{"paper_id":"f3817a25-0a7f-4cca-a0af-e6d8d1dc455b","body_text":"INTRODUCTION \nReview question / Objective PICOS \nFramework: Population: Women with \nsymptomatic adenomyosis, particularly \nthose experiencing dysmenorrhea. Intervention: \nTreatment with dienogest. Comparator: None. \nO u t c o m e s : D e g r e e o f i m p r o v e m e n t i n \ndysmenorrhea and differences in response among \ndifferent patient subgroups. Study Design: \nSystematic review and meta-analysis.\nReview Question: How effective is dienogest in \nalleviating dysmenorrhea in women with \nadenomyosis? Are there speci fic patient \nsubgroups that respond better to dienogest \ntreatment? \nRationale Research Background and Purpose:\nAdenomyosis is an estrogen-dependent condition \ncharacterized by the invasion of endometrial tissue \ninto the uterine muscle layer, leading to \ndysmenorrhea, heavy menstrual bleeding, chronic \npelvic pain, and infertility, which severely impacts \nthe quality of life of affected patients. Traditional \ntreatments, such as surgery, non-steroidal anti-\ninflammatory drugs (NSAIDs), and hormonal \ntherapy, have shown some effectiveness but are \nlimited due to side effects or their unsuitability for \nwomen who wish to preserve fertility. Recently, \ndienogest, a synthetic progestin with anti-\ninflammatory and antiproliferative properties, has \ngained attention for its potential in alleviating \nadenomyosis-related symptoms, particularly \ndysmenorrhea.\nResearch Questions:\nHow effective is dienogest in alleviating \ndysmenorrhea in women with adenomyosis?\nAre there speci fic patient subgroups that \ndemonstrate a better response to dienogest \ntreatment?\nHypothesis:\nINPLASY 1\nInternational Platform of Registered Systematic Review and Meta-analysis Protocols\nINPLASYDienogest Treatment of Symptomatic Adenomyosis: \nAn In-Depth Meta-Analysis\nChen, YS; Lin, SH; Xie, X; Yi, JS; Liu, XS; Guo, SW.\nADMINISTRATIVE INFORMATION  \nSupport -  None. \nReview Stage at time of this submission - Data extraction. \nConflicts of interest - YC, JY , SL, XX and XL have no conflict of interest. \nS.W.G. is a Board member of the Asian Society of Endometriosis and \nAdenomyosis, a member of the Scienti fic Advisory Board of the \nEndometriosis Foundation of America, Heranova BioSciences, and \nFimmCyte AG, and has provided paid consultancy advice to the \ncompanies, as well as to Sound Bioventures, and BioGeneration, but \nthese activities had no bearing on this work. \nINPLASY registration number: INPLASY202480119 \nAmendments - This protocol was registered with the International \nPlatform of Registered Systematic Review and Meta-Analysis Protocols \n(INPLASY) on 26 August 2024 and was last updated on 26 August 2024.\nCorresponding author: \nYishan Chen\nys.chen@outlook.com\nAuthor Affiliation:                   \nFujian Maternity and Child Health \nHospital, Fujian Medical University, \nFuzhou, Fujian, China.\nChen et al. INPLASY protocol 202480119. doi:10.37766/inplasy2024.8.0119\nChen et al. INPLASY protocol 202480119. doi:10.37766/inplasy2024.8.0119 Downloaded from https://inplasy.com/inplasy-2024-8-0119/\nINPLASY202480119\ndoi: 10.37766/inplasy2024.8.0119 \nReceived: 26 August 2024\nPublished: 26 August 2024\n\nCertain patient subgroups (e.g., based on age, \nduration of disease, severity of lesions, or other \nphysiological characteristics) may respond better \nto dienogest treatment.\nResearch Design and Methods:\nConduct a systematic review and meta-analysis to \nevaluate the existing literature on the efficacy and \nsafety of dienogest in treating adenomyosis.\nAnalyze the characteristics and outcomes of \ndifferent studies to identify patient subgroups that \nmay benefit more from dienogest treatment.\nData Analysis:\nAssess the effectiveness of dienogest in alleviating \ndysmenorrhea.\nUse statistical analysis methods, such as subgroup \nanalysis and multivariable regression analysis, to \ndetermine the patient characteristics that influence \ntreatment outcomes.\nExpected Contributions:\nThe findings will help clinicians better understand \nthe role of dienogest in treating adenomyosis, \nparticularly in alleviating dysmenorrhea. By \nidentifying specific patient subgroups, the research \nwill contribute to the development of more \npersonalized treatment strategies, enhancing \ntreatment efficacy and patient satisfaction.\nCondition being studied Adenomyosis is a \ncondition where endometrial tissue grows into the \nuterine muscle, leading to symptoms such as \npainful periods, heavy menstrual bleeding, chronic \npelvic pain, and infertility. This disorder significantly \naffects the quality of life for those affected. While \nsurgical options like hysterectomy can effectively \nmanage symptoms, they are not suitable for \nwomen who wish to maintain fertility. This has \ncreated a demand for e ffective non-surgical \ntreatments. Among these, dienogest, a synthetic \nhormone with anti-inflammatory and anti-growth \nproperties, has shown promise in reducing pain \nand bleeding in women with adenomyosis. \nHowever, there is still much to learn about which \npatients benefit most from this treatment, making \nfurther research essential. \nMETHODS \nSearch strategy Based on the comprehensive \nsearch conducted by Ali et al. in PubMed, Web of \nScience, Cochrane Library, and Embase \ndatabases, we conducted an extensive literature \nsearch using the same MeSH terms, keywords, \nand their combinations: “dienogest and \nadenomyosis.” Our search focused on studies \npublished in English from January 2024 to August \n2024. \nParticipant or population Women with \nsymptomatic adenomyosis, particularly those \nexperiencing dysmenorrhea. \nIntervention Treatment with dienogest. \nComparator None. \nStudy designs to be included Based on the \ncomprehensive search conducted by Ali et al. in \nPubMed, Web of Science, Cochrane Library, and \nEmbase databases, we conducted an extensive \nliterature search using the same MeSH terms, \nkeywords, and their combinations: “dienogest and \nadenomyosis.” Our search focused on studies \npublished in English from January 2024 to August \n2024. \nEligibility criteria Inclusion criteria: based on the \ncomprehensive search conducted by Ali et al. [6]in \nPubMed, Web of Science, Cochrane Library, and \nEmbase databases, we conducted an extensive \nliterature search using the same MeSH terms, \nkeywords, and their combinations: “dienogest and \nadenomyosis.” Our search focused on studies \npublished in English from January 2024 to August \n2024. After a meticulous screening process, a total \nof 23 studies were selected for further analysis. \nExclusion criteria: (1) reviews, animal experiments, \ncase reports, conference abstracts, conference \nproceedings, editorial letters, guidelines or \ncommentary; (2) duplicated studies; (3) \npublications for which full text was not available. \nInformation sources PubMed, Web of Science, \nCochrane Library, and Embase databases\nMain outcome(s) For all retrieved studies, pain \nscores on dysmenorrhea were designated as the \nprimary outcome, including the initial pain scores \nand scores following dienogest treatment per the \nVisual Analogue Scale (VAS) . \nQuality assessment / Risk of bias analysis We \nused a modified Newcastle-Ottawa Scale to \nassess the quality and the risk of bias of the \nincluded studies. Each study was evaluated across \nthree categories: selection (up to three stars), \ncomparability (four stars), and outcome (two stars). \nSelection was assessed based on recruitment \nbias, selection of consecutive patients, and power \ncalculation. Comparability was evaluated based on \nadjustments for four confounding factors, including \nthe dose of dienogest administered, concurrent \ntreatments (analgesics and hemostatics), age \nunder 40, and the use of other hormonal \ncontraceptives. The primary outcome was scored \nbased on at least three months of follow-up with \nINPLASY 2Chen et al. INPLASY protocol 202480119. doi:10.37766/inplasy2024.8.0119\nChen et al. INPLASY protocol 202480119. doi:10.37766/inplasy2024.8.0119 Downloaded from https://inplasy.com/inplasy-2024-8-0119/\n\ndienogest treatment and the completeness of \nfollow-up (loss to follow-up <10%). We emphasis \ncomparability, setting a threshold of seven stars \nwith at least three in this category. \nStrategy of data synthesis Stata 17.0 (StataCorp. \nLLC, College Station, TX, USA) and R version 4.4.0 \nwere used for the data analyses. The heterogeneity \nof included studies was assessed using the Q test \n(I2 value). If p > 0.1 and I2 ≤ 50%, a fixed-effect \nmodel was used for meta-analysis; otherwise, a \nrandom-effect model was used. The pooled \nestimate of Δ (reduction in VAS scores after \ntreatment),were calculated based on sample sizes. \nPossible publication bias was assessed using \nfunnel plots, in which Δ’s were plotted against their \ncorresponding standard errors, a measure of \nprecision [11] and statistically with Begg’s and \nEgger’s tests. If bias is absent, small-sized studies \nwould have the Δ estimates that are widely \nscattered and symmetrically about the true, yet \nunknown Δ, which would be approximated by \nlarger-sized studies that provide more accurate \nestimates. In this case, the plot would resemble a \nfunnel with the tip pointing roughly towards the \ntrue Δ. If a publication bias is present, the plot \nwould be asymmetric because some negative \nstudies are not published. Sensitivity analysis was \nalso performed.to evaluate the impact of each \nstudy on the pooled estimate of Δ.\nThe comparison of distributions of continuous \nvariables between two groups was made using the \nWilcoxon’s rank test. Pearson's or Spearman's \nrank correlation coe fficient was used when \nevaluating correlations between two variables \nwhen both variables were continuous or when at \nleast one variable was ordinal. To evaluate which \nfactors were associated with the Δ, multiple linear \nregression analysis was used. P values of < 0.05 \nwere considered statistically significant.\nSubgroup analysis The subgroup analysis in the \nmeta-analysis included the following aspects:\n1）Baseline Severity of Dysmenorrhea:\nPatients were categorized based on their baseline \ndysmenorrhea Visual Analog Scale (VAS) scores.\nSevere Dysmenorrhea: Baseline VAS score ≥7.\nMild to Moderate Dysmenorrhea: Baseline VAS \nscore <7.\nTreatment Duration:\n2）The effectiveness of dienogest was analyzed \nbased on the duration of treatment.\nLonger Treatment Duration: ≥12 months.\nShorter Treatment Duration: <12 months.\n3）Age of Patients:\nThe impact of dienogest was analyzed across \ndifferent age groups.\n4）Study Type:\nThe analysis considered whether the studies were \nrandomized controlled trials, observational studies, \nor other types of research.\n5）Study Quality:\nThe effectiveness of dienogest was also evaluated \nbased on the quality of the studies included in the \nanalysis.\nThese subgroup analyses helped determine that \ndienogest was effective in reducing dysmenorrhea \nsymptoms across various conditions, including \ndifferent severities of dysmenorrhea, treatment \ndurations, patient ages, study types, and study \nquality.\nSensitivity analysis Sensitivity analysis evaluates \nthe robustness of research findings by \nsystematically excluding individual studies. \nLanguage restriction Our search focused on \nstudies published in English. \nCountry(ies) involved China. \nKeywords A d e n o m y o s i s , d i e n o g e s t , \ndysmenorrhea. \nContributions of each author \nAuthor 1 - Yishan Chen - Investigation; Data \ncuration; Methodology; Roles/Writing - original \ndraft; Writing - review & editing.\nEmail: ys.chen@outlook.com\nAuthor 2 - Shunhe Lin - Investigation; Data \ncuration.\nAuthor 3 - Xi Xie - Data curation; Methodology.\nAuthor 4 - Jingsong YI - Roles/Writing - original \ndraft.\nAuthor 5 - Xishi Liu - X.L.: Project administration; \nResources; Supervision; Writing - review & editing.\nAuthor 6 - Sun-Wei Guo - Conceptualization; \nFormal analysis; Funding acquisition; Investigation; \nResources; Validation; Visualization; Roles/Writing \n- original draft; and Writing - review & editing.\nEmail: hoxa10@outlook.com\nINPLASY 3Chen et al. INPLASY protocol 202480119. doi:10.37766/inplasy2024.8.0119\nChen et al. INPLASY protocol 202480119. doi:10.37766/inplasy2024.8.0119 Downloaded from https://inplasy.com/inplasy-2024-8-0119/","source_license":"CC0","license_restricted":false}