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Medical Management of Acromegaly with Octreotide
by Larry Katznelson, M.D.

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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 (>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 2 ng/ml 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 (<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 < 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, including bromocriptine (parlodel) will normalize GH and IGF-1 levels in only up to 8% of patients. Therefore, although it is reasonable to attempt a course of bromocriptine as adjuvant medical therapy, it will be effective in only a small minority of patients. In addition, large doses are associated with significant side effects. The most effective form of medical therapy available is the somatostatin analogue, octreotide. Native somatostatin administration results in a marked reduction in circulating growth hormone levels, but the half life is only several minutes and it is therefore inadequate for clinical use. Octreotide, a somatostatin analogue administered subcutaneously, is chemically modified to result in a prolonged half life, less insulin suppression and no post-infusion rebound.

Numerous studies have demonstrated the efficacy of octreotide in the management of acromegaly. The initial octreotide dose is usually 50 mg b.i.d., and doses may be increased to 250 or 500 mg t.i.d. depending on the response of circulating GH and IGF-1 levels. However, most studies show little dose-response effect above 900 mg/day, so this is typically considered the maximum dose. Rarely, patients may respond to the higher dose. GH levels usually decrease within two hours following a subcutaneous octreotide injection. Studies have shown that octreotide results in a decrease in GH and IGF-1 levels in a majority of patients with normalization of IGF-1 levels in up to 60% of patients, indicating biochemical remission. Most patients note a marked improvement in their symptoms of acromegaly including headaches, joint pains and diaphoresis very soon after starting octreotide therapy.

In patients who do not have a significant reduction in GH levels in response to intermittent octreotide injections, more frequent dosing of octreotide may result in a greater clinical response. Octreotide may be administered continuously by a subcutaneous pump to patients with refractory acromegaly to prevent escape of GH between injections. In addition, studies using a long-acting injectable form of octreotide that is administered once a month are underway in Europe and are likely to be initiated here in the near future.

Octreotide therapy is associated with several side effects. The most significant adverse effect is the development of gallstones and ultrasounds should be monitored serially. Other side effects include gastrointestinal disturbances with nausea, abdominal pain and diarrhea which often occur after initiation of therapy but usually resolve within one to two weeks.

Although the majority of patients attain normalization or improvement in IGF-1 levels with octreotide, some show no response. This heterogeneity of clinical response to octreotide is thought to be due to variability in somatostatin receptor number present on these tumors. Since clinical response may be correlated with the number of receptors present on somatotroph adenomas studied in vitro, it would be useful to have a noninvasive test which could determine the presence of octreotide receptors. Recently, an octreotide scan has been developed for this purpose using indium-labeled pentetreotide, a modified octreotide analogue. A PET scan is used to localize binding of the radiolabeled octreotide to the pituitary adenoma, and binding of the radiolabeled octreotide suggests the presence of octreotide receptors. This exciting new development appears to be a most useful means for determining the subset of patients most likely to respond to octreotide therapy.

References

1. Ho KY, Weissberger AJ, Marbach P, Lazarus MB. Therapeutic efficacy of the somatostatin analog SMS 201-995 (Octreotide) in acromegaly. Ann Int. Med. 1990; 112:173-181.
2. Jackson IMD, Barnard LB, Lamberton P. Role of a long-acting somatostatin analogue (SMS 201-995) in the treatment of acromegaly. Am J Med. 1986; 81:94-101.
3. Reubi JC, Landolt AM. The growth hormone responses to octreotide in acromegaly correlate with adenoma somatostatin receptor status. J Clin Endocrinol Metab. 1989; 68: 844-850.
4. Serri O, Somma M, Comtois R, Rasio E, Beauregard H, Jilwan N, Hardy J. Acromegaly: biochemical assessment of cure after long term follow-up of transsphenoidal selective adenomectomy. J Clin Endocrinol Metab. 1985; 61: 1185-1189.
5. Tauber JP, Babin TH, Tauber MT, Vigoni F, Bonafe A, Ducasse M, Harris AG, Bayard F. Long term effects of continuous subcutaneous infusion of the somatostatin analog octreotide in the treatment of acromegaly. J Clin Endocrinol Metab. 1989; 68:917-924.

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