Adrenal Glands

Question 1

Describe anatomical locaton of the adrenal glands.

Answer 1

Lie retroperitoneally on the upper pole of the kidneys.

Question 2

State the embryological origin of the adrenal cortex, and medulla.

Answer 2

Adrenal Cortex
arises from intermediate mesoderm

Chromaffin cells (adrenal medulla) arise from
neural crest cells (particularly, they are modified sympathetic ganglion cells)

Question 3

Describe the anatomy of the adrenal gland.

Answer 3

In adults the adrenal cortex is composed of three zones—the zona glomerulosa, the zona fasciculata, and the zona reticularis.

Chromaffin cells establish the inner portion of the adrenal gland, which is called the adrenal medulla. The chromaffin cells of the adrenal medulla have the potential to develop into postganglionic sympathetic neurons.

The outer connective tissue capsule of the adrenal gland is penetrated by a rich arterial supply coming from three main arterial branches.

Question 4

Identify the main hormones produced by each zone of the adrenal cortex.

Answer 4

PRODUCES STEROID HORMONES

1) Zona Glomerulosa
Mineralocorticoids – e.g. aldosterone

2) Zone fascilculata
Glucocorticoids – e.g. cortisol

3) Zona reticularis
Sex steroids – androgens

Question 5

What factor controls aldosterone production by the zona glomerulosa ? What is the role of aldosterone ?

Answer 5

• Controlled by renin – angiotensin

- Role: electrolyte and fluid homeostasis

Question 6

What factor controls cortisol production by the zona fasciculata ? What is the role of cortisol ?

Answer 6

• Secretion controlled by ACTH

- Role: carbohydrate, lipid and protein Metabolism

Question 7

Describe blood supply of the adrenal cortex, and medulla.

Answer 7

• Supplied by the superior middle and inferior adrenal arteries; anastomose under the capsule
• Cortex receives short cortical arteries run in parallel with the cords of cells to the medulla

• Medulla receives:
- blood draining from the cortex (containing
adreno-corticosteroids which influence the
production of adrenaline by the medullary cells)
- Fresh arterial blood in long cortical arteries

Question 8

Identify short-term stress response of the adrenal gland.

Answer 8

VIA CATECHOLAMINE (ADRENALINE AND NORADRENALINE) as a result of nervous stimulation of the adrenal medulla by the SNS, from the hypothalamus:

1) Increased HR
2) Increased BP
3) Liver converts glycogen to glucose and releases glucose to blood
4) Dilation of bronchioles
5) Changes of blood flow patterns leading to decreased digestive system activity and reduced urine output
6) Increased metabolic rate

Question 9

Identify long-term stress response of the adrenal gland.

Answer 9

VIA MINERALOCORTICOIDS AND GLUCOCORTICOIDS as a result of hormonal stimulation (hypothalamus releases CRH which stimulates anterior pituitary corticotrophs to release ACTH which acts on adrenal cortex):

MINERALOCORTICOIDS

1) Retention of sodium and water by kidneys
2) Increased BV and BP

GLUCOCORTICOIDS

1) Proteins and fats converted to glucose or broken down for energy
2) Increased blood glucose
3) Suppression of immune system

Question 10

Identify the main actions of cortisol on the body.

Answer 10

• It increases blood glucose by stimulating gluconeogenesis in the liver
• Stimulate breakdown of protein in muscle (via decreased protein synthesis using glucose in muscle cells, and increased proteolysis forming AAs which can then feed onto gluconeogensis in the liver)
• Stimulate breakdown of fat in fat cells (via decreased lipogenesis using glucose and instead increased lipolysis forming glycerol which can feed into gluconeogenesis)

-Therefore, increases plasma concentrations of glucose, FAs, AAs

+ Major role in ability to cope with physical (trauma, infection, allergies) or neurological (anxiety, restraint) stresses

+ anti-inflammatory/anti-allergic/anti-immune actions

Question 11

Identify the main causes of Cushing’s disease.

Answer 11

1. ACTH-releasing pituitary tumour
2. Ectopic ACTH-releasing tumour (usually in lungs, pancreas or kidney)
3. Tumour of the adrenal cortex - hyper-secretion of cortisol
4. Administration of pharmacological doses of glucocorticoid drugs

All result in glucocorticoid excess

Question 12

Identify the main clinical features of Cushing’s disease.

Answer 12

1. Hyperglycaemia due to gluconeogenesis in liver- adrenal/steroid diabetes
2. Muscle wasting (loss of protein synthesis in muscle and bone (and most tissues))
3. Increase in FFA in plasma (reduced lipogenesis and enhanced lipolysis)
4. Increased insulin release
5. Tissue edema, hypokalemia, hypertension
6. GI Tract ulceration
7. Immunosuppressive, anti-allergic, and anti-inflammatory actions

Question 13

Describe the physiological actions of increased insulin release, as part of Cushing’s Syndrome.

Answer 13

Redistribution of fat stores to face (moon face), neck, upper trunk
“buffalo hump”; β-cell exhaustion

Question 14

Why does tissue edema, hypoK, hyperT occur as part of Cushing’s ?

Answer 14

Due to increased glomerular filtration (glucocorticoid effect) and water and Na+ retention (mineralocorticoid effects)

Question 15

Why does GI tract ulceration occur as part of Cushing’s ?

Answer 15

Due to excess H+ secretion and decreased mucous production

alkalosis due to increased H+ loss in GI tract and kidney

Question 16

Why do immunosuppressive and anti-allergic and anti-inflammatory actions occur as part of Cushing’s ?

Answer 16

Because decreases in protein synthesis results in increased neural excitability, lymph node lysis, inhibition of haematopoiesis and lymphocyte production

Question 17

What is the treatment for Cushing’s ?

Answer 17

Surgical removal of tumour / decreases in drug dosage

Question 18

Describe mechanisms controlling aldosterone secretion.

Answer 18

Three pathways stimulate glomerulusa cells to synthesize aldosterone:

1) Renin-angiotensin cascade
The liver synthesizes and secretes angiotensinogen. Renin, which is synthesized by the granular (or juxtaglomerular) cells of the juxtaglomerular apparatus (JGA) in the kidney cleaves this angiotensinogen to form ANG I. Finally, angiotensin-converting enzyme (ACE) cleaves ANG I to form ANG II. On the plasma membrane of the glomerulosa cell, ANG II binds to the AT1 receptor, which couples through the Gα q -mediated pathway to phospholipase C (PLC). Stimulation of PLC leads to the formation of (DAG) and IP3. DAG activates PKC. IP 3 triggers the release of Ca 2+ from intracellular stores, thus causing a rise in [Ca2+]i , which activates Ca 2+ -dependent enzymes such as PKC. These changes lead to depolarization of the glomerulosa cell’s plasma membrane, opening of voltage-activated Ca 2+ channels, and a sustained increase in Ca 2+ influx from the extracellular space. This rise in [Ca2+] i is primarily responsible for triggering the synthesis (i.e., secretion) of aldosterone. Aldosterone secretion increases because the rise in [Ca2+]i facilitates the production of pregnenolone either by directly increasing the activity of SCC or by enhancing the delivery of cholesterol to the SCC enzyme in the mitochondria. In addition, increased [Ca 2+ ]i also stimulates aldosterone synthase and in this manner enhances the conversion of corticosterone to aldosterone.

2) ACTH
Increases in ACTH raise [cAMP]i and activate PKA, which phosphorylates large numbers of cytosolic proteins. At some as-yet undefined level, these changes stimulate Ca 2+ influx across the plasma membrane and enhance the synthesis and secretion of aldosterone.

3) Increased plasma K+:
An increase in extracellular K + has a direct action on the glomerulosa cell. Several K + channels maintain the normal resting potential of these cells. Thus, high [K+]o depolarizes the plasma membrane and opens voltage-gated Ca2+ channels. The result is an influx of Ca2+ and a rise in [Ca2+]i that stimulates the same two steps as ANG II—production of pregnenolone from cholesterol and conversion of corticosterone to aldosterone. Unlike the situation for ANG II, the [Ca2+]i increase induced by high [K+]o does not require activation of PLC or release of Ca 2+ from the intracellular stores. Because increased [K+]o and ANG II both act by raising [Ca2+]i , they can act synergistically on glomerulosa cells.

Question 19

Describe structure and cuntion of the juxta-glomerula apparatus.

Answer 19

The JGA is located at the glomerular pole of the nephron, between the afferent and efferent arterioles, where the early distal tubule comes in close proximity to its own glomerulus. Histologically, the JGA comprises specialized epithelial cells of the distal tubule called macula densa cells, as well as specialized smooth-muscle cells of the afferent arteriole, which are called granular cells or juxtaglomerular cells. Macula densa cells and granular cells communicate by means of an extracellular matrix.

Decreases in effective circulating volume—or the associated decreases in systemic arterial pressure—stimulate renin release from the granular cells of the JGA . Enhanced renin release leads to increased levels of ANG II and aldosterone. ANG II negatively feeds back on renin release directly by inhibiting renin release by granular cells (short-loop feedback). ANG II also negatively feeds back on renin release indirectly by acutely increasing systemic arterial pressure, thereby reducing the stimuli to release renin. Finally, aldosterone negatively feeds back on renin release more slowly by enhancing renal Na + reabsorption and thus increasing effective circulating blood volume and blood pressure. Therefore, ANG II and aldosterone complete the regulatory feedback circuit that governs the secretion of aldosterone.

Question 20

Given as glucorticoids CAN bind to mineralocorticoid receptors (with same affinity as to its own receptor), why don’t they have mineralocorticoid affects ?

Answer 20

11 beat-hydroxysteroid dehydrogenase inside the cll metabolises cortisol to cortisone, a product that has little affinity for glucocorticoid or mineralocorticoid receptor into the cell.

HOWEVER,

Glycyrrhetinic acid inhibits 11 beta-HSD, so cortisol is not metabolised and preferentially occuppied MR and GR over aldosterone (and may then have mineralocorticoid effects)
SIMILARLY,
If disease where excess glucocorticoids (e.g. Cushing’s), then insufficient enzyme for all the glucocortioid, which then starts having effects.

Question 21

Identify a disease related to glucorticoid/mineralocortioid deficiency.

Answer 21

Addison’s disease –

primary adrenal cor;cal insufficiency

Question 22

Identify the main causes of Addison’s disease.

Answer 22

1. Tuberculosis/ metastatic tumours (attacking/destroying cortex)
2. Autoimmune adrenalitis - adrenal failure
3. HIV - decreased immunity and increased viral and bacterial infections (that target the cortex)
4. Atrophy due to prolonged steroid therapy

Question 23

Describe clinical features of Addison’s disease.

Answer 23

1) Loss of weight/appetite, muscle weakness, nausea, vomiting
2) Low plasma glucose esp. after fasting (lack of glucocorticoid actions)
3) Low plasma Na+ (hyponatriemia) and high plasma K+ (hyperkalaemia) (due to lack of
mineralocorticoids)
4) Dehydration and hypotension due to 3. - systolic blood pressures 50-80 mmHg
5) Lethargy and dizziness on standing up due to 4
6) Severe cases present with skin pigmentation due to excess ACTH acting as MSH

Question 24

Identify treatment options for Addison’s disease.

Answer 24

1. Glucocorticoid replacement therapy – hydrocortisone administration morning (25mg) /afternoon (12.5 mg)
2. Intravenous saline infusion if severely dehydrated and condition is life- threatening and administration of fludrocortisone (mineralocorticoid agonist)

Question 25

How are Chromaffin cells of the adrenal medulla controlled ?

Answer 25

• Controlled directly by preganglionic sympathetic neurones

thus chromaffin cells are equivalent to postganglionic sympathetic neurones

Question 26

What are the main hormones produced by Chromaffin cells ?

Answer 26

Two populations of chromaffin cells secrete:
• either Epinephrine (adrenaline) (majority of cells)
• or Norepinephrine (noradrenaline)

Also been shown to secrete:
• Dopamine
• Enkephalins (pain control)

Question 27

Identify the main physiological actions of adrenaline.

Answer 27

Depends on type of receptor expressed in the tissue:

• Beta receptors usually involved in increasing cAMP
• Alpha receptors usually suppressing cAMP, or stimulate intracellular Calcium concentration

“1) Both epinephrine and norepinephrine increase glucose levels inducing a hyperglycemic effect. This is achieved directly through stimulation of glycogenolysis and gluconeogenesis in the liver by activation of β and α receptors of the hepatocytes respectively and indirectly through enhancement of glucagon secretion by the α cells of the pancreatic islets of Langerhans. Catecholamines further increase the hyperglycemic effects through inhibition of the insulin mediated glucose uptake by muscle and adipose tissue by blocking the GLUT4 transporters and through inhibition of insulin secretion by the β cells of the pancreatic islets reducing the hypoglycemic effect of insulin. All these effects promote the same objective; an increase of the blood plasma glucose levels.

2) Epinephrine activates adipose tissue lipase which promotes lipolysis increasing the plasma free fatty acid levels which in turn produce energy in the form of ATP either through gluconeogenesis or β oxidation. This lipolytic effect of catecholamines is of vital importance when there is glucose deficiency and consequently ATP and energy deficiency, thus catecholamines lipids are use as an alternate fuel.
3) Epinephrine increases the basal metabolic rate with consequent increase of the nonfacultative thermogenesis. This is achieved by increasing the O2 consumption a state compensated by increasing the minute ventilation. The minute ventilation augments by increasing the tidal volume rather than the respiratory rate
4) Increase of the inotropic effect causes contractility of the cardiac muscle increasing the cardiac output by increasing the stroke volume. Increase of the chronotropic effect increases the SA nodal discharge rate. BP is increased.
5) Catecholamines promote relaxation of the visceral smooth muscle acting through β adrenergic receptors” (decrease kidney and digestive activity, and increase alertness)

Question 28

Describe synthesis, and release of adrenal catecholamines.

Answer 28

1. The activity of the first enzyme in the pathway, tyrosine hydroxylase, which converts tyrosine to l -dopa, is rate limiting for overall synthesis. This enzyme is located within the cytosol of adrenal medullary cells as well as in sympathetic nerve terminals and in specific cells within the CNS.
2. The cytosolic enzyme amino-acid decarboxylase converts l -dopa to dopamine in numerous tissues, including the adrenal medulla.
3. A catecholamine-H + exchanger (vesicular monoamine transporter 1, or VMAT1) moves the dopamine into membrane-enclosed dense-core vesicles called chromaffin granules.
4. Dopamine β-hydroxylase converts dopamine to norepinephrine by hydroxylating the β carbon. This β-hydroxylase is localized to the inner surface of the membrane of granules within the adrenal medulla and sympathetic nerves. In the nerve terminals of post­ganglionic sympathetic neurons, the synthetic pathway terminates at this step, and the granules store the norepinephrine for later secretion. However, the cells of the adrenal medulla convert the norepinephrine to epinephrine in three final steps.
5. Norepinephrine formed in the secretory granules moves out into the cytosol.
6. The cytosolic enzyme PNMT transfers a methyl group from S -adenosylmethionine to norepinephrine, thus creating epinephrine. Substantial amounts of this enzyme are present only in the cytosol of adrenal chromaffin cells.
7. The secretory granules in the adrenal medulla take up the newly synthesized epinephrine. The same VMAT1 catecholamine-H + exchanger noted in step 3 appears to mediate this uptake of epinephrine. The proton gradient is maintained by an H pump (i.e., a vacuolar-type H-ATPase) within the secretory vesicle membrane. Thus, in the adrenal medulla, the secretory granules store both epinephrine and norepinephrine before secretion
8. Upon SNS stimulation release of ACh which binds to receptors and stimulate increase in intracellular Calcium, which causes exocytosis of granules (and thus release of NA, Adrenaline)