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Acromegaly Management in the 21st Century:
An Interactive Case Presentation

Interactive Case Presentation

Ariel Barkan, MD, professor of internal medicine and professor of neurosurgery at the University of Michigan in Ann Arbor, Michigan began the symposium by stating most clinicians are aware of the biology, diagnosis, and treatment of acromegaly only from textbooks and case studies that provide extreme examples of the disease. To personalize the condition, Dr. Barkan introduced Trish McNamara to the audience. Her 10-year ordeal with acromegaly was the subject of the first presentation.

Initial Onset
In 1989, Ms. McNamara, a healthy female in her 20s, began to notice many changes to her body after her third pregnancy. She attributed the changes to a weight gain of 50 pounds after her pregnancy, and had sought no medical attention.

By comparing pre-1985 photos with her appearance in 1993, it was clear that Ms. McNamara’s appearance had changed considerably. She noticed weight gain, changes in bone structure, muscle development, hand/feet growth, and facial puffiness, but had ascribed this to her increased weight.

Six Years Later
In 1995, Ms. McNamara had joint pain, severe headaches, acne, jaw pain, and amenorrhea. Her headaches developed regularly (4-–5 per week) and were quite painful (8 on a 10-point scale). She did not seek medical treatment for any of these conditions and continued to attribute her problems to weight gain, stress, and so forth.

Her acne led to scars and skin tags. She did seek medical treatment from a dermatologist to remove the skin tags. When Dr. Barkan asked her if the dermatologist tried to determine the underlying cause of the acne, she said no.

During this period she also saw a dentist to help with her jaw pain and enlarged tongue. Her front teeth were slowly pushing apart. When Dr. Barkan asked Ms. McNamara if the dentist made any attempt to determine an underlying cause, she said no.

Diagnosis
With the development of amenorrhea, Ms. McNamara suspected she had a hormonal problem. While training to become a nurse in college, she had four head MRIs that were unremarked upon by the training neuroradiologist. During her training she began to think that she might have acromegaly, and communicated her concerns to her physician at her next appointment.

Lab results found that her growth hormone levels were grossly elevated (47 ng/mL) and a MRI revealed a tumor on the left side that had invaded her cavernous sinus. Dr. Barkan said, “for all practical purposes, this tumor was already surgically not curable.”

Initial Treatment Regimens
Her first treatment regimen was transsphenoidal surgery performed by a general surgeon and was unsuccessful. After the surgery, GH dropped from 50 to 40 ng/mL and IGF-1 remained grossly elevated. Dr. Barkan stated that a successful outcome is predicated on using a surgeon who specializes in pituitary tumors.

Ms. McNamara was then given a high dose of the somatostatin analog, octreotide (up to 1,000 ug [micrograms]four times a day [q6hrs]). Her IGF-1 remained grossly elevated, however, and she suffered from extreme side effects (nausea, diarrhea, gallstones). The gallstones required a cholecystectomy.

A second surgery was performed by a more experienced surgeon using the intra-operative MRI technique. This surgery was more successful, leading to GH levels of 5–10ng/mL. Unfortunately, even these GH levels are excessive and her IGF-1 remained high.

Final Treatment
In 1998, Miss McNamara underwent stereotaxic radiation surgery. Immediately after surgery, she did not notice any improvement even though her GH levels were down to about 3 ng/mL. However, her IGF-1 was still grossly elevated.

At this point, she went to the University of Michigan and met Dr. Barkan who put her on pegvisomant (10 mg/d). Within 2 weeks, her IGF-1 was normal, her puffiness decreased, her joint pain disappeared, and her hands/feet decreased in size.

Today, Trish McNamara continues to do well.

Conclusion
Dr. Barkan used this case study to illustrate that for 5 to10 years Trish McNamara went undiagnosed even though she was seen by many medical professionals. Unfortunately these professionals treated the symptoms instead of trying to determine the underlying cause. Ms. McNamara ended the presentation saying, “I think many patients suffer much longer before they are diagnosed even though I personally feel I suffered too long.”


The Prevalence and Prognosis of Acromegaly

In a review of 10 studies on acromegaly, involving 2944 patients, it was estimated that the incidence of acromegaly is 3.3 per million with a prevalence of 58 per million (Pituitary 1999;2:29). The mean age at diagnosis is 44 years and the mean duration of symptoms prior to diagnosis is 8 years (Clin Endolcrinol 1987;26:481), stated David Cook, MD, professor of medicine and head of the Division of Endocrinology at Oregon Health & Sciences University. Most diagnoses are made by either a family physician or internist, and at the time of diagnosis the patient may be complaining from a large array of clinical features, including acral enlargement, arthralgias, maxillofacial changes, excessive sweating, headache, hypogonadal symptoms, as well as carpal tunnel, secondary diabetes, amenorrhea, heart failure, and sleep apnea.

Dr. Cook said that the endocrinologist is often used to confirm the suspicions of the family physician after these clinical features are identified. In some cases, however, the diagnosis is difficult. To illustrate, Dr. Cook told the audience of a 55-year-old woman with uncontrollable diabetes (Endocr Pract 2002; 8:113). The endocrinologist talked to the patient and found out that her shoe size had recently increased and subsequent tests confirmed that she had a mild form of acromegaly.

The wide variety of clinical features that are first presented often make it difficult to think of testing for acromegaly in these patients. Patients with acromegaly can present with non-classic features. For example, one 70- year-old patient presented with impotence. Another common referral comes from unexplained arthritic symptoms.

Prognosis
Most patients with acromegaly will have large tumors requiring surgery. In most centers that specialize in these surgeries, the relapse rate varies greatly (3% - 21%) with an average of approximately 10% over a 10-year period (Pituitary 1999; 2:51). Since the surgery requires that each tumor cell be removed, Dr. Cook stressed that it should be performed in a specialized center.

Patients will have a normal life expectancy if they continue to have normal IGF-1 levels (J Clin Endocrinol Metab 1998;
83:3419; J Clin Endocrinol Metab 1998;83;2730). If IGF-1 remains elevated, however, they have a higher risk of mortality.

Conclusion
Dr. Cook ended his presentation by stating that we should consider acromegaly in a variety of clinical situations including new onset diabetes, incidental pituitary mass lesions, or hypogonadism. Referral should be to an experienced pituitary surgeon and every effort should be made to control serum IGF-1 to improve mortality.

 

Goals of Therapy in the Current Treatment of Acromegaly

“Acromegaly in the great majority of cases is due to the presence of a pituitary GH producing tumor and the hyperproduced GH exerts its influence on all organs and tissues,” stated Dr. Barkan, adding “and all organs and tissues under the influence of growth hormone start producing IGF-1.”

The primary goal of treatment for acromegaly is to remove the tumor and normalize IGF-1. Secondary goals are to control hypopituitarism and alleviate somatic impairments that have arisen.

Surgery
The efficacy of surgery for acromegaly is dependent on the size of the tumor and the experience of the surgeon. In a summary of 17 studies from 1995–1999, the efficacy (as measured by GH < 2.5 µg/L and normal IGF-1 levels) was 40–47% for large tumors and 77–82% for small tumors. Since large tumors account for the majority of cases, the overall efficacy rate is 56–58%. One reason for this poor efficacy is that 75% of patients are operated on by surgeons with little or no pituitary experience.

Radiation
There have been many studies showing that external pituitary radiation is very effective in lowering GH levels to 5–10 µg/L. Recent studies have shown that GH levels should be below 5 µg/L to ensure no metabolic consequences. The more accurate IGF-1 analysis has shown that after 5 years, 24% of the patients had normalized IGF-1 levels but by 10 years, almost 50% of the patients had elevated IGF-1 levels.

Stereotaxic radiosurgery is believed to be more effective than conventional radiation therapy. In a comparison of sterotaxic radiation with conventional radiation, both have a success rate of only 34%.

Pharmacotherapy
Bromocriptine used to be given in most acromegaly patients, but a review of its efficacy between 1975-1990 has shown its efficacy rate is only 10% in normalizing IGF-1.

The dopamine agonist cabergoline has not been extensively studied but a recent review of 5 studies (n = 112) found a success rate of 34% but Dr. Barkan said that there was a large variance in the 5 studies and further studies are needed.

Octreotide, a somatostatin analog, has been more successful. In a review of 43 studies (n = 1182) found 51% of the patients had normalized IGF-1 levels. Dr. Barkan also said, “the big advantage of octreotide or any other somatostatin analog is that in addition to decreasing growth hormone, it also shrinks pituitary tumors in about 60 to 70% of cases.” Similar high efficacy rates have been observed with the somatostatin analog sandostatin (66%
efficacy).

Conclusion
“All the existing modalities for treatment of acromegaly that we have right now have one significant disadvantage: they are directed against the pituitary tumor and pituitary tumor by definition is a neoplastic tissue.” Therefore, surgery must deal with the invasiveness of the tumor. Radiation therapy must deal with radio-resistance of the tumor. Pharma-cologic interventions must deal with the abnormal expression of either dopamine or somatostatin receptors. In summary, better treatment options for acromegaly are desperately needed, especially one that deals with the real problem, elevated IGF-1.

Emerging Therapies for the Management of Acromegaly

The treatment goals for acromegaly are to reduce IGF-1 levels to age- and gender-matched normal, to control GH hypersecretion, to relieve symptoms, to remove or reduce tumor mass, and to preserve pituitary function, stated David Clemmons, MD, professor of medicine at the University of North Carolina School of Medicine in Chapel Hill, North Carolina. Dr. Clemmons thanked Dr. Barkan for introducing the topic of pharmacologic agents used in the treatment of acromegaly and expanded on the list (Table 1) with a discussion of two new agents, the slow-release somatostatin analog lanreotide and the GH receptor antagonist pegvisomant.

Slow- Release Lanreotide
Lanreotide is a slow-release gel tablet that can be administered every 1–2 weeks (SR LAN 30) or every 28 days (SR LAN 60). To date, there have been two studies published with this medication. In the first study (Metab 2002;51:386) a comparison of SR LAN 30 and SR LAN 60 in 20 patients found IGF-1 normalized in 5 of the 20 patients given SR LAN 30 and 7 of 20 patients given SR LAN 60. In a larger study (JCEM 2002;88–99) 107 patients were switched from SR LAN 30 to SR LAN 60 and efficacy of 45%–48% was observed. Dr. Clemmons stated, “although these numbers aren’t strikingly high, if you’re one of the lucky 50% who do normalize, this is a reasonable form of therapy.”

Pegvisomant
Pegvisomant acts as a GH antagonist to block the production of IGF-1. In a large study (NEJM 2000;341–1171) involving patients with severe acromegaly who had not responded to other treatments, a comparison of pegvisomant (10 mg, 15 mg, or 20 mg) with placebo was performed. In this study there was a dose dependent decrease in IGF-1 levels (Figure 1) with the majority of the patients achieving normal serum IGF-1 (percent of patients reaching normal IGF-1: 7% placebo; 54%, 10 mg pegvisomant; 81%, 15 mg; 89%, 20 mg). Similar dose dependent improvements were seen with measurements of patients’ ring size and overall well-being. In an open label extension of the study (Lancet 2001;358:1754) patients were allowed to titrate up to 40 mg and the efficacy rate for IGF-1 normalization was 97%.

Conclusion
Acromegaly is associated with an increased morbidity and mortality particularly if there’s a residual elevation in IGF-1. Fortunately, treatment that normalizes the GH axis can restore life expectancy to normal but this will usually require multiple treatment modalities. The addition of new pharmacologic agents that can help reduce IGF-1 to normal will be a welcome addition to the treatment of acromegaly. Lanreotide has shown efficacy in normalizing IGF-1 in approximately 50% of patients. Pegvisomant has shown efficacy in IGF-1 normalization in 97% of patients.

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