Growth Hormone Antagonists

GROWTH HORMONE ANTAGONISTS

The need for antagonists of GH stems from the tendency of GH-producing cells (somatotrophs) in the anterior pituitary to form GH-secreting tumors. 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 gastroin-testinal tract. Acromegaly adversely affects the skeletal, muscular, cardiovascular, respiratory, and metabolic systems. When a GH-secreting adenoma occurs before the long bone epiphyses close, it leads to the rare condition, gigantism. Small GH-secreting adenomas can be treated with GH antagonists. These include somatostatin analogs and dopamine receptor agonists, which reduce the production of GH, and the novel GH receptor antago-nist pegvisomant, which prevents GH from activating GH signal-ing pathways. Larger pituitary adenomas produce greater amounts of GH and also can impair visual and central nervous system func-tion by encroaching on nearby brain structures. These are treated with transsphenoidal surgery or radiation.

Somatostatin Analogs

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 inhibits the release of GH, TSH, glucagon, insulin, and gastrin.

Exogenous somatostatin is rapidly cleared from the circulation, with an initial half-life of 1–3 minutes. 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.

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; the carcinoid syndrome; gastrinoma; gluca-gonoma; nesidioblastosis; the watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome; and diabetic diarrhea. 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.

Octreotide acetate injectable long-acting suspension is a slow-release microsphere formulation. It is instituted only after a brief course of shorter-acting octreotide has been demonstrated to be effective and tolerated. Injections into alternate gluteal muscles are repeated at 4-week intervals in doses of 20–40 mg.

Adverse effects of octreotide therapy include nausea, vomiting, abdominal cramps, flatulence, and steatorrhea with bulky bowel movements. Biliary sludge and gallstones may occur after 6 months of use in 20–30% of patients. However, the yearly inci-dence of symptomatic gallstones is about 1%. Cardiac effects include sinus bradycardia (25%) and conduction disturbances (10%). Pain at the site of injection is common, especially with the long-acting octreotide suspension. Vitamin B₁₂ deficiency may occur with long-term use of octreotide.

A long-acting formulation of lanreotide, another octapeptide somatostatin analog, was approved by the FDA in 2007 for treat-ment of acromegaly. Lanreotide appears to have effects comparable to those of octreotide on reducing GH levels and normalizing IGF-I concentrations.

Pegvisomant

Pegvisomant is a GH receptor antagonist used to treat acromegaly. It is the polyethylene glycol (PEG) derivative of a mutant GH, B2036. Like native GH, pegvisomant has two GH receptor bind-ing sites. However, one of the pegvisomant GH receptor binding sites has increased affinity for the GH receptor, whereas its second GH receptor binding site has reduced affinity. This differential receptor affinity allows the initial step (GH receptor dimerization) but blocks the conformational changes required for signal transduc-tion. Pegvisomant is a less potent GH receptor antagonist than is B2036, but pegylation reduces its clearance and improves its overall clinical effectiveness. When pegvisomant was administered subcu-taneously to 160 patients with acromegaly daily for 12 months or more, serum levels of IGF-I fell into the normal range in 97%; two patients experienced growth of their GH-secreting pituitary tumors and two patients developed increases in liver enzymes.