Update on Acromegaly
Laurence Katznelson, M.D. and Beverly M.K. Biller, M.D.

Acromegaly is a rare disorder, with over 95% of cases due to excessive secretion of growth hormone (GH) by a benign pituitary tumor. These adenomas result from a monoclonal proliferation of pituitary somatotroph cells, leading to increased GH secretion. At the liver, GH stimulates secretion of insulin-like growth factor-1 (IGF-1). IGF-1 mediates many of the peripheral somatic effects of GH.

Figure 1. Hand of a 39 year old woman with acromegaly (R) next to the hand of a healthy woman of the same age and height (L), demonstrating the classic hand enlargement in acromegaly. In addition to such external manifestations of the disease, most patients also have systemic morbidity.

In addition to the classic somatic changes in acromegaly such as enlargement of the hands and feet (Figure 1), this disorder is associated with significant medical comorbidities including sleep apnea, hypertension, Type II diabetes, and hypertrophic cardiomyopathy. Sleep apnea is found in over 50% of patients with acromegaly. All of these comorbidites improve with biochemical control of the disorder. In addition, acromegaly is associated with an increased risk of premature mortality. Studies have shown that control of acromegaly, with GH and IGF-1 normalization, results in a mortality rate no different from the general population. This demonstrates the clear benefit of biochemical control on long-term health in such patients.

The diagnosis of acromegaly is based on three key findings: 1) clinical features, 2) demonstration of an elevated IGF-1 level, and 3) inability to suppress serum GH to less than 1 ng/ml following an oral glucose challenge (OGTT). Following biochemical confirmation of the disorder, a head MRI is performed. In most patients, a macroadenoma (>1cm) will be found, but some patients may have microadenomas or no clear lesion.

Because it is a rare disorder and development of the clinical features is typically insidious, patients often have acromegaly for many years before the diagnosis is made. In some cases, the diagnosis may be obvious based on clinical evaluation. However, in others, the disease may be subtle, particularly in early stages of the disorder. It is prudent to ask about other symptoms of acromegaly in patients with new onset hypertension, sleep apnea, carpal tunnel syndrome and diabetes, as this may be a treatable cause of such morbidities.

The primary mode of therapy for acromegaly is usually transsphenoidal surgery to reverse mass effect and attempt biochemical cure. Surgical cure is dependent on surgical skill and experience (see next article in this Bulletin) as well as the size and location of the tumor. Cure, defined as normalization of IGF-1 levels and normalization of the GH response to an OGTT, is demonstrated in up to 88% of patients with microadenomas (<1cm) if performed by an expert pituitary surgeon. In contrast, surgery is curative in only 50-65% of acromegalic patients with macroadenomas, in the best centers. Residual disease following transsphenoidal surgery is therefore common, and patients with persistent disease require further therapy.

Medical management is a highly useful adjuvant therapy for patients with acromegaly. Dopamine agonists have the advantages of being oral medications and being the least expensive medical option. However, high doses are usually needed, and despite increasing doses, which may produce side effects, bromocriptine (Parlodel) is not effective in most patients.

Hand of a 39 year old woman with acromegaly (R) next to the hand of a healthy woman of the same age and height (L), demonstrating the classic hand enlargement in acromegaly. In addition to such external manifestations of the disease, most patients also have systemic morbidity.

This medication only successfully normalizes GH and IGF-1 levels in <10% of patients. The longer acting dopamine agonist, cabergoline (Dostinex), is often better tolerated than bromocriptine, and may have better efficacy compared to bromocriptine in acromegaly. In one study, cabergoline administration resulted in normal IGF-1 levels in 39% of subjects. Patients with more modest biochemical activity and hyperprolactinemia appear to be the most sensitive to cabergoline. Thus, this may be a reasonable option to try in patients with mildly elevated IGF-1 levels.

Most patients note a marked improvement in symptoms of acromegaly soon after starting octreotide therapy, including headaches, joint pains and diaphoresis.

Somatostatin analogs, such as octreotide, are more effective than dopamine agonists in the medical management of acromegaly. Octreotide administration results in a decrease in GH and IGF-1 levels in a majority of patients, with up to 60% attaining normalization of IGF-1 levels, indicating biochemical remission. Tumor size and level of GH hypersecretion are important prognostic factors, as well as the presence of somatostatin receptors on tumor cells. Most patients note a marked improvement in symptoms of acromegaly soon after starting octreotide therapy, including headaches, joint pains and diaphoresis. The most significant adverse effect of somatostatin analogs is the development of gallstones. However, the frequency of development of symptomatic gallstones varies widely among studies, and the need for serial ultrasounds is controversial. Other side effects include gastrointestinal disturbance with nausea, abdominal pain and diarrhea which often occur upon initiation of therapy, but usually resolve within one to two weeks.

Octreotide is administered in the majority of cases as Sandostatin LAR (long acting release formulation of Sandostatin). Sandostatin LAR is available in three doses: 10 mg, 20 mg, and 30 mg; the long-acting preparation allows it to be administered just once a month via intramuscular injection. Another depot formulation of the somatostatin analog lanreotide is available in Europe and a new somatostatin analogue is under investigation in the United States.

A different mechanism of action is represented by the growth hormone antagonist, pegvisomant (Somavert). Pegvisomant is a human GH molecule that has been altered to compete with natural GH for binding to its receptor and, additionally, to prevent receptor activation. Rather than acting at the pituitary tumor, pegvisomant blocks hepatic production of IGF-1. This lowering of IGF-1 levels occurs without decreasing GH (levels of GH actually rise, but it is blocked at the receptor). In a double-blind, placebo-controlled study, pegvisomant was administered as nightly subcutaneous injections to 112 patients with acromegaly for three months. IGF-1 levels normalized in 90% of subjects. This included patients resistant to somatostatin analogs. In an open label extension protocol, pegvisomant was administered for up to two years in more than 90 subjects. In this study, normal IGF-1 levels were achieved in 97% of subjects. In another study in patients with acromegaly and diabetes, pegvisomant was effective in lowering endogenous insulin and glucose levels. In this study, oral hypoglycemic agents were discontinued in some patients as glucose management improved. Therefore, pegvisomant is a highly effective medication, useful in patients resistant to other acromegaly medications, and may be particularly useful in patients with concomitant diabetes. Side effects of pegvisomant include hepatitis and the potential risk of tumor growth. Serial liver tests and MRI monitoring are therefore very important during treatment.

Radiation therapy is a potential adjuvant therapy for patients with residual disease, however, there is a long waiting period until it is effective. In patients treated with conventional radiation, it takes up to ten years for over half of subjects to attain GH levels <5 ng/ml and normalization of IGF-1 is more difficult to achieve. Hypopituitarism is a significant complication of radiation therapy, and there is a small (1-2%) risk of secondary neoplasia developing in the radiation field. There are data suggesting that targeted radiotherapy using stereotactic techniques such as gamma knife or proton beam modalities may lead to more rapid biochemical control, with less risk of hypopituitarism. However, further studies are necessary to confirm such claims. Therefore, in most patients not cured with surgery, medical management is necessary in lieu of, or in combination with, radiation.

In summary, an operation by an expert pituitary surgeon is the first line of treatment of acromegaly. In those patients not cured, there is a strong role for adjuvant medical therapy for acromegaly. Both dopamine agonists and somatostatin analogs act at the level of the pituitary adenoma, and are effective at lowering GH and IGF-1 levels in a large number of patients. Pegvisomant acts in the periphery by blocking the effects of GH and preventing production of IGF-1 by the liver, and is effective in the majority of patients. More clinical experience is necessary to determine the precise roles of these medical options in the therapy of acromegaly.

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