Week 8 (stress) physiology Flashcards
Where is ADH produced?
hypothalamus
Where is ADH released?
posterior pituitary
origin difference between anterior and posterior pituitary
- posterior pituitary develops from a downgrowth of the hypothalamus called the infundibulum. The neurons of the hypothalamus extend their axons down into the posterior pituitary
- anterior pituitary is derived from another
What hormones does the anterior pituitary gland release?
- growth hormone
- gonadotropins (FSH, LH)
- prolactin
- ACTH (–cortisol)
- Thyroid stimulating hormone/ TSH (–T3, T4 hormones)
removal of pituitary and replacement.
- replace at ectopic site - no reversal
- replace under hypothalamus —> blood vessels grow back to connect to hypothalamus and have connection to hypothalamic factors.
parvocellular AVP neurons’ role
- releases ADH in the hypothalamus and affects the anterior pituitary.
- these neurons send projections to the median eminence.
- AVP/ADH and CRH all regulate ACTH release.
CRH stimulation of ACTH release
- acts specifically on tissues with CRH receptor.
- through adenylyl cyclase, ATP converts to cAMP and activates PKA
- PKA will stimulate ACTH production and
- secretion.
type of CRH receptor
GPCR
ACTH secretion
PKA stimulates Ca2+ influx and release of ACTH from vesicles
how does ADH affect ACTH
(IP3 and DAG) acting through PKC, it will increase the production of ACTH
ADH vs CRH effect on ACTH secretion
CRH plays the main role of ACTH secretion
ACTH’s receptor
(GPCR) MC2 Receptor - specifically on adrenal glands
ACTH effect on Cortisol levels
- Through MC2R - PKA is activated
- PKA changes gene expression to increase Cortisol production.
Adrenal gland cholesterol source
- a minor portion is from adrenal synthesis using acetate
- the majority of the cholesterol usage comes from LDL in circulation - dietary.
What (production or secretion) determines the cortisol level
As a steroid hormone cortisol cannot be stored in vesicles.
what does StAR do?
it is a regulatory enzyme/protein that controls how much cholesterol gets in the cell’s mitochondria.
The enzyme promotes the transportation of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM)
cytochrome p450 enzymes
Cytochrome P450s are a group of oxidative enzymes and Six P450 enzymes participate in steroidogenesis
P450SCC does…
first step of cholesterol processing, catalyzes breakage of the bond between positions 20 and 22 in the cholesterol side chain
what are the 2 rate-limiting enzymes for cortisol production?
P450SCC (cleavage enzyme)
StAR (regulatory protein)
Cortisol acts through…
- through cortisol receptors to modify gene expression (relatively slower)
- GR also has non-genomic actions (rapid)
non-genomic actions of cortisol
- fast acting through kinases including PI3K, MAPK, and AKT.
For example: CORT-activated GR can regulate gap junction and faciliate intercellular communication through MAPK-dependent connexin phosphorylation. - negative feedback to the pituitary and hypothalamus
selectivity of genomic vs nongenomic CORT pathway
therapeutic benefits might be derived from selectively targeting GR-dependent genomic or non-genomic pathways
cortisol effects
Response to stress:
1. nutrition metabolism - mobilise glucose (plasma)
2. increase appetite
3. anti-inflammatory effects - expected to be injured in stress.
including: reduces immune response.
cortisol as a drug and side effects
due to its anti-inflammatory and immunosuppressive actions, glucocorticoid is a widely prescribed drug.
excessive and prolonged usage lead to many side effects including disrupted metabolism and osteoporosis.
selective glucocorticoid receptor agonists (SEGRAs)
Novel potential: which could keep the negative regulation of some pro-inflammatory gene expressions, but
get rid of positive feedback pathways that may lead to cortisol resistance or other negative effects.
ACTH and cortisol rhythm throughout 24 hrs
- low during the night, starting to get high before waking up - mobilise glucose.
- high during the day
cortisol in circulation
most are bound to cortisol binding globulin ready for local action of tissues.
plasma cortisol pattern
pulsatile
constant CRH effect on ACTH compared to pulsatile
ACTH and Cortisol are still released in pulses.
But the magnitude is smaller.
Why is ACTH release pulsatile even when CRH is released in a constant rate
- ACTH-induced gene expression in the adrenal gland is slow
- but cortisol released can rapidly feedback to pituitary through non-genomic actions.
This DELAY leads to pulsatile ACTH.
delayed feedback from CORT in stress
Fast feedback mechanisms, such as the binding of glucocorticoids to their receptors, initiate rapid responses like the release of endocannabinoids, which quickly dampen the HPA axis activity.
This rapid regulation is complemented by slower, genomic actions that involve changes in gene expression, providing long-term adjustments to the stress response.
What experiment shows that pulsatile ACTH is necessary? (mice)
Inhibition of pituitary release of ACTH in mice - exogenous glucocorticoid.
Only pulsatile ACTH can efficiently stimulate the release of corticosterone.
What abnormality will constant ACTH lead to in terms of CORT production?
If ACTH was released in a constant rate…
gene expression of key enzymes in the adrenal gland will be reduced drastically
for example:
- StAR
- P450SCC
Pulsatile CORT effect on behaviour
With pulsatile CORT, the brain performs better in distinguishing emotions on people’s faces.
- processing emotions.
what commonly leads to Addison’s disease?
Tuberculosis
- Induces autoimmune attack on the adrenal gland that leads to adrenal gland hyposecretion - low cortisol
pigmentation in addison disease patients
Increased ACTH that leads to stimulation of MC1 receptors on the skin. (melanocortin receptors)
What conditions lead to adrenal gland hyposecretion?
Addison’s disease
congenital adrenal hyperplasia
congenital adrenal hyperplasia effect on enzymes
Loss of steroidogenic enzymes: lack of steroid hormone synthesis
Leads to deficiency in other enzymes like StAR and CYP11B1:
- cholesterol is not converted to CORT
- lack of cortisol synthesis
congenital adrenal hyperplasia other apparent symptoms?
the accumulation of cholesterol or other CORT precursors lead to abnormal androgen production.
ambiguous genitalia
Cushing’s disease
a pituitary adenoma – a benign tumor in the pituitary gland.
drug use that leads to sustained high cortisol
In chronic arthritis:
excess/prolonged steroid therapy
Cushing’s syndrome and protein
Increased protein catabolism and reduced protein production.
Protein loss in Cushing’s leads to
Muscle atrophy
cushings and osteoporosis
Increased bone resorption, decreased calcium retention in the body.
physiological definition of stress
Any condition that:
- alters
- potentially alter
body’s normal homeostasis.
Various modalities of stress:
- Psychological
- metabolic
- physical
metabolic stress
metabolic imbalance
physical stress
- pain
- blood loss
- movement restriction
what releases ACTH in the anterior pituitary
corticotroph cells
Chronic stress adaption..
Cortisol release affects the limbic system that +/-vely feedback to stressors.
- Commonly, high CORT has -ve feedback to stressors from the limbic system
- will reduce response from stressors
- ADAPT to stressors.
limbic system in stress response
- hippocampus (a role in memory) Excessive cortisol can damage neurons in the hippocampus, impairing memory and learning. It can also cause the hippocampus to shrink will reduce HPA axis activation,
- amygdala may enhance CORT secretion, during chronic stress, the amygdala’s hyperactivity results from a reduction in inhibitory control due to altered GABAergic function, stimulate AVP neurons.
chronic stress consequences
sustained HIGH level of cortisol:
same effects as Cushing’s syndrome
1. cardiovascular diseases
2. muscle atrophy
3. anxiety
4. cognitive decline - memory
high CORT and depression
High cortisol means worse remission rate for depression.
chronic stress - prolonged high CORT and feedback
LOSS of CORT -ve feedback - raises setpoint for HPA axis and cortisol, observed in the nocturnal dip.
1. sustained high CORT
2. desensitises glucocorticoid receptors in the brain
3. less -ve feedback of CORT to the HPA axis
4. overactive HPA axis
rat exposure to cat (HPA axis)
Hypothalamus plays the essential role in responding to chronic stress.
1. increased CORT and ACTH
2. decreased CORT and ACTH after habituation
3. constant increase of CRH (even during habituation)
protein levels in median eminence during stress.
Reduced CRH in median eminence
- Reduction due to secretion, they are all gone.
hypothalamic response to chronic stress (ways to increase hormone)
- Hypothalamus releasing more CRH
- CRH neurons are more excitable and increased in size
vasopressin in chronic stress
Vasopressin is released synergistically to CRH release.
- colocalization at CRH neurons
- production by vasopressin neurons
Boosting the HPA axis.
(CORT receptor) GR levels in chronic stress
Reduced compared to control, LESS negative feedback.
The response of target tissues to cortisol may be of greater significance than the actual levels of the hormone itself.
sustained high CRH - chronic stress effect on pituitary - CRH receptor and binding
More sensitivity and higher baseline ACTH
1. increased CRH receptor due to higher CRH drive.
2. decreased CRH binding - a reflection of sustained high CRH in which the receptors are internalised due to activation.
why do CRH receptors increase in number in chronic stress
- higher CRH —> drives to more CRH receptors
- Pituitary has less negative feedback from CORT due to sustained high CORT.
chronic activation of CRH receptor at the pituitary leads to..
decreased CRH binding - constant internalisation of receptor - less membrane bound
pretreatment of CORT effect on pituitary stimulation experiment (rat model)
A rat pretreated with cortisol shows less pituitary gland stimulation – lower ACTH peak.
chronic stress vs control’s effect on anterior pituitary
chronic stress makes the pituitary more sensitive:
- a CRH dose can make the anterior pituitary produce more ACTH than normal.
adrenal gland activation period after ACTH stimulation
After ACTH stimulation of adrenal gland, the adrenal gland STAYS ON for a while, cannot be suppressed despite low ACTH after.
chronic stress effect on adrenal gland
adrenal gland has more response to ACTH now.
HIGHER cort levels and peaks from stimulation.
what sort of stress could there be?
- early life stress
- PTSD
early life stress
in utero - or - early post-natal
How to show that pre-natal stress actually pre-natal
cross fostering - give them to a non-stressed mother
can pre-natal stress be reversed?
Yes. By increased maternal care
