Neuroendocrine Unit, Division of Endocrinology and Metabolism, Hospital das Clínicas, University of São Paulo Medical School, São Paulo, Brazil.
Laboratório de Endocrinologia Celular e Molecular/LIM25, Disciplina de Endocrinologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.
J Clin Endocrinol Metab. 2023 Jun 16;108(7):e450-e457. doi: 10.1210/clinem/dgad020.
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.
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.
Observational, retrospective, and cross-sectional study.
This study took place at the Neuroendocrinology Unit of Clinics Hospital, Medical School of University of São Paulo, Brazil, a tertiary referral center.
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.
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).
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.
敲除催乳素受体基因（PRL-R）的小鼠是催乳素瘤的动物模型，催乳素通过自分泌/旁分泌抑制催乳素细胞增殖。最近，催乳素瘤患者中发现了 PRL-R 的变体，其频率高于基因组数据库中的个体。
我们分析了广泛催乳素瘤患者队列中 PRL-R 变体的频率，并评估了它们与临床、实验室和影像学特征以及卡麦角林的激素反应的关系。
观察性、回顾性和横断面研究。
巴西圣保罗大学医学院临床医院神经内分泌学系，这是一家三级转诊中心。
研究参与者包括接受卡麦角林治疗的散发性催乳素瘤成人，其中治疗反应定义为用高达 3 毫克/周的剂量使催乳素正常化。从血样中提取 DNA，通过聚合酶链反应技术和自动测序分析 PRL-R。分析 PRL-R 变体与血清催乳素水平、最大肿瘤直径、肿瘤鞍旁侵袭性以及对卡麦角林的反应之间的关系。
我们发现了 6 种 PRL-R 变体：p.Ile100(76)Val、p.Ile170(146)Leu、p.Glu400(376)Gln/p.Asn516(492)Ile、p.Glu470Asp 和 p.Ala591Pro；后两种是新发现的催乳素瘤患者中的变体。与基因组数据库相比，变体 p.Glu400(376)Gln/p.Asn516(492)Ile 和 p.Ala591Pro 在患者中更为常见，并且之前描述的使用计算机分析显示 p.Asn516(492)Ile 具有致病性潜力。PRL-R 变体与男性性别（P = 0.015）、更高的血清催乳素水平（P = 0.007）、更大的肿瘤（P = 0.001）和卡麦角林耐药性（P < 0.001）相关。
催乳素/催乳素受体系统似乎与催乳素瘤的发生和卡麦角林耐药性有关。需要进一步的研究来更好地了解 PRL-R 变体的作用及其作为治疗靶点的潜力。
