1.87 Stress 3

Question 1

Explain the HPA axis…

Answer 1

Hypothalamus 
CRH by paraventricular nucleus 
Anterior pituitary 
ACTH from corticotrophs 
Adrenal medulla 
Corticosteroids

Question 2

What are the actions of corticosteroids?

Answer 2

Metabolism
Immunisupression
Brain neurochemistry
Cognitive function

Question 3

What are the types of major corticosteroids, give examples…

Answer 3

Glucocorticoids e.g. cortisol

Mineralocorticoids e.g. aldosterone

Question 4

What are the mechanisms of action for mineralocorticoid?

Answer 4

i. Mineralocorticoid receptors (MR)
• High affinity so occupied most of the time
• Only expressed in certain tissues e.g. kidney, heart, colon, hippocampus

Question 5

What is the mechanism of action of glucocorticoid?

Answer 5

ii. Glucocorticoid receptors (GR)
• Low affinity so only activated by high levels during morning or by stress
Ubiquitously expressed

Question 6

What happens to the receptor complex once bound in the cytoplasmic receptor?

Answer 6

1. Corticosteroid:receptor complex dimerises and is transported to the nucleus
2. Complex binds to steroid responsive elements e.g. glucocorticoid response elements (GREs) on DNA stimulating or inhibiting protein synthesis
   NB: Steroids can also have rapid non-
   genomic effects

Question 7

What are the acute actions of corticosteroids?

Answer 7

• Positive actions of corticosteroids that contribute to homeostatic response to acute stress include:
1. Increased glucose availability - mainly through breakdown of proteins and fats
2. Reduction in some vegetative functions
○ e.g. growth, tissue repair, sleeping, sexual performance, feeding
3. Maintenance of blood volume and pressure
4. Actions on cognitive and emotional processes and alertness

Question 8

Explain the diurnal expression of cortisol

Answer 8

Chronic stress results in dysregulation of the circadian control rhythm - over activation of GR receptor

Question 9

What are the chronic actions of corticosteroids?

Answer 9

• Damaging actions of chronically high corticosteroids:
1. Heart disease and hypertension
2. Gastric diseases – e.g. ulcers
3. Muscle and tissue wastage
4. Susceptibility to infection
5. Susceptibility to neoplastic diseases (excessive division of cells)
6. Depression
7. Premature aging of the brain
NB: Physiological and pathological effects of
corticosteroids are potential side effects of long
term corticosteroid medications
Stress effects on the immune syste

Question 10

What effects does stress have on the immune system?

Answer 10

1. Up-regulate the expression of anti-inflammatory proteins
   
   2. Down-regulate the expression of pro-inflammatory proteins
      Decrease the number and activity of leukocytes

Question 11

How does stress alter both SNS and HPA immune system?

Answer 11

• Leukocytes have receptors for cortisol
• The SNS innervates lymphoid organs
• Cytokines influence the production of CRH in the hypothalamus
Lymphocytes can synthesise ACTH

Question 12

Do psychosocial factors have an effect on acute respiratory tract infections?

Answer 12

Psychosocial factors (perceived stress, negative mood, anxiety and depression) are associated with increased susceptibility to acute respiratory tract infections.

Question 13

How is HPA hyperactivity related to cancer?

Answer 13

• Corticosteroids can modulate cellular processes that protect against the formation of cancer, e.g.
• DNA repair
• Regulation of cell growth
• Stress is associated with a reduction in the activity of natural killer and cytotoxic T cells
both cell types can target abnormally growing cells for destruction

Question 14

How can stress affect wound repair?

Answer 14

Stress disrupts production of some proinflammatory cytokines which causes a delay in wound repair

Question 15

How can HPA dysfunction cause a mood disorder?

Answer 15

mood disorder patients also have:
• Raised CRH levels in CSF
• Enlarged pituitary glands
Enlarged adrenal glands

Question 16

Why is steroid negative feedback important?

Answer 16

Steroid negative feedback onto MR and GR is an important process for keeping neuroendocrine systems under tight control and preventing the long term damaging effects

Question 17

Where the steroid negative feedback occur on the HPA axis?

Answer 17

1. In the hippocampus and other limbic areas it increases inhibitory input to the paraventricular nucleus (PVN)
2. In the PVN it:
   ○ switches off cell activity (immediate response)
   ○ reduces the synthesis of CRH (delayed response)
   In the pituitary it reduces the synthesis of ACTH

Question 18

What is the link between hpa axis and depression?

Answer 18

Depressed patients have an impaired negative feedback of corticosteroids

Question 19

What are the GR receptor levels like in suicide victims?

Answer 19

Glucocorticoid receptor (GR) levels are reduced in post- mortem tissue from depressed suicide victims

Question 20

What effect does chronic anti depressants have on GR receptor levels?

Answer 20

Chronic antidepressant treatment increases GR levels

Question 21

What is the relationship between PTSD and depression and brain atrophy?

Answer 21

In PTSD although cortisol may not be increased, GR levels are raised and the periodic and marked HPA responses associated with re-experienced trauma will increase potential damage to the hippocampus
Hippocampal damage leads to effects on cognition and to impaired negative feedback to the HPA