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      Morbidity and mortality in patients with hyperprolactinaemia: the PROLEARS study

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          Abstract

          Purpose

          High serum prolactin concentrations have been associated with adverse health outcomes in some but not all studies. This study aimed to examine the morbidity and all-cause mortality associated with hyperprolactinaemia.

          Methods

          A population-based matched cohort study in Tayside (Scotland, UK) from 1988 to 2014 was performed. Record-linkage technology was used to identify patients with hyperprolactinaemia that were compared to an age–sex-matched cohort of patients free of hyperprolactinaemia. The number of deaths and incident admissions with diabetes mellitus, cardiovascular disease, cancer, breast cancer, bone fractures and infectious conditions were compared by the survival analysis.

          Results

          Patients with hyperprolactinaemia related to pituitary tumours had no increased risk of diabetes, cardiovascular disease, bone fractures, all-cause cancer or breast cancer. Whilst no increased mortality was observed in patients with pituitary microadenomas (HR = 1.65, 95% CI: 0.79–3.44), other subgroups including those with pituitary macroadenomas and drug-induced and idiopathic hyperprolactinaemia demonstrated an increased risk of death. Individuals with drug-induced hyperprolactinaemia also demonstrated increased risks of diabetes, cardiovascular disease, infectious disease and bone fracture. However, these increased risks were not associated with the degree of serum prolactin elevation ( P trend > 0.3). No increased risk of cancer was observed in any subgroup.

          Conclusions

          No excess morbidity was observed in patients with raised prolactin due to pituitary tumours. Although the increased morbidity and mortality associated with defined patient subgroups are unlikely to be directly related to the elevation in serum prolactin, hyperprolactinaemia might act as a biomarker for the presence of some increased disease risk in these patients.

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          Most cited references31

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          New insights in prolactin: pathological implications.

          Prolactin is a hormone that is mainly secreted by lactotroph cells of the anterior pituitary gland, and is involved in many biological processes including lactation and reproduction. Animal models have provided insights into the biology of prolactin proteins and offer compelling evidence that the different prolactin isoforms each have independent biological functions. The major isoform, 23 kDa prolactin, acts via its membrane receptor, the prolactin receptor (PRL-R), which is a member of the haematopoietic cytokine superfamily and for which the mechanism of activation has been deciphered. The 16 kDa prolactin isoform is a cleavage product derived from native prolactin, which has received particular attention as a result of its newly described inhibitory effects on angiogenesis and tumorigenesis. The discovery of multiple extrapituitary sites of prolactin secretion also increases the range of known functions of this hormone. This Review summarizes current knowledge of the biology of prolactin and its receptor, as well as its physiological and pathological roles. We focus on the role of prolactin in human pathophysiology, particularly the discovery of the mechanism underlying infertility associated with hyperprolactinaemia and the identification of the first mutation in human PRLR.
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            A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development.

            Understanding how the timing of exposure to endogenous hormones influences cancer development is critical to elucidating disease etiology. Prolactin increases proliferation and cell motility, processes important in later stage tumor development, suggesting that levels proximate (versus distant) to diagnosis may better predict risk. Thus, we calculated relative risks (RR) and 95% confidence intervals (CI) for prolactin levels on samples collected 10 years before diagnosis/reference date. There was an increased risk for higher proximate prolactin levels [RR, >15.7 vs. ≤8.1 ng/mL (i.e., top vs. bottom quartiles) = 1.20; 95% CI, 1.03-1.40; Ptrend = 0.005], but not for distant levels (RR = 0.97; Ptrend = 0.94); results were similar among women with two blood samples (Pinteraction, proximate vs. distant = 0.07). The positive association was stronger for ER(+) disease (RR = 1.28; Ptrend = 0.003) and postmenopausal women (RR = 1.37; Ptrend = 0.0002). Among postmenopausal women, the association was strongest for ER(+) disease (RR = 1.52) and lymph node-positive cases (RR = 1.63). Our data suggest that prolactin levels measured <10 years before diagnosis are most strongly associated with postmenopausal breast cancer risk, especially for ER(+) tumors and metastatic disease. This corresponds with biologic data that prolactin is etiologically important in tumor promotion. ©2013 AACR.
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              Gestational Diabetes Mellitus From Inactivation of Prolactin Receptor and MafB in Islet β-Cells

              β-Cell proliferation and expansion during pregnancy are crucial for maintaining euglycemia in response to increased metabolic demands placed on the mother. Prolactin and placental lactogen signal through the prolactin receptor (PRLR) and contribute to adaptive β-cell responses in pregnancy; however, the in vivo requirement for PRLR signaling specifically in maternal β-cell adaptations remains unknown. We generated a floxed allele of Prlr, allowing conditional loss of PRLR in β-cells. In this study, we show that loss of PRLR signaling in β-cells results in gestational diabetes mellitus (GDM), reduced β-cell proliferation, and failure to expand β-cell mass during pregnancy. Targeted PRLR loss in maternal β-cells in vivo impaired expression of the transcription factor Foxm1, both G1/S and G2/M cyclins, tryptophan hydroxylase 1 (Tph1), and islet serotonin production, for which synthesis requires Tph1. This conditional system also revealed that PRLR signaling is required for the transient gestational expression of the transcription factor MafB within a subset of β-cells during pregnancy. MafB deletion in maternal β-cells also produced GDM, with inadequate β-cell expansion accompanied by failure to induce PRLR-dependent target genes regulating β-cell proliferation. These results unveil molecular roles for PRLR signaling in orchestrating the physiologic expansion of maternal β-cells during pregnancy.
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                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                November 2017
                12 September 2017
                : 6
                : 8
                : 580-588
                Affiliations
                [1 ]Division of Molecular and Clinical Medicine School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
                [2 ]Department of Endocrinology and Diabetes Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
                [3 ]JJR Macleod Centre for Diabetes Endocrinology and Metabolism (Mac-DEM), Aberdeen Royal Infirmary, University of Aberdeen, Aberdeen, UK
                Author notes
                Correspondence should be addressed to E Soto-Pedre; Email: e.soto@ 123456dundee.ac.uk
                Article
                EC170171
                10.1530/EC-17-0171
                5633062
                28954743
                a29680f1-9051-43c9-9c9a-638958d90e64
                © 2017 The authors

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License..

                History
                : 24 August 2017
                : 12 September 2017
                Categories
                Research

                hyperprolactinaemia,prolactin,pituitary gland,breast cancer,mortality

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