Intracranial germinomas (GE) are malignant neoplasms most commonly found in the suprasellar region, which may cause anterior and particularly posterior pituitary hormone deficits with central diabetes insipidus (DI). Differential diagnosis of pituitary stalk thickening includes granulomatous, inflammatory, infectious, and neoplastic lesions. Although careful analysis of clinical, laboratory, and imaging findings may facilitate the diagnosis, transsphenoidal biopsy is indicated to confirm the disease, as the correct diagnosis directs the appropriate treatment.
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 PCR 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 six 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 two 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 PRL/PRL-R 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.
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