S2: Steroids of the Adrenal Cortex Flashcards
(45 cards)
What are the two parts the adrenal gland is divided into?
Adrenal Cortex
Adrenal Medulla
What do the adrenal cortex and medulla secrete?
Adrenal cortex is the outer layer and secretes steriods
Adrenal medulla is the inner layers and secrete catecholamine’s (mainly adrenaline)
What are the three classes of steroids?
Glucocorticoids - Mainly cortisol in mammals
Mineralocorticoids - Aldosterone
Androgens - sex steroids (can be metabolised in other tissues to become more potent)
What disease does excess glucocorticoids and adrenal insufficiency cause?
Excess glucocorticoids = Cushing’s
Adrenal insufficiency: (primarily cortisol): Addisons
Describe blood supply to adrenal glands
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.
What are the 3 zones that cortical tissue is histologically divided into?
- Zona glomerulosa
- Zona fasiculata
- Zona reticularis
What does the cortical tissue having tissue specific enzyme expression mean?
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.
What substance does steroid synthesis begin from?
Cholesterol
What enzymes are used in steroid synthesis?
Cytochrome enzyme
How is cholesterol converted to progesterone?
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.
Where is aldosterone, cortisol and androstenedione produced?
This occurs due to zone specific expression of enzymes:
- Aldosterone - zona glomerulosa
- Cortisol - zona fasiculata
- Androstenedione - zona reticularis
What is the functions of the adrenal steroids?
- 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.
Describe how cortisol has a glucose conserving effect
It is essential to prevent fatal hypoglycemia
- Stimulates gluconeogenesis in the liver
- Catabolic functions - Lipolysis (release FA from stores) and Proteolysis. These released AA can be fed into the gluconeogenesis pathway.
- Cortisol antagonises the effect of insulin by counteracting the expression of GLUT-4 transporter (insulin induced receptor that allows uptake of glucose into muscle + adipose tissue). This increases insulin levels -> cortisol promotes insulin resistance.
- However, action of insulin is to promote lipogenesis, so although cortisol promote lipolysis the increase in insulin also promotes lipogenesis.
What happens in excess cortisol?
In people with 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.
Functions of glucocorticoids
- Decreased glucose utilisation (glucose sparing - maintaining blood glucose during fasting)
- Proteolysis
- Gluconeogenesis (mainly from AA)
- Lipolysis
- Anabolic actions on liver - Cardiovascular Function
- Required for vascular integrity
- Cortisol deficiency can lead to inappropriate vasodilation (low BP)
- Cortisol excess can cause hypertension via mineralocorticoid receptor
Anti-inflammatory, immunosuppressive function
- Effective drugs in highly profitable industry
- However, prolonged use can lead to side effect of excess cortisol
Explain effect of glucocorticoids on inflammatory mediators derived from arachidonic acid (anti-inflammatory)
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 including prostaglandins. Together the prostaglandins mediate the inflammatory response, the vasodilatation, increase in vascular permeability, attraction of leucocytes. Another class of signalling 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 signalling molecules.
What are prostaglandins?
Prostaglandins are lipid derived signalling molecules, their effects are paracrine (local, diffusion).
- They mediate inflammatory responses by increases vasodilation and attracting leucocytes.
How is Arachindonic acid formed?
It is converted from phospholipid with the enzyme phospholipase A2
Arachindonic acid is the mother substance for inflammation
Describe structure of glucocorticoid receptor
- Nuclear receptor family
- One gene for it but alternate splicing on 9th exon can lead to 2 major isoforms ( alpha and beta)
- Characteristic 3 domain structure
Describe the mechanism of glucocorticoid receptors
- The receptor will bind its ligand (in this case cortisol), via the sequence in the ligand binding domain
- The receptor dimerises
- Bound receptor can bind to DNA by the DNA binding domain to the hormone response element of target gene
This is why nuclear receptors are controllers of transcription, they can turn on or turn off the transcription of numerous target genes by binding to the beginning of the gene at promoter region (in this case glucocorticoid response element)
Following binding of the receptor to the glucocorticoid response element, 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.
Transactivation – Where glucocorticoid receptor enhances transcription of the target gene -> (so increased )
Transrepression – Where glucocorticoid receptor represses transcription of target gene
What type of action are glucocorticoids though to have on genes?
Many anti-inflammatory effects of GCs thought to be due to transrepression of genes, which is why it is major therapeutic target (could develop more specific drugs).
Funtion of mineralocortioid aldosterone
The mineralocorticoid aldosterone has a function of actively retaining salt via the kidney and hence retaining water passively.
What does the mineralocorticoid receptor do?
The mineralocorticoid receptor (a nuclear receptor), induces expression (transactivation) of genes for the Na+/K+ ATPase and a particular type of K+ channel (active secretion of potassium).
It also has a role in volume regulation via RAAS.
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. (in macula densa) or sympathetic activity it will activate the renin-angiotensin pathway, through the juxtaglomerular apparatus in the nephron.
Describe how aldosterone is secreted
There is first the conversion of angiotensinogen to angiotensin I by the enzyme renin. Circulating angiotensin I is converted to angiotensin II by ACE (angiotensin converting enzyme).
Ang II stimulates aldosterone secretion, which will be released according to need for sodium/water retention
