Acromegaly and Growth Hormone

Question 1

Acromegaly - Ix

Answer 1

Acromegaly: investigations

Growth hormone (GH) levels vary during the day and are therefore not diagnostic. The definitive test is the oral glucose tolerance (OGTT) with serial GH measurements. Serum IGF-1 may also be used as a screening test and is sometimes used to monitor disease

Oral glucose tolerance test
in normal patients GH is suppressed to < 2 mu/L with hyperglycaemia
in acromegaly there is no suppression of GH
may also demonstrate impaired glucose tolerance which is associated with acromegaly

A pituitary MRI may demonstrate a pituitary tumour

Oral Glucose Tolerance Test (OGTT)
Growth hormone levels and blood glucose levels are also connected. In someone without acromegaly, a higher blood glucose level usually causes the body to stop producing GH. Therefore, a doctor will purposely raise your blood glucose level using an OGTT and watch how your GH level responds.

Question 2

Acromegaly - Diagnosis: Example Question

Answer 2

A 47-year-old builder presented with paraesthesia in both hands which was worse at night. His hands felt swollen, although they were not painful, and he had needed to buy a larger pair of work gloves. When at work he found that his hands felt weak. Over the past six months he had been experiencing urinary frequency, fatigue and increased thirst.

He had a past medical history of obesity and hypertension and his brother had type II diabetes mellitus. His only medication was ramipril. He was a heavy smoker with a 20 pack year history.

On examination of the arms there was weakness of thumb abduction bilaterally and diminished sensation over the radial three and a half digits. Percussion over the palmar aspect of the wrist reproduced the paraesthesia he described on presentation. On examination of the chest and abdomen there were areas of pigmentation in both axillae and striae over the abdomen. He had a protruberent abdomen and an elevated body mass index (BMI).

Which of the following investigations is most likely to be diagnostic?

Magnetic Resonance Imaging of the Pituitary and visual field testing
Fasting glucose on three occasions, glycosylated haemoglobin (HbA1c) and a 9am cortisol measurement
Growth hormone measurement and dexamethasone suppression test
Nerve conduction studies and electromyogram (EMG)
> Oral glucose tolerance test with serum glucose, IGF-1 and growth hormone measurements

This gentleman has bilateral carpal tunnel syndrome with an underlying diagnosis of acromegaly.

The features in the question which point to the diagnosis of acromegaly include the presence of a recent increase in hand size and known complications of acromegaly such as diabetes mellitus (polyuria and polydipsia), acanothosis nigricans (pigmentation in the axillae) and carpal tunnel syndrome.

The increased BMI and striae could be indicative of underlying Cushings disease but in this case this were red herrings.

The diagnosis of acromegaly is made when there is a failure to suppress the release of growth hormone during an oral glucose tolerance test. This test also allows the diagnosis of diabetes mellitus to be made. Due the diurnal variation in growth hormone levels, a random measurement is not helpful in making a diagnosis.

Although an MRI scan of the pituitary and visual field testing are very important investigations and can confirm the presence of a pituitary adenoma they will confirm or exclude a diagnosis of acromegaly.

A fasting glucose and HbA1c measurement may aid the diagnosis of diabetes mellitus but not acromegaly.

A 9am cortisol and dexamethasone suppression test could be used to investigate Cushings syndrome and therefore are not relevant here.

Nerve conduction studies and electromyography would confirm the diagnosis of carpal tunnel syndrome but the underlying cause i.e. acromegaly.

Question 3

Acromegaly - Fx

Answer 3

Acromegaly: features

In acromegaly there is excess growth hormone secondary to a pituitary adenoma in over 95% of cases. A minority of cases are caused by ectopic GHRH or GH production by tumours e.g. pancreatic

Features
•coarse facial appearance, spade-like hands, increase in shoe size
•large tongue, prognathism, interdental spaces
•excessive sweating and oily skin
•features of pituitary tumour: hypopituitarism, headaches, bitemporal hemianopia
•raised prolactin in 1/3 of cases → galactorrhoea
•6% of patients have MEN-1

Question 4

Acromegaly - Cx

Answer 4

Complications
•hypertension
•diabetes (>10%)
•cardiomyopathy
•colorectal cancer

Question 5

Acromegaly - Example Question

Answer 5

A 55-year-old male presents to his general practitioner with a 2-month history of sweating, fatigue and daytime tiredness. He attributed his tight wedding ring to ‘fluid retention’ and in the last 2 weeks, he has been experiencing worsening headaches and deterioration in his vision. He has otherwise no past medical history and does not take any regular medications.

Which of the following findings would be in keeping with the above?

 Homonymous hemianopia 
 Overbite 
 > Positive Tinel's sign 
 Reduced FVC on spirometry 
 Dysdiadochokinesia 

This is a case of acromegaly which is caused by excessive growth hormone secretion. In adults, the excess growth hormone secretion is usually caused by a benign growth hormone-secreting pituitary adenoma.

It is often associated with hypertension, diabetes, obstructive sleep apnoea, carpal tunnel syndrome, colonic polyps/malignancies, cardiomyopathies, and arrhythmias.

1. Homonymous hemianopia: this is false because the visual field disturbance associated with a pituitary tumour is bitemporal hemianopia
2. Overbite: patients with present with underbite, or prognathism
3. Positive Tinel’s sign: this is true in carpal tunnel syndrome
   4 and 5: these features are not characteristic of acromegaly

Question 6

Acromegaly - Mx:

Answer 6

Acromegaly: management

Trans-sphenoidal surgery is first-line treatment for acromegaly in the majority of patients

Dopamine agonists
for example bromocriptine
the first effective medical treatment for acromegaly, however now superseded by somatostatin analogues
effective only in a minority of patients

Somatostatin analogue
for example octreotide
effective in 50-70% of patients
may be used as an adjunct to surgery

Pegvisomant
GH receptor antagonist - prevents dimerization of the GH receptor
once daily s/c administration
very effective - decreases IGF-1 levels in 90% of patients to normal
doesn’t reduce tumour volume therefore surgery still needed if mass effect

External irradiation is sometimes used for older patients or following failed surgical/medical treatment

Question 7

Acromegaly Monitoring - Example Question

Answer 7

A 55-year-old male presented to his general practitioner with a 4-month history of sweating, fatigue and daytime tiredness. He attributed his tight rings to ‘fluid retention’ and has been experiencing worsening headaches and deterioration in his vision.

He was diagnosed with acromegaly and underwent surgery for this condition 1 month ago. He has been feeling well since and has not experienced any new symptoms.

Which of the following investigations would be most useful for monitoring the effect of his therapy?

	MRI pituitary
	Echocardiography
	Growth hormone levels
	> Insulin-like growth factor levels
	Oral glucose tolerance test

Insulin-like growth factors (IGF-1) have a long half-life and so is a useful measurement to assess growth hormone secretion and therefore screen for acromegaly and monitor the response to therapy. Serum IGF-1 is the most feasible parameter to assess clinical disease activity, in everyday practice in the outpatient clinic setting. It is monitored every 6 months, and growth hormone (GH) levels are done yearly.

Note: Oral glucose tolerance test (plus GH levels) is not helpful for patients receiving somatostatin analogues, and for patients receiving GH receptor antagonist therapy, only IGF-1 should be measured.

Question 8

Growth Hormone

Answer 8

GH is an anabolic hormone secreted by the somatotroph cells of the anterior lobe of the pituitary gland - it has actions on multiple organ systems and is important in the postnatal growth and development. GH is also responsible for changes in protein, lipid and carbohydrate metabolism

SOURCE = Anterior Pituitary
FUNCTION = Postnatal growth and development
Numerous actions on protein, carb and fat metabolism
MoA:
- acts on transmembrane receptor for growth factor
- binding of GH to receptor > receptor dimerisation
- acts directly on tissues and also indirectly via insulin-like growth factor 1 (IGF-1) primarily secreted by the liver

Conditions assoc with GH Disorders:
Excess GH = Acromegaly
GH Deficiency = Results in short stature

Question 9

Regulation of GH

Answer 9

Increases Secretion:

• GHRH (Growth Hormone Releasing Hormone) - released in pulses by the hypothalamus
• Fasting
• Exercise
• Sleep

Decreases Secretion:

• Glucose
• Somatostatin (itself increased by somatomedins, circulating insulin-like growth factors, IGF-1 and IGF-2)