The adrenals and their hormones

Question 1

Where are the adrenal glands found

Answer 1

▪ Embedded on the superior pole of each of the two kidneys – each has its own capsule. ▪ Sometimes called the suprarenal glands.

Question 2

Describe the vasculature of the adrenal glands

Answer 2

Left adrenal vein drains into renal vein

Right adrenal vein drains into IVC

Both adrenals have many arteries but only one vein

Question 3

Why is it important that the adrenal glands are supplied by lots of arteries

Answer 3

A high rate of delivery of substrates and nutrients

Question 4

Describe the inner zones of the adrenal gland

Answer 4

▪ The Medulla. ▪ The Cortex – Split into 3 zones: o Zona Glomerulosa (outer) o Zona Fasciculata (middle) – Cells line up as strings. o Zona Reticularis (inner)

Question 5

Describe how the zona fasciculata can be differentiated from the outer glomerulosa and inner reticularis cells

Answer 5

It is made up of ‘chains’ of cells giving the effect of bundles.

Question 6

Describe the blood flow to the adrenal cortex

Answer 6

The blood flow to the adrenal cortex is from the arteries that feed the outside of the gland. There are two ways in which the blood passes to these zones: ▪ Through the cells (most of the blood). ▪ Some vessels go through the cortex to access the medulla. The tributary of central vein is found in the adrenal medulla.

Question 7

Describe the hormones released by the adrenal medulla

Answer 7

▪ Made up of chromaffin cells (post-ganglionic nerve fibres in a specialised form that can be readily stained with chromic acid salts). ▪ This means it is part of the sympathetic nervous system where the cells innervated will release their substances (not as NT) as hormones into the circulation. ▪ CATECHOLAMINES are associated with chromaffin cells.

Question 8

Describe the hormones released by the adrenal cortex

Answer 8

▪ Cortical hormones are steroids so they are known as corticosteroids. ▪ CORTICOSTEROIDS are associated with the cortex.
These hormones are essential to life.
Different zones produce different corticosteroids.

Question 9

Describe the capsule that surrounds the adrenal glands

Answer 9

Tough, fibrous capsule surrounds the gland to provide protection.

Question 10

Describe the specific products of the adrenal cortex

Answer 10

CORTEX – Corticosteroids:

▪ Mineralocorticoids – E.G. Aldosterone. o Made in Zona Glomerulosa. ▪ Glucocorticoids – E.G. Cortisol. o Made in Zona Fasciculata & Reticularis. ▪ Sex Steroids – E.G. Androgens & Oestrogens. o Made in Zona Fasciculata & Reticularis.

All steroid hormones are derived from cholesterol.

Question 11

Describe the specific products of the adrenal medulla

Answer 11

MEDULLA – Catecholamines: ▪ Adrenaline (epinephrine) – 80% ▪ Noradrenaline (norepinephrine) – 20% ▪ Dopamine – very small amounts.

Question 12

Describe the consequence of the vein being in the medulla

Answer 12

Anything produced in the cortex has to drain through the medulla to enter the vein.

Question 13

What is the consequence of steroid hormones being lipophilic

Answer 13

Corticosteroids are steroid hormones and hence are lipophilic. This means that they cannot be stored to a great extent as they would simply cross the lipid component of cell membranes and move out of the cells into the general circulation once synthesised. Therefore they are synthesised ‘on demand’ when the adrenocortical cells are stimulated appropriately.

Question 14

What is the basic structure of cholesterol called

Answer 14

The cyclopentanoperhydrophenanthrene nucleus.

Question 15

Why are steroid hormones lipophilic

Answer 15

Because of their cholesterol backbone

Question 16

Why are different hormones produced in different regions of the adrenal cortex

Answer 16

Presence of different enzymes in the mitochondria of the different zones.

Question 17

Describe the uptake of cholesterol into the cells

Answer 17

The original pre-cursor molecule is cholesterol which can reach the cells from the blood mainly as LDL cholesterol, or can be synthesised from acetyl coA from within the cell. The first most important step in corticosteroid synthesis is the rate-limiting transport of intracellular cholesterol across the outer to the inner mitochondrial membrane, where, in the presence of the enzyme p450scc it is converted into pregnenolone. A specific steroidogenic acute regulatory (stAR) protein mediates this transport process, which is controlled by the adenohypophysial hormone corticotrophin.

Question 18

Describe how mineralocorticoids, such as aldosterone, are synthesized

Answer 18

In the glomerulosa cells, progesterone is converted to deoxycorticosterone by 21-hydroxylase, which is found in the microsomes and endoplasmic reticulum. Deoxycorticosterone is then converted to corticosterone by the mitochondrial enzyme 11beta-hydroxylase. In humans corticosterone, a weak mineralocorticoid, is converted to the far more potent aldosterone by aldosterone synthase.

Question 19

Why can’t the zona fasciculata and reticularis produce aldosterone

Answer 19

They don’t have aldosterone synthase and so cannot produce aldosterone.

Question 20

Describe the synthesis of cortisol

Answer 20

Pregnenolone enters the cytoplasm where it is converted to progesterone by the enzyme 3beta-hydroxysteroid dehydrogenase. 17alpha hydroxylase converts progesterone into 17alpha-hydroxyprogesterone. This enzyme is located in the microsomal-endoplasmic reticulum fraction. 21 hydroxylase then converts 17alpha-hydroxyprogesteron into 11beta-deoxycortisol. 11beta-deoxycortisol is converted into cortisol by 11beta-hydroxylase.

Question 21

Describe the synthesis of androgens

Answer 21

Pregnenolone can be converted into 17alpha-hydroxypregenelone by 17alpha-hydroxylase. This can then be converted into dehydroepiandrosterone (DEHA) by the same enzyme. 3beta-hydroxysteroid dehydrogenase then converts DEHA into androstenedione.

Question 22

Why can’t the adrenals produces testosterone, oestrogen and dihydrotestosterone

Answer 22

No 17beta-hydroxysteroid dehydrogenase to convert androstenedione into testosterone.
No aromatase to convert testosterone into oestradiol.
No p450c5 to convert testosterone into dihydrotestosterone.

Question 23

Where does cortisol synthesis mainly take place

Answer 23

The fasciculata cells.

Question 24

Where does androgen synthesis mainly take place

Answer 24

The reticularis cells

Question 25

Describe the androgens produced in the adrenals

Answer 25

▪ Androgens produced in the cortex are weak and are made powerful in the testes. ▪ Androstenedione is a less weak androgen and can be converted to testosterone and dihydrotestosterone. ▪ Androgens are the precursors of oestrogens.

Question 26

Describe how cortisol is transported in the blood

Answer 26

o 80% bound to corticosteroid binding globulin (CBG or transcortin). o 10% bound to albumin. o 10% unbound → Bioactive.

Question 27

Describe how aldosterone is transported in the blood

Answer 27

o ~60% bound to CBG. o ~40% unbound → Bioactive.

Question 28

Describe how the levels of circulating cortisol change throughout the day

Answer 28

8am 140-690 nmol/l
4pm 80-330 nmol/l
Cortisol has a diurnal rhythm- meaning it is synchronised with the day/night cycle. It may or may not be a circadian rhythm.

Question 29

Describe the levels of aldosterone in the circulation

Answer 29

Aldosterone is NOT controlled by the pituitary gland so time of day is not important but position is important as it is involved in the control of fluid and balance. o Upright (orientation) – 140-560 pmol/l.

Question 30

What is key to remember about the difference in cortisol levels and aldosterone levels

Answer 30

Levels of cortisol are measured in NANOmol/l whereas aldosterone is measured in PICOmol/l so there is a 1000-fold difference. I.E. More cortisol than aldosterone.

Question 31

Describe the nature in which cortisol is released

Answer 31

Cortisol is released in pulses. This means that its release is controlled by the pituitary gland.

Question 32

What type of receptors can cortisol bind to

Answer 32

Cortisol is not very selective and so can bind to both glucocorticoid and mineralocorticoid receptors.

Question 33

What type of receptors can aldosterone bind to

Answer 33

Mineralocorticoid receptors

Question 34

Despite the fact that cortisol levels are 1000x higher than aldosterone levels, why isn’t cortisol constantly binding to mineralocorticoid receptors

Answer 34

The kidneys have an enzyme which converts bioactive cortisol to cortisone (inactive) using enzyme: 11bhydroxysteroid dehydrogenase 2. o The enzyme constantly removes cortisol so it doesn’t interfere with the MR. This allows aldosterone to bind and elicit its effects inside the cell. The placenta and brain also possess this enzyme. It is important that it’s present in the placenta as cortisol can inhibit growth, hence you don’t want it to cross the placenta to the foetus.

Question 35

Describe how Cushing’s syndrome can increase mineralocorticoid activity

Answer 35

In the presence of excess glucocorticoids, the 11BHSD2 enzyme system becomes saturated and increased mineralocorticoid activity occurs.

Question 36

Describe, basically how aldosterone can stimulate Na+ reabsorption

Answer 36

In the cells of the distal convoluted tubule and cortical collecting ducts aldosterone regulates the synthesis of an apical membrane sodium channel and also subunits of the basolateral Na+K+ATPase. The enhanced activity of the Na+K+ATPase maintains the low intracellular Na+ concentration, which allows Na+ to enter the cell down their electrochemical gradient through the aldosterone-regulated apical Na+ channels from the tubular fluid. The overall effect of aldosterone is therefore to stimulate the reabsorption of sodium ions from the tubular fluid into the circulation. This is particularly important in the kidneys but also in the sweat glands, gastric glands and the colon.

Question 37

Describe, basically how aldosterone can stimulate K+ secretion

Answer 37

Aldosterone also stimulates the synthesis of a potassium channel in the apical membrane of its target cells in the distal nephron, and plays a major role in potassium balance by promoting the secretion of this ion into the tubular fluid, and ultimately its secretion in the urine. The increase in sodium reabsorption across the apical membrane produces a negatively charged tubular lumen which provides the driving force for the secretion of potassium ions into the tubular fluid. Therefore, aldosterone is an important, direct physiological regulator for controlling renal potassium secretion and hence the plasma potassium concentration.

Question 38

Describe, basically, how aldosterone can stimulate H+ secretion

Answer 38

In the intestinal tract a Na+/H+ exchange transporter is stimulated by aldosterone, increasing the absorption of Na+ and Cl- across the cells and into the general circulation in exchange for H+. So it will have an effect on pH regulation of the blood

Question 39

Describe how aldosterone increases the fluid volume of the blood

Answer 39

1. Aldosterone stimulates reabsorption of Na+ so plasma osmolality increases in presence of aldosterone. 2. Increased osmolality stimulates release of vasopressin. 3. VP stimulates water reabsorption in kidney collecting duct → Aldosterone increases fluid volume of blood.
   This is a long-term mechanism by which the arterial blood pressure is maintained.

Question 40

Describe the cells in the kidney that are involved in the release of renin

Answer 40

▪ In the nephron, the glomerulus receives blood from the afferent arteriole and blood leaves via efferent. ▪ Macula densa ells lining the ascending limb of loop of Henle touch the granular cells that line the afferent arteriole. ▪ The Granular (next to glomerulus) touch the Macula Densa cells (line the loop of Henle). ▪ The cells of Macula Densa respond to Na+ concentration changes The granular cells are a source of the ENZYME – RENIN, important in the production of aldosterone.

Question 41

What are the granular cells also known as

Answer 41

The juxta-glomerular cells

Question 42

What are the causes of renin release

Answer 42

Decreased Renal Perfusion Pressure (associated with decreased arteriole blood pressure). Increased Renal Sympathetic Activity (direct to juxta-glomerular cells). i. The JGC (juxta-glomerular apparatus) has sympathetic innervation. ii. The sympathetic system is activated when the blood pressure falls. iii. This leads to renin release. Decreased Na+ load to top of the loop of Henle. i. Decreased Na+ concentration at the top of the loop of Henle. ii. This leads to activation of JGA and the release of renin.

Question 43

What else can change renin release

Answer 43

Various hormones such as vasopressin and catecholamines also exert an influence on the renin-angiotensin system. Vasopressin decreases renin release and while there is evidence for a direct effect on the JG cells, it s likely it can also exert an indirect negative influence through its vasopressor activity.
▪ Corticotrophin – Has a permissive effect as it will enhance the renin-angiotensin system. ▪ Potassium levels in the blood – Increase in K+ stimulates aldosterone production leading to increased secretion of K+.

Question 44

Describe how renin stimulates the release of aldosterone in the renin-angiotensin system

Answer 44

1. Liver produces angiotensinogen (large protein). 2. Renin (released by JGC) breaks down angiotensinogen to angiotensin I. 3. Then, ACE (angiotensin converting enzyme) converts angiotensin I to angiotensin II. 4. Angiotensin II stimulates the zona glomerulosa to produce aldosterone.

Question 45

Describe the other effects of angiotensin 2

Answer 45

it is a vasoconstrictor. Stimulatory control on vasopressin production. It also stimulates the thirst centre in the lateral hypothalamus.

Question 46

Describe the mechanism of action of aldosterone when it binds to its receptor

Answer 46

1. Aldosterone passes through the cell membrane and binds to intracellular receptors. 2. Hormone-receptor complex moves to the nucleus and acts as a transcription factor when binded to DNA. 3. Many proteins produced are enzymes or pumps. a. Proteins may stimulate pumps like ATPase on baso-lateral membrane to pump sodium into blood. b. Aldosterone stimulates synthesis of ion channels – i.e. Na+ channels in apical membrane.

Question 47

What is an indirect effect of aldosterone

Answer 47

Increased water reabsorption.

Question 48

What is needed for normal physiological action of cortisol

Answer 48

Cortisol heavily binding to mineralocorticoid receptors, whilst partially binding to glucocorticoid receptors.

Question 49

What do you want cortisol to do in times of stress

Answer 49

Optimal GR binding, lower MR binding, and then return to normal as quickly as possible.

Question 50

What are the effects of cortisol on glucose

Answer 50

Increases gluconeogenesis and glycogenesis. Results in an overall increase in blood glucose concentration. The initial non-carbohydrate precursors are certain amino acids derived from protein breakdown which produce pyruvate and oxaloacetate, and glycerol from lipid catabolism (cortisol increases lipid catabolism and protein catabolism). It also prevents glucose from being stored in the peripheries (skeletal muscle) and fat storage (adipocytes) as these are not accessible and we want the fatty acids for gluconeogenesis. It does this by decreasing blood flow to these areas. Reducing the expression of GLUT 4 receptors and inhibiting lipoprotein lipase.

Question 51

What is the effect of cortisol on memory at physiological levels

Answer 51

Pro-memory

Question 52

What is the significance of the dantate gyrus

Answer 52

It is where new memories are laid down, stored and produced

Question 53

Describe how cortisol and serotonin work together in memory formation

Answer 53

The hippocampus has a rich serotoninergic innervation
and several studies have claimed that altering 5-HT (serotonin) can itself change the number of dividing granule cells in the dentate gyrus. Activation of 5-HT1A receptors has been reported to increase cell proliferation in the dentate gyrus.
Cortisol and serotonin have a reciprocal relationship within the hippocampus. Serotonin increasing the sensitivity of the hippocampus to cortisol, and cortisol increasing 5HT1A receptor density.

Question 54

What is the role of cortisol on inflammation at physiological levels

Answer 54

Anti-inflammatory, to maintain homeostasis, so inflammation doesn’t run off uncontrollably.

Question 55

What are the effects of caffeine and alcohol on cortisol levels

Answer 55

They increase cortisol levels

Question 56

What is the effect of chronic stress on memory formation

Answer 56

Chronic stress=chronically high cortisol levels
Cortisol binds more to GR receptors
Cortisol destroys hippocampus
Hippocampus shrinks
Less capacity to form memories
Long term memory is impaired

Question 57

What are the effects of a large amount of cortisol

Answer 57

▪ ANTI-INFLAMMATORY Action ▪ IMMUNOSUPPRESSIVE Action ▪ ANTI-ALLERGIC Action These are all associated with decreased production of molecules such as prostaglandins, leukotrienes and histamine etc. as well as on the movement and function of leukocytes and production of interleukins.

Question 58

List the physiological actions of cortisol

Answer 58

▪ Metabolic Effects: o Stimulates peripheral protein catabolism. ▪ Cushing’s Syndrome (excessive production of cortisol) – arms and legs are very thin due to atrophy of the muscles. o Hepatic gluconeogenesis. o Fat metabolism. o Enhances effects of glucagon and catecholamines. o Stimulates glycogenesis . o Makes tissues less responsive to insulin. o OVERALL: Increase blood glucose concentration. ▪ Some mineralocorticoid effects. ▪ Some renal (increase excretion of water) and cardiovascular effects. ▪ Some other random effects (e.g. on bone, CNS, growth)

Question 59

What happens in people who do not have 11BHSD2

Answer 59

Mineralocorticoid excess syndrome
Cortisol-induced sodium retention
Hypokalaemia
Hypertension

Question 60

Describe the control of cortisol

Answer 60

▪ Corticotrophs are controlled by hypothalamic hormones. ▪ Cortisol has negative feedback effects directly to the pituitary and indirectly to the hypothalamus. ▪ ACTH has an auto-negative feedback loop to the hypothalamus. ▪ There is a circadian rhythm for cortisol which originates from the biological clock which resides in the suprachiasmic nucleus. ▪ Because of the variation in cortisol levels with time, blood sampling needs to be carefully arranged.

Question 61

Describe the mechanism of action of cortisol

Answer 61

▪ Cortisol binds to intracellular receptors and has a GENOMIC effect.

1. One of the proteins produced by the cell is annexin 1. 2. Annexin 1 leaves the cell and has an autocrine effect – binds to itself. 3. The binding has an effect on a phospholipase enzyme which works on the phospholipase in the membrane to produce arachidonic acid (precursor for prostaglandins). 4. Cortisol blocks the production of arachidonic acid thereby decreasing prostaglandin synthesis.

Question 62

Describe the actions of adrenal androgens

Answer 62

Synthesised in zona reticularis
= dehydroepiandrostenedione (DHEA), DHEAS, androstenedione
Weak biological activity – but converted to more active androgens eg testosterone by enzymes in peripheral tissues
Women = adrenal production of DHEA and DHEA-S contributes substantially to overall androgen production and effects
Men = the adrenal contribution to androgen production is very small

Question 63

When do the adrenal androgens become important

Answer 63

▪ Particularly important in post-menopausal women as a precursor for oestrogen (and androgen) synthesis by target tissue in the absence of ovarian steroids.