Steroids of Adrenal Cortex Flashcards
(41 cards)
Describe adrenal blood flow
- adrenals above kidneys
- arterial blood comes in at outer cortex
- drains via capillaries into + via medulla
- venous end drains out at inner medulla.
What’s cortical tissue divided into?
Zona glomerulosa
Zona fasiculata
Zona reticularis
What’s layer-specific enzymes?
steroid synthesis in 1 layer inhibits diff enzymes in subsequent layers –> functional zonation of cortex with different hormones made in each layer
Describe steroid synthesis
-cholesterol
-cytochrome enzymes allow conversion of diff substances
-cholesterol enter cell in the zona glomerulosa
-cholesterol where it is converted into pregnenolone. -pregnenolone stay in cell:
pregnenolone -> progesterone or
enter blood + move down to zona fasiculata under action of new enzyme become new molecule which could stay or move on
What does end result of the zone specific expression of enzymes means?
only aldosterone produced in zona glomerulosa
only cortisol produced in zona fasiculata
only androstenedione produced in zona reticularis
Actions of adrenal steroids?
- Mineralocorticoids: salt + water balance
- Glucocorticoids: metabolism + immune function
- Stress increases release, but minimal levels vital for normal function
- Androgens: ‘weak androgens’
What’s mineralocorticoid function?
-Sodium retention:
active reabsorption of sodium (with associated passive reabsorption of water)
active secretion of potassium
-Volume regulation (RAAS)
How mineralocorticoids affect volume regulation RAAS?
- fine-tunes sodium reabsorption in aldosterone-sensitive distal nephron.
- aldosterone only regulates sodium conc in the extreme -because water passively follows at these sites
- to change conc requires loss or gain of pure water, which requires ADH
Describe control of aldosterone secretion
- angiotensinogen -> Ang I via enzyme renin. Circulating angiotensin I
- Ang I -> Ang II via ACE
- Ang II stimulates aldosterone secretion
- released according to need for sodium/water retention.
- cortisol + aldosterone have similar affinities for mineralocorticoid receptor
- circulating cortisol conc > aldosterone
- so why doesn’t cortisol bind to mineralocorticoid receptor -> stimulate salt + water retention (it would bypass system of renin-angiotensin pathway)
- happens when cortisol levels too high
- doesn’t happen due to the enzyme 11beta-hydroxysteroid dehydrogenase type 2
- present in kidney + rapidly metabolises cortisol -> inactive cortisone
- so only aldosterone activates receptor
What does mutation that leads to inactivation of 11beta-hydroxysteroid dehydrogenase type (11B-HSD2) lead to?
Syndrome of apparent mineralocorticoid excess (AME)
However anything that interferes with functioning of this enzyme can lead to it
Role of enzyme 11beta-hydroxysteroid dehydrogenase type 1?
present in kidney + rapidly metabolises cortisol -> inactive cortisone so only aldosterone activates the receptor
Role of enzyme 11beta-hydroxysteroid dehydrogenase type 1?
present in kidney + rapidly metabolises cortisol -> inactive cortisone so only aldosterone activates mineralocorticoid receptor
What activates RAAS?
decreased perfusion or increased [Na] sensed by macula densa / SNS via juxtaglomerular apparatus in nephron
What’s decreased perfusion or increased [Na] detected by?
macula densa
SNS
Role of mineralocorticoid / nuclear receptor?
- control of gene transcription
- induces expression of genes for Na/K-ATPase + specific type of K channel
- increase Na/K-ATPase activity
- increase Na grad between cell + tubular fluid
- Na move into cell so retained
Role of serum/glucocorticoid regulated kinase 1 (SGK1)?
aldosterone-induced genes
controls sodium reabsorption by phosphorylating + inactivating a factor that keeps plasma membrane ENaC channels expressed at low levels
Why does licorice intoxication occur?
licorice contains glycyrrhizinic acid = inhibits 11-beta-hydroxysteroid dehydrogenase
Functions of glucocorticoids?
Decreased glucose utilization (glucose sparing)
CVS
Anti-inflammatory, immunosuppresive
How do glucocorticoids decrease glucose utilization + why?
Proteolysis
Gluconeogenesis (mainly from AA)
Lipolysis
maintenance of blood glucose – vital for survival during fasting
How do glucocorticoids affect CVS vascular integrity?
Required for vascular integrity
hypocortisolism: inappropriate vasodilation, hypotension
hypercortisolism: hypertension
How are glucocorticoids anti-inflammatory?
Immunosuppresive
60 yrs of GC therapy
Highly profitable industry
Effective drugs
Effects of glucocorticoids on inflammatory mediators derived from arachidonic acid?
-arachidonic acid is mother of inflammation :
lipid derived substance that’s converted via
phospholipase A2 .
-arachidonic acid converted into many substances eg prostaglandins
-prostaglandins : lipid derived signaling
molecules, effects are paracrine (local, diffusion), mediate inflammatory response: vasodilatation, increase in vascular permeability, attraction of leucocytes.
-another class of signaling paracrine molecules are leukotrienes involved too
-cortisol inhibits formation of arachidonic acid
-cuts off at source production of inflammatory signaling molecules
Describe glucocorticoid receptor
Member of nuclear receptor super-family
3-domain structure
Describe how glucocorticoid receptor controls transcription
-1 gene, but alternate splicing of 9th exon–> 2 major
isoforms of it α + β
-receptors have a DNA binding domain + ligand binding domain
-receptor bind its ligand (cortisol), via seq in ligand
-receptor dimerises
-bound receptor binds to DNA via DNA binding domain to the hormone response element of target gene (glucocorticoid response element)
-nuclear receptors controllers of transcription
-can turn on/off transcription of numerous target genes
-if beginning of gene, promoter region has hormone response element (glucocorticoid response element) = target for the glucocorticoid receptor
