ABSTRACT
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.
Subject(s)
Pituitary Neoplasms , Prolactinoma , Male , Humans , Animals , Mice , Prolactinoma/drug therapy , Prolactinoma/genetics , Dopamine Agonists/therapeutic use , Cabergoline/therapeutic use , Receptors, Prolactin , Pituitary Neoplasms/drug therapy , Pituitary Neoplasms/genetics , Prolactin/genetics , Ergolines/pharmacology , Ergolines/therapeutic use , Retrospective Studies , Cross-Sectional Studies , Mice, KnockoutABSTRACT
The aim of this study was to evaluate the level of physical activity and cardiorespiratory fitness in teenagers with type 1 diabetes mellitus (T1D) in comparison with healthy scholar participants. Total of 154 teenagers (T1D = 45 and CON = 109). Height, weight, cardiorespiratory fitness (VO2max), and the level of physical activity by the Bouchard's Physical Activity Record were measured, and glycated hemoglobin (HbA1c) in T1D. The VO2max was lower in the T1D (38.38 ± 7.54) in comparison with the CON (42.44 ± 4.65; p < .05). The VO2max had correlation with the amount of time of moderate-to-vigorous physical activity (r = .63; p = .0001) and an inverse correlation with sedentary activities (r= -0.46; p = .006). In the T1D the levels of HbA1c had an inverse correlation with the amount of time of moderate-to-vigorous physical activity (r= -0.34; p = .041) and correlation with the BMI z-score (r = .43; p = .017). Only 37,8% of the participants in the T1D reached the adequate amount of daily moderate-to-vigorous intensity physical activity, in the CON 81,7% reached the WHO's recommendation. CONCLUSION: T1D had less cardiorespiratory capacity then healthy controls, the teenagers of T1D with lower BMI z-score and that dedicated a greater time in moderate-to-vigorous intensity physical activity demonstrated a better glycemic control.
