Hypersecretion of Anterior Pituitary Hormones

Question 1

What is hyperpituitarism?

Answer 1

Excess production of adenohypophysial hormones (and the symptoms associated with it)

Question 2

What is the usual cause of hyperpituitarism?

Answer 2

Isolated pitiuitary tumours (i.e. just within pituitary so hasn’t spread - pituitary adenoma)
The tumour can also originate from non-endocrine tissue → ectopic

Question 3

What symptom is associated with pituitary adenoma?

Answer 3

Visual field defects - specifically bitemporal hemianopia due to the tumour compressing the optic chiasm which is located directly above the pituitary gland
NOTE: a pituitary adenoma can also cause other cranial nerve defects as the pituitary gland is surrounded by cranial nerves laterally, so lateral expansion could lead to compression of these nerves

Question 4

State the disease resulting from hypersecretion of:
Corticotrophin (ACTH)
Thyrotrophin (TSH)
Gonadotrophin 
Prolactin
Somatotrophin (GH)

Answer 4

Cortictrophin (ACTH) - Cushing’s disease (excess cortisol)
Thyrotrophin (TSH) - Thyrotoxicosis
Gonadotrophins - Precocious puberty in children (i.e. earlier than usual)
Prolactin - Hyperprolactinaemia
Somatotrophin - Gigantism/Acromegaly

Question 5

What is thyrotoxicosis?

Answer 5

Excessive thyroid hormone in the bloodstream due to any cause
EXAMPLES:
Hyperthyroidism = overactive thyroid gland
Thyroiditis = inflammation of thyroid gland which causes large amounts of thyroid hormone to leak into the bloodstream due to the cell damage
Excessive intake of thyroxine by someone being treated for hypothyroidism

Question 6

What is a pathological cause of hyperprolactinaemia?

Answer 6

Prolactinoma = most common functioning (i.e. hormone secreting) tumour
Most commonly microadenomas (< 10 mm in diameter)
NOTE: some tumours can be non-functioning = do not secrete any hormones - mutations may have affected hormone production/secreting properties as well as normal cell division

Question 8

What is an effect of high prolactin?

Answer 8

It suppresses pulsatile secretion of GnRH which is necessary for the secretion of FSH and LH → inhibition of FSH and LH secretion

Question 9

State two physiological causes of hyperprolactinaemia.

Answer 9

Pregnancy

Breast feeding

Question 10

State the symptoms of hyperprolactinaemia in men.

Answer 10

Galactorrhoea but this uncommon (since milk ejection requires oestrogen and men don’t have enough oestrogen for this - i.e. appropriate steroid background usually inappropriate)
Loss of libido
Erectile dysfunction
Infertility

Question 11

State the symptoms of hyperprolactinaemia in women.

Answer 11

Galactorrhoea = milk production which is unrelated to the normal production of milk during breastfeeding
Secondary amenorrhoea = menstrual cycles did happen but then stopped (or oligomenorrhoea = infrequent menstrual cycles)
Loss of libido
Infertility

Question 12

How do dopamine receptor agonists work?

Answer 12

Normally, dopamine released from hypothalamic dopaminergic neurones bind to D2 (dopamine) receptors on the anterior pituitary lactotrophs to INHIBIT prolactin secretion
Dopamine receptor agonists stimulate these D2 receptors the same way resulting in reduced prolactin secretion
They can also lead to reduced tumour size - lactotrophs are less active so they shrink
NOTE: administered orally

Question 14

What is used to treat hyperprolactinaemia?

Answer 14

Dopamine receptor agonists – bromocriptine and cabergoline

Question 15

What is the epiphyseal plate

Answer 15

Epiphyseal plate = growth plate
A hyaline cartilage plate at each end of a long bone - part of a long bone where new bone growth takes place to make the bone longer
In adults who have stopped growing, there is no longer an epiphyseal plate as all the cartilage has been replaced by bone - growth plate fusion

Question 16

What does excess growth hormone cause in children and in adults?

Answer 16

Children – gigantism (they grow really tall)

Adults – acromegaly (can’t grow tall because epiphyseal plate has fused)

Question 16

How does acromegaly present?

Answer 16

Insidious in onset - signs and symptoms progress gradually (can remain undiagnosed for many years and patients often have to bring in old photos to help with diagnosis in order to identify facial changes associated with acromegaly)
Untreated, excess GH is associated with increased morbidity and mortality

Question 17

What is excess growth hormone usually due to?

Answer 17

Benign GH-secreting pituitary tumour (adenoma)

Question 18

What grows in acromegaly?

Answer 18

Periosteal bone (membrane covering outer surface of all bones except at the end of long bones) - results in increased bone width
Cartilage
Fibrous tissue
Connective tissue
Internal organs (cardiomegaly, splenomegaly, hepatomegaly, etc.)

NOTE: cartilage and fibrous tissue are just types of connective tissue

Question 19

Describe the side effects of dopamine receptor agonists.

Answer 19

Nausea and vomiting - stimulation of the vomiting centre in the medulla oblongata
Dyskinesias = uncontrolled, involuntary movement - dopamine in the brain is involved in motor control, and a sudden increase in dopamine could overload the system
Postural hypotension - activation of dopamine receptors reduced BP by a variety of mechanisms
Pathological gambling - reward system over activated

Question 20

What is impaired glucose tolerance?

Answer 20

When blood sugar levels are higher than normal due to insulin resistance, but not high enough to be diagnosed as T2DM
In this stage, the patient is considered pre-diabetic, so the patient will most likely become diabetic if they do not manage their condition and even at this stage they are at a higher risk of cardiovascular disease

Question 21

What are the complications of acromegaly?

Answer 21

Obstructive sleep apnoea
Hypertension
Cardiomyopathy (disease of heart muscle)
Increased risk of cancer

Question 22

How can acromegaly cause obstructive sleep apnoea?

Answer 22

Bone and soft-tissue changes surrounding the upper airway lead to narrowing of the airway and subsequent airway collapse during sleep when there is a lack of muscle tone keeping all the structures in their correct place

Question 23

How can acromegaly cause hypertension?

Answer 23

Direct effects of GH &/or IGF-1 on vascular tree - maybe too much could have cause vascular smooth muscle hypertrophy leading to increased TPR
GH mediated renal sodium reabsorption

Question 24

How can acromegaly cause cardiomyopathy?

Answer 24

Hypertension and DM could lead to cardiovascular problems - hypertension could increase afterload and increase risk of atherosclerosis; DM increases risk of hypertension and can also increase risk of cardiomyopathy by other complex mechanisms
Direct toxic effects of excess GH on myocardium - GH stimulates muscle growth leading to hypertrophy of myocardium, restricting ventricular filling and hence CO

Question 25

How does acromegaly cause increased risk of cancer?

Answer 25

Excessive GH can lead to growth in various tissues, so can result in colonic polyps, which regular screening with colonoscopy - each polyp has a small chance of developing into a cancerous tumour → colorectal cancer

Question 26

What other hormone aside from GH is often high in acromegaly?

Answer 26

Prolactin
This may reflect a tumour which is secreting GH AND prolactin
Hyperprolactinaemia will cause secondary hypogonadism as high prolactin suppresses the pulsatile secretion of GnRH from the hypothalamus

Question 27

What are the main causes of death in acromegaly?

Answer 27

Cardiovascular disease (main)
Respiratory complications
Cancer
NOTE: you could also have complications like these in children with gigantism because excess GH does not only affect the growth plates

Question 28

What is an oral glucose tolerance test?

Answer 28

When a patient is given oral glucose and blood samples are taken to determine how quickly the glucose is cleared from the blood

Question 29

State some common clinical manifestations of acromegaly.

Answer 29

Excessive sweating (hyperhidrosis) - sweat glands enlarge
Headache - could be due to pituitary tumour which is increasing pressure in that area
Enlargement of supraorbital ridges, nose, hands and feet, thickening of lips and general coarseness of features
Enlarged tongue (macroglossia)
Mandible grows causing protrusion of lower jaw (prognathism)
Carpal tunnel syndrome (causes pain, numbness and tingling in hand and arm) - due median nerve compression by growth of nearby structures
Barrel chest - vertebral bodies become enlarged and elongated, ribs thicken
Kyphosis (excessive outward curvature of spine leading to hunched back) - intervertebral discs thicken in some regions and thin in others

Question 30

Explain the GH pattern in the oral glucose tolerance test in a normal individual and a patient with acromegaly.

Answer 30

Normal:
Once an oral glucose load is given, blood sugar levels will increase which will lead to increased insulin secretion
Insulin will inhibit GH secretion as they generally work against each other, leading to the decrease in GH
After a while, blood sugar levels will have decreased again (due to effects of insulin, glucose being used up in respiration) so more GH will be secreted to increase blood glucose levels before GH levels return to its baseline value
Acromegaly patient:
There is no clear explanation for why this happens, therefore known as a ‘paradoxical’ rise in GH

Question 31

What are the metabolic effects of acromegaly?

Answer 31

Excess GH causes an increase in endogenous glucose production (by gluconeogenesis, glycogenolysis) and a decrease in muscle glucose uptake → increased blood glucose concentration
This leads to increased insulin production but GH inhibits the effects of insulin → insulin resistance
This leads to impaired glucose tolerance which develops into T2DM

Question 32

Why are dopamine receptor agonists used to treat acromegaly?

Answer 32

GH secreting pituitary tumour cells often have D2 receptors and dopamine has the effect of inhibiting GH release on these cells (similar effect to prolactin)

Question 33

What are some ways of diagnosing acromegaly?

Answer 33

You can do a serum (blood plasma - clotting factors) test to see if IGF I is elevated - this is indicative of excessive GH production
GH is secreted in a pulsatile hormone so it cannot be randomly measured, therefore IGF I is easier to measure (not produced in a pulsation fashion - remains at a constant level throughout the day)
You can also do an oral glucose tolerance (failed suppression) test

Question 33

How can an oral glucose tolerance test be used to diagnose acromegaly?

Answer 33

This is when a patient is given an oral glucose load and their GH secretion is monitored
Giving glucose should cause a decrease in GH release in a normal individual (curve: DECREASE from baseline (0-2hrs) → increase from baseline (2-4hrs) → return to baseline)
In someone with acromegaly, giving glucose will cause a paradoxical rise in growth hormone release (curve: INREASE from baseline (0-2hrs) → return to baseline)

Question 33

State some of the treatments for acromegaly.

Answer 33

Transsphenoidal Hypophysectomy = removal of the pituitary gland through the nose → 1st line of treatment (i.e. most preferred)
Medication:
somatostatin analogues (e.g. ocreotide)
dopamine receptor agonists (e.g. cabergoline)
Radiotherapy

Question 34

What is the problem with using somatostatin analogues?

Answer 34

Somatostatin analogues act as an ‘endocrine cyanide’- i.e. they inhibit the release of many hormones
This includes inhibition of gut hormones resulting in GI side effects (e.g. nausea, diarrhoea, gallstones)
Therefore, use of somatostatin analogues to treat acromegaly should not be a long-term/permanent option

Question 35

How is a somatostatin analogue used in the treatment of acromegaly?

Answer 35

It is administered as an injection: either short acting OR as a monthly depot (slow release, slow acting)
It can be used short-term before surgery to shrink the size of the pituitary adenoma which would make resection/removal easier
It would also reduce GH secretion in the meantime before surgery takes place
If surgery does not completely cure the excessive GH secretion then it can also be used post-operatively
If radiotherapy is being used as the treatment, then it can be used while waiting for radiotherapy to take effect which is a slow process
NOTE: a somatostatin analogue has to be used instead of somatostatin because somatostatin has too short a half life