Cabergoline - A New Dopamine
Agonist for the Therapy of Prolactinoma
by Beverly M. K. Biller M.D.

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The treatment of choice for prolactinomas is dopamine agonist administration, which results in tumor shrinkage, normalization of prolactin, and restoration of gonadal function in the majority of patients. However, the only dopamine agonist available for this disorder in the United States is bromocriptine. Its use is limited by a high incidence of side effects, a short duration of action, and a lack of effectiveness in some patients. Several other agents have been tested over the last decade in the United States with varying resuIts. However, cabergoline, a long-acting oral doparnine agonist specific for the D2 receptor, has received the most attention recently, and is currenily the only dopainine agonist being pursued for this indication in the U. S.

The most interesting feature of cabergoline in terms of patient comphance is its extremely long half-life. Most patientscan be treated with a single weekly dose, is in contrast to the 1-3 times daily administration required for brornocriptine. Particularly in the population most prone to microprolactinomas, healthy young women without other medical disorders, a once weekly therapy is extremely appealing. What information is available about cabergoline and what is its current status in the United States?

Webster, et al. conducted a European study comparing cabergoline to bromocriptine in the treatment ofhyperprolactinemic amenorrhea. A total of 459 women, the majority of whom had microprolactinomas or idiopathic hyperprolactinernia, were treated with either cabergoline or bromocriptine in a double blind study for 8 weeks, followed by an open label study for 16 weeks during which dose adjustments were made according to response Eighty-three percent of the women treated with cabergoline attained normal prolactin levels in comparison with 59% of women treated with bromocriptine. Seventy-two percent of cabergoline-treated women attained ovulatory cycles or became pregnant during therapy in contrast to only 52% of those treated with bromocriptine. Amenorrhea persisted in 7% of women treated with cabergoline versus 16% of women treated with bromocriptine. Cabergoline was better tolerated than bromocriptine with 3% of women discontinuing cabergoline versus 12% stopping bromocriptine due to intolerance. Gastrointestinal symptoms were significantly less frequent, less severe, and of shorter duration in cabergoline treated patients. The authors concluded that cabergoline is more effective and better tolerated than bromocriptine in women with hyperprolactinemic amenorrhea.

Figure 1. The decline in serum prolactin level in a patient treated with cabergoline. The dotted line indicates the normal range.

In a United States multicenter study of patients with macroprolactinomas, we have also found cabergoline to he effective and well tolerated. Fifteen patients (8 women, 7 men) ages 18-76 years were followed in an open label, 48-week dose escalation trial of cabergoline administered once weekly. Eleven patients had received prior therapy with other dopamine agonists. The prolactin levels decreased by 93.6% with normal levels obtained in 73% of patients at doses of 0.5-3.0 mg per week. Three of 5 patients who had failed to normalize prolactin on prior dopamine agonists achieved normal levels. Gonadal function was restored in all hypogonadal men and in 75% of premenopausal women with amenorrhea. Tumor size decreased in 11 of 15 patients, but tumor shrinkage may have been compromised by the fact that many patients had achieved substantial decreases in tumor mass on prior dopamine agonists. Side effects were minimal, with no patients discontinuing the medication due to intolerance.

Currently, cabergoline is available under a compassionate use protocol from Pharmacia/Upjohn in Kalamazoo, MI, based on individual requests by each patient's physician. In addition, a new multicenter, international trial is available for patients with macroprolactinonias and serum prolactin levels >200. This study is being conducted in a number of European centers and one United States site, the Neuroendocrine Clinical Center at Massachusetts General Hospital. This one year study is designed to confirm the effectiveness of this therapy in patients with macroprolactinomas. In particular, the focus of the study is to determine whether cabergoline is as effective at tumor shrinkage as bromocriptine. For this reason all patients enrolled are required to have had no prior therapy with any dopamine agonists, in order to avoid studying patients who have already experienced some tumor shrinkage with other agents.

In summary, cabergoline appears to be a more effective and better tolerated dopamine agonist in the therapy of prolactinomas. Patient compliance is high, related to the few mild side effects and once-weekly dosing. Further study is needed to confirm this, and to lead to its availability in the United States.

References

1. Webster J, et al. 1994. Comparison of cabergoline and bromocriptine in the treatment of hyperprolactinemic amenorrhea. N Engl J Med 31:904-909.

1. Biller BMK, et al. 1996. Treatment of prolactin secreting macroadenomas with once weekly agonist cabergoline. J Clin Endocrinol Metab 81:2338-43.

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