Pharmacologic Resistance in Prolactinoma Patients

Abstract

Pharmacologic resistance to dopamine agonists is defined here as failure to normalize PRL levels and failure to decrease macroprolactinoma size by >or=50%. Failure to normalize PRL levels is found in about one-quarter of patients treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. Failure to achieve at least a 50% reduction in tumor size occurs in about one-third of those treated with bromocriptine and 10-15% of those treated with pergolide or cabergoline. The cause of dopamine resistance is primarily a decrease in D(2) receptors but the receptors have normal affinity for dopamine. Treatment approaches for patients resistant to dopamine agonists include changing to another dopamine agonist and increasing the dose of the drug as long as there is continued response to the dose increases and no adverse effects with higher doses. Transsphenoidal surgery is also an option. Clomiphene, gonadotropins, and GnRH can be used if fertility is desired. For those not desiring fertility, estrogen replacement may be used unless there is a macroadenoma, in which case control of tumor growth is also an issue and dopamine agonists are generally necessary. In many patients modest or even no reduction in tumor size may be acceptable as long as there is not tumor growth. Hormone replacement (estrogen or testosterone) may cause a decrease in efficacy of the dopamine agonist so that it must be carried out cautiously. Reduction of endogenous estrogen, use of selective estrogen receptor modulators, and aromatase inhibitors are potential experimental approaches.

Prolactinomas resistant to standard doses of cabergoline: a multicenter study of 92 patients

“…Further studies are necessary to better evaluate the prevalence of AIP mutations in sporadic-resistant prolactinomas. The biological basis of pharmacological resistance remains poorly understood (9,18). Research has mainly focused on the D2R, reporting a reduced number of binding sites (19), reduced gene expression (20), impaired balance between its short and long isoforms (21), and genetic polymorphisms (22).…”

“…Although no consensus has yet been reached about the definition of pharmacological resistance to DA drugs, the most widely accepted criterion is a failure to normalize PRL levels (2,6,9), which can be associated with a lesser degree of tumor shrinkage. In a large study on dose-response relationships in prolactinoma patients with macroadenomas receiving CAB as first-line treatment, disease control was obtained by a weekly dose of !1.5 mg in most patients (O80%) (10).…”

New concepts in prolactin biology

“…Despite the acknowledged efficacy of dopamine agonists for treating prolactinomaassociated hyperprolactinemia, dopamine resistance accounts for 10-15% of the cases. In such patients, therapeutic strategies include increased doses of the same dopamine analog, use of alternative ones, surgery or radiotherapy (Molitch 2005b). While all above strategies target the pituitary tumor, PRLR antagonist could be viewed as alternative means to treat systemic consequences of hyperprolactinemia by targeting the PRLR in periphery.…”

Characterization of resistance to the prolactin-lowering effects of cabergoline in macroprolactinomas: a study in 122 patients

“…In the absence of PRL normalization and/or tumor shrinkage, current recommendation is to progressively increase the dose of CAB (12,13,19), as no major side effects of long-term treatment have been reported yet in the setting of hyperprolactinemia. Furthermore, in the absence of established doses at which CAB has its maximal antisecretory and/or antitumoral effects, very high doses have been used occasionally (up to 1.0-3.0 mg daily).…”