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Acromegaly Epidemiology
Acromegaly is a rare disease with a prevalence of 50 to 70 cases per million and an incidence of 3 to 4 new cases per million annually1. Diagnosis generally occurs 10 to 15 years after the onset of pathological growth hormone (GH) secretion1.
The Pathophysiology of Acromegaly
The somatic growth and metabolic dysfunction associated with acromegaly result from excess secretion of GH and subsequent elevation of circulating and locally produced insulin-like growth factor-1 (IGF-1). In healthy individuals, GH secretion is under the dual regulation of growth hormone-releasing hormone (GHRH) and somatostatin, with variations in the secretion of somatostatin being the primary mode of regulation2.
The interaction of GHRH and somatostatin, as well as fluctuations in levels of somatostatin, regulate GH secretion3. Hypersecretion of GH and IGF-1 may be caused by4:
- Primarily, GH-secreting adenoma(s) of the pituitary resulting from clonal expansion of a single mutated cell
- Rarely, GHRH- and GH-secreting neoplasms such as gangliocytomas of the hypothalamus and carcinoid tumors
GH-secreting tumors have a large number of receptors for somatostatin5 and, thus, are frequently responsive to therapy with analogues of somatostatin such as Sandostatin® LAR Depot (octreotide acetate for injectable suspension).
GH, growth hormone; GHRH, growth hormone-releasing hormone; IGF-1, insulin-like growth factor-1; SRIF, somatotropin-releasing inhibitory factor. Adapted with permission from Melmed2.
The Role of GH and IGF-1
Rather than stimulating growth directly, GH induces the release of IGF-1, which promotes DNA, RNA, and protein synthesis, as well as cell and tissue growth6. GH, or somatotropin, is responsible for the growth of almost all cells and tissues. GH activity encompasses both of the following:
Direct effects (anti-insulin effects) such as increased lipolysis and increased glucose mobilization. The direct growth promoting actions of GH include6:
- Induction of insulin resistance in peripheral tissues
- Hyperinsulinism
- Lipolysis
- Ketogenesis
- Hyperglycemia
- Sodium and water retention
Indirect effects (insulin-like effects) result from GH stimulation of IGF-1 production, causing effects such as growth of skeletal muscle, connective tissue, soft tissue, and bone-epiphyseal cartilage. Indirect growth-promoting actions of GH are mediated by the induction of growth factors, or somatomedins, the most important of which is somatomedin-C, or IGF-1. IGF-1 is produced by cells primarily in the liver, but also is present in the kidney, pituitary gland, GI tract, muscle, and cartilage2,6. Like insulin, the indirect IGF-1 dependent growth-promoting actions of GH include3,6:
- Induction of protein synthesis
- Amino acid transportation
- Muscle mass, cartilage, and bone growth
- DNA and RNA synthesis
Clinical Aspects of Acromegaly
Structural Changes
The structural changes that occur with acromegaly cause chronic pain. These changes include1:
- Skeletal overgrowth deformities, particularly of the hands, feet, and face
- Cardiovascular disease (hypertension, enlarged heart)
- Arthropathy
- Neuropathy
- Respiratory obstruction
In addition to magnetic resonance imaging (MRI) or computed tomography (CT) imaging, somatostatin receptor scintigraphy (SRS) may be used to obtain images of pituitary adenomas. In this procedure, radiolabeled octreotide is injected into the systemic circulation. Since pituitary adenomas frequently contain elevated numbers of somatostatin receptors, the radioactive octreotide binds to these receptors and can be detected subsequently as bright spots in the resulting images7,8.
Physiologic and Morphologic Changes
Specific signs and symptoms of the disease can include9:
Adapted with permission from Harris9.
Changes in Appearance with Acromegaly
Cardiovascular System and Acromegaly
The cardiovascular system is particularly affected in acromegaly. Acromegalic cardiomyopathy seems to be correlated with the duration of disease, with a constellation of different abnormalities occurring10.
Acromegalic cardiomyopathy develops during the disease from the early to the advanced stage. The different abnormalities may be recognized using appropriate cardiological investigations.
INDICATIONS AND USAGE
Sandostatin® LAR Depot (octreotide acetate for injectable suspension) is indicated for patients in whom initial treatment with immediate release Sandostatin® (octreotide acetate) Injection has been shown to be effective and tolerated for:
- Long-term maintenance therapy in acromegalic patients who have had inadequate response to surgery and/or radiotherapy or for whom surgery and/or radiotherapy is not an option (the goal of treatment in acromegaly is to reduce GH and IGF-1 levels to normal).
- Long-term treatment of the severe diarrhea and flushing episodes associated with metastatic carcinoid tumors.
- Long-term treatment of the profuse watery diarrhea associated with VIP-secreting tumors.
In patients with carcinoid syndrome and VIPomas, the effect of Sandostatin Injection and Sandostatin LAR Depot on tumor size, rate of growth and development of metastases has not been determined.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions:
- Gallbladder abnormalities may occur: Patients should be monitored periodically.
- Glucose Metabolism: Hypoglycemia or hyperglycemia may occur. Blood glucose levels should be monitored when Sandostatin LAR Depot treatment is initiated or when the dose is altered. Antidiabetic treatment should be adjusted accordingly.
- Thyroid Function: Hypothyroidism may occur. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended.
- Cardiac Function: Bradycardia, arrhythmia, conduction abnormalities, and other EKG changes may occur. The relationship of these events to octreotide acetate is not established because many of these patients have underlying cardiac disease. Use with caution in at-risk patients.
- Nutrition: Octreotide may alter absorption of dietary fats. Monitoring of vitamin B12 levels is recommended during therapy with Sandostatin LAR Depot. Patients on total parenteral nutrition (TPN) and octreotide should have periodic monitoring of zinc levels.
Drug Interactions: The following drugs require monitoring and possible dose adjustment when used with Sandostatin LAR Depot: cyclosporine, insulin, oral hypoglycemic agents, beta-blockers, bromocriptine. Octreotide has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Drugs mainly metabolized by CYP3A4 and which have a low therapeutic index should be used with caution.
Adverse Reactions: The most common adverse reactions occurring in patients receiving Sandostatin LAR Depot are:
- Acromegaly: biliary abnormalities (52%), diarrhea (36-48%), cholelithiasis (13-38%), abdominal pain or discomfort (11-29%), flatulence (26%), influenza-like symptoms (20%), constipation (19%), headache (15%), anemia (15%), hyperglycemia (15%), injection site pain (2-14%), hypertension (13%), dizziness (12%), fatigue (11%), nausea (10%), vomiting (7%), hypothyroidism (2%), hypoglycemia (2%), and goiter (2%).
- Carcinoid Tumors and VIPomas: biliary abnormalities (62%), injection site pain (20-50%), nausea (24-41%), abdominal pain (10-35%), fatigue (8-32%), headache (16-30%), hyperglycemia (27%), back pain (8-27%), constipation or vomiting (15-21%), dizziness (18-20%), sinus bradycardia (19%), pruritus (18%), URTI (10-18%), myalgia (4-18%), flatulence (9-16%), arthropathy (8-15%), rash (15%), generalized pain (4-15%), sinusitis (5-12%), conduction abnormalities (9%), hypoglycemia (4%), and arrhythmia (3%).
