HPA axis and adrenal hormones Flashcards
What is the adrenal axis (hypothalamic-pituitary-adrenal axis)?
Complex set of interaction and feedback loops between the hypothalamus, pituitary, and adrenal glands. It regulates the body’s response to stress, immune function, energy expenditure, mood, emotions and libido.
Where are the adrenal glands located?
Just above each kidney
What are the hormones released from the adrenal glands?
Cortisol, aldosterone, adrenaline and noradrenaline.
What are adrenal glands composed of?
Outer cortex and an inner medulla
What are 3 classes of steroid hormones produced and released into the circulation by the adrenal cortex?
Mineralocorticoids – mainly aldosterone
Glucocorticoids – mainly cortisol (hydrocortisone)
Androgens – sex hormones
What does the adrenal inner medulla produce?
Adrenaline and noradrenaline through direct control of the hypothalamus.
What are the effects of adrenaline and noradrenaline?
Fight or flight response. Increased heart rate, blood pressure and muscle perfusion.
What ions do steroids have an effect on?
Increased Na reabsorption
Increased K secretion
Aldosterone regulation half-life?
20 mins (short)
What are the two effects that aldosterone is regulated by?
Direct Indirect (most important)
What is direct effects on aldosterone stimulated by?
Stimulated by low plasma Na or K (action on zona glomerulosa cell of adrenal cortex)
What is indirect effects on aldosterone stimulated by?
Stimulated by angiotensin II (renin angiotensin system)
Aldosterone regulation (5)
- Low blood volume stimulates the release of angiotensin II.
- Angiotenis II stimulates the adrenal cortex to produce aldosterone.
- Aldosterone has a number of different action including: sodium reabsorption, water reabsorption, potassium excretion]
- Aldosterone, therefore, causes a net increase in blood volume
- Increased blood volume inhibits the production of angiotensin II via negative feedback.
What is aldosterone?
A mineralocorticoids that regulates Na and K.
What does aldosterone act on to regulate Na and K?
Mineralocorticoid receptors in distal tubules increase Na reabsorption and K secretions.
What are the effects of no aldosterone?
Low Na and High K Leads to depolarization of plasma membrane Cardiac arrythmia Muscle weakness Hypotension
What does adrenal hypersecretion cause?
Conn’s syndrome
Symptoms of aldosterone hypersecretion (Conn’s syndrome)
Hypertension
High Na
Low K
Oedema (water retention)
Treatment of aldosterone hypersecretion?
MR (Mineralocorticoid receptors) antagonist/aldosterone antagonist
- spironolactone – lack of selectivity leads to side effects
- Eplerenone – fewer side effects
What does adrenal hyposecretion cause?
Addison’s syndrome
Symptoms of aldosterone hyposecretion (Addison’s syndrome)
Hypotension and vascular collapse Low NA dehydration High K Cardiac arrythmias Potentially fatal
Treatment of aldosterone hyposecretion?
Mineralocorticoid agonist
Fludrocortisone – longer half-life than aldosterone
Why is aldosterone inappropriate for treatment for hyposecretion?
Short aldosterone half-life means it is not used for drug treatment
What other things use fludrocortisone as treatment?
Postural hypotension or symptomatic hypotension treatment involves fludrocortisone
Cortisol half life
90 minutes
What are the three effects that cortisol is regulated by?
- Metabolic (physiological)
- Anti-inflammatory (supraphysiological)
- Immunosuppressive (supraphysiological)
What does cortisol act on?
Glucocorticoid receptors to regulate transcription
What are the metabolic effects of cortisol?
- Liver - Glucose production (gluconeogenesis)
- Skeletal muscle - Increase in protein degradation (Increased a.a.)
- Adipose tissue - Increased lipolysis (Increased free fatty acids and glycerol for gluconeogenesis)
- Bone - Matrix protein breakdown (Increased a.a. for gluconeogenesis)
- Mobilisation of energy stores in time of stress
Where are the metabolic effects of cortisol? (5)
- Liver
- Skeletal muscle
- Adipose tissue
- Bone
- Mobilisation of energy stores in time of stress
What is the metabolic effect in the Liver?
- Glucose production (gluconeogenesis)
What is the metabolic effect in the Skeletal muscle?
- Increase in protein degradation (Increased a.a.)
What is the metabolic effect in the Adipose tissue?
- Increased lipolysis (Increased free fatty acids and glycerol for gluconeogenesis)
What is the metabolic effect in the Bone?
- Matrix protein breakdown (Increased a.a. for gluconeogenesis)
What effects does cortisol have at supraphysiological level?
Inhibits chronic and acute inflammation (immunosuppressed)
What increases cortisol?
Stress as it activates the HPA axis. Illness Trauma Burns Surgery
When is the most cortisol naturally produced?
Morning when you wake up to get you through the day.
What does hypercortisolemia cause?
Cushing’s syndrome
How does Cushing’s syndrome occur?
Excess cortisol, usually exogenous corticosteroid use. Endogenous causes include, adrenal or pituitary tumors (Cushing’s disease).
What is Cushing’s syndrome?
Set of symptoms resulting from exposure to increased levels of cortisol -Endogenous or exogenous sources -Chronic excess -Loss of normal feedback mechanisms -Loss of circadian rhythm of cortisol secretion
Diagnosis of Cushing’s syndrome
Overnight dexamethasone suppression tests
- Give dexamethasone at midnight
- Serum cortisol in morning
- If normal – dex dose will cause negative feedback/suppression and reduce cortisol level
- In Cushing’s there is no cortisol suppression
Why can you not use a random plasma cortisol?
Time, stress and illness can impact level.
Cushing’s syndrome 4 effects that cause symptoms
Anti-inflammatory and immunosuppressive effects
Mineral corticoid effects
Mood effect
Metabolic Effects
Cushing’s syndrome Anti-inflammatory and immunosuppressive effects
- risk of infection
- poor wound healing
Cushing’s syndrome Mineral corticoid effects
- hypertension
- oedema
Cushing’s syndrome Mood effect
- depression
- Euphoria
Cushing’s syndrome Metabolic Effects
Lipolysis and fat redisposition - Centripedal obesity - Shoulder fat - Moon face Muscle protein degradation - Weakness - Skin transparency Bone protein degradation - Osteoporosis Gluconeogenesis - Diabetes mellitus
Latrogenic Cushing’s treatment
stop causative medications
Tumour Cushing’s treatment
surgical removal/radiotherapy
Cushing’s treatment Metyrapone (3)
- Inhibitor in adrenal cortex
- blocks the synthesis of cortisol, can be used pre-op
- specialist use
Cushing’s treatment Ketoconazole
May have a direct effect on corticotropic tumour cells in patients with Cushing’s disease
What does hypocortisolemia cause?
Addison’s Disease
How does Addison’s Disease occur?
Destruction of the adrenal cortex
What is Addison’s Disease?
-Reduced production of glucocorticoids such as cortisol), mineralocorticoids (such as aldosterone), and adrenal androgens (such as dehydroepiandrosterone).
The absence or cortisol leads to increased production of adrenocorticotrophic hormone (ACTH) because negative feedback to the pituitary gland is reduced.
Diagnosis of Addison’s Disease
- Low Na, high K (due to reduced mineralocorticoid)
- Low glucose
- Serum cortisol
- Short ACTH stimulation test
Addison’s - Classification
- Primary – adrenal failure
- Secondary – pituitary problem with ACTH synthesis
- Tertiary – hypothalamic problem
Addison’s Disease treatment
- Replace steroids
- Specialist input
List some symptoms of Addison’s Disease
Persistent, non-specific Fatigue Hyperpigmentation Weight loss Loss of appetite Premature satiety Nausea and vomiting Abdominal pain Cravings for salt Muscle weakness/cramps Joint pain Postural dizziness/hypotension Headache Low grade fever Thirst Anxiety and depression
When is the highest dose of cortisol replacement (steroids) given?
In the morning then reduced throughout the day
Why should you not take cortisol replacement (steroids) before bed?
It keeps you awake
List some symptoms of Adrenal insufficiency
Fatigue Weight loss Failure to thrive (in children) Anorexia Skin crease hyperpigmentation Buccal pigmentation Low blood pressure Postural hypotension Abdominal discomfort
List some symptoms of Adrenal crisis
Nausea and vomiting Severe weakness Tachycardia Reduced consciousness Syncope Confusion Fever/unexplained pyrexia Hypovolemic shock Abdominal guarding/pain
What is the physiological level of steroids produced by the body?
About 7.5mg a day
What happens to the normal adrenal response when steroids are given?
It suppresses the adrenal response as the body has been given steroids. About 2-3 weeks of use will completely turn drive off.
What happens if steroids stopped abruptly?
Adrenal crisis as the body can no longer make own steroids as the mechanism has been switched off.
How are steroids weaned?
Around 5mg off prednisolone dropped every week to help turn back on natural adrenal production.
For long term users, when they reach 7.5mg you may need to wean slower.
Who is at risk of adrenal crisis?
People with Addison’s
People on steroids
They are steroid dependent.
When may a patient require higher doses of steroids?
Patients with adrenal insufficiency that before acutely ill, or trauma/surgery as they body is under more stress.
What is the blanket rule for acutely unwell patients that have adrenal insufficiencies?
Sick days = double steroids
What corticosteroid does not put you into adrenal crisis?
Fludrocortisone, as it regulates sodium and water for BP.
What is important for steroid users?
Steroid emergency card so it is known in emergency situations.
What is the hormone that stimulates the cortisol release?
ACTH
Short Synacthen test (SST)
Chemically similar drug to ACTH administered at night
Plasma cortisol measured in the morning.
A normal function will show a rise
Why does a normal function will show a rise in cortisol (SST)?
Stimulated ACTH, stimulated adrenal cortex to release cortisol.
What can make it hard to interpret SST?
Someone who is on steroids as their cortisol level will already be up.
What other drugs may be considered for someone who is on steroids?
Bone pretension and GI protection
What dose of tablet are usually used to give steroid users who are weaning?
5mg as you can easily change dose, and not a risk of over/under dose. (5 tablets -> 4 tablets etc)
What are the anti-inflammatory effects of cortisol used for?
- Asthma
- Topical inflammatory conditions
- Autoimmune disease/ transplants
- Neoplastic disease of lymphocytes (e.g.Hodgkins disease)
- Transplant rejection
What receptor do the steroids act on for anti-inflammatory effect for conditions such as asthma?
Glucocorticoids receptor (GR), drugs with high affinity to GR are effective anti-inflammatory and immunosuppressive agents.
