Hypersecretion of anterior pituitary hormones

Question 1

What is a common feature of hypersecretion of anterior pituitary hormones

Answer 1

Usually just one type of hormone- not the whole gland

Question 2

Summarise hyperpituitarism

Answer 2

Symptoms associated with excess production of adenohypophysial hormones
Usually due to isolated pituitary tumours but can also be ectopic (i.e. from non-endocrine tissue) in origin
can quite often be associated with visual field and other (e.g. cranial nerve) defects
as well as endocrine-related signs and symptoms

Question 3

What is meant by an ectopic cause

Answer 3

Neuroendocrine tumours- densely packed tumour full of peptide hormones- similar to peptide hormones
Carcinoid tumours of the gut can release too much ACTH- Cushing’s- but the pituitary gland is itself fine.

Question 4

Why are both eyes affected by bitemporal hemianopia

Answer 4

o Both eyes may be affected by bitemporal hemianopia as the decussation of nerves is at the optic chiasm (where the pituitary is)

Question 5

Describe the optic chiasm

Answer 5

At the optic chiasm, fibres from the nasal retinae cross. Light from the outer (temporal) aspects of the visual fields strikes the nasal aspect of the retina. Hence compression (by growth of a suprasellar tumour) of these crossing fibres at the optic chiasm means that there is loss of vision from the outer temporal visual fields.

Question 6

Describe perimetry

Answer 6

Look straight ahead- look at screen with flashes and press button when you see the flashes- normal person can see all the flashes- no black.
However, a person with bitemporal hemianopia may not be able to see all of the flashes- some black spots

Question 7

Describe what the consequences of excesses in each hormone

Answer 7

ACTH (corticotrophin) à Cushing’s disease.
TSH (thyrotrophin) à Thyrotoxicosis.
LH, FSH (gonadotrophins) à Precocious puberty in children.
Prolactin à Hyperprolactinaemia.
GH à Gigantism, Acromegaly.

Question 8

What is the usual cause of hypersecretion of anterior pituitary hormones?

Answer 8

Pituitary adenoma

Question 9

Differentiate between the pathological and physiological causes of hyperprolactinaemia

Answer 9

Physiological
	pregnancy 
	breastfeeding
Pathological
	prolactinoma (often microadenomas < 10mm diameter)

Question 10

What happens to GnRH pulsatility during puberty

Answer 10

Becomes much more frequent and much more rapid

Question 11

List the symptoms of hyperprolactinaemia due to a prolactinoma seen in females

Answer 11

galactorrhoea (milk production)
secondary amenorrhoea (or oligomenorrhoea)- often the presenting complaint and why picked up earlier in women- due to lack of FSH and LH
loss of libido
infertility

Question 12

List the symptoms of hyperprolactinaemia due to a prolactinoma seen in males

Answer 12

galactorrhoea uncommon (since appropriate steroid background usually inadequate)
loss of libido
erectile dysfunction
infertility

Question 13

Can men with prolactinomas present with galactorrhoea

Answer 13

Galactorrhoea occurs in oestrogen-primed breasts
Generally, men don’t have enough oestrogen to be able to lactate
However, some men with breast hypertrophy (gynaecomastia) complain of milk production

Question 14

Differentiate between loss of libido and impotence

Answer 14

Loss of libido-due to low testosterone
Lack of testosterone causes a lack of sexual drive, which is unlike the impotence which is seen in diabetes for example.
In the latter case, diabetic patients have a normal sex drive (libido), but seek medical attention for their erectile dysfunction (impotence) usually due to associated cardiovascular problems.

Question 15

How do prolactinomas often present in male patients

Answer 15

In the male with a prolactinoma, the patient does not perceive any problem at all, and occasionally a spouse might complain about ‘lack of interest’ and encourage referral, or eventually the patient presents with a large prolactinoma and features of hypopituitarism .

Question 16

What is a consequence of a difference in timings of the presentation of prolactinomas in males and females

Answer 16

Female patients- often see microprolactinomas
Male patients - often see macroprolactinomas
Probably true only because we fail to diagnose the males when their tumours are small.

Question 17

Summarise the pathophysiology of treatment for prolactinomas

Answer 17

Dopamine from dopaminergic neurones binds to D2 receptors on the lactotrophs and switches OFF prolactin secretion.
Will reduce the size of the tumour too- only tumour tat can be managed medically (without surgery)

Question 18

What are D3 receptors involved in

Answer 18

The reward system in the brain.

Question 19

Summarise the treatment of hyperprolactinaemia

Answer 19

Medical treatment is 1st line 
Dopamine receptor (D2) agonists
Decrease prolactin secretion
Reduce tumour size
Examples:
BROMOCRIPTINE
CABERGOLINE
Oral administration

Question 20

What should we do when the tumour does not shrink whilst being treated with dopamine agonists

Answer 20

If the tumour does not shrink, it is important to reconsider the diagnosis, as it is possible that the patient always had disconnection hyperprolactinaemia , and this differential diagnosis is difficult to confim

Question 21

State the side effects of dopamine receptor agonists

Answer 21

Nausea and vomiting
Postural hypotension
Dyskinesias (loss of voluntary movement)
Depression (exhaustion of dopamine stores)
Pathological gambling (see BNF!)- dopamine receptors are part of the reward system (D3)- some of these are activated- need someone who knows the patient well to monitor them- individual will have no insight on this.

Question 22

What should be done in patients who cannot tolerate dopamine receptor agonists

Answer 22

i.e those with schizophrenia are made much worse by dopamine agonists, surgery and/or radiotherapy are options to be considered

Question 23

Essentially, how do we diagnose prolactinomas

Answer 23

The combination of a raised circulating prolactin level with a visible prolactin tumour on the MRI scan suggests that there is a prolactinoma but it is essential that the diagnoses of disconnection hyperprolactinaemia or other causes of hyperprolactinaemia are excluded. The size of the tumour and the relative height might be useful. For example, a prolactin level over 6000 mU.L-1 can only be due to a prolactinoma. Levels between 1000 and 6000 mU L-1 are more difficult to interpret, and can be due to a small macroprolactinoma, or to a large tumour causing disconnection from the hypothalamus- patients should be reviewed by MDT

Question 24

Compare the effects of excess growth hormone in humans and in adults

Answer 24

§ Childhood = gigantism. Adulthood = acromegaly.

§ Usually due to BENIGN GH secreting pituitary adenoma (of the somatotrophs)

Question 25

Why don't we see gigantism in adults

Answer 25

``` The epiphyses of long bones have fused, therefore linear growth is unlikely but other tissues undergo hypertrophy where possible, and a very stereotypic appearance occurs. Prognathic Jaw Frontal Bossing Spade Hands Wide spaced teeth ```

Question 26

Summarise the metabolic defects of acromegaly

Answer 26

The metabolic effects of excess GH cause increased risk of diabetes, hypertension and vascular disease resulting in a raised morbidity. Can lead to impaired glucose tolerance (diabetes mellitus)- increasing the risk of infection.

Question 27

Summarise acromegaly

Answer 27

Insidious in onset Signs and symptoms progress gradually (can remain undiagnosed for many years) Untreated, excess GH is associated with increased morbidity and mortality Death = Cardiovascular disease 60% Respiratory complications 25% Cancer 15%

Question 28

What are the most serious complications of excess growth hormone?

Answer 28

``` Cardiovascular problems (majority) and respiratory problems This is mainly due to organ growth ```

Question 29

What are the metabolic effects of acromegaly?

Answer 29

Increased insulin response to oral glucose leading to insulin resistance This causes impaired glucose tolerance (in 50%) and diabetes mellitus (in 10%)

Question 30

What grows in acromegaly

Answer 30

``` periosteal bone cartilage fibrous tissue connective tissue internal organs (cardiomegaly, splenomegaly, hepatomegaly, etc.) ```

Question 31

Summarise the clinical features of acromegaly

Answer 31

excessive sweating (hyperhidrosis) headache 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 (median nerve compression) barrel chest, kyphosis

Question 32

Which symptoms does treatment for acromegaly relieve

Answer 32

``` Excessive sweating (hyperhydrosis) Headache ```

Question 33

What can be used to aid the diagnosis of acromegaly

Answer 33

Photo- showing the changes in features of the patient

Question 34

Describe the risk of cancer in patients taking GH replacement

Answer 34

Non-existent (unlike patients suffering from acromegaly)- as GH is not being released all the time

Question 35

Summarise the management of cancer risk in patients with acromegaly

Answer 35

Whilst cancer is not a common presentation of acromegaly, once they are diagnosed, we need to organise regular cancer screenings (colonoscopies)- to monitor their risk

Question 36

Why do patients with acromegaly have gaps between their teeth

Answer 36

Lantern Jaw | Rapid growth of jaw creates gaps between the teeth

Question 37

Why is it futile to measure GH in patients with acromegaly

Answer 37

Because the secretion of GH is pulsatile in normal individuals, a random blood GH concentration measurement is unlikely to be useful unless it is zero, in which case it excludes acromegaly. A high level could be due either to acromegaly, or to the chance of hitting the pulse of a normal GH secretion.

Question 38

Outline how acromegaly can lead to diabetes Mellitus

Answer 38

Increased endogenous muscle production, decreased muscle glucose uptake. Increase insulin production- eventually leading to insulin resistance Impaired glucose tolerance Diabetes mellitus

Question 39

List the common complications of acromegaly

Answer 39

Obstructive sleep apnoea Hypertension Cardiomyopathy Increased risk of cancer

Question 40

Describe obstructive sleep apnoea

Answer 40

Bone and soft tissue changes (growth) surrounding the upper airway- leading to narrowing and subsequent collapse during sleep

Question 41

Describe hypertension

Answer 41

Direct effects of GH/IGF-1 on vascular tree | GH mediated renal sodium absorption

Question 42

Describe cardiac myopathy

Answer 42

Damage to heart muscle- big, baggy heart that cannot pump properly- excess GH is toxic to the heart Hypertension, DM, direct toxic effects of GH on myocardium

Question 43

Describe the increased risk of cancer

Answer 43

GH makes everything grow and it’s being released all the time Colonic polyps, regular screening with colonoscopy

Question 44

Describe the co-secretion of prolactin with GH in patients with acromegaly

Answer 44

Prolactin is often high in patients with acromegaly- reflecting the fact that the tumour is secreting both GH and prolactin Hyperprolactinaemia will cause secondary hypogonadism (see clinical features of hyperprolactinaemia)- need pulsatility to drive LH and FSH- high prolactin has an inhibitory effect- stopping pulsatility- no signal to make LH or FSh

Question 45

Describe the diagnosis of acromegaly

Answer 45

If diagnosis is suspected, suppression of GH secretion using a glucose tolerance test should be performed. GH levels fall to zero during glucose tolerance testing in normal individuals, but this does not happen in patients with acromegaly. A somatotroph adenoma paradoxically will have the opposite effect, and may result in an increase in GH levels which will confirm the diagnosis. The final diagnostic test is to measure the level of IGF-1, which is used as a marker of long term GH exposure

Question 46

Why is it essential to measure IGF-1

Answer 46

Starvation can give a false positive response. In addition, levels of GH and IGF-1 need to be measured to monitor response to treatment.

Question 47

Summarise the diagnosis of acromegaly

Answer 47

``` GH pulsatile – so random measurement unhelpful Elevated serum IGF-1 Failed suppression (‘paradoxical rise’) of GH following oral glucose load – oral glucose tolerance test ```

Question 48

Summarise the treatment of acromegaly

Answer 48

``` Surgery (trans-sphenoidal) – 1ST LINE Medical Somatostatin analogues e.g. OCTREOTIDE Dopamine agonists (GH secreting pituitary tumours frequently express D2 receptors) e.g. CABERGOLINE Radiotherapy ```

Question 49

What is the first line treatment for acromegaly and describe the procedure

Answer 49

Tran sphenoidal surgery - by which the tumour is removed by suction through a hole made in the body of the sphenoid bone approached up through the nasal sinus). Following the surgery- all the patient's pituitary axes need to be reassessed.

Question 50

State the treatment options for acromegaly

Answer 50

``` Transsphenoidal Hypophysectomy Radiotherapy Chemotherapy: · Octreotide (somatostatin analogue) · Bromocriptine and Cabergoline (dopamine receptor agonists ```

Question 51

Summarise the use of somatostatin analogues

Answer 51

‘Endocrine cyanide’ Injection: sc (short acting) or monthly depot GI side effects common eg nausea, diarrhoea, gallstones can occur (can't absorb fats properly) Reduces GH secretion and tumour size Pre-treatment before surgery may make resection easier Use post-operatively if not cured or whilst waiting for radiotherapy to take effect (slow- radiotherapy effects take a while to kick in)

Question 52

Why should surgery be the first line treatment in patients with acromegaly

Answer 52

Unlike prolactinomas, shrinkage of somatotrophinomas doesn't occur- making surgery a viable early option for patients.

Question 53

Give 2 examples of somatostatin analogues

Answer 53

lanreotide | octreotide

Question 54

Which symptoms do patients tend to notice first

Answer 54

Changes in ring size or shoe size

Question 55

What is IGF-2 more important for

Answer 55

The growing foetus

Question 56

Describe the follow up that should be done post-operation

Answer 56

if the GH levels are low enough, no further therapy will be warranted. Some patients progress to requiring radiotherapy and drugs. All patients with acromegaly require annual pituitary review, to ensure that they are in optimum pituitary hormone replacement therapy if needed.

Question 57

14. What are the clinical uses of octreotide?

Answer 57

It can be used short-term before surgery to shrink the size of the pituitary adenoma It can be used long-term if it can’t be controlled by other means It is used as a treatment for other neuroendocrine tumours e.g. carcinoid tumours

Question 58

Describe the administration, distribution and metabolism of octreotide.

Answer 58

Octreotide is administered SC or IM 3/day It is retained in extracellular fluid Half-life = 2-4 hour

Question 59

State some of the side effects of octreotide.

Answer 59

GI tract disturbance (because somatostatin is produced by the small intestine as well) Initial reduction in insulin secretion causing hyperglycaemia (octreotide inhibits the production of insulin by the beta cells) Rarely gallstones

Question 60

What is used to treat hyperprolactinaemia?

Answer 60

Dopamine agonists – bromocriptine and cabergoline

Question 61

Describe the pharmacokinetics and side-effects of bromocriptine.

Answer 61

``` Administered orally 1/day Heavily plasma protein bound Half-life = 7 hours (hepatic metabolism) Side effects: · Nausea/vomiting/abdominal cramps · Dyskinesias · Psychomotor excitation · Postural hypotension · Vasospasm in fingers and toes ```

Question 62

State some other uses of bromocriptine.

Answer 62

Suppression of lactation Cyclical benign breast tumours (and cyclic breast pain) Also used in acromegaly but doesn’t have the same beneficial effect on tumour size Parkinson’s disease

Question 63

Describe the pharmacokinetics and side-effects of cabergoline

Answer 63

Taken orally 1-2/week Half-life = > 45 hours Side effect: same as bromocriptine but less pronounced