Resistance to Cabergoline as Compared with Bromocriptine in Hyperprolactinemia: Prevalence, Clinical Definition, and Therapeutic Strategy

Abstract

To evaluate the prevalence of resistance to cabergoline treatment, we studied 120 consecutive de novo patients (56 macroadenoma, 60 microadenoma, 4 nontumoral hyperprolactinemia) treated with cabergoline (CAB) compared with 87 consecutive de novo patients (28 macroadenoma, 44 microadenoma, 15 nontumoral hyperprolactinemia) treated with bromocriptine (BRC) for 24 months. Resistance was evaluated as inability to normalize serum PRL levels (first end point) and to induce tumor shrinkage (second end point).After 24 months, PRL normalization and tumor shrinkage after CAB and BRC treatments, respectively, were obtained in 82.1% and 46.4% of macroprolactinomas (P < 0.001) and in 90% vs. 56.8% of microprolactinomas (P < 0.001). The median doses of CAB and BRC able to fulfill the two criteria of treatment success were 1 mg/wk and 7.5 mg/d in macroprolactinomas, 1 mg/wk and 5 mg/d in microprolactinomas, and 0.5 mg/wk and 3.75 mg/d in nontumoral hyperprolactinemia. Hyperprolactinemia persisted in 17.8% of macroprolactinomas, 10% of microprolactinomas, and after CAB at doses of 5-7 mg/wk and in 53.6% of macroprolactinomas, 43.2% of microprolactinomas, and 20% of nontumoral hyperprolactinemic patients, after BRC at doses of 15-20 mg/d. In these resistant macro-and microprolactinomas, the maximal tumor diameter was reduced by 43.7 ؎ 3.6% and 22.1 ؎ 3.7% and by 59.3 ؎ 7.1% and 4.3 ؎ 2.1% after CAB and BRC, respectively (P < 0.001).In conclusion, long-term CAB treatment induced the successful control of hyperprolactinemia associated with tumor shrinkage in a higher proportion of patients than did BRC treatment. In a small number of patients (i.e. 17.8% of macroprolactinomas and 10% of microprolactinomas), however, CAB treatment did not normalize serum PRL levels despite reducing tumor mass, even at very high doses. Therefore, an absence of tumor shrinkage cannot be considered as end point to indicate resistance to CAB, and increasing the dose of CAB higher than 3 mg/wk does not seem to be helpful in controlling PRL hypersecretion. (J Clin Endocrinol Metab 86: 5256 -5261, 2001) Patients and Methods PatientsFrom 1996 to 1998, 120 consecutive de novo patients with hyperprolactinemia (90 women and 30 men, aged 15-72 yr) were admitted to our Department and were included into this study after their informed Abbreviations: BRC, Bromocriptine; CAB, cabergoline; CT, computed tomography; DA, dopamine agonist; MRI, magnetic resonance imaging.

Advances in the Treatment of Prolactinomas

“…Cabergoline treatment is also effective and safe in patients with prolactinomas with onset in childhood or adolescence (see Section X). The superiority of cabergoline over bromocriptine was supported by a comparative retrospective study by Di Sarno et al (207). Based on these data, cabergoline treatment is clearly indicated as the primary approach to macroprolactinomas.…”

“…In head-to-head randomized, prospective comparison studies (202), retrospective analyses (207), and general clinical experience, cabergoline has been shown to be more effective in lowering PRL levels to normal, reducing tumor size, and having less adverse effects. As noted below, patients are less likely to be resistant to the therapeutic effects of cabergoline; furthermore, most patients found to be resistant to bromocriptine subsequently respond to cabergoline.…”

“…Varying definitions of dopamine agonist responsiveness and resistance are used throughout the literature, including failure to normalize PRL levels, failure to reduce PRL levels sufficiently to achieve ovulation, or failure to enable a 50% reduction of hyperprolactinemia (207,282,291,292). In addition, there are no standard dose thresholds to which a dopamine agonist should be titrated to assign an individual to the status of "dopamine agonist resistant".…”

Beneficial Effects of High Doses of Cabergoline in the Treatment of Giant Prolactinoma Resistant to Dopamine Agonists: A Case Report with a 21-Year Follow-Up

“…Resistance to bromocriptine is defined as the absence of normalization in prolactin levels when patients are treated with the maximum tolerable dose or with 15 mg daily [25, 26]. On the other hand, resistance to cabergoline is defined as the lack of normalization in prolactin levels and no decrease in tumor mass by at least 50% at a dose of 2.0 mg per week [23, 26-28]. Our patient met these criteria for both agonists.…”

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“…In 10-20% of cases prolactinomas can be resistant to DA therapy as a result of reduced numbers of D2 receptors [76].…”