Steroids Glucocorticoids Flashcards
In what three ways is cortisol regulated?
- circadian rhythm
- stress
- feedback (cortisol and ACTH)
What causes the pulsatile secretion of cortisol?
- combination of positive and negative control on CRH secretion
What is the short feedback in the regulation of cortisol?
- ACTH inhib own secretion
What is the long feedback in the regulation of cortisol?
- cortisol paths
- fast (non-nuclear): cortisol acts on pituitary or hypothalamus depending on the rate of change of cortisol levels
- slow (nuclear): depends on the absolute levels of cortisol to decrease ACTH synthesis
What are the three mechanisms for neuroendocrine control?
- episodic/circadian rhythm of ACTH release
- stress responsiveness of HPA axis
- feedback inhibition by cortisol of ACTH release
What time of day do we see a rise in ACTH and glucocorticoid?
- in the morning
- CRH and ACTH peak before awakening and decline during the day
ACTH and cortisol follow a ____ _____ but so does body temperature.
- circadian rhythm
For what three reasons is body temperature used as a marker for circadian rhythm?
- studying hypothalamus is invasive
- heart rate and work level are noninvasive but dominated by external influence
- core body temperature is easily measured and suitable marker
What are the five cues for circadian rhythm?
- sleep pattern
- light/dark
- feeding time
- physical work
- stress
What are are five ways that the circadian rhythm becomes dysregulated?
- CNS/pituitary
- Cushing’s syndrome
- liver disease
- renal failure
- drug addication
What plays important roles in maintaining alertness and modulating sleep?
- hypothalamic-pituitary-adrenal axis
What does CRH play a role in?
- stress response
- circadian dependent alerting and cueing
Where is CRH found?
- in the hypothalamic paraventricular nucleus
The circadian rhythm of cortisol secretion derives from connections between?
- PVN and the primary endogenous pacemaker, the suprachiasmatic nucleus (SCN)
Where is the CRH released from and in what way?
- released from the parvocellular cells of PVN
- in a circadian-dependent pulsatile fashion
What are circadian rhythms generated by?
- endogenous clocks which can function independently from external cues
Where is the main circadian clock located in mammals?
- suprachiasmatic nuclei of the anterior hypothalamus
- situated just above optic chiasm on each side of third ventricle
Around how many neurons are in each nuclei (SCN)?
~10, 000 for mouse
~16, 000 for humans
What does lesions of the SCN result in? What does grafting SCN tissue onto lesions result in?
- abolish locomotor activity rhythms and more
- restores its circadian rhythmicity with characteristics of the donor
The SCN is the ___ ___ in the organism.
master clock
What is the circadian clock in the SCN reset by and why is this important?
- it can function autonomously but can be reset by light-dark cycles
- this ensures that it is entrained to 24 hour cycles
What kind of input does the “core” of the SCN receive?
- photic input from the retina through the retino-hypothalamic tract
What kind of response does the photic input result in?
- induction of various genes
- chromatin remodeling
Photoreceptive cells that are involved in entrainment of the SCN clock are ____ from those involved in vision, and constitute a subset of ____ _____ cells.
- distinct
- retinal ganglion
The SCN also receives non-photic input. Where is this from?
- neuropeptide Y projections from intergeniculate leaflet
- serotonergic projections from median raphe nucleus
What does the suprachiasmatic nucleus controls and how?
- various rhythms (body temp, activity, hormone levels)
- through nervous projections to other nuclei of the hypothalamus and other brain regions
Specifically how are sleep-wake cycles regulated?
- through projections from the SCN to the dorsomedial hypothalamus and posterior hypothalamic area
What can the central clock be adjusted by?
- light or day-night cycles of the environment
Where is rhythmic information relayed to?
- pineal gland, pituitary, periphery through autonomic nervous system
Peripheral oscillators can by entrained by which three things?
- neuronal pathways
- hormones
- feeding rhythms!
What are the external time cues tat entrain circadian rhythm?
- feeding schedule
- light
- activity
- social cues
What are the central outputs of the SCN?
- sleep-wake cycles
- cognitive performance
What are the peripheral outputs of the SCN?
- heart
- liver
- muscle
- kidney
What do the outputs of the SCN ultimately affect?
- physiology and behaviour
What are the adrenal disorders?
- Cushing syndrome
What is cushing syndrome characterized by?
- excess cortisol (hyperadrenocorticism)
- caused by adrenal tumor or excess ACTH
What are the 4 main symptoms of cushing syndrome?
- Protein depletion
- Fat redistribution
- Mental problems
- Inhibition of bone formation (suppression of calcium absorption)
In what two situations are excess levels of glucocorticoids seen?
- excessive endogenous production of cortisol
2. Administration of glucocorticouds for therapeutic purposes
What is cushing’s disease?
- specific type of cushing’s syndrome due to excessive ACTH from a pituitary tumor
What is addison’s disease?
- insufficient production of cortisol
- often aldosterone deficiency
- hypoadrenocorticism
What are the common causes of addison’s disease?
- infectious disease
- autoimmune destruction of adrenal cortex
What are the symptoms of addison’s disease?
- cardiovascular disease, lethargy, disarrhea, and weakness
- hypoglemciam, Na and K imbalances, hypotension, weight loss, and weakness
Why is addison’s disease on the rise?
- association with AIDs and cancer
- can be side effect of glucocorticoid treatment
Addison disease results in a hyposecretion of?
- glucocorticoids and mineralocorticoids
Underproduction of cortisol causes downstream effects. What are these?
- lack of effect on target tissues
- lack of negative feedback on the pituitary
- increase in pituitary ACTH secretion stimulates melanin synthesis
What could glucocorticoid therapy lead to?
- if taking glucocorticoids in excess leads to negative feedback and gland atrophy and addisons disease
What is the main mineralocorticoid?
- aldosterone
What enzyme is specifically expressed in the zona glomerulosa? What does it lack?
- p450aldo
- lacks 17alpha-hydroxylase so cannot produce cortisol or androgens
What are the physiological effects of mineralocorticoids?
- regulating extracellular concentrations of minerals
- major target is distal tubule of the kidney (exchange Na and K)
What happens if there is an imbalance or loss of minerals?
- leads to rapidly life-threatening abnormalities in electrolyte and fluid balance
What are the three primary physiological effects of aldosterone?
- increased active resorption of sodium
- increased passive resorption of water
- increased renal excretion of potassium
- all result in increase in blood pressure and volume
How does aldosterone specifically increase resorption of sodium?
- activation of sodium channels (aldosterone-regulated kinase)
- stimulation of transcription of Na-K ATPase gene
What is the major effect of aldosterone?
- conserve body sodium
- conservation of water follows
What regulates aldosterone secretion?
- concentration of potassium ion in extracellular fluid
- angiotensin II
- sodium deficiency stimulates aldosterone secretion
How does the concentration of potassium in the extracellular fluid regulate aldosterone secretion?
- increase plasma K
- increase aldosterone secretion (pump K out and take up Na)
How does angiotensin II regulate the secretion of aldosterone?
- decreased renal blood stimulates increase in angiotensin II which increases aldosterone secretion
- if blood pressure high, release atrial natriuretic peptide, decrease blood pressure, decrease water and sodium, decrease aldosterone secretion
What does the renin-angiotensin system do?
- regulates blood pressure
What is a source of renin?
- juxtaglomerular cells
What inhibits renin secretion?
- excess aldosterone
What is ACE?
- angiotensin-converting enzyme
- angiotensin I to II
What is the renin-angiotensin-aldosterone axis?
- angiotensinogen get converted to angiotensin I by renin
- angiotensin I to II by ACE
- activates angiotensin II receptors
What does activation of angiotensin II receptors result in?
- aldosterone secretion
- vasoconstriction
- sympathetic activation
- all contribute to blood pressure regulation
What does mineralocorticoid receptor bind with equal affinity?
- aldosterone and cortisol
Since cortisol serum concentrations are higher is this an issue with the mineralocorticoid receptor?
- no
- aldosterone-responsive cells express enzyme 11-beta-hydroxysteroid dehydrogenase
What does 11-beta-hydroxysteroid dehdrogenase do?
- converts cortisol to cortisone
- allows aldosterone to bind its receptor without competition
Why does chronic licorice intoxication occur?
- licorice inhibits 11-beta-hydrozysteroid dehydrogenase
- no inactivation of cortisol
- net effect similar to aldosterone excess (pseudohyperaldosteronism - endogenous mineralcorticoid secretion is normal)
What is chronic licorice intoxication?
- syndrome of water and sodium retention coupled wit low plasma K hypertension and low renin activity
