bruising
Reddish/purple stretch marks
Proximal myopathy (gluteal and femoral muscles)
Central obesity
Give five examples of less Cushing-specific signs and symptoms
Depression Hair thinning Menstrual irregularity Poor wound healing Hypertension
Give three examples of ACTH-dependent Cushing syndrome signs and symptoms
Acne
Hirsutism (male hair growth in females)
Hyperpigmentation
Give two examples of generalised signs and symptoms of Cushing’s syndrome
Weight gain
Fatigue
What are the causes of too much glucocorticoid?
Iatrogenic (exogenous glucocorticoid use)
ACTH-dependent Cushing’s syndrome
ACTH-independent Cushing’s syndrome
What are the two variations of ACTH-dependent Cushing’s syndrome?
1) Pituitary-dependent Cushing’s syndrome=Pituitary adenoma
2) Ectopic Cushing’s due to ectopic ACTH secretion=small cell lung carcinoma/carcinoids
What is the cause of ACTH-independent Cushing’s syndrome?
Adrenocortical adenoma/carcinoma
What are three methods of diagnosing Cushing’s syndrome?
1) Dexamethasone overnight suppression test
2) 24hr urinary free cortisol (>130micrograms/24hr)
3) “midnight cortisol” (above late night reference range)
What is the process of the dexamethasone overnight suppression test?
1mg dexamethasone tablet at 11pm, measure serum cortisol at 8-9am, cortisol levels remain high (>50nmol/L)
What is the role of dexamethasone in the dexamethasone overnight suppression test?
It mimics cortisol effects by binding to GC receptors in hypothalamus and pituitary gland which causes downregulation of ACTH and suppression of endogenous cortisol->Cushing’s patients not responsive to this suppression
What is the first stage of differential diagnosis for Cushing’s syndrome?
9am Plasma ACTH
ACTH suppressed=adrenal
ACTH normal/high=pituitary/ectopic
What is the second stage of differential diagnosis for Cushing’s syndrome?
High Dose Dex Test and CRH test=pituitary adenoma responds, ectopic tumours don’t
Inferior petrosal sinus sampling
What happens when response to High Dose Dex Test and CRH test occurs?
MRI to identify pituitary adenoma
What happens when no response to High Dose Dex Test and CRH test occurs?
CT scan of chest and abdomen to identify ectopic tumours
What is the third stage of differential diagnosis for Cushing’s syndrome?
Imaging-CT adrenals/MRI pituitary
What are the surgical treatments for Cushing’s syndrome?
Pituitary=transsphenoidal surgery
Bilateral adrenalectomy:
Adrenal adenoma=laparoscopic adrenalectomy
Adrenocortical adenoma=open adrenalectomy
What are the actions of drug treatments for Cushing’s syndrome?
Block cortisol-producing adrenal enzymes
Block glucocorticoid receptor (GC antagonist)
Disrupt adrenal redox balance and thereby steroidogenesis and cell proliferation
What is the treatment for Cushing’s syndrome due to exogenous steroid use?
Causative agent slowly withdrawn
What is the follow up after Cushing’s syndrome treatment?
Surgery: review regularly until HPA axis recovery and monitor for recurrence
Non-surgical Rx: review regularly for safety and efficacy
Ensure CV, metabolism and bone health are protected long-term
