{"paper_id":"de3b4cd4-ef65-4d86-9d27-94dc53292eeb","body_text":"Main Subject: Obstetrics and Gynecology                                                                                Meta-Analysis Article  | JOGCR. 2023; 8(2): 105-112 \n     Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \n Journal of Obstetrics, Gynecology and Cancer Research | ISSN: 2476-5848 \n \nEvaluation of Levonorgestrel-Releasing Intrauterine System (LNG) in The \nManagement of Uterine Adenomyosis: An Update Systematic Review and \nMeta- Analysis \n \nKhor Chun Kit, Christine Na Sin Ee, Jackie Wong Kee Hung, Aiswaryaa Devi A/P Tambi Selvam,  \nChan Sue Vern, Lee Lionel, Hussein Akl, Kavitha Nagandla*  \n \nDepartment of Obstetrics and Gynaecology, International Medical University, Seremban, Malaysia \n \nArticle Info  ABSTRACT \n  \n          10.30699/jogcr.8.2.105 \n \n \n \nBackground & Objective:  Adenomyosis is a common benign endometrial disease \nwhich causes abnormal uterine bleeding in premenopausal women and affects the \nquality of life.  The definitive treatment is hysterectomy; however, medical treatment is \nan option for those who wish to preserve fertility. This systematic review aims to assess \nthe efficacy of levonorgestrel-releasing intrauterine device as medical management in \nwomen who have adenomyosis. \nMaterials & Methods: We searched PubMed, Cochrane and Scopus databases from \nJanuary 2000 to November 2019 for relevant studies containing the use of \nlevonorgestrel-releasing intrauterine device (LNG -IUD) in managing patients with \nultrasonographic diagnosis of adenomyosis. Main outcome measures in the study are \nmenstrual blood loss (milliliters), pain score measured in 10 cm-visual analogue scale, \nand uterine volume. \nResults: Pooled results from meta-analysis showed that after LNG-IUD treatment for \nadenomyosis, there is significant reduction in dysmenorrhoea, measured using Visual \nAnalogue Scale after 6 months (Standardized Mean Difference (SMD): 3.68; Cl: 2.11-\n5.25) , 12 months (SMD: 4.23; CI: 2.99-5.48), 24 months (SMD: 4.69; CI: 3.40-5.97) \nand 36 months (SMD: 4.01; CI: 3.57-4.45); significant reduction in menstrual bleeding \nafter 6 months (SMD: 2.52; CI: 1.15-3.89), 12 months (SMD: 3.43; CI: 1.64-5.22) and \n24 months (SMD: 3.57; CI: 1.88-5.26); significant reduction in uterine volume after 6 \nmonths (SMD: 0.49; CI: 0.04- 0.93), 12 months (SMD: 0.80; CI: 0.11- 1.48) and 24 \nmonths (SMD: 0.86; CI: 0.15-1.58).  \nConclusion: LNG-IUS is an effective method in alleviating the symptoms of \nadenomyosis.  It is a valuable long-term alternative for the treatment of adenomyosis \nfor young and perimenopausal women in terms of dysmenorrhoea and heavy \nmenstrual bleeding. \nKeywords: Lenonorgestrel Intrauterine Fevice (LNG -IUD), Adenomyosis, \nDysmenorrhea  \nReceived:  2022/10/10; \nAccepted: 2022/12/25; \nPublished Online: 22 Feb 2023; \n \n \nUse your device to scan and read the \narticle online \n  \nCorresponding Information:  \nKavitha Nagandla, \nDepartment of Obstetrics and Gynaecology, \nInternational Medical University, Seremban, \nMalaysia \n \nEmail: kavitha.nagandla@gmail.com \n \n \n \n \n \n \nCopyright © 2023, This is an original open-access article distributed under the terms of the Creative Commons Attribution-noncommercial 4.0 International License \nwhich permits copy and redistribution of the material just in noncommercial usages with proper citation. \n \n \nIntroduction\nAdenomyosis is characterized by the invasion of \nendometrial tissue into myometrium. Most of the \naffected women presented with abnormal uterine \nbleeding, dyspareunia, dysmenorrhea and infertility, \nwhereas a proportion are asymptomatic (1). These \nsymptoms can severely impact the quality of life due to \nthe pain, and complications may arise from heavy \nmenstrual bleeding (2).   \nThe main objective of the management in \nadenomyosis is to improve the quality of life of \naffected women, as the symptoms are distressing (3). \nEven though the definitive treatment of adenomyosis is \nhysterectomy, the treatment can be different based on \nthe types of disease. For instance, management of focal \nadenomyosis is straightforward and simple, giving \nmedical treatment and if it fails, a focal adenomyosis \nresection, even so, surgery is only at an efficacy as low \nas 50% due to the difficulty in determining the \nextent of the disease (4).  On the other hand, the \nmanagement of diffuse adenomyosis is challenging as \nwe can only depend solely on medical therapy to \npreserve the uterus as focal excision becomes \nimpossible particularly in women of child -bearing age \n(5). \nAs of recently, the surgical approach to adenomyosis \nremains controversial as many kinds of surgical \nmanagement whichwere attempted as an alternative to \nlaparotomy, seems to have a higher risk of uterine \nrupture (6). Although there are minimally invasive \n\n\nKhor Chun Kit et al. 106 \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \nsurgical management options, robust evidence to \nsupport is lacking (7). \nThe use of pharmacological treatment such as \ngonadotropin-releasing hormone analogue (GnRHa) \nsuppresses the anterior pituitary gland and \ndownregulates the production of follicle stimulating \nhormone and luteinising hormone. Subsequently, \nGnRHa will prevent ovulation and reduce the estrogen \nproduction, as a result it will re duce the complication \ncaused by adenomyosis (8). At the same time GnRHa \nimproves pregnancy outcomes, however it is not a \nlong-term treatment as it causes multiple complications \ndue to its hypoestrogenic status. In addition, the use of \nlevonorgestrel releas ing intrauterine device (LNG -\nIUD) shows successful long -term treatment for \nreduction of bleeding, pain and uterine volume with an \noverall satisfaction of 72% (9). This is achieved by \ninducing decidualization which suppresses the \nglandular tissues leading t o atrophy of the uterus and \nultimately induce amenorrhea in some (10).  \n This systematic review aims to compile \nevidence that measures the efficacy of levonorgestrel -\nreleasing intrauterine device as a management for \nuterine adenomyosis, so we are able to p rovide a \ncomprehensive assessment of the efficacy of LNG-IUS \nto give healthcare professionals a clearer idea of its \nefficacy to make better treatment choices. Specific \nobjectives include to compare menstrual blood loss \n(milliliters) difference in reported pain score measured \nin 10 cm-visual analogue scale in the included studies, \nand to compare the measured uterine volume changes \namong the included studies. \n \nMethods \nSearch Strategy \nThe electronic database of PubMed, Cochrane and \nScopus were searched from January 2000 until \nNovember 2019 for studies which described the role of \nlevonorgestrelintrauterine device in management of \nadenomyosis. The Mesh terms and text word were \ncombined using Boolean operators ‘AND’ and ‘OR’, \nadapting the search to the rules of each database. The \nfollowing keywords were used: \n(‘levonorgestrelintrauterine device’ or ‘levonorgestrel \nIUD’) AND (‘treatment’ or ‘management’) AND \n(‘adenomyosis’) AND (‘trial’). The reference lists of \nall known review articles were examined for additional \nrelevant citations. \nInclusion and Exclusion Criteria \nAll prospective studies investigating the effect of \nlevonorgestrel-intrauterine system in management of \nadenomyosis were considered eligible for inclusion. \nThe articles had to be written in English and published \nfrom 2000 to 2019. \nThe following criteria were used to determine the \nstudy eligibility:   \na. Populations: Women who were diagnosed by \ntransvaginal ultrasound e xamination (TVS) or \ntransabdominal ultrasound (TAS) for adenomyosis \nwith symptoms of dysmenorrhea, and menorrhagia. \nb. Intervention: Treatment with levonorgestrel \nintrauterine system  \nc. Outcomes: menstrual blood loss (milliliters), \npain score measured in 10 cm -visual analogue scale, \nand uterine volume \nData extraction  \nTitles and abstracts of all identified studies were \nscreened, and the full paper of the preselected articles \nwas read by two researchers (CN and AIS). Data from \nthe articles was extracted ind ependently by both \nresearchers. Any disagreements were resolved by \nconsultation with a third reviewer (JK). \nAssessment of study quality \nQuality Evaluation  \nThe 22 -item Strengthening the Reporting of \nObservational Studies in Epidemiology (STROBE) \nchecklist (11) was used to evaluate the standard \nreporting of the studies. The methodological quality of \nobservational studies was assessed using the \nNewcastle-Ottawa Scale by Wells et  al. (12). T his \nsystematic review was written in accordance with the \nproper order. We utilized the Preferred Reporting Items \nfor Systematic Reviews and Meta-Analyses (PRISMA) \nchecklist.  \nStatistical analysis \nResults from the articles were described using \nmean, standar d deviation, absolute and relative \nfrequencies. The mean and standard deviation were \nabstracted from the studies. A meta- analysis was \nperformed on pooled data from homogeneous studies, \nwhich are defined as studies that assessed outcomes \nusing the same vali dated questionnaire(s), with a \nsimilar study design (i.e.: assessment done pre-  and \npost-treatment) and for the same follow -up period. \nTreatment outcomes evaluated for the meta -analysis \nincluded VAS score for dysmenorrhea, menstrual \nblood loss (using PBAC)  and uterine volume. Meta-\nanalysis was performed using the generic inverse \nvariance method with random effects using Review \nManager (RevMan) version 5.3, Pooled results \ncomparing before and after treatment outcomes were \ndescribed as Standardized Mean Difference (SMD). \nSMD of zero means that there is no difference before \nand after treatment. SMD value of 0.2 indicates a small \neffect of the treatment, a value of 0.5 indicates a \nmedium effect and a value of 0.8 or larger indicates a \nlarge effect. A p -value <0. 05 was considered \nsignificant. \n \n \n \n\n107 Levonorgestrel-Releasing Intrauterine System (LNG) \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \nResults \nSelected studies characteristics \nThe present study identified 222 articles.  Of the 221 \narticles, nine full -text studies were evaluated for \ninclusion, of which 5 were excluded for not reporting \nclinical outcomes, a nd not evaluating patients both \nbefore and after treatment. A total of four articles were \nincluded in the final systematic review for qualitative \nanalysis synthesis and all studies were allowed for \nmeta-analysis. Included studies are prospective studies. \nFigure 1\n. \n \n \nFigure 1. Flowchart for selection of studies \n \nThe main diagnostic imaging method for \nadenomyosis was transvaginal ultrasound (TVS) \nexamination. Degree of dysmenorrhea was assessed by \na 10-cm linear visual analogue scale (VAS), in which \n0 represented no pain and 10 represented the most \nsevere pain. For the severity of menstrual blood loss, it \nwas measured by the Pictorial Blood Assessment Chart \n(PBAC). Uterine volume was calculated by using the \nformula of ovoid: volume = D1 x D2 x D3 x \n0.52.  Recruited subject underwent insertion of \nlevonorgestrel-intrauterine system (LNG -IUS). The \nLNG-IUS is composed of a T -shaped polyethylene \ncore surrounded by a reservoir of 52 mg of LNG, which \nis delivered to the endometrium at a release rate of 20 \nmcg/day in a sustained fashion for five years. \nBaseline characteristics of patients included for \ntreatment with LNG-IUD are shown in Table 1\n. A total \nof 1287 patients with adenomyosis were included. \n \nTable 1. Summary of study characteristics and interventions for adenomyosis from individual studies \nAuthor, year Study design Intervention Age Total (n) Treatment in \nmonths STROBEScore \nSheng et al., 2009 (5) Prospective \nlongitudinal LNG-IUD 36.80 ± 4.30 94 36 19 \nCho et al., 2008 (13) Prospective \nlongitudinal LNG-IUD 39.89 ± 3.91 47 36 21 \nAlizzi et al., 2018 (14) Prospective \nlongitudinal LNG-IUD 44.50 ± 2.50 46 24 21 \n\n\nKhor Chun Kit et al. 108 \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \nAuthor, year Study design Intervention Age Total (n) Treatment in \nmonths STROBEScore \nLi et al., 2019 (15) Prospective \nlongitudinal LNG-IUD 36.00 1100 60 22 \n \nEffect on dysmenorrhea (Figure 2) \nThree out of four of the included studies with a total \nof 1241 patients evaluated the effect of levonorgestrel-\nreleasing intrauterine system on dysmenorrhoea using \nVAS measured at 6, 12, 24 and 36 months after \ntreatment. Pooled results from meta-analysis showed a \nsignificant reduction in VAS after 6 months (SMD: \n3.68; CI: 2.11-5.25), 12 months (SMD: 4.23; CI: 2.99-\n5.48), 24 months (SMD: 4.69; CI: 3.40- 5.97) and 36 \nmonths (SMD: 4.01; CI: 3.57-4.45). \n \n \n \n \n \nFigure 2. Meta-analysis of the effect of LNG-IUD on dysmenorrhea (VAS score) at baseline, \n6 months, 12 months, 24 months and at 36 months. \n \nEffect on menstrual blood loss (Figure 3) \nThree studies with a total of 1193 pat ients evaluated \nthe effect of levonorgestrel -releasing intrauterine \nsystem on menstrual blood loss using Pictorial Blood \nAssessment Chart (PBAC) at six, twelve and twenty -\nfour months after treatment. Pooled results from meta-\nanalysis showed a significant reduction in menstrual \nbleeding after 6 months (SMD: 2.52; CI: 1.15-3.89), 12 \nmonths (SMD: 3.43; CI: 1.64- 5.22) and 24 months \n(SMD: 3.57; CI: 1.88-5.26). \nEffect on uterine volume (Figure 4\n) \nFour studies with a total of 1287 patients evaluated \nthe effect of levonorgestrel -releasing intrauterine \nsystem on uterine volume at 6, 12 and 24 months after \ntreatment. Pooled results from the meta -analysis \nshowed a significant reduction in uterine volume after \n6 months (SMD: 0.49; CI: 0.04- 0.93), 12 months \n(SMD: 0.80; CI: 0.11- 1.48) and 24 months (SMD: \n0.86; CI: 0.15-1.58). \nThis image cannot currently be displayed.\n\n\n109 Levonorgestrel-Releasing Intrauterine System (LNG) \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \n \n \n \nFigure 3. Meta-analysis of effect of LNG-IUD on menstrual blood loss (PBAC) at baseline, 6 months, 12 months and at \n24 months. \n \n \n \n \n \nFigure 4. Meta-analysis of effect of LNG-IUD on uterine volume at baseline, 6 months, 12 months, 24 months \nand at 36 months \n\n\nKhor Chun Kit et al. 110 \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \nDiscussion \nBased on the studies included in this analysis, \nlevonorgestrel-releasing intrauterine system are \neffective in reducing the symptoms in adenomyosis. \nThis can be seen in its significant effect on \ndysmenorrhoea, menstrual blood loss and uterine \nvolume. These results are similar to a recent meta -\nanalysis done by Abbas et al.  in agreement with our \nfindings (16). In the present meta-analysis, LNG-IUS \nexhibited significant improvement in VAS score and \nmenstrual blood loss starting from 6 months until 36 \nmonths after insertion. LNG-IUS has medium effect on \nthe uterine volume on 6 months, improves significantly \non 12 and 24 months, but has minimal effect 36 months \nonward after insertion.  \nThe reduction of pain is explained by Sheng et al. as \nthe effect of high concentration of levonorgestrel on the \nectopic endometrium, which results in glandular \natrophy and stromaldecidualization  (5). They also \nexplained that it could be due to effect on the ectopic \nendometrium, resulting in endometrial inactivity which \nreduces prostaglandin activity. Besides that, another \nexplanation proposed is that the direct effect of \nprogestin leads to a  reduction in the invasion and \nprogression of myometrial hypertrophy. In Cho et al. \nthe explanation of reduction of pain were related to the \neffects of LNG -IUD on endometrium or on the \nvascular supply to the pelvis with relief from pelvic \ncongestion (13). LNG-IUS also showed to reduce the \nprostaglandin release within the endometrium and \ntherefore minimize the dysmenorrhea event as reported \nin Farquhar et al. (17).  \nThe uterine volume in most studies decreased after \nthe insertion of LNG -IUS. However, Cho et al. study \nrevealed that its efficacy began to decrease two years \nafter the insertion, it might be due to the tachyphylaxis \neffect of LNG -IUS, which the concentrati on of the \nlevonorgestrel diminished after a certain period (13). \nThere was a high expulsion rate of the device in the \nstudy by Sheng et al . which could be the reason for \npremature removal (5). Irregular bleeding followed by \nlow abdominal pain is also the r eason for premature \nremoval. The other side effect noted in the study is \nweight gain. But we cannot conclude that the device \ncauses weight gain (18).  \nPBAC scores and hemoglobin levels improved \nsignificantly in six months after insertion. Bleeding \nvolume and hemoglobin had a good ability to predict \nfailure of implantation, while uterine volume had \nexcellent ability to predict failure. This is shown in the \nstudy by Alizzi et al. (14)\n  \nTVS as a diagnostic tool for adenomyosis is \nappropriate compared to MRI because it is of low cost \nand convenient for use in outpatient clinics (2, 19) .  \nHowever, it has a few false positive or false negative \ncases noticed in a few studies in this analysis. Without \nincorporating other evaluating tools such as MRI or \nhistopathology studies, this might have given rise to \nmisdiagnosis (15, 20). \nIn this meta -analysis, we concede the presence of \nlimitation. The small number of high -quality studies \nwith larger size of study group lead to bias in this study. \nIn addition, our meta -analysis employees pre -post \neffect size in which the difference between baseline \nand post -test within one (treatment group) due to \nlimitation of databases and comparative studies. As a \nresult, the SMD will be highly influenced under the \nnatural processes and characteristics of the patients and \nsettings, and these cannot be discerned from the effects \nof the intervention. Furthermore, the search is limited \nto only English, thus might lead to missing out some \nimportant, related studies that can boost up the \nreliability of the analysis. \n \nConclusion \nFrom the systematic review, LNG -IUS is promising \nfor management of symptomatic adenomyosis in terms \nof relieving dysmenorrhea and heavy menstrual \nbleeding. For patients with the diagnosis of \nadenomyosis, the LNG -IUS was observed to improve \ndysmenorrhea and heavy menstrual bleeding over time \nand is effective for the reduction of uterine volume. \nHowever, the efficacy of LNG -IUS on uterine volume \nmay begin to decrease, 36 months after insertion. This \nreview suggests that LNG -IUS is an effective method \nin alleviating the symptoms of adenomyosis; hence it \nimproves quality of life of the patient. It is a valuable \nlong-term alternative for the treatment of adenomyosis \nfor young and perimenopausal women, and it is a good \nstrategy to reduce the number of hysterectomies in \nwomen with adenomyosis.  \n \nFound or Financial Support \nThe work proposal was permitted and funded by the \nInternational Medical University, Ethics Committee. \n \nAuthor’s Contributions \nKC and CN, AD considered the study, interpreted the \nresults, and co -wrote the manuscript. CS and LL \ncollected the data, assisted with information \ninterpretation, and co -wrote the manuscript. HK, KN \ncontributed to scientific writing. All the authors read \nand accepted the last manuscript. \n \nAcknowledgments \nThis work would not have been possible without the \nsupport of International Medical University for giving \nus the opportunity in writing this paper. We would also \nlike to give special thanks to Professor Teng Cheong \nLieng, wh o has been providing his professional \nguidance throughout the process of completing the \n\n111 Levonorgestrel-Releasing Intrauterine System (LNG) \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \npaper. Lastly, we would like to thank everyone who has \ndirectly or indirectly helping us in publishing the paper. \n \nConflict of Interest \nThe author declared no conflict of interest. \nReferences \n \n1. Peric H, Fraser IS. The symptomatology of \nadenomyosis. 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[DOI:10.1055/s-0033-1350840]  \n[PMID] [PMCID] \n20. Tsui K-H, Lee W-L, Chen C-Y, Sheu B-C, Yen M-\nS, Chang T -C, et al. Medical treatment for \nadenomyosis and/or adenomyoma. Taiwan J \nObstet Gynecol. 2014;53(4):459-65.  \n[DOI:10.1016/j.tjog.2014.04.024] [PMID\n] \n\nKhor Chun Kit et al. 112 \n      Volume 8, March – April 2023       Journal of Obstetrics, Gynecology and Cancer Research \n \n \n \n \n \n \n \nHow to Cite This Article:  \n \nChun Kit, K., Sin Ee, CN., Kee Hung, JW., A/P Tambi Selvam, AD., Sue Vern, C., Lionel, L., et al. Evaluation of \nLevonorgestrel-Releasing Intrauterine System (LNG) in The Management of Uterine Adenomyosis -An Update \nSystematic Review and Metanalysis. J Obstet Gynecol Cancer Res. 2023; 8(2):105-12. \nDownload citation:  \nBibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks","source_license":"CC0","license_restricted":false}