Acromegaly

Growth hormone stimulates the production of insulin-like growth factor-I (IGF-I), which is produced in the liver and many other tissues. IGF-I is the main mediator of the actions of growth hormone. Acromegaly is usually caused by excessive secretion of growth hormone by a pituitary macroadenoma or microadenoma. Other rare causes include increased growth hormone-releasing hormone (GHRH) from hypothalamic tumours, ectopic GHRH or growth hormone from non-endocrine tumours, e.g. lung cancer, cancer of the pancreas, carcinoid, medullary carcinoma of the thyroid. Acromegaly causes an overgrowth of all organ systems, bones, joints and soft tissues.

• Incidence is 3-4 per million subjects per year.¹
• Acromegaly most often occurs in adults aged 30-50 years.

Often an insidious onset and symptoms may precede the diagnosis by several years.

Symptoms

• Due to tumour:
  • Headaches
  • Visual field defects: the most common defect is a bitemporal hemianopsia.
• Due to excess of growth hormone:
  • Gradual change in appearance due to the effects on cartilage and soft tissues: enlargement of hands and feet, growth of the jaw, coarsening of facial features, increase in ring and shoe size. Ask the patient to bring in a photograph of themself to compare with their current appearance.
  • Excessive sweating and oily skin
  • Macroglossia may cause obstructive sleep apnoea leading to daytime tiredness.
  • Articular overgrowth of synovial tissue and hypertrophic arthropathy occur. Arthritis, back pain and kyphosis are common.
  • Nerve compression symptoms may occur, especially carpal tunnel syndrome.
  • Widespread osteoarthritis of the weight-bearing joints.

Signs

• Facial features: frontal bossing, thickening of the nose, macroglossia, prognathism.
• Women may have mild hirsutism.
• Enlarged thyroid gland with a multinodular goitre.
• Enlarged extremities with sausage-shaped fingers are signs of acromegaly.
• Skin is oily and has skin tags. Skin tags are possible markers for colonic polyps.
• Visceral hypertrophy includes the heart, liver and kidneys. Cardiac features include hypertension, left ventricular hypertrophy, cardiomyopathy and arrhythmias.

• Visual field tests.
• Blood glucose; serum phosphate, urinary calcium and serum triglycerides may also be raised.
• Random growth hormone: often not diagnostic because of episodic secretion and short half-life of the hormone.
• Glucose tolerance test: growth hormone is normally inhibited by glucose. The diagnosis of acromegaly can be confirmed by documenting an elevated IGF-I level in combination with failure of growth hormone to suppress after oral glucose to below 0.3 micrograms per litre, when growth hormone is measured with a highly sensitive and specific assay.²
• IGF-I: long half-life and so is useful measurement to assess growth hormone secretion and therefore screen for acromegaly and monitor the effect of therapy.³
• IGF-binding protein-3 (IGFBP-3): is the main binding protein for circulating IGF and is increased in acromegaly. Can be useful in the diagnosis of acromegaly.
• GHRH concentration can be obtained if clinically indicated.
• Assessment of other pituitary hormones: prolactin, adrenal, thyroid, and gonadal hormones.
• MRI of pituitary and hypothalamus: more sensitive than CT scan.
• CT scan: for lung, pancreatic, adrenal or ovarian tumours that may secrete ectopic growth hormone or GHRH.
• Cardiac assessment: ECG, echocardiogram.

• Trans-sphenoidal surgery is the treatment of choice in most cases. Remission rates are 80-85% for microadenomas and 50-65% for macroadenomas.⁴ Patients with residual disease can then be offered adjuvant treatment.
• Some patients may need medical treatment or radiotherapy after surgery to reduce growth hormone levels.
• Dopamine agonists: bromocriptine has limited effectiveness but cabergoline is more effective and may reduce the size of the tumour in about 50% of patients. Tumours that also secrete prolactin have a better response rate to dopamine agonists.
• Somatostatin analogues: octreotide and lanreotide are analogues of the hypothalamic release-inhibiting hormone somatostatin. Somatostatin analogues are more effective than dopamine agonists in the treatment of acromegaly.⁵
• Pegvisomant: recently introduced; genetically modified analogue of human growth hormone and is highly selective growth hormone receptor antagonist. Has been shown to normalize IGF-I levels in 90-100% of patients. Growth hormone levels increase during treatment and no decrease in tumor size is seen. Pegvisomant is licensed for the treatment of acromegaly in patients with inadequate response to surgery, radiation or somatostatin analogues.
• Radiotherapy: used as an adjuvant for large invasive tumours and when surgery is contraindicated.

Complications of acromegaly include:
• Ischaemic heart disease, cardiac failure, cerebrovascular disease
• Diabetes
• Acromegalic arthropathy affects up to 70% of patients and involves both the axial and peripheral skeleton¹
• Obstructive sleep apnoea
• Increased incidence of colonic polyps and adenocarcinoma of the colon¹
• Patients may develop hypopituitarism immediately after surgery, or several years after radiotherapy.
• Damage caused by the tumour may result in hyperprolactinaemia and deficiencies of glucocorticoids, sex steroids and thyroid hormone.

• High levels of growth hormone, even when the patient has no symptoms, are associated with a 2-3 fold increase in mortality.⁶
• Tumor size: microadenoma (tumour less than 10mm) is associated with a better prognosis than macroadenoma, mainly because persistence of disease after surgery is more common with macroadenomas.
• Reduction of growth hormone response to a glucose load is the most important factor in increasing survival. Raised growth hormone levels following treatment are associated with significantly increased mortality rates.
• Hypertension, cardiovascular disease and diabetes are poor prognostic factors.
• Long duration of symptoms is also a poor prognostic factor.