Acromegaly

Notes

Definition & classification

Acromegaly & gigantism are related conditions caused by an excess of growth hormone (GH)

Acromegaly occurs in adulthood, following epiphyseal fusion. It typically occurs in the fourth decade of life. Gigantism, occurring in childhood due to GH prior to epiphyseal fusion, is defined as height > 2 SD for the patient’s age and sex.

Physiology

Growth hormone, also termed somatotropin, is a peptide hormone that is produced and released by somatotropic cells within the anterior pituitary.

1. Growth hormone releasing hormone

Growth hormone releasing hormone (GHRH) is released from the arcuate nucleus of the hypothalamus. 

It is transported via the hypophyseal portal system to the anterior pituitary. Here it stimulates the release of growth hormone.

2. Growth hormone

Growth hormone (GH) is released from the somatotropic cells of the anterior pituitary in response to GHRH. 

It stimulates the release of insulin-like growth factor -1 (IGF-1). Growth hormone exhibits pulsatile secretion and levels may vary widely during the day. In general, IGF-1 has steadier levels.

 3. Insulin-like growth factor -1

IGF-1 is produced and released by the liver. It has widespread growth promoting effects.

This axis features negative feedback, in which IGF-1 and GH release leads to the inhibition of GHRH and stimulation of somatostatin release. Somatostain is a negative regulator of growth hormone secretion. 

Aetiology

Pituitary adenomas acccount for > 90% of cases of acromegaly.

Pituitary Adenoma

Pituitary adenomas may be functional (secrete hormones) or non-functional. Functional pituitary adenomas may lead to excess prolactin secretion (hyperprolactinaemia), excess ACTH secretion (Cushing's disease), or excess growth hormone secretion (acromegaly/gigantism).

Functional pituitary tumours are the commonest causes of acromegaly and gigantism. In > 90%, excess GH is secreted by a pituitary adenoma.

Other (rare)

Other causes of acromegaly are rare. They are usually related to excess secretion of GH from an ectopic source or hypothalamic dysfunction (e.g. hypothalamic tumours).

Clinical features

Acromegaly typically has an insidious onset and is often diagnosed late.

Gigantism tends to have a more dramatic presentation. Increased linear growth is marked, yet soft tissue features tend to be less pronounced.

Clinical features in both conditions may be related to the excess growth hormone secretion and mass effects of the adenoma.

Growth hormone excess

In gigantism, increased linear growth is the cardinal feature. In both conditions enlargement of hands, feet, lips and nose may be seen.

Examination should look for wide spaced teeth, prognathism and frontal bossing. Male patients may note a deepening of their voice and some develop carpal tunnel syndrome.

There is an increased risk of colorectal cancer; some centres advocate regular colonoscopy.

Mass effects

Macroadenomas may result in mass effects. These include:

  • Headaches
  • Visual loss (bitemporal hemianopia)
  • Features of hypopituitarism 

Hyperprolactinaemia 

Concomitant hyperprolactinaemia may occur, particularly in gigantism.

Features of hyperprolactinaemia include galactorrhea, dysmenorrhoea, hypogonadism and infertility. 

 

Investigation & diagnosis

Investigations are targeted at diagnosis of the condition and its many complications.

Serum IGF-1

Whilst GH shows a great deal of variation depending on the time of day and various stressors, IGF-1 has remarkably constant levels.

Raised serum IGF-1 reflects periods of excess GH. 

Glucose tolerance test

This is a highly specific diagnostic test. The patient is given 100g of glucose orally. Serum GH can be measured before and after glucose stimulation. 

In healthy individuals, GH release is suppressed following the administration of exogenous glucose (i.e. < 0.6 mcg/L).

In patients with acromegaly, GH levels are increased above the testing threshold. Interestingly, in some patients undergoing a glucose tolerate test, a paradoxical rise in GH may be seen. Although uncommon, this may complicate the diagnosis. 

Pituitary MRI

As mentioned above a pituitary adenomas affecting the somatotrophs is the most common cause of gigantism and acromegaly.

An MRI of the pituitary both confirms the diagnosis and helps guide surgical management.

Management

The management of acromegaly may involve a number of modalities, both medical and surgical.

Surgery

Surgery is typically first-line therapy. Success rates are variable, dependent on both the size and location of the adenoma. Microadenomas tend to have better results than macroadenomas. 

Recurrence following surgery is common, estimated at > 10%.

Radiotherapy

Radiotherapy is generally reserved for cases where surgery fails. It is rarely used as a primary therapy.

Radiotherapy is normally combined with a medical therapy. The biochemical response to radiotherapy can be slow, taking more than 10 years.

The biggest risk of radiotherapy is the development hypopituitarism; therefore, it is generally avoided in those of reproductive age.

Medical

Somatostatin receptor agonists (e.g. Octreotide) are the mainstay of medical management. Somatostatin is a negative regulator of GH and it can be used as primary therapy. However, it is usually used as a bridge to surgery.

Other medical options include:

  • Dopamine agonists (e.g. Bromocriptine): causes shrinkage of tumours.
  • Growth hormone antagonists (e.g. Pegvisomant): lowers IGF-1 levels.

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