The cabergoline-resistant prolactinoma patient: new challenges

What do we do with the patient with a prolactinoma who is resistant or only partially responsive to a dopamine agonist? Fortunately, this is an infrequent problem. Only about one quarter of patients are unable to normalize their prolactin (PRL) levels with bromocriptine, and more than three quarters of these can be treated successfully with cabergoline (1). Because of overall greater efficacy and tolerability, cabergoline has generally become the treatment of choice for most patients with prolactinomas. In this issue of the Journal, Ono et al. (2) found that 11 of 60 previously untreated patients (18.3%) required more than 2 mg/wk cabergoline to normalize PRL levels. Of these, four required 3 mg/wk, two required 6 mg/wk, four required 9 mg/wk, and one required 11 mg/wk to normalize PRL levels. They also reported 26 resistant patients who required similar doses. Of 150 patients, normalization of PRL was eventually achieved in all but one, but doses had to be raised to high levels in many (2). In another study, Di Sarno et al. (3) found that 10 of 56 patients (17.9%) with macroadenomas, and six of 60 patients (10%) with microadenomas required larger than usual doses of cabergoline, but they used only a maximum of 7 mg/wk and did not achieve PRL normalization in any of these resistant patients. We’ve also encountered a number of resistant patients and reported one who had small, continued, stepwise reductions in PRL as the dose of cabergoline was increased to 3 mg/d (4). This discussion regarding dopamine agonist resistance has dealt only with PRL levels and not tumor size reduction. Although most patients have some tumor size reduction if they have substantial PRL reductions, this is not invariable, and a discordance can occur between these two outcomes (1). However, a patient who has minimal or no PRL reduction will also have no tumor size reduction. The major problem clinically is the patient with primary dopamine resistance. Patients who initially respond to a dopamine agonist and later become resistant are far less common; reasons include noncompliance, institution of gonadal steroid replacement which causes dopamine resistance in the lactotrophs, and the fortunately rare development of a carcinoma (1). In other cases, the cause of this secondary lack of response is not known. Resistance to dopamine agonists does not involve impairment of drug absorption or drug affinity to the dopamine D2 receptor (1). Rather, resistance is associated with a decrease in D2 receptor gene transcription, resulting in a 4-fold decrease in the number of D2 receptors on the cell membrane (1). In addition, there is a decrease in the G protein that couples the D2 receptor to adenylyl cyclase, further decreasing the ability of dopamine to inhibit PRL secretion (1). There are several possible approaches for treatment of patients who are resistant to dopamine agonists. Patients taking bromocriptine should simply be converted to cabergoline, because most will then respond (1). For the patient resistant to cabergoline, the most common approach is to increase the dose of cabergoline, as long as a reduction in PRL levels can be demonstrated with each stepwise increase. Patients generally tolerate such dose increases quite well. In the report of Ono et al. (2), 14 of 150 patients had transient adverse effects, including headache, stomach discomfort, dizziness, constipation, sleepiness, anorexia, nasal congestion, and leg edema. We can also draw upon the experience obtained in patients with Parkinson’s disease who are treated with doses of cabergoline up to 3–6 mg/d. In these patients, gastrointestinal side effects have been reported in 33%, dizziness in 26%, sleep disturbance in 21%, constipation in 19%, edema in 13%, and dyskinesias in 2% (5). The use of high doses of dopamine agonists in Parkinson’s disease, however, has recently drawn attention to a new and potentially more serious issue, that of cardiac valvular abnormalities. This phenomenon was first reported in 2002 for pergolide (6) and in 2004 for cabergoline (7). Subsequently, other reports have shown a 3to 6-fold increased risk of valvular abnormalities in Parkinson’s disease patients treated with high doses (3–6 mg/d) of pergolide and cabergoline (8–12). In a metaanalysis done by Simonis et al. (11), 34% of patients treated with