Corticosteroid Prodcution Flashcards by Izzie Setford

What are steroid hormones derivative of?

Enzymatic modification of cholesterol

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Which enzymes regulate steriodogenesis?

The ones that convert cholesterol into the steroid hormone of interest

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Where are the enzymes that convert cholesterol to steroid hormones located?

Mitochondria

Smooth ER

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What is the typical feature of a steroid hormone?

A ring structure

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Steroid hormones are lipid soluble, what does this mean?

They are freely permeable to membranes
They aren’t stored, but immediately released after synthesis
Have to be carried in the blood complexed to specific binding globulins

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Which binding globulin carrier cortisol?

Corticosteroid binding globulin

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Why are the adrenal glands yellow?

High concentration of cholesterol

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What is the arterial supply of the adrenal glands

Superior, middle and inferior suprarenal arteries

- centrepetal blood flow supplies all the layers

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What’s the venous drainage of the adrenal gland?

Arterial blood starts at the outer surface of the gland, and trickles down into the medullary vein
The veins emerge from the hilum of each gland and join to become the suprarenal vein
Suprarenal veins join the IVC (on the right) and the left renal vein (on the left)

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What is the nervous supply of the adrenal glands?

Nerves derived from the coeliac plexus and thoracic splanchnic nerves
Nerves supply the chromaffin cells of the adrenal medulla

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Describe the layers within the adrenal gland.

Fibrous capsule
Zona glomerulosa - clusters of small cells, fewer lipids
Zona fasciculata - large cells arranged in cords
Zone reticularis - smaller cells in a haphazard arrangement
Medulla - chromaffin cells and numerous capillaries

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What does each layer of the adrenal gland produce?

Zona glomerulosa - mineralocorticoids
Zona fasciculata - glucocorticoids
Zona reticularis - androgens
Medulla - catecholamines

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Give two examples of mineralocorticoids, their action and regulation.

Aldosterone, deoxycorticosterone
Regulated by the RAS system
These control blood pressure and sodium homeostasis

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Give two examples of glucocorticoids, regulation and function.

Cortisol, corticosterone
Regulated by ACTH
Helps to regulate carbohydrates

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Give two examples of androgens, regulation and function.

DHEA, androstenedione
Regulated by ACTH
Important source of androgens in women
- testosterone in the testes is much more active in men

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Sources of cholesterol

Taken up from circulation

Synthesised de novo from acetyl-CoA

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What is the rate limiting step of cholesterol biosynthesis

HMG-CoA reductase

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How does cholesterol enter the cell from the circulation?

LDL complex is taken into cells via LDL receptors

Broken down into esterified cholesterol and then free cholesterol

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What is the first enzymatic step in the creation of steroid hormones?

Conversion of cholesterol to pregnenolone - by cleaving a side chain of the cholesterol

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Where is the enzyme that catalyses the cholesterol to pregnenolone reaction located, and what is it?

Cytochrome P450 (with cofactor)
Located in the inner mitochondrial membrane

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What it the rate limiting step in the cholesterol to pregnenolone reaction?

The transport of free cholesterol from the cytoplasm to the mitochondria

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Which protein moves cholesterol from the cytoplasm into the mitochondria?

Steroidogenic acute regulatory protein - StAR

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Roughly speaking, how are hormones produced from pregnenolone?

There is a progressive shortening of side chains by the various enzymes

Which enzyme converted pregnenolone to progesterone (aldosterone pathway)?

3b-HSD

Which enzyme convertes progesterone to 11-deoxycorticosterone (aldosterone pathway?

CYP-21A1

Which enzyme converts 11-deoxycorticosterone to corticosterone (androgen pathway)?

CYP-11B1/2

Which enzyme coverts corticosterone to 18-OH-corticosterone and then aldosterone?

CYP-11B2

Cortical adrenal hyperplasia blocks the action of CYP21A1, CYP17A1 and CYP11B1. Production of which hormones will be affected by this?

Androgens - CYP21A1 failure blocks progesterone to 11-deoxycorticosterone conversion Cortisol and androgens - CYP17A1 failure blocks conversion of pregnenolone to 17-OH-pregnenolone and this to DHEA

What are the 6 domains receptors consist of?

A/B - control which gene is activated C - DNA binding domain - 2 zinc fingers binds to specific DNA sequences D - hinge regions controls movement of the receptor to nucleus E- Ligand binding domain binds steroids F- C-terminal domain

Where are the binding sites for steroid hormones?

Intracellular

What happens to the steroid once it binds to the receptor?

The receptor-steroid complex enters the nucleus and binds to a glucocorticoid response element in the DNA

What does binding of the steroid-receptor complex to the glucocorticoid response element activate?

Gene transcription to produce mRNA

What is the function of mRNA produced from steroid binding?

It's translated into a protein which meditated the effects | - target cell response

Where are glucocorticoid receptors found?

Everywhere

Where are mineralocorticoid receptors found?

``` Distal nephron Salivary glands Sweat glands Large intestine Brain Vascular tissue Heart ```

What can bind to mineralocorticoid receptors?

Aldosterone>deoxycorticosterone>cortisol>dexamethsone

What can bind to a glucocorticoid receptor?

Dexamethasone>corticosterone>cortisol=aldosterone

Which hormone (aldosterone or cortisol) has higher plasma concentration levels, and why is this a problem in terms of receptor binding?

Cortisol is 100-500nmol/l in blood Aldosterone is 100-500pmol/l in blood Cortisol being so high means it could much more easily bind to all the MR receptors

What is the mechanism that protects mineralocorticoid receptors from illicit occupation by glucocorticoids?

11beta-HSDII catalyses the conversion of cortisol (active) to cortisone (inactive) in selective tissues - e.g the kidney

What inhibits the 11beta-HSDII enzyme, and what are the consequences?

Liquorice | - causes cortisol to act like aldosterone (high BP and decrease urine output)

Briefly describe the actions of cortisol

``` Increases lipolysis Maintains hunger levels Stimulates gluconeogensis/permissive effect on glucagon Increased breakdown of skeletal muscles Memory, learning, mood Increases bone restoration Acts as an insulin antagonist Immune suppression ```

Actions of aldosterone

Sodium and water retention - kidney, salivary and sweat glands Activates basolateral sodium/potassium pumps on the principle cells of the distal tubule and collecting duct Upregulates ENaC channels Stimulates potassium secretion into lumen Effects on heart and vascular system

What regulated cortisol and androgen production in the adrenal glands?

The HPA axis

What regulated aldosterone production in the adrenal gland?

RAS system and plasma potassium

What is special about the manner in which cortisol is released?

Circadian rhythm - highest at about 9 in the morning | - small highs a midnight and 6pm

What precursor molecule does ACTH arise from?

POMC - proopiomelanocortin | - this is broken down into ACTH, beta-lipoprotein and the amino terminal fragment

What does breakdown of beta-lipotropin create?

Gamma-lipoprotein and beta-endorphin Gamma-lipoprotein breaks down further into beta-MSH and met-enkephalin Melanocytes stimulating hormone (MSH) controls skin pigmentation Beta-endorphin and met-enkephalin control pain alleviation and euphoria

Why does your skin get darker during Addison's?

Because in Addison's the body is producing lots of ACTH due to lack of negative feedback ACTH arises from POMC which also produces MSH during its creation - MSH darkens the skin

What type of receptor is an ACTH rector?

G-protein coupled receptor

What happens when ACTH binds to its receptor?

Activation of adenylyl cyclase, which increases cAMP concentrations and activates PKA PKA activation causes a calcium influx - rapid and long term actions

What cellular changes occur when ACTH (causing calcium influx)?

Stimulation of cholesterol to enter the mitochondria Increased transcription of genes coding for steroidogenic enzymed -e.g. CYP11B2

Describe the angiotensin II receptor, and what it activates once bound.

A G-protein coupled receptor - activating phosphlipase C | - hydrolysis PIP2 to from two messengers - inositol triphosphate (IP3) and diacyl glycerol (DAG)

What is the function of IP3?

Causes stored calcium to be released - intracellular calcium rise activates calcium-calmodulin dependent protein kinases (CaMKs) which stimulate StAR transcription and cholesterol uptake into the mitochondria

What problems are associated with high levels of aldosterone?

``` Increased sodium reabsorption Volume expansion Hypokalaemia Low renin Hypertension ```

What are the problems with high levels of cortisol (Cushing's syndrome)

``` Weight gain Ruddy face Moon face Peripheral myopathy Buffalo hump Osteoporosis Hypertension Striae ```