A. ADRENAL GLAND AND HORMONES Flashcards
how many adrenal glands do we have
2 - sit on top of kidneys
2 main parts of adrenal gland
- outer cortex
- inner medulla
where are catecholamines released from
adrenal medulla
examples of catecholamines
- adrenaline (fight or flight - speed up heart rate)
- noradrenaline
- dopamine
where are adrenal steroid hormones released from
adrenal cortex
examples of adrenal steroid hormones
- glucocorticoids (gluco = involved in glucose metabolism, corticoids = cortex) eg - cortisol
- mineralocorticoids (mineral = electrolytes) eg - aldosterone
- weak androgens (like male sex hormones but weaker) eg - dehydroepiandrosterone and androstenedione
what is the name of the endocrine axis relating to adrenal gland
hypothalamus-pituitary-adrenal axis
what hormone is the central regulator of the hypothalamic-pituitary-adrenal axis
CRH = corticotropin-releasing hormone released by hypothalamus (+ve)
what hormone is the released by anterior pituitary in HPA axis
ACTH = Adrenocorticotropic hormone (+ve)
what activates the feedback loop in the HPA axis and reduce cortisol production
exogenous glucocorticoids
what is the only adrenal steroid hormone involved in feedback control
glucocorticoids ie - cortisol
(androgens and aldosterone regulated by ACTH (and other unknown factors), but no feedback on CRH/ACTH)
what is aldosterone secretion stimulated by
- increased plasma potassium levels and angiotensin II (largely independent of ACTH)
what is the renin-angiotensin-aldosterone system (RAAs)
- critical regulator of blood volume, electrolyte balance and systemic vascular resistance
- aldosterone is a part of the RAAs
what effects does aldosterone have on the kidney
- stimulates reabsorption of sodium and water into blood from filtrate causing an increase in blood volume
- causes increased secretion (excretion) of potassium during formation of urine (lost in urine)
what effect does angiotensin II have on blood vessels
vasoconstriction
main effects of activation of RAAs
- increases vascular resistance
- increased blood volume
= increased BP
where does aldosterone principally act
- DCT and collecting duct of kidney
what is Conn’s syndrome
- excess aldosterone causing hypokalaemia and hypertension
- due to adrenal tumour or primary hyperaldosteronism
- accounts for 1% of all causes of hypertension
treatment of Conn’s syndrome
- surgery to remove tumour
- aldosterone receptor antagonists (eg - spironolactone)
what % of all androgenic activity does DHEA and androstenedione account for in a woman’s body
- 50% (other 50% from testosterone)
- axillary/pubic hair growth and libido
what % of all androgenic activity does DHEA and androstenedione account for in a man’s body
- 10%: insignificant contribution due to more potent testosterone
what type of corticoid is cortisol
glucocorticoid AND mineralocorticoid
what stimulates increased cortisol production
stress:
emotional - anxiety, fear
physiological - pain, fever, hypoglycaemia, injury, surgery etc
what causes endogenous circadian rhythms
suprachiasmatic nucleus in the hypothalamus
how does cortisol plasma levels vary with typical diurnal rhythm
- peak in early morning
- trough in late evening (tired)
- associated with sleep-wake cycle
what do exogenous steroids do
- we need to limit suppressive action of steroids on cortisol secretion by mimicking normal cortisol hormone levels:
as a single dose in morning as this is when levels are high (eg - oral in asthma)
high dose AM, low dose PM (Addison’s disease)
what are the 3 main actions of cortisol
- metabolic effects
- anti-inflammatory/immunosuppressive effects
- role in adaptation to stress
what metabolic effect does cortisol have
- counter-regulatory to insulin
- build up of glycogen stores which is a readily source of glucose due to increased amino acids and FFA and glycerol
effects of cortisol on muscle
- decreases glucose uptake (via insulin-mediated GLUT-4)
- increases protein breakdown
- decreases protein synthesis
effects of cortisol on adipose tissue
- decreases glucose uptake (via insulin-mediated GLUT-4)
- increases lipolysis
- decreases lipogenesis
effects of cortisol on liver
- increases gluconeogenesis
- increases glycogen synthesis (easily broken down to glucose ie if stress lasts longer)
when does cortisol have anti-inflammatory/immunosuppressive effects
- at high physiological levels of natural glucocorticoids cortisol
how does cortisol have anti-inflammatory effects
- stimulates production of annexin 1 (lipocortin 1)
- this inhibits PLA₂ which is an enzyme that generates arachidonic acid - the precursor for prostanoids and leukotrienes (therefore decreased inflammatory mediators)
- decrease number and activation of T-lymphocytes
- decrease production of cytokines (interleukins, TNF-alpha)
- stabilises lysosomes
- decrease NO production
etc…
when would glucocorticoid analogues (prednisolone, dexamethasone) be used
- anti-inflammatory: asthma, UC, rheumatoid arthritis, skin conditions, rhinitis etc
- immunosuppression: organ transplantation
- replacement therapy: Addison’s disease
- pre-term labour to enhance foetal lung maturation
what is stress
- a state of threatened homeostasis or disharmony
- body responds by a complex repertoire of physiological and behavioural mechanisms to re-establish homeostasis
what is a stressor
- a stimulus that induces state of stress
- psychological/emotional - anxiety, fear
- physiological - pain, fever, hypoglycaemia, injury, heavy exercise etc
physiological mechanisms to re-establish homeostasis
re-direction of energy
- increased CV tone, ventilation
- increased glucose availability
- decreased energy-consuming activities like digestion and reproduction as you are dealing with stress
behavioural mechanisms to re-establish homeostasis
- increased arousal, alertness, vigilance
what hormones are involved in the integrated stress response system
- SNS and adrenaline
- CRH-ACTH-cortisol
*these 2 are the main ones - RAAs, AVP, GH (when stressed, thyroid hormones decreased)
how does the SNS and adrenaline react to stress
- increase cardiac output and ventilation
- divert blood flow to muscles and heart
- mobilisation of glycogen and fat stores
- fight or flight
*need cortisol for this to happen (permissive action of cortisol)
how does cortisol react to stress
- breaks down proteins and fats
- shift from protein and fat stores in favour of expanded glycogen stores (in case stress situation is prolonged) and plasma glucose availability
- amino acids available for tissue repair if physical damage
- in stress-activated immune responses (acute infection) cortisol protects body against damage from potential over-activation of immune defence mechanisms (anti-inflammatory/immunosuppressive effect)
- cortisol is a good hormone normally as it’s for everyday functioning
what does prolonged elevated cortisol levels lead to (chronic)
- muscle wasting (catabolic effect on muscle)
- hyperglycaemia
- GI ulcers (decreased prostaglandins so decreased mucus and increased acid production)
- impaired immune response (due to anti-inflam and immunosuppressive effects of high cortisol)
what syndrome can excess glucocorticoid cause
Cushing’s syndrome
what disease can adrenal insufficiency cause
Addison’s disease
what is the main cause of Cushing’s syndrome
- exogenous glucocorticoid: high-dose, long-term use of glucocorticoids
- most common cause = excessive steroid medication use
primary defect causing Cushing’s syndrome (endocrine cause)
- adrenal tumour: autonomous secretion of cortisol
- ACTH and CRH levels are low due to -ve feedback from high cortisol levels
what is the most common cause of Cushing’s syndrome - secondary (endocrine cause)
- Cushing’s disease: ACTH-secreting pituitary tumour in anterior pituitary
- excessive ACTH production
- ACTH levels remain high as the tumour cells have impaired responsiveness to negative feedback from high cortisol levels
*syndrome = excess but can be from anywhere
what is another secondary defect causing Cushing’s syndrome (endocrine cause)
- ectopic ACTH-producing tumour (small cell lung/pancreatic/ovarian tumour etc)
- ectopic tumour cells lack feedback control
- we see a decrease in CRH and ACTH when lots of cortisol activates -ve feedback
what signs and symptoms of Cushing’s syndrome does altered fat deposition cause
- truncal obesity
- ‘moon’ face
- dorsal fat pad ‘buffalo hump’
what signs and symptoms of Cushing’s syndrome does breakdown of protein, muscle wasting, loss of collagen cause
- thin skin which is easily bruised
- muscle weakness (hypokalaemia also)
- poor wound healing
- skinny arms and legs
- purple striae (stretch marks with truncal obesity)
what signs and symptoms of Cushing’s syndrome does immunosuppression cause
- skin infections
what signs and symptoms of Cushing’s syndrome does mental changes cause
- sleep disturbances
- depression
what signs and symptoms of Cushing’s syndrome does altered bone metabolism cause
- hypertension due to excess mineralocorticoid activity and sodium and water retention
- diabetes due to hyperglycaemia and insulin resistance
- osteoporosis
treatment of Cushing’s syndrome
- localisation of tumours (anterior pituitary - MRI, adrenal - abdominal CT/MRI scan, bronchial tumour - chest x-ray, ACTH-secreting tumours - octrescan)
- surgery or radiotherapy
- drugs to inhibit steroidogenesis eg: metyrapone, trilostane
Pre-operative (preparation for surgery) OR palliative (if can’t remove tumour, improve QoL)
(rarely used for long-term therapy)
what causes primary adrenal insufficiency in Addison’s disease
- rare, chronic condition due to failure of adrenal glands (adrenal cortex)
- gradual destruction of adrenal tissue (often autoimmune or by HIV or TB)
*main cause is autoimmune
what are the levels of the 3 adrenal hormones in Addison’s disease
- low aldosterone
- low cortisol
- low androgens
- elevated ACTH as -ve feedback not activated (CRH levels also high)
symptoms of Addison’s disease
- postural hypotension
- muscle weakness
- fatigue
- lethargy
- hyponatraemia
- hyperkalaemia
- increased pigmentation
- loss of appetite/unintentional weight loss
- nausea, vomiting
*due to loss of glucocorticoid/mineralocorticoid activity
what causes increased pigmentation in Addison’s disease
- increased melanin content in skin
- increased ACTH release results in increased melanocyte-stimulating hormone levels
- hyperpigmentation seen in skin creases (knuckles and knees), old scars, gums and inside of the cheek
what can you test for adrenal failure
- decreased cortisol and increased ACTH levels
- synacthen test (stimulation test): give ACTH, cortisol should go up
- adrenal auto-antibodies (if suspect auto-immune disease)
treatment for adrenal failure
- life-long hormone replacement
- glucocorticoid: hydrocortisone (20mg AM, 10mg PM to mimic diurnal variation) and
mineralocorticoid: fludrocortisone (daily)
*higher doses of glucocorticoids are given during times of illness or major stress (e.g. surgery)
what causes secondary adrenal insufficiency in Addison’s disease
- lack of ACTH production (tumour, damage to pituitary)
- low cortisol, with normal aldosterone levels (RAAs intact)
- or due to excessive exogenous glucocorticoid use (secondary adrenal suppression) as activates -ve feedback loop and we get a decrease in ACTH
- often in patients with long-term, high-dose glucocorticoid use
- suppression of ACTH levels leading to suppression &
atrophy of adrenal cortex (so low endogenous cortisol)
what can excess exogenous glucocorticoids lead to
- cushingoid appearance: truncal obesity, dorsocervical fat pads, striae and secondary adrenal suppression
what happens when there is a sudden withdrawal of exogenous steroid
- symptoms of acute adrenal insufficiency: fatigue, nausea, vomiting, anorexia, weight loss, hypotension, myalgia
- due to lack of endogenous cortisol activity
- looks like Addison’s disease
what is classified as an adrenal crisis
- acute adrenal insufficiency & expressed when patient is under stress (e.g. infection) as not making enough cortisol
- leads to hypotension, circulatory failure, potentially death
- medical emergency
- urgent treatment: i.v. fluids, hydrocortisone to replace cortisol (i.v, then oral)
