Antagonists of GH are used to reverse the effects of GH-producing cells (somatotrophs) in the anterior pituitary that tend to form GH-secreting tumors. Hormone-secreting pituitary adenomas occur most commonly in adults. In adults, GH-secreting adenomas cause acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, and the gastrointestinal tract. When a GH-secreting adenoma occurs before the long bone epiphyses close, it leads to a rare condition, gigantism. Larger pituitary adenomas produce greater amounts of GH and also can impair visual and central nervous system function by encroaching on nearby brain structures. The initial therapy of choice for GH-secreting adenomas is endoscopic transsphenoidal surgery. Medical therapy with GH antagonists is introduced if GH hypersecretion persists after surgery. These agents include somatostatin analogs and dopamine receptor agonists, which reduce the production of GH, and the novel GH receptor antagonist pegvisomant, which prevents GH from activating GH signaling pathways. Radiation therapy is reserved for patients with inadequate response to surgical and medical therapies.
Somatostatin, a 14-amino-acid peptide (Figure 37–2), is found in the hypothalamus, other parts of the central nervous system, the pancreas, and other sites in the gastrointestinal tract. It functions primarily as an inhibitory paracrine factor and inhibits the release of GH, TSH, glucagon, insulin, and gastrin. Somatostatin is rapidly cleared from the circulation, with a half-life of 1–3 minutes.
Phe7Phe68Asn510LysLysThrPheCysCysThr-olAcetateD-PheD-Trp411Cys312Gly213AlaCys114TrpThr9LysPheThrSerSSSSSomatostatinOctreotideFIGURE 37–2 Above: Amino acid sequence of somatostatin. Below: Sequence of the synthetic analog, octreotide.
The kidney appears to play an important role in its metabolism and excretion.
Somatostatin has limited therapeutic usefulness because of its short duration of action and multiple effects in many secretory systems. A series of longer-acting somatostatin analogs that retain biologic activity have been developed. Octreotide, the most widely used somatostatin analog (Figure 37–2), is 45 times more potent than somatostatin in inhibiting GH release but only twice as potent in reducing insulin secretion. Because of this relatively reduced effect on pancreatic beta cells, hyperglycemia rarely occurs during treatment. The plasma elimination half-life of octreotide is about 80 minutes, 30 times longer than that of somatostatin.
Octreotide, 50–200 mcg given subcutaneously every 8 hours, reduces symptoms caused by a variety of hormone-secreting tumors: acromegaly, carcinoid syndrome, gastrinoma, glucagonoma, insulinoma, VIPoma, and ACTH-secreting tumor. Other therapeutic use indications include diarrhea—secretory, HIV associated, diabetic, chemotherapy, or radiation induced—and portal hypertension. Somatostatin receptor scintigraphy, using radiolabeled octreotide, is useful in localizing neuroendocrine tumors having somatostatin receptors and helps predict the response to octreotide therapy. Octreotide is also useful for the acute control of bleeding from esophageal varices.