Metabolism S9 - Disorders of Adrenal and Pituitary Glands

Question 1

List the hormones produced in the Anterior pituitary gland and include the cell type that produces them.

Answer 1

TSH - Thyrothrophs

ACTH - Corticotrophs

Growth Hormone - Somatotrophs

LH and FSH - Gonadotrophs

Prolactin - Lactotrophs

Question 2

What are the three zones of the adrenal cortex?
List them from Apical descending

Also, give the type of hormone secreted from each layer, along with an example of a hormone of that type.

Answer 2

Zona Glomerulosa:

Mineralocorticoids
E.g. Aldosterone (C21)

Zona Fasciculata:

Glucocorticoids
E.g. Cortisol, Corticosterone (C21)

Zona Reticularis:

Androgens
E.g. Testosterone (C19)

Question 3

What is produced in the Medulla of the Adrenal Gland?

Answer 3

Adrenaline

Question 4

Describe in detail how ACTH stimulates synthesis of Cortisol.

Answer 4

ACTH is hydrophilic and so binds to cell surface receptors in the zona fasciculata and reticularis.

Receptors are melanocortin type 2 receptors (aka Corticotrophin receptors)

This receptor uses cAMP as a secondary messenger

This leads to activation of cholesterol esterase increasing conversion of cholesterol esters to free cholesterol

Cortisol production from free cholesterol is therefore increased.

It also stimulates other steps in the synthesis of Cortisol from Cholesterol

Question 5

What are the metabolic effects of Cortisol?

Relate this to location where applicable.

Answer 5

Increased proteolysis

Decreased Amino acid uptake and protein synthesis

Increased Gluconeogenesis and glycogenolysis in liver

Increased lipolysis in adipose tissues

(High levels of cortisol increase Lipogenesis in adipose tissue)

Question 6

What effects does cortisol have that aren’t metabolic?

Answer 6

Direct effects on cardiac muscle, bone and the immune system

Question 7

Describe the effects of aldosterone on the body.

What are the effects of over or undersecretion?

Answer 7

Stimulates Na+ reabsorption in the kidney in exchange for K+ or H+

Oversecretion increased Na+ and water retention and increases loss of K+ causing hypertension and muscle weakness

Undersecretion does the opposite, causing hypotension

Question 8

What is the effect of androgens on the body?

What is the effect of oversecretion of androgens in a female?

Answer 8

Stimulate growth and development of male genital tract and male secondary characteristics.

Eg. Height, Voice deepening, Body shape, Facial and body hair and anabolic effects on muscle proteins

In females, oversecretion leads to:

Hair growth, acne, menstrual problems, increased muscle bulk and deepening voice

Question 9

Describe the effects of Oestrogen on the body

Answer 9

Stimulate development of female genital tract, breast and secondary female characteristics such as:

Broad hips, accumulation of fat in breasts and buttocks, body hair distribution

They are weakly anabolic and decrease circulating cholesterol levels

Question 10

Describe the structure of Cortisol.

Answer 10

C21 steroid

Lipophilic

Question 11

How do C21 steroids differ from other steroids?

Answer 11

Number of C atoms
Presence of functional groups
Distribution of C=C double bonds

Question 12

How are steroids transported around the body?

Answer 12

They are lipophilic therefore must be transported bound to plasma proteins

(90% transcortin - 10% free and active)

Question 13

How are steroids synthesised in the body?

Answer 13

Synthesised from cholesterol via progesterone in a series of enzyme catalysed reactions

Question 14

Describe the mechanism of action of cortisol upon its target cells

Answer 14

Cortisol crosses the plasma membrane as it is lipophilic

Binds to cytoplasmic receptors

The hormone receptor complex then enters the nucleus to interact with specific regions of DNA

This interaction changes rates of transcription of specific genes

The effect may therefore take some time to manifest.

Question 15

Describe the mechanism of action of Adrenaline upon its target cells

Answer 15

Adrenaline is hydrophilic and so doesn’t cross the plasma membrane

Instead it binds to adrenoreceptors on the cell surface

A secondary messenger then affects cell activity

Question 16

How is cortisol secretion controlled?

What type of control does cortisol itself exert on the brain?

Answer 16

Through the HPA axis

Hypothalamus releases Corticotrophin releasing hormone

Which stimulates the Anterior Pituitary to release ACTH

Which in turn stimulates release of Cortisol

Cortisol exerts negative feedback control on both the Hypothalamus and the Anterior Pituitary

Question 17

What is Corticotrophin releasing hormone released in response to?

Hint: Think about what CRH release leads to

Answer 17

Physical stressors (temperature, pain)

Chemical stressors (hypoglycaemia)

Emotional stressors

Question 18

How are catecholamines synthesised?

Where are catecholamines stored?

Answer 18

Series of enzyme catalysed steps that convert:

Tyrosine to Dopa

Dopa to Dopamine

Dopamine to Noradrenaline

Noradrenaline to Adrenaline (via methylation)

Stored in the adrenal medullary cells in vesicles

Question 19

Why is adrenaline released and what effects does it have on the body?

Answer 19

Released as part of the fight/flight/fright response in response to stress situations

Its effect include:

Increased cardiac output and blood supply to muscle

Increased mental alertness

Increased Glycogenolysis in liver and muscle

Increased lipolysis in adipose tissue

Question 20

What are the clinical consequences of oversecretion of adrenaline?

Why might this overproduction occur?

Answer 20

Hypertension
Palpitations
Sweating
Anxiety
Pallor
Glucose intolerance

Overproduction normally a result of tumour (Phaemochromocytoma)

Question 21

What peptides can be derived from POMC?

Answer 21

Post translational processing of POMC produces different biologically active peptides such as:

ACTH
alpha-MSH
Beta-Endorphin

Question 22

How does ACTH lead to increased pigmentation in certain areas of the body?

Answer 22

ACTH’s primary sequence contains the alpha-MSH sequence.

This gives ACTH some alpha-MSH like activity when present in excess.

Question 23

What are the possible causes of Cushing’s syndrome?

Answer 23

Adrenal cortex tumour (adenoma)

Ectopic ACTH secretion

Both result in excess secretion of cortisol/glucocorticoids

Question 24

What are the clinical effects of excess cortisol secretion?

Answer 24

Cushing’s Syndrome:

Increased muscle proteolysis and hepatic gluconeogenesis that can lead to hyperglycaemia, polyuria and polydipsia (Steroid Diabetes)

Wasting of muscles of the limbs

Increased lipogenesis in adipose

Deposition of fat in the abdomen neck and face (Moon shape face, dorso-cervical fat pad and central weight gain)

Purple striae on lower abdomen, upper arms and thighs reflecting proteolysis of proteins in the skin.

Easy bruising results from proteolysis and lipolysis in skin and subcutaneous tissue.

Immunosupressive, anti-inflammatory and anti-allergenic reactions leading to increased susceptibility to bacterial infections and producing acne

May be back pain and collapse of ribs due to osteoporosis caused by disturbance of Ca2+ metabolism and loss of bone matrix proteins

Mineralocorticoid effects of cortisol may produce hypertension due to Na+ and fluid retention

Question 25

What may be the cause of Addison’s disease?

Answer 25

Diseases of the adrenal cortex (auto-immune destruction) reduce glucocorticoids and mineralocorticoids

Disorders of the pituitary or hypothalamus lead to decreased secretion of ACTH or CRH - only affecting glucocorticoids

Both of these have the effect of lowering levels of cortisol secretion.

Question 26

What are the clinical effects of too little cortisol secretion as a consequence of autoimmune destruction of the adrenal medulla?

Answer 26

Addison’s Disease:

Insidious onset with initial non-specific symptoms such as:

Tiredness, extreme muscular weakness, anorexia, vague abdominal pain, weight loss, occasional dizziness and dehydration

More specific sign is increased pigmentation due to increased ACTH secretion (due to lack of negative feedback from cortisol)

Decreased blood pressure due to Na+ and fluid depletion

Postural hypotension

Hypoglycaemia (esp. on fasting) due to decreased catabolism

Question 27

What factors may exacerbate Addison’s disease and what might this exacerbation lead to?

Answer 27

Stress, trauma or severe infection can lead to the development of an Addisonian crisis.

Symptoms of this include:

Nausea, vomiting, extreme dehydration, hypotension, confusion, fever and even coma.

Question 28

How must an Addisonian crisis be treated?

Answer 28

Must be treated immediately with IV cortisol and fluid replacement (dextrose in saline) to avoid death.

Question 29

What are the 3 tests for adrenal cortical function?

Answer 29

Measurement of ACTH/Cortisol levels

Dexamethasone Suppression test

Synacthen test

Question 30

How is an ACTH/Cortisol level test carried out?

Answer 30

Measurement of cortisol/ACTH directly in plasma

OR

24hr cortisol and cortisol breakdown products (17-hydroxysteroids) measured in urine

Question 31

How is a dexamethasone suppression test carried out?

How does it work?

What response might someone with Cushing’s have?

Answer 31

Patient given oral Dexamethasone that suppresses ACTH and therefore cortisol secretion. Cortisol levels then monitored.

If cortisol is suppressed by >50% this is characteristic of Cushing’s as even though the disease pituitary is relatively insensitive to cortisol, it does retain some sensitivity to potent synthetic steroids.

Suppression will not occur in adrenal tumours or ectopic ACTH secretion

Normal response will exclude Cushing’s disease

Question 32

What is the Synacthen test and why is it carried out?

What response is normal and what indicates abnormality?

Answer 32

Administration of Synacthen (synthetic analogue of ACTH) via intra muscular injection

This normally increases the plasma cortisol by >200nmol/L

Abnormal response indicates Addison’s disease, normal response rules this out.

Question 33

Explain the structure of Steroid receptors

What class of proteins do these receptors belong?

What other types of receptors are in this class of proteins?

Answer 33

Steroid receptors are Nuclear DNA binding proteins

They include 3 main regions:

• Hydrophobic hormone binding region
• DNA binding region
• Variable region

This class of proteins also includes Thyroid and vitamin D receptors

Question 34

Explain the concept of ‘Sequence homology’ in hormone receptors.

Give examples of receptors with sequence homology to glucocorticoid receptors and explain the consequence of this.

Answer 34

Glucocorticoid receptors primary sequence is similar to that of other hormone receptors that may be present in the cell, this is known a ‘sequence homology’

Examples of receptors that have sequence homology with glucocorticoid receptors are:

Mineralocorticoid receptors - 64%

Androgen receptors - 62%

Oestrogen receptors - 31%

Thyroid receptors - 24%

Therefore cortisol will bind weakly (with low affinity) to mineralocorticoid and androgen receptors.

Binding to alternative receptors may become significant when high levels of a hormone are present