PRL-R Variants Are Not Only Associated With Prolactinomas But Also With Dopamine Agonist Resistance

Autor: Andrea Ramos de Castro Moreira, Ericka Trarbach, Cristina Bellotti Formiga Bueno, Anna Louise Stellfeld Monteiro, Isabella Pacetti Pajaro Grande, Mario Padula, Gustavo Arantes Rosa Maciel, Andrea Glezer
Rok vydání: 2023
Předmět:
Zdroj: The Journal of Clinical Endocrinology & Metabolism.
ISSN: 1945-7197
0021-972X
DOI: 10.1210/clinem/dgad020
Popis: Context Knockout prolactin receptor gene (PRL-R) mice are animal models for prolactinomas and PRL acts via autocrine/paracrine inhibiting lactotroph proliferation. Recently, variants of the PRL-R were identified in prolactinoma patients and their frequency was higher compared to individuals from the genomic database. Objective We analyzed PRL-R variants frequency in an extensive cohort of prolactinoma patients and evaluated their association with clinical, laboratorial, and imaging characteristics and hormonal response to cabergoline. Design Observational, retrospective, and cross-sectional study. Setting This study took place at the Neuroendocrinology Unit of Clinics Hospital, Medical School of University of São Paulo, Brazil, a tertiary referral center. Patients and Methods Study participants included adults with sporadic prolactinomas treated with cabergoline, where response to therapy was defined by prolactin normalization with up to 3 mg/week doses. DNA was extracted from blood samples and the PRL-R was analyzed by polymerase chain reaction techniques and automatic sequencing. The association of PRL-R variants with serum prolactin levels, maximal tumor diameter, tumor parasellar invasiveness, and response to cabergoline was analyzed. Results We found 6 PRL-R variants: p.Ile100(76)Val, p.Ile170(146)Leu, p.Glu400(376)Gln/p.Asn516(492)Ile, p.Glu470Asp e p.Ala591Pro; the last 2 are newly described in prolactinomas’ patients. The variants p.Glu400(376)Gln/p.Asn516(492)Ile and p.Ala591Pro were more frequent amongst patients compared to genomic databases, and the p.Asn516(492)Ile showed pathogenic potential using in silico analysis as previously described. PRL-R variants were associated with male sex (P = 0.015), higher serum PRL levels (P = 0.007), larger tumors (P = 0.001), and cabergoline resistance (P < 0.001). Conclusions The prolactin/prolactin receptor system seems to be related to prolactinoma tumorigenesis and cabergoline resistance. Additional studies are needed to better understand the PRL-R variants’ role and their potential as therapeutic targets.
Databáze: OpenAIRE
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