Immunohistochemical Comparison of Dopamine-2 Receptor Expression in Resistant and Non-Resistant Prolactinomas

<b>Background:</b> Dopamine agonists (DAs) are first-line therapy for prolactin-secreting pituitary adenomas; however, a small proportion of tumors are resistant. Previous reports suggested that reduced D2R mRNA expression might cause resistance. This study aimed to determine if resistant prolactinomas express D2R protein. We also explored a role of estrogen receptor alpha (ERα) expression in DA resistance. <b>Methods:</b> We retrospectively selected 15 tumor specimens from 13 total patients (8 controls from 8 patients, 7 from 5 resistant patients) with resected lactotroph cell-type tumors. We reviewed age at diagnosis, tumor size, initial prolactin level, medical treatment, and reason for surgery. Immunohistochemistry was performed for D2R, prolactin, and ERα protein expression. <b>Results:</b> D2R expression was positive in seven of eight controls vs. two of seven in resistant tumors (<i>p</i> = 0.02). ERα expression did not significantly correlate with DA resistance. The two D2R expressing resistant tumors were ERα negative and both derived from a pre-pubertal female, supporting prior reports suggesting ERα may modulate DA therapy response. <b>Conclusions:</b> Our study introduces a reproducible method for assessing D2R protein expression in prolactinomas using commercially available D2R antibodies. Our findings align with current evidence indicating that lack of D2R expression, previously indicated by decreased mRNA levels, is common in DA-resistant prolactinomas and provide a basis for discontinuation of DA therapy to avoid potential harm to these patients.