Adrenal-gland Hormones

Question 53

In the adrenal gland, where are norepinephrine & adrenaline synthesized?

Answer 53

Norepinephrine & adrenaline are catecholamines (amine hormones, derived from tyrosine), which are produced in the adrenal medulla.

Question 54

Form superficial to deep, what are the three zones of the adrenal cortex?

Answer 54

(capsule)

Zona glomerulosa

Zona fasciculata

Zona reticularis

(medulla)

Question 55

What type of hormone is synthesized in the Zona glomerulosa of the adrenal cortex?

Answer 55

Mineralcorticoids, a class of steroid hormones. Most importantly, aldosterone.

Question 56

What is aldosterone, where is it made and what does it do?

Answer 56

Aldosterone is a steroid hormone of the mineralcorticoid class, produced from cholesterol, like all steroid hormones. It is synthesized by the zona glomerulosa cells in the outer band of the adrenal cortex of the adrenal gland.

It acts mainly on the distal tubules and collecting ducts of the kidney nephron to cause the conservation of sodium, secretion of potassium, increased water retention, and increased blood pressure.

The overall effect of aldosterone is to increase reabsorption of ions and water in the kidney – increasing blood volume and, therefore, increasing blood pressure.

Aldosterone has exactly the opposite function of the atrial natriuretic hormone secreted by the heart.

Question 57

What type of hormone is produced in the zona fasciculata of the adrenal cortex?

Answer 57

Glucocorticoids, a class of steroid hormones, is produced by the zona fasciculata cells in the largest, middle band of the adrenal cortex.

Cortisol is the most important glucocorticoid secreted by the zona fasciculata.

NB In rodents, corticosterone, not cortisol, is secreted by the zona fasciculata. Corticosterone is also a glucocorticoid hormone.

Question 58

What type of hormone is made in the zona reticularis of the adrenal cortex?

Answer 58

Adrenal androgens, aka adrenal sex hormones.

Question 59

Zona glomerulosa cells in the adrenal cortex are:

a. Cuboidal
b. Columnar
c. Squamous
d. Stratefied epithelial

Answer 59

b. Columnar, arranged in irregular cords

Question 60

Zona fasciculata cells in the adrenal cortex are:

a. Cuboidal
b. Polyhedral
c. Foamy-looking
d. Arranged in irregular cords

Answer 60

b & c

Polyhedral & foamy-looking, due to the cholesterol for glucocorticoid synthesis. They are arranged in STRAIGHT cords radiating out toward the medulla.

Question 61

Zona reticularis cells of the adrenal cortex are:

a. Larger than zona fasciculata cells
b. Intermediate-sized, between zona glomerulosa and zona fasciculata cells
c. Anastomose with each other
d. Arrange in cords projecting in many directions

Answer 61

b, c & d

Cells within this zone are intermediate in size, arranged in cords that project in many different directions and anastomose with one another.

Question 62

How is the adrenal medulla innervated?

Answer 62

The adrenal medulla is richly innervated by preganglionic sympathetic fibers. Additionally, small numbers of sympathetic ganglion cells are commonly observed in the medulla. Ganglion cells are round or polygonal with prominent nuclei.

Question 63

What is the most common cell in the adrenal medulla, and what is it responsible for?

Answer 63

Chromaffin cells.

Synthesis of catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin cells in the medulla and converted to norepinephrine and epinephrine.

Question 64

Where are catecholamines such as norepinephrine and epinephrine synthesized and how are they released into the bloodstream?

Answer 64

Catecholamines are synthesized by the adrenal gland, specifically from the amino-acid tyrosine taken up by chromaffin cells in the adrenal medulla.

Catalyzed by different enzymes, the tyrosine is converted to DOPA, then dopamine, then norepinephrine & epinephrine.

Norepinephine and epinephrine are stored in electron-dense granules which also contain ATP and several neuropeptides.

Secretion of these hormones is stimulated by Ach release from preganglionic sympathetic fibers innervating the medulla. Many types of “stresses” stimulate such secretion, including exercise, hypoglycemia and trauma.

Following secretion into blood, the catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other serum proteins.

Question 65

After the catecholamines norepinephrine & epinephrine are secreted into the bloodstream from the adrenal medulla, how do they bind to receptors in target cells, such as skeletal myocytes?

Answer 65

Following secretion into blood, catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other serum proteins.

They bind to adrenergic receptors on the surface of target cells.

These receptors are prototypical examples of seven-pass transmembrane proteins that are coupled to G proteins which stimulate or inhibit intracellular signalling pathways.

Question 66

In general, what is the effect on target cells of norepinephrine & epinephrine binding to G-protein-coupled receptors on the plasma membrane?

Answer 66

In general, circulating epinephrine and norepinephrine have the same effects on target organs as direct stimulation by sympathetic nerves, although their effect is longer lasting.

Note though that complex physiologic responses result from adrenal medullary stimulation because there are multiple receptor types which are differentially expressed in different tissues and cells.

Question 67

List the major adrenergic receptors and what types of catecholamines they bind.

Answer 67

Alpha 1 - Epinephrine, Norepinphrine

Alpha 2 - Epinephrine, Norepinphrine

Beta 1 - Epinephrine, Norepinphrine

Beta 2 - Epinephrine

Question 68

What are the similarities & differences between Alpha 1 & Alpha 2 adrenergic receptors?

Answer 68

Both are G-protein coupled receptors (GPCR), which are transmembrane proteins that pass through the target cell’s plasma membrane seven times.

They both bind to the catecholamines epinephrine & norepinphrine.

Alpha-1 receptors, when bound, increase free calcium within a cell. Its effects include:

• Constriction of smooth muscle
• Vasoconstriction of coronary arteries
• Vasoconstriction of veins
• Decrease motility of smooth muscle in GIT (sympathetic response)

Alpha-2 receptors, when bound, decrease cAMP within a cell. Its effects are inhibitory:

• Supression of release of norepinephrine (noradrenaline) by negative feedback.
• Decrease release of acetylcholine in pre- and post-synaptic nerve terminals
• Inhibition of lipolysis in adipose tissue
• Inhibition of insulin release in pancreas
• Contraction of GIT sphincters
• Decreased secretion from salivary gland
• Relax gastrointestinal tract (presynaptic effect)

Question 69

What are the similarities & differences between beta-1 & beta-2 adrenergic receptors?

Answer 69

Both are transmembrane, G-protein-coupled receptors that bind catecholamines.

Both bind epinephrine.

Both increase cAMP within the cell, but Beta-2 can be both stimulatory AND inhibitory. Beta-1 is only stimulatory.

Beta-2 only binds epinephrine while Beta 1 binds both norepinephrine & epinephrine.

Beta-1 is stimulatory when it binds to norepinephrine or epinephrine. Actions include:

• stimulate viscous, amylase-filled secretions from salivary glands
• Increase cardiac output
• Increase heart rate in sinoatrial node (SA node) (chronotropic effect)
• Increase atrial cardiac muscle contractility. (inotropic effect)
• Renin release from juxtaglomerular cells.
• Lipolysis in adipose tissue.

Beta-2 can be both stimulatory & inhibitory, depending on where it is located. Actions include:

• Relaxation of smooth muscle in uterus (inhibits labour), GIT (delays digestion) & bronchi & detrusor muscle (delays micturition) - mostly fight-or flight
• Dilation of blood vessels to increase perfusion of organs such as hepatic artery, coronary artery and skeletal muscle (sympathetic effect)

Question 70

List some of the major effects on the body of the adrenal-medulla catecholamines norepinephrine and epinephrine.

Answer 70

Increased rate and force of contraction of the heart muscle: this is predominantly an effect of epinephrine acting through beta receptors.

Constriction of blood vessels: norepinephrine, in particular, causes widespread vasoconstriction, resulting in increased resistance and hence arterial blood pressure.

Dilation of bronchioles

Stimulation of lipolysis in fat cells: this provides fatty acids for energy production in many tissues and aids in conservation of dwindling reserves of blood glucose.

Increased metabolic rate: oxygen consumption and heat production increase throughout the body in response to epinephrine. Medullary hormones also promote breakdown of glycogen in skeletal muscle to provide glucose for energy production.

Dilation of the pupils

Inhibition of certain “non-essential” processes: an example is inhibition of gastrointestinal secretion and motor activity.

Question 71

Where is the enzyme 17-alpha-hydroxylase found in the adrenal gland, and what are the major products of its catalysis?

Answer 71

17-alpha-hydroxylase is found in the zona fasciculata and the zona reticulata of the adrenal gland. It is necessary for the synthesis of 17-hydroxypregnenolone and 17-hydroxyprogesterone, which are precursors to cortisol and androgens.

Question 72

Aldosterone & Cortisol can bind to the same mineral corticoid receptor and the same DNA sequence serves as a hormone response element for the steroid-bound forms of both mineralocorticoid and glucocorticoid receptors.

So, how can aldosterone stimulate specific biological effects when blood concentrations of cortisol are 2000-fold higher than aldosterone?

Answer 72

In aldosterone-responsive cells, cortisol is effectively destroyed, allowing aldosterone to bind its receptor without competition. Target cells for aldosterone express the enzyme 11-beta-hydroxysteroid dehydrogenase, which has no effect on aldosterone, but converts cortisol to cortisone, which has only a very weak affinity for the mineralocorticoid receptor. In essence, this enzyme “protects” the cell from cortisol and allows aldosterone to act appropriately.

Some tissues (e.g. hippocampus) express abundant mineralocorticoid receptors but not 11-beta HSD - they therefore do not show responses to aldosterone because aldosterone is not present in quantities sufficient to compete with cortisol.

Question 73

What are the major controls of aldosterone secretion from the zona glomerulosa of the adrenal cortex?

Answer 73

Concentration of potassium ions in extracellular fluid: Small increases in blood levels of potassium strongly stimulate aldosterone secretion.

Angiotensin II: Activation of the renin-angiotensin system as a result of decreased renal blood flow (usually due to decreased vascular volume) results in release of angiotensin II, which stimulates aldosterone secretion.

Other factors that increase secretion:

ACTH adrenocorticotropic hormone (short-term stimulation only)

Sodium deficiency.

Factors that suppress aldosterone secretion:

ANP atrial naturetic hormone

High sodium concentration

Potassium deficiency

Question 74

What is Addison’s disease?

Answer 74

Aka hypoadrenocorticism - deficiency of glucocorticoid (esp. cortisol) and mineralcorticoid (esp. aldosterone)

Without treatment by mineralocorticoid replacement therapy, a lack of aldosterone is lethal, due to electrolyte imbalances and resulting hypotension and cardiac failure.

Most commonly, Addison’s is a result of infectious disease (e.g. tuberculosis in humans) or autoimmune destruction of the adrenal cortex.

Clinical signs:

cardiovascular disease, lethargy, diarrhea, and weakness.

Question 75

What are glucocorticoid’s (cortisol’s) effects on metabolism?

Answer 75

Stimulation of gluconeogenesis, particularly in the liver: This pathway results in the synthesis of glucose from non-hexose substrates such as amino acids and lipids and is particularly important in carnivores and certain herbivores. Enhancing the expression of enzymes involved in gluconeogenesis is probably the best known metabolic function of glucocorticoids.

Mobilization of amino acids from extrahepatic tissues: These serve as substrates for gluconeogenesis.

Inhibition of glucose uptake in muscle and adipose tissue: A mechanism to conserve glucose.

Stimulation of fat breakdown in adipose tissue: The fatty acids released by lipolysis are used for production of energy in tissues like muscle, and the released glycerol provide another substrate for gluconeogenesis.

Question 76

What are cortisol’s effects on immune function?

Answer 76

Glucocorticoids have potent anti-inflammatory and immunosuppressive properties.

Question 77

How is cortisol secretion from the zona fasciculata of the adrenal cortex controlled?

Answer 77

ACTH from the anterior pituitary:

ACTH is itself secreted under control of the hypothalamic peptide corticotropin-releasing hormone (CRH).

Virtually any type of physical or mental stress results in elevation of cortisol concentrations in blood due to enhanced secretion of CRH in the hypothalamus.

Cortisol secretion is suppressed by classical negative feedback loops. When blood concentrations rise above a certain theshold, cortisol inhibits CRH secretion from the hypothalamus, which turns off ACTH secretion, which leads to a turning off of cortisol secretion.

The combination of positive and negative control on CRH secretion results in pulsatile secretion of cortisol.

Question 78

How does ACTH from the anterior pituitary (synthesized by corticotroph cells in the pars distalis) stimulate secretion of cortisol and other glucocorticoids by zona fasciculata cells (and to a lesser extent, zona reticularis) cells in the adrenal cortex?

Answer 78

ACTH binds to receptors in the plasma membrane of cells in the zona fasiculata and reticularis of the adrenal. Hormone-receptor engagement activates adenyl cyclase, leading to elevated intracellular levels of cyclic AMP which leads ultimately to activation of the enzyme systems involved in biosynthesis of cortisol from cholesterol.

Question 79

What is Cushings Disease?

Answer 79

Aka hyperadrenocorticism - excessive levels of glucocorticoids due to:

Excessive endogenous production of cortisol, which can result from a primary adrenal defect (ACTH-independent, like an adrenal tumour) or from excessive secretion of ACTH (ACTH-dependent, like a pituitary tumour).

or

Administration of glucocorticoids for theraputic purposes. This is a common side-effect of these widely-used drugs.

Clinical signs:

hypertension, apparent obesity, muscle wasting, thin skin, and metabolic aberrations such as diabetes.

Question 80

What are the TWO basic pathways (excluding the enzymes) for the biosynthesis of glucocorticoid Cortisol in the Zona Fasciculata of the adrenal cortex?

Hint: Both have six basic steps, starting with cholesterol.

Answer 80

Pathway 1:

1. Cholesterol
2. Pregnenolone
3. 17-alpha-hydroxy-pregnenolone
4. 17-alpha-hydroxy-progesterone
5. Deoxycortisol
6. Cortisol

Pathway 2 (cuts out 17-alpha-hydroxy-pregnenolone but adds progesterone):

1. Cholesterol
2. Pregnenolone
3. Progesterone
4. 17-alpha-hydroxy-progesterone
5. Deoxycortisol
6. Cortisol

Question 81

What are the TWO basic pathways (excluding the enzymes) for the biosynthesis of adrenal androgen Oestrogen (& Oestrone) in the Zona Reticularis of the adrenal cortex?

Hint: Both have seven basic steps, starting with cholesterol.

Answer 81

Pathway 1:

1. Cholesterol
2. Pregnenolone
3. 17-alpha-hydroxy-pregnenolone
4. DHEA (dehydroepiandrosterone)
5. Androstenedione
6. Testosterone
7. Oestradiol > Oestrone

Pathway 2 (skips 17-alpha-hydroxy-pregnenolone & DHEA but adds progesterone & 17-alpha-hydroxy-progesterone):

1. Cholesterol
2. Pregnenolone
3. Progesterone
4. 17-alpha-hydroxy-progesterone
5. Androstenedione
6. Testosterone
7. Oestradiol > Oestrone

Question 82

What test is used to confirm hyperadrenocorticism, aka Cushings, or hypoadrenocorticism, aka Addison’s?

What drug is central to the test, and how does it work?

Answer 82

ACTH-stimulation test:
This test takes advantage of the stimulatory effect of ACTH on glucocorticoid (cortisol) production by the adrenal cortex.
Syntacthen is a synthetic form of ACTH. Injection of Synacthen would generate an increase of cortisol production of about DOUBLE the normal amount in the healthy animal. Double cortisol = normal.

If the post-Synacthen level of cortisol exceeds 600 nmol/L, then hypersecretion of cortisol (Cushings syndrome) is confirmed. Some dogs with adrenal tumours that are constitutively producing cortisol may not respond at all to Synacthen but would likely have very high resting cortisol levels.

If there is no cortisol production, then adrenal hypofunction (Addison’s disease) is confirmed.

Question 83

Can the ACTH-stimulation test determine whether the hyperadrenocorticism (Cushings) or hypoadrenocorticism (Addison’s) is due a defect in the pituitary gland (pituitary-dependent) or the adrenal gland (adrenal-dependent)?

Answer 83

No.

Use the Dexamethasone test for that, because it takes advantage of cortisol’s negative-feedback effect on ACTH.

The ACTH-stim test CAN be used to distinguish between iatrogenic hyperadrenocorticism (from overuse of glucocorticoid steroid drugs to treat inflammation, for example; an extra-adrenal source) and spontaneous hyperadrenocorticism.

If the cause is iatrogenic hyperadrenocorticism, there would be little response to the Synacthen because its cortisol levels would continue to be heightened by the extra-adrenal source.

Question 84

What is Dexamethasone and what is it used for with regard to diagnosis of over- or under-production of cortisol?

Answer 84

Dexamethasone is a synthetic cortisol.

Use this test to determine whether a Cushings case (hyperadrenocorticism, ie., too much cortisol) is due to a defect higher up, ie., in the hypothalamic-anterior pituitary, or whether it’s a defect in the adrenal gland.

This tests takes advantage of cortisol’s negative-feedback effect on production of corticotropin-releasing hormone (CRH) by the hypothalamus and ACTH production & secretion by the anterior pituitary. The inhibition on CRH & ACTH would result in a fall in cortisol production.

A low-dose injection of Dexamethasone would normally result in a DECREASE in cortisol levels to less than 50 nmol/L eight hours after administration in a healthy animal. <50 nmol/L = normal

If there is no change in cortisol level, then adrenal-dependent hyperadrenocorticism (ADH) could be confirmed, because it would suggest that an adrenal tumour is producing cortisol constitutively to keep the cortisol level steady. No change in cortisol = adrenal tumour

If there is a drop in cortisol secretion, but one where the level stays about 50 nmol/L and then starts to rise again, then you could confirm PDH, ie., a defect in the anterior pituitary, where ACTH is made. This is because the test shows that the pituitary is responsive to the Dexamethasone and reduces its production of ACTH, which reduces the production of cortisol by the adrenal gland, but since the cortisol levels rise again suggest the pituitary simply continues to make more ACTH due to the presence of a tumour. Drop in cortisol then rise again = pituitary tumour

Question 85

How is mitotane used to regulate hormone synthesis in the hypothalamic-pituitary-adrenal axis?

Answer 85

Mitotane is a drug that destroys the zona fasciculata & zona reticularis of the adrenal cortex, but leaves the zona glomerulosa intact so that aldosterone synthesis can continue

• *↓ cortisol**
• *↓ DHEA (oestradiol, testosterone)**

Question 86

What is Conn’s Disease?

Answer 86

Aldosterone excess aka primary hyperaldosteronism

Aetiology:

↑ autonomous aldosterone secretion due to presence of usually single adrenal adenoma in zona glomerulosa

Sequelae:

Hypertension due to ↑ water & Na+ retention
Muscle weakness & cardiac arryhtmias due to hypokalemia (remember when K+ leaves cell, it prevents Ca++ from entering cell, preventing contraction; aldosterone takes Na+ in, kicks K+ out)

Question 87

What test do you use to test a dog with polyuria for ADH deficiency or non-responsiveness to ADH (anti-diuretic hormone)?

Answer 87

Water-deprivation test:

If dog continues to excrete dilute urine, it could mean it is suffering from Central Diabetes Insipidus, when ADH is not secreted from the pituitary – or Nephrogenic Diabetes Insipidus, when the collecting ducts are not responsive to ADH (this is untreatable).

Also use ACTH-stimulation test:

Synacthen, synthetic ACTH, should increase glucorticoid (cortisol) secretion from the adrenal cortex.

Question 88

What is desmopressin?

Answer 88

It’s synthetic ADH. It causes reduction in water loss into urine (thus an increase in urine osmolarity) as water is retained in the plasma and extracellular fluid rather than excreted in urine.