HPA axis and Adrenal Hormones Flashcards
what are the 2 main adrenal steroid hormones?
- Aldosterone (mineralocorticoid)
2. 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, hypotension
What is the mechanism of action of steroids in DNA transcription?
- Small molecules, lipid soluble, diffuse into the cell
- Binds to receptor & 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 hyper-secretion?
Conn’s 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:
1. 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 24hour cycle) - stimulus
- Feedback - inhibitor
what disorder is associated with hypercortisolaemia?
Cushings syndrome - Adrenal or pituitary tumour
what disorder is associated with hypocortisolaemia?
Addisons disease
what are the metabolic effects of Cushing syndrome?
- Lipolysis and fat redisposition (Centripedal obesity, Shoulder fat, Moon face)
- Muscle protein degradation (Weakness, Skin transparency)
- Bone protein degradation (Osteoporosis)
- Gluconeogenesis (Diabetes mellitus)
what are the anti-inflammatory and immunosuppressive effects of Cushing syndrome?
- risk of infection
- poor wound healing
what is used to treat Cushing syndrome?
- metyrapone (blocks the synthesis of cortisol)
- Surgical removal of tumor
how many different hypothalamic releasing factors/hormones are there?
7
which hypothalamic releasing factors/hormone can have effects on the HPA axis?
Somatatostatin (GHRIF) receptor agonist
what do we treat Addison’s disease with?
Glucocorticoids
what are the 2 main steroids released from the adrenal cortex?
- aldosterone
2. hydrocortisone/cortisol
what are the two main steroid receptors called?
- Mineralocorticoids (MR)
2. Glucocorticoid (GR)
which receptors does aldosterone have a high and low affinity for?
High for MR
Low for GR
which receptors does cortisol have a high and low affinity for?
High for MR
Low for GR
which steroid hormone is predominantly bound to the Mineralocorticoid receptor (MR) at basal levels?
cortisol
Cortisol binds to MR at basal levels and even with an increase in aldosterone levels, it remains unchanged. How does aldosterone then get to bind to MR?
- MR are distributed in specialised tissues (kidney/colon/bladder)
- In these areas MR is associated with high levels of an enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD)
- 11ß-HSD metabolises/ removes cortisol creating space for aldosterone to bind when needed
what protects the foetus, in a pregnant woman, from elevated cortisol in the bloodstream?
11ß-HSD
