Acromegaly is characterized by a number of clinical features including enlargement of the hands and feet, facial changes including frontal bossing, enlarged mandible and increased dental spacing, arthralgias, diaphoresis, sleep apnea, hypertension, diabetes mellitus, and hypertrophic cardiomyopathy. The development of this syndrome is insidious and patients typically have acromegaly for many years before the diagnosis is made. Approximately 90% of all somatotroph tumors, which causes this disorder in almost all cases, are macroadenomas (greater than 1 cm) at diagnosis. Such tumors frequently cause local anatomic compression, resulting in visual field deficits, headaches, hypopituitarism, and cranial nerve palsies. There is a 2 to 5 fold increase in the mortality rate in acromegalic patients largely due to cardiovascular and cerebrovascular disease. There is also an increased rate of malignancy associated with acromegaly, with colon cancer the best characterized.
The pulsatile release of growth hormone (GH) by normal somatotroph cells is regulated by growth hormone releasing hormone (GHRH), which stimulates GH secretion, and somatostatin, which decreases secretion. At the liver, GH stimulates secretion of somatomedin C, also known as insulin-like growth factor 1 (IGF-1), which mediates many of the peripheral somatic effects of GH. IGF-1 feeds back at the level of the hypothalamus and pituitary resulting in a reduction in GH secretion.
The diagnosis of acromegaly is based on three key findings: 1) clinical evidence, 2) demonstration of an elevated IGF-1 level, and 3) inability to suppress serum GH to less than 1 ng/ml (or less than 0.4 ng/ml, depending on the assay) following an oral glucose challenge (OGTT).
The primary mode of therapy for acromegaly is surgery to reverse the mass effect and attempt biochemical cure. Surgical cure is dependent on surgical skill and experience as well as the size of the tumor. The literature regarding cure rates following surgery is complicated by the fact that different series use various definitions of cure. Cure, defined as normalization of IGF-1 levels and normalization of the GH response to an OGTT, is demonstrated in 59 and 88% of patients with microadenomas (less than 1cm). In contrast, only 22 and 65% of acromegalic patients with macroadenomas are cured following transsphenoidal surgery. Residual disease following transsphenoidal surgery is therefore common, indicating the need for adjuvant therapy. Radiation therapy is a potential adjuvant therapy for patients with residual disease, however, there is a delayed and often incomplete effect and only 1/2 to 2/3 of subjects attain GH levels less than 5 ng/ml by 10 years. Hypopituitarism is a significant complication of radiation therapy.
Adjunctive therapy is critical, particularly because persistent acromegaly is associated with the increased mortality and risk of malignancy. Medical management is a highly useful adjuvant therapy for patients with residual disease. Medical therapy can be used alone or during the interval between administration of radiation and normalization of the serum IGF-1 level. Dopamine agonists will normalize GH and IGF-1 levels in 10-20% of patients. Therefore, although it is reasonable to attempt a course of cabergoline as adjuvant medical therapy, it will be effective in only a minority of patients. In addition, large doses are associated with significant side effects.
There are two other classes of pharmaceutical agents that are very effective in patients with acromegaly. These include somatostatin analogs and GH receptor antagonists. Somatostatin analogs (octreotide and lanreotide) are given by injection and are effective at normalizing IGF-1 levels in 25-50% of patients with acromegaly and reducing the size of the tumor in about 25% of patients. There are long-acting forms of these medications that are administered on a monthly schedule. Somatostatin analog therapy is associated with several side effects, including an increased risk for developing gallstones and gastrointestinal disturbances with nausea, abdominal pain and diarrhea which often occur after initiation of therapy but usually resolve within one to two weeks. In addition, glucose control may worsen in patients who have diabetes mellitus or prediabetes.
The GH receptor antagonist, pegvisomant, is effective at normalizing IGF-1 levels in up to 95% of patients with acromegaly. It must be administered daily by injection, and is usually well-tolerated, but can be complicated by injection site reactions. Because it blocks GH receptors at the liver to prevent generation of IGF-1 and does not act on the tumor itself, it is not effective for tumor control. Therefore, it is not used for treatment of large tumors, unless accompanied by other forms of treatment that are effective for tumor control, such as radiation or somatostatin analog therapy.