Lecture 82: HPA axis and adrenal hormones

What is the HPA axis?

A complex interaction between the hypothalamus, pituitary gland, and adrenal glands, regulating stress response, immune function, energy expenditure, mood, and libido

What is the process of the HPA axis/cascade?

1. Corticotropin-releasing hormone (CRH) is secreted by the hypothalamus. The release of CRH is influenced by stress levels, time of day and serum cortisol levels.

2. CRH binds to pituitary gland causing increased production of adrenocorticotropic hormone (ACTH)

3. ACTH is released into the bloodstream to the adrenal glands, where it binds to adrenal cortex

4. The binding of ACTH stimulates release of cortisol into the bloodstream (wide range of effects)

5. Increased serum cortisol levels inhibit the production of CRH and ACTH via negative feedback, preventing the overproduction of cortisol

Where are the adrenal glands located and what do they produce?

Located just above each kidney and produces hormones including cortisol, aldosterone, adrenaline, noradrenaline

What are the three classes of hormones produced by the adrenal cortex and their main examples?

Mineralocorticoids → aldosterone (regulates Na⁺ and water balance)

Glucocorticoids → cortisol (stress response, metabolism)

Androgens → sex hormones (e.g. DHEA)

What does the adrenal medulla produce?

Adrenaline and noradrenaline (both have similar physiological effects) during periods of stress

What is the mechanism of action of steroid hormones?

1. Steroid hormones diffuse through the cell membrane (lipid-soluble)

2. Bind to intracellular receptors in cytoplasm or nucleus

3. Form a hormone–receptor complex which enters nucleus

4. Complex binds to DNA at hormone response elements (HREs) → alters gene expression

5. mRNA translated to new protein or more/less of an existing protein → produces effects (e.g. ↑ Na⁺ reabsorption, ↑ K⁺ secretion)

How does the renin–angiotensin–aldosterone system (RAAS) respond to low blood volume?

1. Low blood volume stimulates release of angiotensin II

2. Angiotensin II stimulates adrenal cortex to produce aldosterone

3. Aldosterone assists in sodium and water reabsorption and potassium excretion

4. Aldosterone, therefore, causes a net increase in blood volume

5. Increased blood volume inhibits production of angiotensin II via negative feedback

What are the physiological effects of aldosterone?

↑ Na⁺ reabsorption

↑ K⁺ excretion

→ ↑ blood volume and blood pressure

Where and how does aldosterone act?

Acts on mineralocorticoid receptors

Found in kidneys, colon, and sweat glands

Regulates fluid and electrolyte balance

What happens when aldosterone is absent?

↓ Na⁺, ↑ K⁺

→ membrane depolarisation

→ cardiac arrhythmias, muscle weakness, hypotension

What conditions result from aldosterone dysregulation?

Hypersecretion → hypertension

Hyposecretion → hypotension

What is Conn’s syndrome?

Hypersecretion of aldosterone, leading to hypertension, hypokalaemia, metabolic alkalosis and oedema

What are the symptoms of Conn’s syndrome?

Muscle weakness, fatigue, and increased thirst due to fluid retention

What are the treatment options for Conn’s syndrome?

Mineralocorticoid receptor antagonists e.g. spironolactone and eplerenone

What is Addison’s disease?

A condition of adrenal insufficiency resulting in low levels of cortisol and aldosterone (hyposecretion), causing fatigue, weight loss, and hypotension

What are the symptoms of Addison’s disease?

Persistent fatigue, hyperpigmentation, GI issues, weight loss, N/V, abdominal pain, craving salt, joint pain, muscle weakness/cramps or hypotension

What does treatment of Addison’s disease involve?

Steroid replacement therapy with mineralocorticoid agonist e.g. fludrocortisone

What are the 3 main effects of cortisol?

1. Metabolic regulation

2. Anti-inflammatory responses

3. Immunosuppressive actions

How is cortisol produced and transported in the body?

Produced in zona fasciculata of adrenal cortex

Synthesised via hydroxylase enzymes

Travels bound to albumin and specific binding proteins

How does cortisol exert its effects?

Binds to glucocorticoid receptors (GR) and alters gene transcription

What is the metabolic effects of cortisol in the liver?

Stimulates gluconeogenesis, enhancing glucose production to maintain blood sugar levels during stress

What is the metabolic effects of cortisol in skeletal muscle?

Promotes protein degradation, leading to increased amino acid availability for gluconeogenesis

What is the metabolic effects of cortisol in adipose tissue?

Increases lipolysis, releasing free fatty acids and glycerol into the bloodstream for energy production

How does cortisol mobilise energy stores during stress?

Contributes to bone matrix protein breakdown

How does cortisol exert anti-inflammatory effects?

Induces lipocortin which inhibits phospholipase A₂

→ ↓ inflammatory mediators (prostaglandins and leukotrienes)

→ ↓ acute and chronic inflammation

What cellular processes are reduced by cortisol?

Capillary permeability

Leukocyte phagocytosis

Histamine release

Mononuclear cell activity

Tissue repair/proliferation

How does cortisol cause immunosuppression?

Inhibits NF-κB, ↓ cytokine production, ↓ lymphocyte production which decreases immune response

What is the overall effect of cortisol on inflammation and immunity?

Reduces acute and chronic inflammation and autoimmune reactions BUT also ↓ healing and immune protection

What is the pathophysiology of Cushing’s syndrome?

Aka hypercortisolaemia, results from prolonged exposure to elevated cortisol levels from:

• Endogenous or exogenous sources

• Chronic excess

• Loss of normal feedback mechanism

• Loss of circadian rhythm of cortisol secretion

What is a significant counselling point for patients taking steroids?

Take it in the morning because it impacts circadian rhythm so will affect sleep

How is Cushing’s syndrome diagnosed?

Diagnosis involves measuring plasma cortisol levels, which are typically elevated - interpret based on impact of time, stress and illness

Key diagnostic tool is overnight dexamethasone suppression test

How does the overnight dexamethasone suppression test work?

Give dexamethasone at midnight and do a serum cortisol in the morning

• Normal individuals - dexamethasone dose with cause negative feedback and reduce cortisol level

• Cushing's - no cortisol suppression so high level

What are some symptoms of Cushing’s syndrome?

Risk of infection, poor wound healing, hypertension, oedema, depression or euphoria (mood swings)

What are the metabolic effects of Cushing’s syndrome?

Lipolysis/fat redistribution (belly obesity/moon face)

Muscle protein degradation - weakness, skin transparency

Bone protein degradation - osteoporosis

Gluconeogenesis - diabetes mellitus

What are the treatment options for Cushing’s syndrome?

Stop causative medications

Drug dosage titrated against cortisol levels

Metyrapone or ketoconazole may be used, or surgery

How is adrenal insufficiency classified?

Primary → problem in the adrenal glands (adrenal failure)

Secondary → problem in the pituitary (↓ ACTH production)

Tertiary → problem in the hypothalamus (↓ CRH production)

How is Addison’s disease diagnosed?

Confirmed through low sodium and high potassium levels, low glucose, and a short ACTH stimulation test

What is the ACTH stimulation (short Synacthen) test?

A test used to assess adrenal function and differentiate primary from secondary/tertiary adrenal insufficiency by measuring the cortisol response to ACTH

How does the ACTH stimulation test work?

Give synthetic ACTH (Synacthen)

Measure cortisol response

What are the signs and symptoms of an adrenal crisis?

Severe weakness, tachycardia, reduced consciousness, syncope, unexplained pyrexia, abdominal pain