Bulletin Volume 4, Issue 1, Winter 1997

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Articles in this issue:

Stereotactic Proton Irradiation of Pituitary Adenomas.
Acromegaly: Complications and Therapeutic Update.
Pituitary Journal Review: Discussion of Recent Articles of Interest Related to Pituitary Disease.


Prolactinomas Resistant to Standard Dopamine Agonists Respond to
Chronic Cabergoline Treatment.

Pituitary Irradiation is Ineffective in Normalizing Plasma Insulin-Like Growth Factor-1 in Patients with Acromegaly.

Acromegaly is characterized by enlargement of the hands and feet, facial changes including frontal bossing, enlarged mandible and increased dental spacing, arthralgias, fatigue, diaphoresis, sleep apnea, hypertension, diabetes mellitus, and hypertrophic cardiomyopathy. Because it is a rare disorder and development of these clinical features is insidious, patients typically have acromegaly for many years before the diagnosis is made. Approximately 90% of all somatotroph tumors, which cause this disorder, are macroadenomas (>1 cm) at diagnosis. Therefore, these tumors frequently cause local anatomic compression, resulting in visual field deficits, headaches, hypopituitarism and cranial nerve palsies.

The pulsatile release of growth hormone (GH) by normal pituitary 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 I (IGF-I). IGF-I mediates many of the peripheral somatic effects of GH and feeds back at the level of the hypothalamus and pituitary resulting in a reduction in GH secretion. Therefore, GH and IGF-I levels are held in tight balance.

The diagnosis of acromegaly is based on three key findings: 1) clinical evidence, 2) demonstration of an elevated IGF-I level, and 3) inability to suppress serum GH to less than 2 ng/ml following an oral glucose challenge (OGTT).

Why do we treat? Short term benefits of therapy include improvement of symptoms such as headaches, which are often debilitating. In addition, there are long-term complications of acromegaly that are of concern. There is a 2 to 5 fold increase in the mortality rate in acromegalic patients and this is largely due to cardiovascular and cerebrovascular disease. In a recent long-term follow-up of 79 subjects, therapy (regardless of modality) of acromegaly with resultant reduction of GH to < 5 ng/ml was associated with a decrease in the risk of mortality to that expected for the population. Therefore, given this provocative although limited data, successful management of acromegaly may negate the mortality risk.

There are multiple medical complications associated with acromegaly. In part because of hypertension, there is cardiac involvement that includes left ventricular hypertrophy and congestive heart failure. Sleep apnea syndrome (both central and obstructive) is detected in up to 80% of subjects and may result in considerable morbidity. Acromegalics may also develop significant arthropathy that may lead to pain and necessitate joint replacement. Left ventricular mass, sleep apnea syndrome, and arthralgias may improve with therapy.

Patients with acromegaly may also be at enhanced risk for cancer, and colon cancer is the most prevalent. This risk is particularly increased in men over 40 years with a positive family history of colon cancer and multiple skin tags. Other malignancies, including breast cancer, have been described. Although it seems likely, it is unknown whether successful treatment of acromegaly will reduce the risk of neoplasia.

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. 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). In contrast, up to 50-65% 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 effect in that 1/2 to 2/3 of subjects attain GH levels < 5 ng/ml by 10 years. Hypopituitarism is a significant complication of radiation therapy. Therefore, in most patients, medical management may be necessary in surgically non-cured patients in lieu of or in combination with radiation.

Medical management is a highly useful adjuvant therapy for patients with residual disease. Dopamine agonists, including bromocriptine (parlodel) may normalize GH and IGF-1 levels, but in only 8% of patients. Therefore, it may be reasonable to attempt a course of bromocriptine as adjuvant medical therapy, but it may have limited value. In addition, large doses are often required and this therapy may be associated with significant side effects.

The most efficacious form of medical therapy available includes somatostatin analogs, such as octreotide. Many 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 300-900 mg per day is an effective dose. Octreotide administration 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 very soon after starting octreotide therapy, including headaches, joint pains and diaphoresis. The most significant adverse effect of somatostatin analogs is the development of gallstones, so ultrasounds should be obtained initially. However, the development of symptomatic gallstones are very rare and the need for serial ultrasounds is controversial. Other side effects include gastrointestinal disturbances with nausea, abdominal pain and diarrhea which often occur after initiation of therapy but usually resolve within 1 to 2 weeks.

An exciting new approach to the management of acromegaly is the development of longer acting somatostatin analogs that may be administered intramuscularly at 2 to 4 week intervals. These analogs are currently under active investigation. Efficacy of these analogs appears similar to that of shorter acting preparations, and, in theory, long-acting analogs may have greater efficacy because of continuous versus intermittent GH suppression. The additional benefit of requiring injections at monthly intervals versus multiple times during the day makes these analogs preferable.

The MGH Neuroendo-crine Unit is currently initiating studies involving administration of these long-acting analogs to patients with acromegaly. Physicians interested in this study should contact Dr. Katznelson at 617-726-3874.

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. 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.

3. Bates A.S., Van’t Hoff W., Jones J.M. Does treatment of acromegaly affect life expectancy? Metab. 1995;44: 1-5.

Pituitary Journal Review: Discussion of Recent Articles of Interest Related to Pituitary Disease
Beverly M.K. Biller, M.D.

"Prolactinomas Resistant to Standard Dopamine Agonists Respond to Chronic Cabergoline Treatment"
A Colao, A DiSarno, F Sarnacchiaro et al. 1997 J Clin Endocrinol and Metab 82:876-83

With the recent United States approval of cabergoline for hyperprolactinemia, there is increasing interest in this new, long-acting dopamine agonist. A recent JCEM article provides interesting information about the effectiveness of this medication in patients who have prolactinomas which failed to respond to other dopamine agonists.

This study, conducted in Italy, evaluated the response to cabergoline in 27 patients who had previously been shown to be resistant to bromocriptine. Resistance was defined as absent or poor response of prolactin (PRL) and/or lack of tumor shrinkage despite at least 3 months of 15 mg bromocriptine daily. The majority of the patients were also resistant to quinagolide, another dopamine agonist available in Europe. Nineteen of the subjects had macroprolactinomas and 8 had microprolactinomas; 9 were men, 18 were women, and ages ranged from 15 to 64 years. The majority of patients (7/9 men and 17/18 women) had gonadal dysfunction.

Cabergoline was administered at a starting dose of 0.25 mg once weekly for the first week, twice weekly for the second week, and 0.5 mg twice weekly thereafter. Progressive upward adjustment of the dose was made on the basis of serum PRL levels, with a maximum dose in this study of 3 mg/wk, administered as 0.5 mg six days/week.

A significant finding of this study was that the majority of patients (15 of 19 macroadenomas and all 8 microadenomas) attained a normal PRL level during the 22 months of therapy, despite the fact that none of them had done so on a relatively high dose of bromocriptine. In three of the remaining patients, PRL levels declined substantially, with only one patient being withdrawn from the study at 3 months because of complete absence of effect.

Another important finding was that tumor shrinkage (which was defined conservatively, with at least 25% reduction required by MRI scan) occurred in 9/19 macroprolactinomas and 4/8 microprolactinomas. Gonadal dysfunction improved in two-thirds of patients, headaches resolved in the majority of patients and galactorrhea resolved in all women experiencing this symptom. No subject discontinued the medication due to intolerance, and it was well tolerated by the 16 patients who had experienced side effects on other dopamine agonists.

One criticism of the study, in a letter to the Editor (JCEM 1997, 82:2756), was that the claimed effectiveness of cabergoline for cases of bromocriptine resistance might have been overestimated, with the higher success rates actually due to greater tolerability, resulting in higher compliance. The authors countered that, while this may be true, the net result remained greater effectiveness of cabergoline.

This study is important because it suggests that the majority of patients previously unable to be treated with dopamine agonists can be successfully managed with cabergoline. While the number of subjects was small, the demonstration of PRL normalization in all microprolactinoma patients warrants a trial of this dopamine agonist in such patients not responsive to bromocriptine. This study also suggests that cabergoline may be particularly beneficial to patients with macroprolactinomas, as it will reduce the number of such patients who require transsphenoidal surgery due to failure of medical treatment.

"Pituitary Irradiation is Ineffective in Normalizing Plasma Insulin-Like Growth Factor-1 in Patients with Acromegaly"
A Barkan, I Halasz K Dornfeld et al. 1997 J Clin Endocrinol Metab 82: 3187-91

Radiation therapy has been employed in patients with residual acromegaly following transsphenoidal surgery. However, most of the literature about its effectiveness antedated the use of IGF-1 normalization as a key criterion for cure, and therefore reported success based on lowering growth hormone (GH) to below 5 mcg/L. It is now recognized that this level is substantially higher than in normals, and does not represent acceptable control of acromegaly. A recent JCEM article addresses the effectiveness of radiation therapy for treatment of this disorder using IGF-1 measurements.

In this retrospective study, charts were reviewed from 140 acromegalics treated in Michigan over a 21 year period. Of these, data from 38 patients who underwent radiation therapy and had IGF-1 levels obtainable from the records were evaluated. The main finding of the study was that only 2 patients (5%) achieved age-and sex-adjusted normal IGF-1 levels while off medical therapy. An interesting observation was that the majority of these patients had GH levels below 5 mcg/L, again indicating that this criterion does not indicate adequately biochemical control.

There are several problems with this study. First, the number of patients analyzed was fairly small. Another issue was that because of the retrospective design spanning a 21 year period, and the fact that many patients had obtained blood tests at local labs, IGF-1 measurements were made by an enormous variety of methods at many different laboratories with no consistency in normal ranges. To address this problem, the authors report plasma IGF-1 values as a percentage of the upper limit of normal for each lab conducting the test. The most important problem with the study is that over half of these patients (20/38) had been followed for fewer than 5 years, and older data using GH levels suggest a continued effect of radiation even ten years after its administration.

In the accompanying JCEM editorial, van der Lely, de Herder and Lamberts suggest reserving radiation therapy for those patients with large, infiltrating pituitary tumors which cannot be cured surgically nor controlled medically with somatostatin analogue therapy. A critical question which remains is whether the newer stereotactic radiosurgical techniques such as gamma knife or proton beam (see article by Drs. Allan F. Thornton and Jay S. Loeffler in this issue) will be more successful at normalizing IGF-1 levels, using a careful prospective analysis.

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