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      Global Prevalence of Macroprolactinemia among Patients with Hyperprolactinemia: A Systematic Review and Meta-Analysis

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          Abstract

          Hyperprolactinemia (hPRL) often poses a diagnostic dilemma due to the presence of macroprolactin. Understanding the prevalence of macroprolactinemia (mPRL) has an important implication in managing patients with hPRL. The primary aim of this study was to determine the prevalence of mPRL globally and to explore selected factors influencing the prevalence estimate. Studies with original data related to the prevalence of mPRL among patients with hPRL from inception to March 2020 were identified, and a random effects meta-analysis was performed. Of the 3770 records identified, 67 eligible studies from 27 countries were included. The overall global prevalence estimate was 18.9% (95% CI: 15.8%, 22.1%) with a substantial statistical heterogeneity (I 2 = 95.7%). The highest random effects pooled prevalence was observed in the African region (30.3%), followed by Region of the Americas (29.1%), European (17.5%), Eastern Mediterranean (13.9%), South-East Asian (12.7%), and Western Pacific Region (12.6%). Lower prevalence was observed in studies involving both sexes as compared to studies involving only female participants (17.1% vs. 25.4%) and in more recent studies (16.4%, 20.4%, and 26.5% in studies conducted after 2009, between 2000 and 2009, and before 2000, respectively). The prevalence estimate does not vary according to the age group of study participants, sample size, and types of polyethylene glycol (PEG) used for detection of macroprolactin (PEG 6000 or PEG 8000). With macroprolactin causing nearly one-fifth of hPRL cases, screening for mPRL should be made a routine before an investigation of other causes of hPRL.

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          Assessing risk of bias in prevalence studies: modification of an existing tool and evidence of interrater agreement.

          In the course of performing systematic reviews on the prevalence of low back and neck pain, we required a tool to assess the risk of study bias. Our objectives were to (1) modify an existing checklist and (2) test the final tool for interrater agreement. The final tool consists of 10 items addressing four domains of bias plus a summary risk of bias assessment. Two researchers tested the interrater agreement of the tool by independently assessing 54 randomly selected studies. Interrater agreement overall and for each individual item was assessed using the proportion of agreement and Kappa statistic. Raters found the tool easy to use, and there was high interrater agreement: overall agreement was 91% and the Kappa statistic was 0.82 (95% confidence interval: 0.76, 0.86). Agreement was almost perfect for the individual items on the tool and moderate for the summary assessment. We have addressed a research gap by modifying and testing a tool to assess risk of study bias. Further research may be useful for assessing the applicability of the tool across different conditions. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Diagnosis and management of hyperprolactinemia: results of a Brazilian multicenter study with 1234 patients.

            The aim of the study was to evaluate clinical and laboratorial features of 1234 patients with different etiologies of hyperprolactinemia, as well as the response of 388 patients with prolactinomas to dopamine agonists. A total of 1234 hyperprolactinemic patients from 10 Brazilian endocrine centers were enrolled in this retrospective study. PRL measurement, thyroid function tests, and screening for macroprolactin were conducted. Patients were subdivided as follows: 56.2% had prolactinomas, 14.5% drug-induced hyperprolactinemia, 9.3% macroprolactinemia, 6.6% non-functioning pituitary adenomas, 6.3% primary hypothyroidism, 3.6% idiopathic hyperprolactinemia, and 3.2% acromegaly. Clinical manifestations were similar irrespective of the etiology of the hyperprolactinemia. The highest PRL levels were observed in patients with prolactinomas but there was a great overlap in PRL values between all groups. However, PRL>500 ng/ml allowed a clear distinction between prolactinomas and the other etiologies. Cabergoline (CAB) was more effective than bromocriptine (BCR) in normalizing PRL levels (81.9% vs 67.1%, p 500 ng/ml were exclusively seen in patients with prolactinomas. CAB was significantly more effective than BCR in terms of prolactin normalization, tumor shrinkage, and tolerability.
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              The impact on clinical practice of routine screening for macroprolactin.

              Macroprolactin has reduced bioactivity in vivo and accumulates in the sera of some subjects, resulting in pseudo-hyperprolactinemia and consequent misdiagnosis. We have audited our experience of routine screening for macroprolactin using polyethylene glycol (PEG) precipitation over a 5-yr period in a single center. Application of a reference range for monomeric prolactin (the residual prolactin present in macroprolactin-depleted serum) for normal individuals revealed that 453 of 2089 hyperprolactinemic samples (22%) identified by Delfia immunoassay were explained entirely by macroprolactin. The percentage of hyperprolactinemic samples explained by macroprolactinemia was similar across all levels of total prolactin (18, 21, 19, and 17% of samples from 700-1000, 1000-2000, 2000-3000, and greater than 3000 mU/liter, respectively). Application of an absolute prolactin threshold after polyethylene glycol treatment of sera, rather than the traditional method, i.e. less than 40% recovery, minimizes the opportunity for misclassification of patients in whom macroprolactin accounted for more than 60% of prolactin and the residual bioactive prolactin was present in excess. Macroprolactinemic patients could not be differentiated from true hyperprolactinemic patients on the basis of clinical features alone. Although oligomenorrhea/amenorrhea and galactorrhea were more common in patients with true hyperprolactinemia (P < 0.05), they were also frequently present in macroprolactinemic patients. Plasma levels of estradiol and LH and the LH/FSH ratio were significantly greater in macroprolactinemic compared with true hyperprolactinemic subjects (P < 0.05). Reduced use of imaging and dopamine agonist treatment resulted in a net cost savings, offsetting the additional cost associated with the introduction of screening. Routine screening of all hyperprolactinemic sera for macroprolactin is recommended.
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                Author and article information

                Journal
                Int J Environ Res Public Health
                Int J Environ Res Public Health
                ijerph
                International Journal of Environmental Research and Public Health
                MDPI
                1661-7827
                1660-4601
                06 November 2020
                November 2020
                : 17
                : 21
                : 8199
                Affiliations
                [1 ]Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia; noorazlin79@ 123456usm.my (N.A.A.C.S.); juliakb@ 123456usm.my (J.O.); anizamj@ 123456usm.my (A.M.J.); noorazliyana@ 123456usm.my (N.S.); tusti@ 123456usm.my (T.S.T.I.); dr_wannorlina@ 123456usm.my (W.N.W.A.)
                [2 ]Unit of Biostatistics and Research Methodology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kubang Kerian 16150, Kelantan, Malaysia; anisyo@ 123456usm.my
                Author notes
                [* ]Correspondence: najibmy@ 123456usm.my
                Author information
                https://orcid.org/0000-0001-5030-4393
                https://orcid.org/0000-0002-6860-1430
                https://orcid.org/0000-0003-4165-2673
                https://orcid.org/0000-0002-9064-8235
                https://orcid.org/0000-0002-7739-8323
                https://orcid.org/0000-0001-7483-1585
                Article
                ijerph-17-08199
                10.3390/ijerph17218199
                7664288
                33171973
                bd7914ed-6cb1-4920-b6a2-a03b0118f2c4
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 27 September 2020
                : 04 November 2020
                Categories
                Review

                Public health
                macroprolactin,macroprolactinemia,big-big prolactin,prolactin,hyperprolactinemia,prevalence,meta-analysis

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