Lecture 10: HPA Axis And Adrenal Hormones Flashcards
What are the 2 main adrenal steroid hormones?
- Aldosterone (mineralocorticoid)
- Cortisol (glucocorticoid)
What does aldosterone do?
- Regulates Na and K balance:
- Acts on distal tubules to increase sodium reabsorption and potassium secretion (Na+ in K+ out)
What happens with low aldosterone levels?
- Reduced Na, increased K
- Leads to depolarisation of plasma membrane, cardiac arrhythmia, muscle weakness
What is the mechanism of action of steroids in DNA transcription?
- Small molecules, lipid soluble, diffuse into the cell
- Binds to receptor and increases receptors affinity for nucleus
- Receptor/steroid complex diffuses towards nucleus
- Receptors bind to specific Hormone Response Elements (HREs) of DNA as dimers (HRE have specific short imperfect palindromic sequences located upstream of promoters of target genes)
- Binding of the receptor to HRE either stabilises (positive regulation) or interferes with (negative regulation) the binding of transcription factors
What do steroids regulate the transcription of?
- Steroids regulate transcription of mRNA and ultimately leads to changes in protein synthesis
What regulates aldosterone synthesis/secretion?
- Direct:
-stimulated by low plasma Na + or high K + (action on zona glomerulosa cells of adrenal cortex)
Indirect:
-stimulated by angiotensin II (renin angiotensin system - RAS)
Explain how RAS regulates aldosterone secretion?
- reduced Na reabsorption/renal flow
- Renin is therefore released
- this causes the conversion of angiotensinogen
to angiotensin I and finally to angiotensin II. - This results in vasoconstriction and aldosterone release
What syndrome occurs from aldosterone hypersecretion?
Conns syndrome
- hyperplasia/tumor of the adrenal z. Glomerulosa
- Secondary to renal artery stenosis (reduced renal perfusion and increased renin)
what disorders involve aldosterone hypersecretion?
- Conn’s syndrome - causes the hypersecretion resulting in Na and water retention (excessive reabsorption) and Hypokalaemia (excessive secretion of K)
- Hypertension
How do we treat disorders involving aldosterone hypersecretion?
Mineralocorticoid antagonist:
- Spironolactone
- Eplerenone
what are the side effects of Spironolactone?
- menstrual disorders
- loss of libido
Between Spironolactone and Eplerenone, which has more side effects and why?
Spironolactone because it is less selective
what disorders involve aldosterone hyposecretion?
- Addison’s disease - Autoimmune - attacks adrenals causing the aldosterone insufficiency
- Hypotension and vascular collapse - symptoms of the insufficiency
How do we treat disorders involving aldosterone hyposecretion?
Mineralocorticoid agonist
- Fludrocortisone
where is cortisol (glucocorticoid) synthesised and released?
- by Zona fasciculata
What does cortisol regulate?
- Acts on glucocorticoid receptors (GR) to regulate transcription
What are the 3 main effects of cortisol?
- metabolic
- anti inflammatory
- immunosuppressive
What are the cortisol metabolic effects in the:
a. Liver
b. Skeletal muscle
c. Adipose tissue
d. Bone
a. Liver - gluconeogenesis
b. Skeletal muscle - protein degradation
c. Adipose tissue - lipolysis (Increased free fatty acids and glycerol for gluconeogenesis)
d. Bone - matrix protein breakdown for gluconeogenesis
These all provide every in times of stress
How does cortisol have anti-inflammatory effects?
- Cortisol induces lipocortin enzyme which in turn inhibits phospholipase A2
- this prevents membrane phospholipid binding to the cell to stimulate free arachidonic acid
- this prevents the arachidonic acid pathway occurring so no prostaglandins and other inflammatory mediators at work.
- Reduced capillary permeability
- reduced phagocytic action of leucocytes
- Reduced histamine release
- Reduced activity of mononuclear cells and proliferation/ repair of tissue
How does cortisol have immunosuppressive effects?
- Direct effect on NF-κB - reduced transcription and release of cytokines
- reduced Lymphocyte production (especially T4 helper cells)
what is the Hypothalamic Pituitary Adrenal (HPA) axis/cascade?
- stimulus causes hypothalamic nuclei to release cortisol releasing hormone (CRH) to the anterior pituitary
- the anterior pituitary then releases Adrenocorticotropic hormone (ACTH) to the adrenals
- Cortisol is then released from the adrenals
what three things regulate cortisol levels?
- stress (mental and physical) - stimulus
- Circadian clock (the 24hr cycle) - stimulus
- Feedback - inhibitor
What disorder is associated with hypercortisolaemia?
- Cushing syndrome - Adrenal or pituitary Tumour
What disorder is associated with hypocortisolaemia?
- Addisons disease
