Clinical Advances in Acromegaly Management

At an industry-sponsored symposium held in conjunction with the American Association of Clinical Endocrinologists’ 2003 Annual Meeting and Clinical Congress, four leaders in acromegaly research and treatment presented the latest information on the diagnosis and treatment of this disease. Among the topics included were goals of treatment to impact on morbidity and mortality, insulin-like growthfactor I (IGF-1) as a biomarker for diagnosis and management, variations of clinical presentation of the disease and a new treatment algorithm.

This program was supported by an unrestricted educational grant from Pharmacia Corporation.

The Role of IGF-1 and Growth Hormone in the Diagnosis and Management of Acromegaly

In the majority of cases, patients with acromegaly have a growth hormone (GH)-producing pituitary tumor with a resultant increase in circulating levels of GH. Under the influence of GH, there is an increase in production of insulin-like growth factor-1 (IGF-1).

“Right away this tells us there are at least two potential biochemical targets to measure in patients with acromegaly: GH and IGF-1,” said Ariel L. Barkan, MD, Professor of Internal Medicine and Neurosurgery at the University of Michigan, Ann Arbor. “Which parameter gives us better information about the biochemical activity of the disease?”

That GH is increased in the majority of acromegaly cases can be documented in many different ways. However, the interassay variability is high and a single normal or slightly elevated GH cannot serve as a reliable parameter.

Another factor is the highly pulsatile nature of GH secretion. Many of the samples taken during GH peaks overlap with those seen in control subjects. This is yet another reason why a single test of GH is not reliable for the diagnosis of acromegaly.

The glucose tolerance test (GTT) has been suggested as a way around pulse concerns. Even this test has problems that are worrisome.

A recent study by Vierhapper and colleagues reviewed the results of GTT studies on 200 normal controls, IGF-1 in 500 normal controls and both tests in about 100 patients with acromegaly. Age, sex and body mass index (BMI) were the criteria studied. They found, for the first time in the literature, that GH nadirs post-glucose are not stable throughout the population (Vierhapper H, et al. Metabolism.2003;52:181).

They then took 44 patients from this group who had “normal” post-glucose GH, defined as below 1 microgram per liter. Even using the 99% confidence interval from the controls, post-glucose GH in this group was normal in 100% of cases.

“Even in the presence of normal GH suppression, 25% still had elevated IGF-1,”said Dr. Barkan. “This tells us right away that IGF-1 and suppressed GH probably reflect different facets of acromegaly.”

Which parameter should be measured and trusted?

According to Dr. Balkan, Dr. David Clemmons provided the answer 25 years ago. His study correlated clinical parameters of acromegaly such as heel pad thickness, blood glucose 60 minutes after oral glucose administration, and fasting blood glucose with IGF-1 or GH.

The results showed that IGF-1 correlated well with clinical activity of acromegaly with R-coefficients around .7 and GH correlates of only .3 (Clem-mons DR, et al. NEJM. 1979;301: 1138).

Multiple studies have shown that un- or under-treated patients with acromegaly have mortality rates between 1.6 and 3.3 times higher than the population at large. Studies have also shown that decreasing GH below 2.5 returns mortality to normal.

Swearingen and others correlated IGF-1 levels with mortality. They found the correlation coefficient and standard mortality ratio was within the normal range. When expressed as exposure to high IGF-1 levels times the number years of active disease, the standard mortality ratio was consistent with those seen in the un- and under-treated patients. According to Dr. Barkan, IGF-1 predicts mortality significantly better than GH (Swearingen B, et al. J Clin Endoncrinol Metab.1998;83:3419).

“In the majority of cases, we have no problem making the diagnosis of acromegaly based on the clinical picture,” said Dr. Barkan. “However, with the recent advances in the sensitivity of both GH and IGF-1 assays, we are starting to see a strange presentation in up to 20% of patients referred for acromegaly.”

These patients have normal growth hormone levels and respond to GTT in a normal manner. The best predictor was trough GH, established by taking samples every ten minutes for 24 hours, obviously not a viable option in clinical management. Even this measure had some overlap with normals. The only parameter that clearly differentiated the group with acromegaly was the IGF-1 (Dimaraki EV, et al. J Clin Endocrinol Metab.2002;87:3537).

The research outlined by Dr. Barkan suggests that GH has a short half-life with levels that change throughout the day, single or mean values are not reliable, normal values are hard to define and dynamic responses are not well understood. IGF-1 has a longer half-life with stable levels, reflects greater daily GH secretion and is responsible for most, if not all, clinical manifestations of acromegaly.

“In my own practice, the biochemical diagnosis of acromegaly is best established by elevated IGF-1 levels,” said Dr. Barkan. “If IGF-1 is elevated, then we should consider therapy.”

Managing the Morbidities Associated with Acromegaly

The comorbidities associated with acromegaly are clinically important from two standpoints. For example, a person may be diagnosed as having diabetes and the clinical endocrinologist remembers that acromegaly is one cause of secondary diabetes. The second is that these comorbidities should be treated early to slow or possibly even reverse some of the complications.

Secondary diabetes is present in 40% of acromegaly patients. Excess GH causes increased insulin resistance. Many times these patients are very lean at the time of diagnosis and gain weight upon treatment because their insulin becomes more effective in the absence of excess GH.

“One clinical pearl is that acromegaly may first present as uncontrolled diabetes causing fatty liver infiltration to lower IGF-1,” said David M. Cook, MD, Professor of Medicine at the Oregon Health and Sciences University in Portland. “At least 90% of circulating IGF-1 is of liver origin, so anything that insults the liver may give you a falsely low IGF-1 level.”

Treatment at this time is largely based on somatostatin analogs to reduce GH levels. He stressed that somatostatin analogues also reduce pancreatic secretion of insulin and can aggravate existing secondary diabetes.

Cancer comorbidity with acromegaly is controversial. A review of the epidemiological literature by Dr. Cook looked at 6 studies of close to 1,900 patients with acromegaly.

“The data suggests that if there is a problem with acromegaly causing cancer, it is colon cancer,” said Dr. Cook. “My approach is a conservative one, so I view acromegaly as a risk factor for colon cancer and suggest a colonoscopy at age 40 in patients with acromegaly and then every five years. This is not totally settled, but I would err on the side of caution.”

Heart problems are also associated with acromegaly. Hypertrophic cardiomyopathy, heart failure and arrhythmias are common causes of mortality. Studies by Colao and others demonstrated that younger patients and those in whom acromegaly is controlled early have a better chance of reversing the cardiac complications (Colao A, et al. J Clin Endocrinol Metab. 2002;87: 3097).

Arthritis often is a presenting clinical feature in acromegaly. According to Dr. Cook, there appears to be an early phase that can be reversed if treated within five years of onset. Later, the chronic changes are irreversible and are treated just like osteoarthritis.

“Much of your interaction with the patient should be focused on the comorbidities, they are very important,” said Dr. Cook. “Understanding the pathophysiology is often helpful in making therapeutic choices.”

Reviewing the Value of Traditional Medical Therapies in Achieving Tight IGF-1 Control

A reduction in lifespan is one of the major reasons physicians should actively treat acromegaly. Rajasoorya and colleagues noted a ten-year reduction in survival when patients with acromegaly were matched with controls. One of the variables that was associated with decreased survival was a post-treatment GH level >2.5 ng/ml (Rajasoorya C, et al. Clin Endocrinol (Oxf). 1994;41:95).

The importance of this last observation was reinforced by the work of Bates et al. They retrospectively studied 79 patients with acromegaly and found an overall increase in mortality (mortality ratio 2.68). However, among those whose post-treatment GH was reduced to <2.5 ng/ml, the mortality risk returned to normal (Bates AS, et al. Q Jour Med.1993;86:293).

Another indicator of how long one might live with acromegaly is IGF-1. Swearingen’s group looked at long term survival following transphenoid surgery. Those with elevated IGF-1 levels had a decrease in survival after surgery when compared to those whose IGF-1 had normalized (Swearingen B, et al. J Clin Endocrinol Metab. 1998;83:3419).

“It is my opinion that every patient with active acromegaly should be treated whether or not they complain of symptoms,” said David Kleinberg, MD, Professor of Medicine at New York University School of Medicine in New York City. “The goals should be to lower IGF-1 to age- and gender-matched normal levels and to control GH hyper-secretion. There are virtually no patients with acromegaly whose disease can not be controlled through a combination of medication, surgery or radiation.”

Estrogen and high-dose testosterone, which metabolizes to estrogen, were the first medical therapies to be used for acromegaly. Estrogen’s mechanism of action is to antagonize the action of GH.

Now, however, there are medicines that work more specifically against acromegaly. Among these are dopamine agonists, somatostatin analogs and growth hormone antagonists.

“The dopamine agonists have been shown to be partially effective in treating some cases of acromegaly,” said Dr. Kleinberg. “When giving dopamine to a normal person, GH should rise. In acromegaly there is a paradoxical response that lowers GH. Unfortunately, it does not lower it enough to be therapeutic most of the time.”

Somatostatin analogs have proved effective in treating acromegaly. These analogs bind avidly to the somatostatin receptors, stay there longer and reduce GH by tying up receptors in the pituitary through which GH is normally regulated by somatostatin.

“It is the patients with high levels of the subtype-2 receptors that respond to this medication and clearly not everybody has that,” said Dr. Kleinberg. “That is why a limited number of patients, up to 65%, respond.”

Newman and her group looked at 26 patients who had no therapy of any kind for acromegaly and also 78 patients in whom previous surgery or radiation therapy had been employed. They compared the effectiveness of octreotide in the two groups. Octreotide was just as effective in both categories, indicating that it might be useful as a primary therapy (Newman C, et al. J Clin Endocrin Metab. 1998;83:3034).

“One major caveat that prevents claiming that medical therapy is as effective as surgery or RT is that a head-to-head, randomized trial of surgery versus medication has not been done,” said Dr. Kleinberg. “Those who claim that one has to debulk the tumor in order for medication to be effective have little data to support their view.”

Octreotide normalizes IGF-1 in approximately 60% of the patients; those with high GH levels are more susceptible. It shrinks tumors in 30%-50% of cases depending on the series. It does require monthly injections by a health professional and the major side effects are GI discomfort and gall stone formation.

“Acromegaly is a disease that shortens life expectancy and can cause serious debilitating disorders,” said Dr. Kleinberg. “Medical therapies can normalize GH and IGF-1 which, in turn, normalizes life expectancy. We conclude that acromegaly should be treated with the aim of reversing signs and symptoms of the disease, controlling co-morbidities and improving longevity.”

Introduction of a New Growth Hormone Receptor Antagonist

The traditional medical treatments for acromegaly work at the level of the pituitary adenoma to diminish GH secretion and lead to a reduction in IGF-1. A new class of medications called growth hormone receptor antagonists (GHRA), pegvisomant being the lead drug, works peripherally to block the function of growth hormones leading to a decrease in IGF-1.

“GHRAs are human growth hormone molecules that have undergone mutations at two sites,” said Laurence Katznelson, MD, Assistant Professor of Medicine at Harvard University in Cambridge, MA. “The first leads to enhanced receptor binding with a capacity much larger than normal GH. The second site prevents dimerization, which is required for signal transduction and production of IGF-1.”

The primary study on pegvisomant was a multicenter trial of 112 patients with acromegaly. There were four arms in the study assessing response to 10 mg, 15 mg or 20 mg doses of the medication and placebo.

After 12 weeks, there was a dose-response normalization of IGF-1. At the 20 mg/day dose, IGF-1 was normalized in 89% of all patients. Even at the lowest dosing, 54% patients had achieved normal IGF-1 within the twelve-week period. The researchers also found a dose-response improvement in clinical parameters such as the fatigue index and soft tissue swelling (Trainer PJ, et al. NEJM. 2000;342:1171).

“Not only are we seeing improvements in metabolic control in terms of IGF-1 levels, but this is in conjunction with improvements in how the patient feels, the quality of life,” said Dr. Katznelson. “This compared very favorably to the efficacy reported for treatment with octreotide and the dopamine agonists.”
One hundred and fifty-two patients were continued in an open-label extension. Pegvisomant was titrated to normalize IGF-1. In the end, normal IGF-1 was achieved in 97% of those participating for 12 months (van der Lely AJ, et al. Lancet. 2001;358:1754).

“The first major point to come out of these trials is that pegvisomant had similar efficacy across age ranges,” said Dr. Katznelson. “The second interesting outcome is that patients responded regardless of the baseline IGF-1 level.”

One issue of concern was a group of patients whose IGF-1 was subnormal using the medication. The significance of this, if any, is not known. Dr. Katznelson suggests titrating medication until a mid-normal IGF-1 value is obtained.

Diabetes is often seen in patients with acromegaly. Dr. Katznelson described sixteen patients being administered pegvisomant for 18 months. There was a significant decrease in insulin levels in these patients. Early results from a study by Dr. Clemmons and colleagues showed that the A1C hemoglobin levels were reduced significantly from 8.1 to 6.3 (Rose DR, et al. Growth Horm IGF Res. 2002;12:418).

At each of the three doses used in the New England Journal of Medicine study, there was also a dose-response increase in GH production, by up to 150% in the 20 mg group.

“Remember we are treating the peripheral action of GH and not the pituitary adenoma itself,” said Dr. Katznelson. “The concern then becomes whether this has any relevance for potential tumor growth.”

Van der Lely and colleagues also assessed tumor volume changes using MRI scans of 92 patients receiving pegvisomant for more than six months. Over time, changes in tumor size were scattered around the mean.

“In terms of tumor size, there was no significant change with up to 24 months of follow-up although there have been several reports of tumor growth,” said Dr. Katznelson. “We do need longer follow-up times to determine the real risk to patients.”

Safety does not seem to be a large concern. Van der Lealy’s study showed no evidence of increased antibody titers or tachyphylaxis. Two of 158 patients had reversible liver enzyme elevations. “I would recommend pegvisomant for patients who are resistant to or intolerant of somatostatin analogs,” said Dr. Katznelson. “Not all agree with this and there are some who think it can be used as a first-line therapy.”

The suggested starting dose for pegvisomant is 10 mg a day given subcutaneously. IGF-1 should be monitored monthly with dosing adjusted in 5 mg increments until normal IGF-1 values are obtained. Liver function tests should be drawn monthly for the first six months and periodically thereafter. Serial MRIs are also suggested. The normal commercial assays are not able to distinguish between the medication and naturally-occurring GH.

“GHRAs work in the periphery to normalize IGF-1 in almost everybody,” said Dr. Katznelson. “It is the most potent medical therapy for acromegaly currently available.”