Lecture 27: Adrenocorticosteroids Flashcards
What are the two main parts of the Adrenal Gland?
The medulla and the cortex
What are the three parts of the cortex?
- Zona glomerulosa
- Zona fasciculata
- Zona reticularis
Which hormone does the adrenal medulla secrete?
Adrenaline
What kind of hormone is adrenaline?
A catecholamine
What kind of hormones does the cortex produce?
Steroid hormones
What is the order of the layers of the cortex from outside to inside?
- Glomerulosa
- Fasciculata
- Reticularis
What does the Zona Glomerulosa secrete?
Aldosterone
What is Aldosterone important for?
Blood pressure regulation through its control on salt balance
What does the Fasciculata secrete?
Cortisol
What does Cortisol have an effect on?
Metabolism and immune response
What does the Zona Reticularis produce?
DHEA which is a precursor for testosterone and estrogen
What is the precursor for all adrenal steroid hormones?
Cholesterol
What does the HPA axis control?
Cortisol release from the zona fasciculata
What does the HPA axis involve?
The hypothalamus, anterior pituitary, and the adrenal cortex
What does ACTH do?
It is released from anterior pituitary and directly activates cells in the zona fasciculata to secrete cortisol
What does CRH do?
It is released from the hypothalamus and activates the anterior pituitary to releases ACTH
When does ACTH stimulate steroid production?
- After meals
* Circadian rhythm (just before waking up)
Why can steroid hormones pass lipid membranes?
Because they are lipid soluble
Why don’t steroid hormone get packaged into vesicles?
Because they will pass through membranes so they have to be synthesized on demand
What does Cortisol exert negative feedback on?
The CRH (hypothalamus) and the ACTH (pituitary)
How does Cortisol affect stress signals?
It suppresses stress signals like cytokines involved in the stress response
What does Cortisol act on?
Glucocorticoid target tissues
What is Renin released by?
The juxtaglomerular apparatus (kidney)
What does Renin do?
It converts Angiotensinogen and Angiotensin I
What converts Angiotensinogen to Angiotensin I?
Renin
What does ACE do?
Converts AT1 to AT2
What converts AT1 to AT2?
ACE
What does AT2 do?
Triggers aldosterone release
What triggers aldosterone release?
AT2
What does Aldosterone do?
Targets the kidneys and promotes Na+/water reabsorption, K+ excretion (Mineralocorticoid Response)
What is the Mineralcorticoid response?
When hormones that act on the kidneys causes Na+/water reabsorption, and K+ excretion
What is the mechanism of steroid hormones?
They diffuse across the membrane and interacts with receptor in the cytoplasm. This causes it to dissociate from the heat shock protein (HSP) and move into the nucleus. The dimerized receptors interact with DNA and influence transcription of target genes at the GRE
How long does it take for steroid hormones?
They take hours to turn on and hours to turn off
What are the two targets of GR binding?
Lipocortin and COX-2
What are the two receptors for Corticosteroids?
- Glucocorticoid receptor
* Mineralocorticoid receptor
What does the Glucocorticoid receptor stimulate?
The GC response
What does the Mineralocorticoid receptor stimulate?
The MC response
What are all the hormones that target the GC and MC receptor derived from?
Cholesterol
What are the two endogenous steroid hormones?
Cortisol and Aldosterone
What are the synthetic hormones that target the steroid hormone receptors?
- Dexamethasone
- Prednisone
- Fludrocortisone
Which receptor does Dexamethasone have a high affinity for?
The GC receptor
Which receptor does Fludrocortisone have a high affinity for?
The MC receptor
Which receptor does Prednisone have a high affinity for?
The GC receptor but it has less affinity than Dexamethasone so it has some affinity for the MC receptor
What receptor does Cortisol have a high affinity for?
Both GC and MC
What receptor does Aldosterone have a high affinity for?
MC but it also has affinity for GC just less than MC
What are some glucocorticoid target issues?
- Adipose
- Muscle
- Liver
What is the inactive form of cortisol?
Cortisone
What enzyme affects the equilibrium between cortisone and cortisol?
11β-hydroxysteroid dehydrogenase type 1
What does 11β-hydroxysteroid dehydrogenase type 1 do?
Activates Cortisol by converting cortisone to cortisol
Where is 11β-hydroxysteroid dehydrogenase type 1 found?
In the liver, adipose and muscle. Places where Cortisol has effects
How does 11β-hydroxysteroid dehydrogenase type 1 affect specificity of Cortisol?
It allows it to be more specifically targeted in tissues that express the enzyme
What are the characteristics of Prednisone?
- Not effective topically
- Widely used (oral intake, injection)
- Must be metabolized to prednisolone to become effective
What are the characteristics Prednisolone?
- Strong topical effect
* Active form of prednisone
What converts Prednisone to the active form?
11β-hydroxysteroid dehydrogenase type 1
Why does cortisol activate the MR receptor but not cause an MR response?
Because tissues that are sensitive to aldosterone express an enzyme called 11β-hydroxysteroid dehydrogenase type 2 that inactivates cortisol
What does 11β-hydroxysteroid dehydrogenase type 2 do?
Inactivates cortisol in tissues that contain the MR receptor
What would happens if people were deficient in 11β-hydroxysteroid dehydrogenase type 2?
Cells with the MR receptor would be susceptible to the effects of cortisol
How does licorice affect 11β-hydroxysteroid dehydrogenase type 2?
It inhibits 11β-hydroxysteroid dehydrogenase type 2 causing the glucocorticoid to have an inappropriate affect in aldosterone target tissues causing BP to go up
What is apparent mineralocorticoid excess?
A genetic disease where there are mutations in 11β-hydroxysteroid dehydrogenase type 2 which breaks down cortisol in aldosterone responsive tissue
How do glucocorticoids/circulating cortisol affect glucose?
They increase circulating glucose
How do glucocorticoids/circulating cortisol affect fat/lipid balance?
They promote fat deposition in the trunk but fat breakdown in the limbs
How do glucocorticoids increase circulating glucose?
Cause glucose synthesis in the liver and inhibit insulin
How do glucocorticoids affect muscle and bones?
It leads to loss of muscle and bone mass in limbs
What is the most common effects of glucocorticoids?
They suppress inflammation and the immune response
What does Phospholipase do?
Cleaves phospholipids into arachidonic acid
What is Arachidonic acid?
The precursor to inflammatory mediators
What does Cyclo-oxygenase 2 (COX2) do?
Generates signalling molecules called prostanoids in inflammation
What are the inflammatory targets of Glucocorticoids?
Glucocorticoids inhibit phospholipase A2 and inhibits Cyclo-oxygenase 2 (COX2)
What are the key glucocorticoid-mediated mechanisms in inflammation?
- Inhibit arachidonic acid synthesis
* Inhibit prostanoid synthesis
What is COX2 and what does it do?
An inflammatory mediator early in the process of inflammation and converts arachidonic acid to various prostanoids
How does Glucocorticoid regulation of COX-2 have it effects?
Because it is lipophilic it affects the transcription of the COX-2 gene leading to long-term suppression of COX-2 expression
What protein is increased in expression by glucocorticoids?
Lipocortins/Annexins
What are Lipocortins/Annexins?
A large family of proteins characterized by annexin repeats
How do Lipocortins/Annexins play a part in anti-inflammatory role?
- Direct effects on Leukocytes, inhibits their tissue infiltration
- Suppression of phospholipase A2 activity which prevents generation of AA
What is Lipocortin expression induced by?
GC receptor activation
What is Addison’s disease?
Chronic adrenocortical insufficiency where there is low production of glucocorticoids and often mineralocorticoids
What is Addison’s treated with?
GC/MC supplementation
What are the symptoms of Addison’s disease?
Fatigue, salt balance, sugar balance problems, skin discorloration
What is Cushing’s syndrome?
Adrenal overactivity leading to excessive cortisol caused by tumors or drug induced
What are the symptoms of Cushing’s symptoms?
- Round face, fat deposition in the trunk
* Muscle loss, osteoporosis - protein and bone catabolism
What do all the therapeutic uses of Glucocorticoids revolve around?
Their anti-inflammatory and immunosuppressive actions
What does negative feedback from glucocorticoid administration do?
Supresses CRH and ACTH production
What are the symptoms similar to if an individual stops taking glucocorticoids abruptly?
Addisonian crisis: Hypoglycemia, hyponatremia, hyperkalemia and low BP
What happens if someone stops taking glucocorticoids abruptly?
Because the glucocorticoids suppress CRH and ACTH production the body won’t produce its own cortisol
What is required when stopping long term course glucocorticoids?
Tapering
What is the metabolic side effects when taking too much glucocorticoids?
Hyperglycemia
What is the immunosuppressive effect when taking too much glucocorticoids?
Latent infection can emerge because they suppress the immune system
What disease do the effects of taking too much glucocorticoids resemble?
Cushing syndrome
What is the Catabolic effect when taking too much glucocorticoids?
Osteoporosis and muscle wasting
What is the anti-inflammatory effect when taking too much glucocorticoids?
Slow wound healing and ulceration
How can non-specific mineralocorticoid effects arise when taking too much glucocorticoids?
Enzymes in the kidneys that deactivate GCs can become saturated, causing them to have effects on MR receptors
Can too much glucocorticoid cause psychosis?
Yes
