Acromegaly is a rare disease that is characterized by abnormal enlargement of the skull, the jaw, the hands and feet, and also of the internal organs.

Cause 

Acromegaly is caused by excessive secretion of growth hormone from the anterior pituitary gland at the base of the brain and is the result of a noncancerous pituitary tumour. If such a tumour develops before puberty, the result is gigantism (in which growth is accelerated) instead of acromegaly.

More commonly, however, the tumour develops after growth in the long bones of the limbs has stopped. This leads to acromegaly, although it may take several years for the symptoms and signs of the condition to appear.

Symptoms and signs 

Symptoms and signs of acromegaly include enlargement of the hands, feet, ears, and nose; a jutting lower jaw; and a long face. There may also be deepening or huskiness of the voice. Symptoms common to any brain tumour, such as headache and visual disturbances, are also possible.

Diagnosis and treatment 

Acromegaly is diagnosed by the measurement of blood levels of growth hormone before and after a quantity of glucose has been administered. Glucose usually suppresses the secretion of growth hormone; if the glucose has no effect on the blood level of the hormone, uncontrolled secretion of growth hormone by the pituitary gland can be confirmed.

CT scanning or MRI (techniques that produce cross-sectional or three-dimensional images of body structures) may be carried out to reveal a tumour or overgrowth of the pituitary gland. A tumour of the pituitary gland may be removed surgically or treated by radiotherapy.

The drug octreotide prevents growth hormone production and may be used to control symptoms by a person awaiting surgery or until the effects of radiotherapy are felt. Bromocriptine sometimes causes the tumour to become smaller.

Acromegaly in detail 

Essentials

Growth Hormone excess causes acromegaly, which develops insidiously with multiple clinical features, most notably including local tumour effects, and increase in size of hands, feet, jaw, and skull. Biochemical diagnosis is made by confirming absence of suppression of GH in the oral glucose tolerance test, and by increased serum IGF-1 levels.

Management options include (1) surgery—with trans-sphenoidal surgery the treatment of choice for most patients; (2) drugs—including dopamine receptor agonists, somatostatin receptor ligands (e.g. octreotide, lanreotide) and GH receptor antagonists (e.g. pegvisomant); and (3) radiotherapy—generally offered for tumours that have recurred or persisted after surgery in patients with resistance to or intolerance of medical treatment.

Introduction

Acromegaly is the syndrome resulting from GH hypersecretion. Its incidence is estimated to be approximately 3 cases per 1 million persons per year, and its prevalence is about 60 per million. More than 90% of patients with acromegaly have a benign monoclonal GH-secreting pituitary adenoma surrounded by nonhyperplastic pituitary tissue. Co-secretion of PRL has been described in about 25% of GH-secreting adenomas. More than 70% of somatotroph tumours are macroadenomas at diagnosis. Younger patients usually present with more rapidly growing tumours. Rarely, acromegaly is associated with familial syndromes, including multiple endocrine neoplasia type I, the McCune–Albright syndrome, familial acromegaly, and Carney’s syndrome. Excess production of GH-releasing hormone (as in central hypothalamic tumours, usually gangliocytomas, and peripheral neuroendocrine tumours, e.g. of the lung) can result in somatotroph hyperplasia and acromegaly.

Clinical features

The clinical features of acromegaly are shown in Bullet list 1. Disease features develop insidiously, and the diagnosis may often take 10 years from presentation. GH-secreting adenomas arising before the closure of epiphyseal bone are associated with accelerated growth and gigantism.

Whether acromegaly is associated with an increased relative risk of cancer is controversial and has been extensively reviewed. Prospective, controlled studies of colonoscopic screening suggest that the risk of colon cancer is nearly twice that in the general population; this probably reflects a tropic IGF-1 effect on the proliferation of epithelial cells. Screening colonoscopy should be performed when the diagnosis of acromegaly is made, with follow-up according to standard guidelines.

The overall standardized mortality ratio of patients with acromegaly is 1.48. Factors contributing to an increased mortality include the higher prevalence of hypertension, hyperglycaemia, or overt diabetes, cardiomyopathy, and sleep apnoea in this population. GH levels of less than 2.5 µg/litre (5 mU/litre) predict longer survival. In some studies, increased IGF-1 levels are associated with higher mortality. However, GH levels seem to be more consistently independent predictors of mortality than are IGF-1 levels.

Bullet list 1 Clinical features of acromegaly

Diagnosis

The biochemical diagnosis is made by confirming absence of suppression of GH in the oral glucose tolerance test and by increased serum IGF-1 levels. With the use of most commercial assays, nadir GH levels of less than 1 µg/litre (2 mU/litre) during the oral glucose tolerance test rule out the diagnosis.

Treatment

The goals of treatment in patients with acromegaly include the elimination of morbidities associated with the disease and normalization of the increased mortality. These aims are achieved by using safe approaches that decrease the mass effects and restore GH and IGF-1 secretion to normal. It should be noted that, with the currently available therapeutic options, normal GH secretion dynamics are only rarely achieved and it is, therefore, more appropriate to define disease control. Disease control implies nadir GH levels of less than 1 µg/litre (2 mU/litre) after the glucose tolerance test and a normal IGF-1 level (for sex and age). It has been recently proposed that for complete control of GH dynamics to be achieved, nadir GH values should be less than 0.4 µg/litre.

Management options include surgery, drugs, and radiotherapy. Trans-sphenoidal surgery remains the treatment of choice for most patients. The success rate depends on the size and extensions of the tumour, the presurgical GH levels, as well as the experience and expertise of the neurosurgeon. Biochemical control has been reported for up to 80% of microadenomas and for up to 40% of macroadenomas. Tumours that have invaded the cavernous sinus cannot be completely removed surgically and the hypersecretion of GH almost invariably persists postoperatively in such patients. Although up to 10% of tumours recur, many recurrences probably represent persistent growth of residual nonresectable tumour tissue.

Medical treatment includes dopamine receptor agonists, somatostatin receptor ligands, and GH receptor antagonists. Dopamine receptor agonists are less costly than other agents, but are only occasionally effective in selected patients. The doses required are usually much higher than in prolactinomas and biochemical control has been reported in less than 15% of the patients. Somatostatin receptor ligands, such as octreotide and lanreotide, bind to somatostatin receptors resulting in suppression of GH secretion.

They also act on the liver to block the synthesis of IGF-1. Octreotide and lanreotide are selective for somatostatin receptors type 2 and 5, which are expressed in more than 90% of the GH-secreting adenomas. Depot preparations—long-acting-release octreotide and a long-acting aqueous-gel preparation of lanreotide—allow for injections every 14 to 28 days maintaining highly effective drug levels. Biochemical control has been reported in approximately 70% of the patients with the pretreatment GH levels affecting the efficacy of these agents (less effective when the GH level is higher). Shrinkage of tumour mass has been reported in about 50% of patients, and generally reverses when treatment is stopped.

Surgical debulking of macroadenomas not amenable to total resection enhances the efficacy of subsequent somatostatin analogue treatment. Somatostatin analogues are indicated following unsuccessful surgery and after radiation therapy, during the period when GH levels remain elevated. They can also be offered as primary treatment to patients with large extrasellar tumours who have no evidence of central compressive effects, those who are too frail to undergo surgery, and those who decline an operation.

Transient diarrhoea, nausea, and abdominal discomfort may occur, but typically resolve within 8 to 10 weeks. Blood glucose levels may rise in some patients. Gallbladder sludge or asymptomatic gallstones develop within 18 months in up to 20% of patients and these conditions should be managed according to standard guidelines. Selective activation of other somatostatin receptors by specific somatostatin receptor ligands results in additive suppression of GH; thus, the ligand pasireotide (SOM230), currently in clinical trials, suppresses levels of GH in patients with resistance to octreotide. Chimeric molecules that recognize both the dopamine D2 receptor and somatostatin receptors may also enhance receptor signalling and provide therapeutic synergy.

Lastly, pegvisomant, a pegylated GH receptor analogue showing enhanced activity for the GH receptor, also prevents the functional GH-receptor signalling. As a result of this, it blocks the GH-mediated IGF-1 generation in nearly 90% of patients. It is indicated for patients whose GH levels are inadequately controlled with other modalities or in those experiencing significant drug side effects. During treatment with pegvisomant, GH levels increase and IGF-1 is the biomarker for monitoring the efficacy of treatment. Elevated hepatic aminotransferase levels have been reported requiring monitoring of the liver function tests monthly for the first 6 months of treatment and 6 monthly thereafter. Probable tumour size should be monitored at 6-month intervals to detect possible continued enlargement.

Radiotherapy (conventional or radiosurgery) is generally offered for tumours that have recurred or persisted after surgery in patients with resistance to or intolerance of medical treatment. Twenty-two per cent of patients achieved a level less than 2.5 ng/ml (5 mU/litre) by 2 years, 60% by 10 years, and 77% by 20 years. The interval to achieve this depends on the pre-irradiation GH level. Insulin-like growth factor-I levels normalize in 63% of patients by 10 years.