Steroids of the Adrenal Cortex Flashcards
Overview
What two parts can the adrenal gland be divided into?
Which one is the outer layer and what does it secrete? what about the other layer?
what are the 3 main classes of steroids?
disease for excess glucocorticoids
disease for adrenal insuffiency
Adrenal gland is divided into two parts the cortex and medulla.
The cortex is the outer layers and secretes steroids, the medulla is the inner layers and secrete catecholamine’s, mainly adrenaline.
There are three classes of these steroids:
Glucocorticoids – Mainly cortisol in mammals
Mineralocorticoids – Aldosterone
Androgens – Have relatively minor effects, these are sex steroids, which can be metabolised in other tissues to become more potent.
- Excess glucocorticoids = Cushing’s
- Adrenal insufficiency: (primarily cortisol): Addisons
Adrenal Blood Flow and Functional Zonation
Where are the adrenals situated? Describe the unique blood supply and where it drains out?
What is the cortical tissue divided into?
What is functional zonation?
How can steroid synthesis in one layer effect another layer?
The adrenals are situated above the kidneys and the blood supply is in such a way that the arterial blood comes in at the outer cortex, drains through network of capillaries into and through the medulla, where at the venous end it drains out at the inner medulla.
The cortical tissue is divided histologically into three zones: Zona glomerulosa, zona fasiculata and zona reticularis.
There is layer/tissue specific enzyme expression, meaning the adrenal cortex zones can each act independently, called functional zonation of the cortex. This allows different hormones to be made in each layer.
Steroid synthesis in one layer can inhibit different enzymes in subsequent layers.
Steroid Synthesis in the Adrenal Cortex
How does steroid synthesis begin?
What enzymes allow conversion of different substances?
where does cholesterol enter the cell and what is it converted into?
what are the two fates of this new molecule?
What is only produced at which zone?
Steroid synthesis begins from cholesterol, the diagram below shows the various pathways. Note you don’t need to learn it completely in detail.
There are cytochrome enzymes on the left and top in bold which allow conversion of different substances.
Running through this, cholesterol could enter into a cell in the zona glomerulosa, where it is converted into pregnenolone.
Pregnenolone could stay in the cell and be converted to progesterone or it could enter back into the blood and move down to the zona fasiculata and under action of a new enzyme become a new molecule. Which could stay or move on etc.
The end result of the zone-specific expression of enzymes means:
• ONLY aldosterone is produced in the zona glomerulosa
• ONLY cortisol in zona fasiculata
• ONLY androstenedione in the zona reticularis.
Actions of Adrenal Steroids
what might increase glucocorticoids release? why is this bad?
actions of other two steroid classes
The glucocorticoids are involved in various aspects of metabolism and immune function. Stress increases release, but minimal levels essential are needed for normal function.
The mineralocorticoids are involved in salt and water balance.
Androgens, also called the ‘weak androgens’, have minimal function in humans with normal gonadal function.
Major actions of cortisol on metabolism and other targets
How does cortisol affect glucose? what effect does this have in the liver, muscles and fat stores?
Cortisol and insulin interaction? specifically how and where does it act? What will this do to insulin and what can it progress to?
What effect will this have on fat stores?
Relate all of this to cushing’s disease
cortisol function with cardiovascular system
glucocortcoids function with inflammation - why can this be bad?
Cortisol has a glucose-conserving effect, it is essential to prevent fatal hypoglycemia.
Cortisol directly stimulates gluconeogenesis in the liver. Cortisol also has various catabolic functions such as lipolysis (release of FA from stores) and proteolysis (particularly in muscles). The released AA can then be fed into the gluconeogenesis pathway.
Cortisol also antagonises the effects of insulin, specifically by counteracting the expression of the GLUT-4 glucose transporter (insulin induced receptor) that usually allows uptake of glucose into muscle and adipose tissue etc.
All of these effects will tend to increase insulin levels -> cortisol is promoting insulin resistance.
Another action of insulin is to promote lipogenesis, so although cortisol promotes lipolysis the increase in insulin also promotes lipogenesis.
In excess cortisol you tend to get promotion of hyperglycemia, insulin resistance (pre-diabetes) and promoting fat storage (with insulin overriding effects of cortisol here), which is why Cushing’s is associated with weight gain.
Multiple other tissues are also affected, in many of these functions of cortisol is required e.g. in CVS to maintain blood pressure, cortisol also tends to depress the inflammatory immune response.
This anti-inflammatory effect is what has made glucocorticoid drugs (drugs that mimic cortisol) very popular.
Summary of functions of glucocorticoids:
• Primary catabolic
• Proteolysis, lipolysis
• Decreased glucose utilisation (glucose sparing)
• Anabolic actions in liver
• Gluconeogenesis (mainly from amino acids)
Overall = maintenance of blood glucose, essential for survival during fasting
Cardiovascular function
o Required for vascular integrity
o Cortisol deficiency can lead to inappropriate vasodilation (low BP)
o Cortisol excess can cause hypertension (via mineralocorticoid receptor)
Anti-inflammatory, immunosuppressive function
o 60 years of glucocorticoid therapy
o Highly profitable industry
o Extremely effective drugs
o But double-edged sword as prolonged use can lead to side effects of excess cortisol
Effects of glucocorticoids on inflammatory mediators derived from arachidonic acid:
What is arachidonic acid and what is it derived from? what can convert it?
What can it be converted into to mediate the inflammatory response? What kind of signalling do this new molecule have?
What is the 3 subclass it can be converted into?
What does cortisol do to arachidonic acid?
Arachidonic acid is like the mother of inflammation, a lipid derived substance that can be converted via phospholipase A2.
Arachidonic acid can be converted into a large number of substances, so both the middle blue box and one on left are prostaglandins.
Prostaglandins are lipid derived signaling molecules, their effects are paracrine (local, diffusion).
Together the prostaglandins mediate the inflammatory response, the vasodilatation, increase in vascular permeability, attraction of leucocytes.
Another class of signaling paracrine molecules are leukotrienes and involved in this also.
Cortisol inhibits the formation of arachidonic acid, it cuts off at the source the production of the inflammatory signaling molecules.
Glucocorticoid Receptor
What type of receptor is this? How many genes and how many forms?
what two domains does the receptor have?
What happen once cortisol binds?
where will it bind in dna? What effect will tis have? what can change the effect?
2 names for how glucocorticoids receptors work
How does this relate to anti-inflammatory effects?
The glucocorticoid receptor is part of the nuclear receptor family of receptors. There is one gene, but alternate splicing can lead to two major isoforms of it.
- The receptors have a DNA binding domain and a ligand-binding domain.
The receptor will bind its ligand (in this case cortisol), via the sequence in the ligand binding domain the receptor dimerises,
Then the bound receptor can bind to the DNA by the DNA binding domain to the hormone response element of the target gene. In this case the glucocorticoid response element.
This is why nuclear receptors are controllers of transcription, they can turn on or turn off the transcription of numerous target genes, whatever their target gene is.
If the beginning of a gene, at the promoter region has the hormone response element, for this case the glucocorticoid response element, then that gene will be a target for the glucocorticoid receptor.
Following binding of the receptor to the GRE, there can either be up-regulation or down-regulation of the transcription of that gene.
- What happens will depend on the gene and the combination of co-factors that are present, either repressor co-factors or activating ones.
The glucocorticoid receptor can work either by
- Transactivation – Where glucocorticoid receptor enhances transcription of the target gene
- Transrepression – Where glucocorticoid receptor represses transcription of target gene.
Many anti-inflammatory effects of GCs thought to be due to transrepression of genes, which is why it is major therapeutic target.
Mineralocorticoids and Function
What is the main effect?
what type of receptor is mineralocorticoid receptor? what effect does it have?
Why does increasing Na+/K+ activity help to retain more sodium?
What controls aldosterone?
What sense drop in Na+ conc? other effects detected? what does this lead to?
pathway to aldosterone secretion
How can cortisol interact with aldosterone?
Why doesn’t high cortisol overide the whole process? name enzyme and where it is situated and what it does?
what is (AME) apparent mineralocorticoid excess?
The mineralocorticoid aldosterone has a function of retaining salt via the kidney and hence retaining water.
The mineralocorticoid receptor (a nuclear receptor), induces expression (transactivation) of genes for the Na+/K+ ATPase and a particular type of K+ channel.
By increasing activity of Na+/K+ you increase the Na+ gradient between the cell and the tubular fluid, so more Na+ is going to move into the cell and hence the circulation and be retained.
Importantly, aldosterone is NOT under the control of the hypothalamo-pituitary axis. It is instead controlled as part of the renin-angiotensin network.
Any drop-in perfusion or a drop in Na+ conc. (sensed in macula densa) or sympathetic activity it will activate the renin-angiotensin pathway, through the juxtaglomerular apparatus in the nephron.
There is first the conversion of angiotensinogen -> angiotensin I by the enzyme renin. Circulating angiotensin I -> angiotensin II by ACE (angiotensin converting enzyme).
Ang II -> aldosterone secretion, which will be released according to need for sodium/water retention.
Cortisol and aldosterone have similar affinities for the mineralocorticoid receptor, i.e. cortisol can bind to the mineralocorticoid receptor with about the same affinity as the intended ligand, aldosterone.
Circulating cortisol concentrations are higher than aldosterone, so why doesn’t cortisol bind to the mineralocorticoid receptor and stimulate salt and water retention (i.e. it would bypass the delicate system of the renin-angiotensin pathway).
This would obviously be bad and can happen when cortisol levels are too high. In general, though it doesn’t happen. This is due to the enzyme 11beta-hydroxysteroid dehydrogenase type 1, which is present in the kidney and rapidly metabolises cortisol to inactive cortisone. This ensures only aldosterone activates the receptor.
A very rare mutation can lead to inactivation of the 11B-HSD1, which leads to syndrome of apparent mineralocorticoid excess (AME). However, note that anything that interferes with the functioning of this enzyme can lead to something such as this:
Metabolism of Cortisol
What does inactivated cortisol turn into in mineralocorticoid responsive tissue?
what does inactivated cortisol turn into in other tissues?
What should be ratio of these two molecules in urine? what if 11B-HSD2 enzyme interefered with? what does it suggest?
Normally, in mineralocorticoid responsive tissue, the enzyme 11B-HSD2 inactivates cortisol to tetrahydrocortisone (THE).
In other tissues, the inactivation of cortisol involves conversion to tetrahydrocortisol (THF) end products.
Normally if you measure THE and THF in the urine they should be of equal amounts, but anything interfering with this enzyme 11B-HSD2, you will end up with less THE relative to the THF end products. This suggests an apparent mineralocorticoid excess (indicative of cortisol activation of mineralocorticoid receptor).
Control of Glucocorticoid Secretion
What controls the secretion?
where is CRH released from and where does it act? what does that release? where does that act? What type of receptor is this last particular receptor and what does it stimulate?
What other factor influences control of cortisol? when does it peak?
Why is this important in diagnosing?
WHat is ACTH? what is it derived from? which gene is it synthesised from?
what can this gene be spliced into? (give two examples and their functions)
What happens if ACTH is high and what will this lead to?
The control of glucocorticoid secretion comes down to the hypothalamic-pituitary axis.
From the hypothalamus we have released corticotrophin-releasing hormone (CRH) and then -> release of adrenocorticotropic hormone/corticotropin (ACTH) from anterior pituitary
The ACTH receptor is GPCR and via cAMP stimulates cholesterol uptake and steroid synthesis. [negative feedback loop present]
Although this is under negative feedback control there is also highly influential circadian rhythm control of cortisol. It seems to always peak early in the morning.
This is important in diagnostic testing as you need to take into account this rhythm (test in morning, normal range will be higher than if tested in eve).
ACTH is a peptide hormone that is synthesised from the pro-opiomelanocortin prohormone gene.
The POMC prohormone can be spliced in various ways to give different signaling molecules, including ACTH and alpha-MSH (melanocyte stimulating hormone), present in skin promoting skin pigmentation by stimulating melanocytes.
ACTH receptor is a member of the melanocortin group of receptors, so ACTH can also bind to other melanocortin receptors. If ACTH is high, then it will bind to melanocortin receptor for alpha-MSH and stimulate melanocytes resulting in skin pigmentation.
Addison’s Disease
what organ is affected? what is this called?
What will low levels of cortisol cause? (symptmoms and pathway)
Why does low cortisol lead to skin pigmentation?
why may you get hypotension? (2 reasons)
What is this cause of this and why does ACTH have no effect?
Common symtoms?
Addison’s disease is a primary adrenal insufficiency, meaning the adrenal cortex is not functioning efficiently to produce sufficient amount of its hormones, especially cortisol and aldosterone.
Low levels of circulating adrenal steroids (cortisol) will via negative feedback result in increased ACTH.
Along with the effects of low cortisol (such as on CVS, low BP), there will also be side-effects of high ACTH such as skin pigmentation due to ATCH on melanocortin receptors.
A loss of aldosterone may result in hypotension, due to loss of water which usually helps maintain blood volume and pressure.
The cause is typically autoimmune destruction of the cells. ACTH acting on the adrenal cortex will have no/little effect because it is the lack of function of the adrenal cortex that is the problem.
Common symptoms:
- Weakness
- Weight loss
- Pigmentation
- Postural hypotension
- Anorexia
Cushing’s syndrome
What is this due to? what is the most common cause?
What is cushing’s disease? what can cause this?
distinguishing between primary and secondary? (what to look out for?
Symtoms of cushing’s
Cushing’s syndrome is the effects of excess glucocorticoids for any reason whatsoever, the most common cause is exogenous (external), as a side effect of glucocorticoid drug treatment.
Cushing’s disease is endogenous due to increased ACTH secretion (so a secondary adrenal disorder), typically due to a pituitary adenoma.
The normal –ve feedback still works, but as there is so much more ATCH, the levels of cortisol are much greater, so –ve feedback working at a much higher level.
The glucocorticoids given are not cortisol but cortisol analogues, so they can activate the negative feedback system leading to low ACTH. Levels of cortisol would be low because of low stimulation from ACTH.
In Cushing’s disease there is an ACTH secreting pituitary tumour which is obviously endogenous, so there is very high levels of ACTH meaning that cortisol will be turned up and despite negative feedback still working we are working at a much higher level.
- Primary – high steroids, low ACTH
- Secondary – would be Cushing’s disease, if it was due to a pituitary tumour, high glucocorticoids and androgens, high ACTH.
Symptoms/Signs: o Central obesity o Slim arms and legs o Bruising, o Hirsuitism (acne, greasy skin, male pattern baldness) -> because of ACTH stimulating weak androgens.
Diagnosis – 24hr cortisol, cortisol/ACTH 9 am and midnight, dexamethasone suppression test and others.
Dexamethasone Suppression Test
What is dexamethasone? and what can it be used for?
How can lung’s cause cushing syndrome and not disease?
What will a low dose inidicate? why?
What will a higher dose indicate?
What if there is no suppression with low or high dose?
what to expect when you give dexamethasone?
Dexamethasone is an exogenous steroid and can be used to diagnose Cushing’s disease -> that ACTH coming from pituitary.
• This is because there are situations where there can be ectopic sources of ACTH (e.g. lung tissue starts releasing ACTH), this would be Cushing’s syndrome but not Cushing’s disease.
Low doses will normally suppress ACTH secretion via negative feedback, if a low dose fails to suppress ACTH secretion then there is Cushing’s.
Higher doses will suppress ACTH secretion in Cushing’s Disease.
• If there is no suppression with low or high dosage, this suggest an ectopic source of ACTH (e.g. a tumour elsewhere) or adrenal tumour.
When you give the dexamethasone, you would expect the next day cortisol to be depressed because it activates the negative feedback system.
In Cushing’s disease, low level dexamethasone would not suppress cortisol, but high doses will suppress it (because the –ve feedback loop is still working).
However, if ectopic source of ACTH, any dose will not be effective because the tumour is not under the feedback control.
This dexamethasone allows to distinguish Cushing’s syndrome from typical Cushing’s disease (pituitary adenoma) from an ectopic source.
