Prolactinomas resistentes a agonistas dopaminérgicos: diagnóstico e manejo

Abstract

Prolactinomas are the more prevalent functioning pituitary tumors, and dopamine agonist drugs (DA) are the main therapeutic option for patients harboring such tumors. Bromocriptine (BRC) resistance, defined as failure to normalize prolactin (PRL) and/or to shrink the tumor is reported in 5 to 18% of the patients treated with this drug, the first DA widely used. Cabergoline (CBG) can bring PRL to normalization and reduce tumor size in up to 86% and 92% of the patients, respectively. Even with this newer DA, a subset of patients does not respond to therapy and are truly resistant. The mechanisms for resistance are not yet fully clarified, so the treatment for the resistant prolactinoma is still a challenge. Transsphenoidal surgery associated or not to radiotherapy is an important tool, but PRL may not normalize, mainly in macroprolactinomas. Treatment with sex steroids or ovulation induction can solve the hypogonadism or infertility, when the tumor growth is under control. New drugs as anti-estrogens, new DA, specific analogs for somatostatin receptor subtypes, chimeric molecules associating dopamine and somatostatin effect, and PRL antagonists are under investigation and can be future alternatives for DA resistance.

Aggressive prolactinoma in a child related to germline mutation in the ARYL hydrocarbon receptor interacting protein (AIP) gene

“…agonists, specially cabergoline, may be related to dopamine-receptor expression in the adenomatous tissue (7)(8)(9)(10), although tumor aggressiveness may be related to AIP mutations in young patients (12,13). Mutations on AIP may be involved in cell proliferation in several ways: multiple protein-protein interactions may lead in particular to AHR stabilization in the cytoplasm, thereby enhancing its ligand-induced nuclear translocation, and modulation of specific phosphodiesterases in some pituitary cells (16,20,21).…”

“…Clinical factors associated with tumor aggressiveness and resistance to dopamine agonists include young age at onset, male gender, large tumor size or cavernous sinus invasion at diagnosis (7)(8)(9)(10).…”