Resistance to dopamine agonists in the treatment of prolactinomas: diagnostic criteria, mechanisms and ways to overcome it

Abstract

The priority treatment approach for prolactinomas is therapy with dopamine agonists, which allows for elimination of clinical symptoms, normalization of prolactin levels, reduction of the adenoma size and prevention of metabolic abnormalities in the majority of patients. Nevertheless, 10 to 20% of patients are resistant to dopamine agonists. The aim of this review is to analyze literature data on the source mechanisms and potential ways to overcome the resistance of prolactinomas to dopamine agonists. The criteria of a prolactinoma's resistance to dopamine agonists are as follows: 1) no normalization of serum prolactin levels and/or 2) no reduction of the adenoma volume by at least 50% after treatment of bromocriptine at a dose of ≤ 15 mg/day or cabergoline at a dose of ≤ 3 mg/week for at least 6 months. Full resistance is characterized by both no biochemical and no anti-tumor effects, whereas in partial resistance, prolactin levels can be decreased but not normalized, or the adenoma size can be reduced by less than 50% of the initial. The clinical and morphological predictors of prolactinoma resistance to dopamine agonists are male gender, young age, big size of the adenoma and its invasion into the sinus cavernosus, hypointensive and/or heterogeneous MRI signal on Т2 weighed images, and cystic components within the tumor. The main molecular genetic markers are: decreased expression of dopamine and estrogen receptors, higher proliferation index Ki-67 ≤ 3%, as well as the MENIN, AIP, SF3B1, PRDM2 gene mutations. In case of resistance to bromocriptine, it is recommended to switch the patient to cabergoline. In partial resistance to standard doses of cabergoline, it is possible to increase the dose up to a maximally tolerated. Neurosurgery and/or radiation surgery is recommended in cases of full resistance to dopamine agonists or an aggressive tumor. For very aggressive/malignant tumors, or in the event of their extended growth after surgery, temozolomide is recommended as adjuvant therapy.