Steroids of the Adrenal Cortex Flashcards
What are the steroids of the adrenal cortex?
Glucocorticoids: principally cortisol in mammals
Mineralocorticoids: aldosterone
Androgens
Excess cortisol (hypercortisolism): Cushing’s syndrome
Adrenal insufficiency (primary): Addison’s disease
What is the adrenal blood flow like and what hormones are synthesised in each zone?
Blood flows from outer cortex to inner medulla which secretes adrenaline and noradrenaline
There are three zones:
The outer zone, zona glomerulosa, this is responsible for aldosterone synthesis
Cortisol is synthesised in the middle zone, called the zona fasciculata
The adrenal androgens are synthesised from the inner zone called the zona reticularis
Layer-specific enzymes; steroid synthesis in one layer can inhibit different enzymes in subsequent layers
Results in functional zonation of cortex with different hormones made in each layer
How are steroids synthesised in the adrenal cortex, taking into account the layers?
Begins with cholesterol
The CYP terminology refers to the gene names of specific steroid synthesis enzymes wither in the mitochondria or SER
In the outer layer cholesterol is converted to pregnenolone
This newly synthesised pregnenolone it can wither be converted to progesterone in the outer layer (eventually ending up as aldosterone) or be washed down into the second layer and be converted to 17-OH pregnenolone
In the middle layer 17-OH pregnenolone may be washed down into the inner layer and converted to DHEA (and eventually adrenal androgens) or commit on the route of cortisol synthesis by being turned into 17-OH progesterone
What is the function of mineralocorticoids?
Sodium retention (whole body sodium) Active reabsorption of sodium (with associated passive reabsorption of water) Active secretion of potassium Volume regulation (part of RAAS)
How is aldosterone secretion controlled?
The function of aldosterone is to increase sodium reabsorption and therefore water volume as well
So ECF volume is increased therefore blood volume is increased
There is a second function of aldosterone and that is to promote potassium secretion
Aldosterone secretion is in a negative feedback loop with potassium
As potassium in the plasma rises aldosterone secretion also rises as a direct stimulation of the adrenal cortex which will promote potassium secretion from the distal nephron
In terms of blood volume the control of aldosterone secretion is via indirect sensors of blood volume with the transducer as the juxtaglomerular apparatus which secretes renin
Angiotensin II increases aldosterone secretion
A drop in perfusion pressure in the afferent arteriole stimulating the JGA
Reduced renal perfusion e.g. vasoconstriction, there will be reduced delivery of salt to the distal tubule where signalling is activated by the macula densa which in turn stimulates the JGA to release renin
And vice versa
How does aldosterone affect different parts of the renal system?
Actions of aldosterone on the ascending loop of Henle, distal convoluted tubule and cortical collecting ducts of the kidney controlling the reabsorption of salt (Na+) and water
Aldosterone binding to the mineralocorticoid receptor MR results in dimerisation translocation to the nucleus and activation of hormone response elements
The effects are:
Increased expression of the ENaC channels to permit more sodium down the electrochemical gradient and at the same time increased expression of the potassium sodium ATPase pump to maintain an equilibrium
Also increases expression of the proton ATPase out of the cell into the lumen
The MR has equal affinity for aldosterone are cortisol
So what is it that prevents cortisol from acting on the MR?
An enzyme, that converts cortisol to cortisone
If cortisol and aldosterone have a similar affinity for aldosterone receptors and circulating cortisol is of a much higher concentration, then why doesn’t it stimulate salt and water retention?
Cortisol is rapidly metabolized to inactive cortisone in the kidney
Requires enzyme, 11beta-hydroxysteroid dehydrogenase type 2
Rare inactivating mutation of 11B-HSD2 leads to syndrome of apparent mineralocorticoid excess (AME)
Called apparent as the signs are what you would get with hyper secretion of aldosterone like in Conn’s disease
Liquorice contains a compound that blocks this enzyme
So there is a thing called liquorice intoxication similar to AME but it’s reversible
What is the function of glucocorticoids?
Decreased glucose utilization (glucose sparing)
Proteolysis
Gluconeogenesis (mainly from amino acids)
Lipolysis
Overall: maintenance of blood glucose – essential for survival during fasting
What are the major actions of cortisol on metabolism and other targets of cortisol action? How does cortisol affect every cell in the body at some point?
Metabolic effects are related to energy balance:
These can be understood as glucose-sparing, to preserve glucose
Cortisol can promote lipolysis so that stored fat can be stored and used as energy
In order to stop plasma glucose from dropping it also increases gluconeogenesis
It also causes insulin resistance in muscle encouraging them to use the fat deposits
It promotes proteolysis, stimulating the release of AAs from body proteins so that they can be used as a substrate for gluconeogenesis
Excess cortisol could lead to hyperglycaemia
So cortisol indirectly causes adipose tissue deposition (weight gain)
Cardiovascular effects:
Cortisol seems to be required to maintain vascular integrity and blood pressure
Excess cortisol leads to hypertension while little cortisol leads to hypotension
Cortisol seems to inhibit epithelium nitric oxide synthase expression so too little cortisol could mean too much NO so vasodilation
Immune effects:
We have ad 60 years of glucocorticoid based therapy, activating the glucocorticoid receptor
There is a trade off between the desired healing effect e.g. suppressing or preventing the inflammatory reaction of asthma in exchange for an undesired metabolic effect such as hyperglycaemia or hypertension
What are the effects of glucocorticoid on inflammatory mediators derived from arachidonic acid
Many of the inflammatory mediators are derived from membrane phospholipids
A particular enzyme, phospholipase A2, that synthesises from phospholipids arachidonic acid which is the first step in the synthesis of a wide variety of local signalling molecules; autocrine and paracrine
This include prostaglandins and leukotrienes two major components of these
Leukotrienes cause smooth muscle contraction in bronchioles and their Overproduction is a major cause of inflammation in asthma
So a key role of cortisol is actually inhibiting this first stage in the synthesis of these immune signalling molecules, arachidonic acid by inhibiting phospholipase A2
Cytokines are also potentially modulated by cortisol
What is the glucocorticoid receptor like?
Member of the nuclear receptor super-family
Characteristic 3-domain structure which involves the DNA binding domain, th eligand binding domain and the domain for the coregulators and repressors
There is just one glucocorticoid receptor gene
What are the regulations of genomic and non-genomic effects in target cells by glucocorticoid receptors?
Cortisol from the ECF will enter the cell and then there are cytosolic glucocorticoid receptors present which it will bind and dimerise with and then translocate to the nucleus
It can act with hormone response elements from other signalling pathways as well e.g. STAT
Transactivation: glucocorticoid receptor (GR) enhances transcription of target gene
Transrepression: GR represses transcription of target gene
Many anti-inflammatory effects of GCs thought to be due to transrepression – major therapeutic research target
How are glucocorticoid and androgen production controlled?
Cortisol and the adrenal androgens are both under control of this hypothalamus- anterior pituitary- adrenal cortex pathway
The system is under negative feedback control
VP: vasopressin (ADH) is primarily under osmotic control, however the overall set point is restrained by cortisol
Lack of cortisol leads to an increase of vasopressin, though CRH may stimulate VP
Corticotropin-releasing hormone (CRH)
Adrenocorticotropic hormone (corticotropin, ACTH)
ACTH receptor: G-protein coupled, via cAMP stimulates cholesterol uptake and steroid synthesis
How is ACTH synthesised?
ACTH is a peptide hormone
ACTH is synthesised from the pro-opiomelanocortin prohormone
ACTH receptor is member of the melanocortin group of receptors
There is some cross-reactivity
Different forms of melanocyte-stimulating hormones bind to melanocortin receptors
ACTH can also bind to other melanocortin receptors
Excess circulating ACTH may cause skin pigmentation
What happens when there’s adrenal insufficiency?
Addison’s disease: primary adrenal insufficiency
In this case the adrenal cortex is damaged, fails to secrete its hormones in a normal amount so reduced cortisol and reduced androgens
So increased CRH and ACH
Secondary (hypopituitarism or secondary to failure in RAAS)
Could be due to enzyme defects in steroid synthesis pathways
