Corticosteroid production and regulation Flashcards
What are steroids derived from?
Steroid hormones are derived from enzymatic modification of cholesterol
how is steroidogenesis regulated?
by controlling the enzymes which convert cholesterol into the steroid hormone
where are Enzymes which produce steroid hormones from cholesterol located?
in mitochondria and smooth ER
are steroid hormones stored after synthesis?
No, they are not stored but synthesized and immediately released
As steroid hormones aren’t water soluble, how are they carried in blood?
they are carried in the blood complexed to specific binding globulins.
what binding globulin carries cortisol?
Corticosteroid binding globulin
where are adrenal glands located?
in abdomen above kidneys
describe the size and colour of adrenal glands
Endocrine glands are 4-6cm
Yellow in colour due to high cholesterol
what are adrenal glands composed of?
Composed of outer cortex and inner medulla
how are the cortex and medulla adrenal glands different ?
Medulla is embryologically and histologically distinct to cortex, they are two different glands
Medulla- rich in blood + nerve supply
Cortex- consists of different zones
what is the arterial supply of adrenal cortex?
superior, middle and inferior suprarenal arteries
How does arterial blood flow and what vessel does it become?
moves towards the centre of the gland and flows into the medullary vein
describe the venous blood flow of the adrenal cortex?
Medullary vein emerges from the hilum before forming the suprarenal veins, which join the inferior vena cava on the right side and the left renal vein on the left
what is the adrenal nerve supply derived from? what do the nerves supply?
derived from the coeliac plexus and the thoracic splanchnic nerves.
The nerves supply the chromaffin cells of the adrenal medulla.
what surrounds the adrenal cortex?
Fibrous capsule
Name the 3 layers of the adrenal cortex
Zona Glomerulosa
Zona Fasciculata
Zona Reticularis
SALT, SUGAR, SEX
describe the cell type in ZG, what hormone it secretes, what it is regulated by and what process it regulates
Cluster of small cells
Regulated by RAS and K+
Produces mineralocorticoids e.g. aldosterone, deoxycorticosterone.
Regulates Na+ homeostasis
Cluster of small cells with ball-like structure
describe the cell type in ZF, what hormone it secretes, what it is regulated by and what process it regulates
Column like cells
Regulated by ACTH
Produces Glucocorticoids e.g. cortisol, corticosterone
Regulates carbohydrate metabolism
describe the cell type in ZR, what hormone it secretes, what it is regulated by and what its role is
Haphazard cell arrangement
Regulated by ACTH
produces adrenal androgens e.g. DHEA, DHEA-sulphate
Sole source of androgens – (important in women as males has testes which make testosterone)
what is found in the medulla?
Chromaffin cells
And Numerous capillaries and veins – produces catecholamines like adrenaline
what is the Rate-limiting enzyme is cholesterol synthesis?
HMG-CoA reductase
in what form is cholesterol taken up by a cell?
in the form of low density lipoprotein (LDL).
what happens after LDL is taken into cells?
It is broken down into esterified cholesterol, and then free cholesterol – ready for steroid biosynthesis
What is the first enzymatic step in steroid synthesis? what enzyme catalyses this reaction? where is it found?
the conversion of cholesterol to pregnenolone
Cytochrome P450 enzyme , found in inner mitochondrial membrane
what is the rate limiting step? what is it carried out by?
the transport of free cholesterol from cytoplasm into mitochondria.
Carried out by Steroidogenic Acute Regulatory Protein (StAR) - which forms a channel to deliver cholesterol to inner mitochondrial membrane
what is the name for the steroidogenic enzyme: Side-chain cleavage enzyme
CYP11A1
what is the name for the steroidogenic enzyme: 3 beta-hydroxysteroid dehydrogenase
3 beta-HSD
what is the name for the steroidogenic enzyme: 17 alpha-hydroxylase
CYP17
what is the name for the steroidogenic enzyme: 21 hydroxylase
CYP21A2
what is the name for the steroidogenic enzyme: 11 beta-hydroxylase
CYP11B1
what is the name for the steroidogenic enzyme: Aldosterone synthase
CYP11B2
what causes Congenital Adrenal Hyperplasia?
21 hydroxylase deficiency
what type of receptors are steroid receptors?
Nuclear receptors
What occurs at each domain of the steroid receptor
A/B: N terminal domain controls which gene is activated
C: DNA binding zone
D: hinge region- controls movement of receptor to nucleus
E: ligand binding domain
F: C-terminal domain
describe the mechanism of action of steroid hormones
Steroid hormone diffuses through plasma membrane
Binds to intracellular cytosolic receptor
Receptor hormone complex enters nucleus and binds to DNA sequence
Binding initiates transcription to produce mRNA
mRNA is translated to protein which mediates cell response
where are glucocorticoid receptors found?
widespread around body
where are mineralocorticoid receptors found?
Distal CT of Nephron, Salivary glands, sweat glands, large intestine, also in brain, vascular tissue and heart
why is cortisol more likely to bind to a mineralocorticoid receptor than aldosterone is to a glucocorticoid receptor?
Plasma Cortisol concentration is much higher than aldosterone
what mechanism protects mineralocorticoid receptor from illicit occupation by glucocorticoids like cortisol?
11 beta-HSDII catalyses the conversion of Cortisol (active) to Cortisone (inactive) in selective tissues e.g. kidney allowing aldosterone to function normally
what inhibits the enzyme 11 beta HSD II?
Liquorice
describe the effects of cortisol on the body
Stimulates gluconeogenesis in liver stimulates lipolysis permissive effect on glucagon counteracts insulin increased skeletal muscle breakdown immune suppression
describe the mechanism of action of aldosterone
Upregulates epithelial sodium channel which increases Na and water reabsorption
Stimulates secretion of K into lumen and secretion of H+ via the H/ATPase in intercalated cells of cortical collecting tubules
describe the role of hypothalamus and anterior pituitary in regulation of cortisol production
Hypothalamus secretes Corticotropin releasing Hormone, which causes Anterior Pituitary to release Adrenocorticotropic hormone (ACTH) which acts on Adrenal cortex to cause cortisol production
at what time of day are cortisol levels higher?
In the morning
What is POMC (propriomelanocortin), in the anterior pituitary, made of? and what does it control
ACTH
Lipotropin
which become:
Beta endorphin
Melanocyte Stimualting hormone
Controls melanin pigmentation (increase ACTh = increase MSH= increase melanin so dark skin)
what type of receptor is ACTH receptor?
G-protein Coupled Receptor
after ACTH binds to G-protien coupled receptors what happens?
Conformation changes in receptor stimulate adenyl cyclase , causing an increase in cAMP, activation
of PKA and calcium influx
what rapid and long term effects does ACTH have to increase cortisol production?
Stimulation of cholesterol delivery to the mitochondria (rapid) -for steroidogensis
Increased transcription of genes coding for steroidogenic enzymes (long-term).
what activates the RAS system?
Activated in response to low blood pressure, plasma sodium
how does Angiotensin II increase aldosterone production?
AngII binds to 7 transmembrane domain G-protein coupled receptor
Activates phospholipase C
Cascade of reactions causes Ca2+ release
this stimulates transcription of StAR and cholesterol uptake into mitochondria
how does potassium increase aldosterone production?
Increase in potassium, increases aldosterone
what is primary aldosteronism and what are the most common causes of it?
High levels of Aldosterone
Most Common Causes:
Aldosterone producing adenoma (unilateral)
Bilateral adrenal hyperplasia
what effects does primary aldosteronism have?
Increased sodium reabsorption, Volume expansion Hypokalaemia (Potassium excretion) Alkalosis (due to hydrogen excretion) Low PRA (plasma renin activity) Hypertension
what is cushing’s syndrome and what are the most common causes of it?
High levels of Cortisol
Caused by:
ACTH producing adenoma (pituitary)
Cortisol producing adenoma (adrenal)
Iatrogenic – caused by large doses of steroids for other medical conditions
in Addison’s disease, there is the inability to make _____ and _____
cortisol and aldosterone
