{"paper_id":"67af1359-57e9-4ea6-96c1-d72027f16d26","body_text":"Unika Soegijapranata1\nGMIT-D-24-00021.pdf\n \nDocument Details\nSubmission ID\ntrn:oid:::28973:145533654\nSubmission Date\nJul 14, 2026, 9:12 AM GMT+7\nDownload Date\nJul 14, 2026, 9:26 AM GMT+7\nFile Name\nGMIT-D-24-00021.pdf\nFile Size\n836.1 KB\n8 Pages\n5,568 Words\n29,454 Characters\nPage 1 of 11 - Cover Page\nSubmission ID\ntrn:oid:::28973:145533654\nPage 1 of 11 - Cover Page\nSubmission ID\ntrn:oid:::28973:145533654\n\n\n5%\nOverall Similarity\nThe combined total of all matches, including overlapping sources, for each database.\nFiltered from the Report\nBibliography\nQuoted Text\nCited Text\nSmall Matches (less than 8 words)\nSubmitted works\nInternet sources\nCrossref database\nExclusions\n1 Excluded Match\nMatch Groups\n21\nNot Cited or Quoted  5%\nMatches with neither in-text citation nor quotation marks\n0\nMissing Quotations  0%\nMatches that are still very similar to source material\n0\nMissing Citation  0%\nMatches that have quotation marks, but no in-text citation\n0\nCited and Quoted  0%\nMatches with in-text citation present, but no quotation marks\nTop Sources\n0%\nInternet sources\n5%\nPublications\n0%\nSubmitted works (Student Papers)\nIntegrity Flags\n0 Integrity Flags for Review\nNo suspicious text manipulations found.\nOur system's algorithms look deeply at a document for any inconsistencies that \nwould set it apart from a normal submission. 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Overlapping sources will not be displayed.\n1\nPublication\nSaghar Salehpour, Hoda Niknam, Nasrin Saharkhiz, Sedighe Hosseini, Mitra Nem…\n<1%\n2\nPublication\nVivek Verma, Hafiz T.A. Khan, Dilip C. Nath, Kenneth C. Land. \"Biostatistical Meth…\n<1%\n3\nPublication\nBalogh, Brigitta. \"Pediatric Laparoscopic Procedures in Special Indications\", Szeg…\n<1%\n4\nPublication\nAlicia Navarro-Cáceres, Leticia Gómez-Sánchez, Nuria Suárez-Moreno, Silvia Arroy…\n<1%\n5\nPublication\nBánhegyi, Róbert János. \"FTO Génpolimorfizmus, Obezitás, 2-es Típusú Cukorbete…\n<1%\n6\nPublication\nJiayu Huang, Zhenke Xiao, Junming Lao, Lingli Pan, Zhou Chen, Yi Lu. \n\"Electroacup…\n<1%\n7\nPublication\nClinton Kwemu Njakoi, Frankline Sevidzem Wirsiy, Carine Njwengba Owajege. \"C…\n<1%\n8\nPublication\nMalcolm G. Munro, Victor Gomel. \"Reconstructive and Reproductive Surgery in Gy…\n<1%\n9\nPublication\nMaria Łuszczyńska. \"Researching Ageing - Methodological Challenges and their E…\n<1%\n10\nPublication\nRoberto R Celis M. \"Design of a Drug Delivery System for Controlled Release of Ci…\n<1%\nPage 3 of 11 - Integrity Overview\nSubmission ID\ntrn:oid:::28973:145533654\nPage 3 of 11 - Integrity Overview\nSubmission ID\ntrn:oid:::28973:145533654\n\n\n© 2025 Gynecology and Minimally Invasive Therapy | Published by Wolters Kluwer - Medknow\n1\nAbstract\nOriginal Article\nIntroductIon\nDeep endometriosis (DE) is a chronic pain, in which women \nexperience the symptoms of pain, such as dysmenorrhea, \nchronic pelvic pain, and dyspareunia. Although medical \ntreatment is helpful for many women and it helps to relieve \nthe symptoms in 50%–80% of cases, 20% of patients still \nshow the symptoms even though laparoscopic surgery \nhas been conducted. [1,2]  In patient‑seeking pregnancy, \noptimal management completed endometriosis surgery is \nmandatory. Although laparoscopic surgery using laparoscopy \nthree‑dimensional (3D) technology has more advantages \nwith obvious advantages in depth perception, precision, \nand surgical strain than laparoscopy 2D technology, \nthere is no significant difference in previous research. [3‑7] \nCurrent guidelines and literature about endometriosis are \nObjectives:  Deep endometriosis (DE) is a common disease in 15%–45% of childbearing‑age women. Combined oral contraceptive \npill (COCP) and dienogest have been used for decades to treat many forms of endometriosis after laparoscopy surgery. This study aims \nto assess the latest evidence on the effect of dienogest compared with the COCP on the pain scores of dysmenorrhea, dyspareunia, and \ndyschezia in DE patients.\nMaterials and Methods: Data from 1363 samples of 9 research literature were taken. The postlaparoscopy surgical patients are divided into \nthe dienogest group and the COCP group. The main symptoms were assessed using a visual analog scale for dysmenorrhea, dyspareunia, and \ndyschezia in addition to the demographic data from patients of the 2 study groups being compared.\nResults: Seven studies show significant differences in dysmenorrhea scores between the dienogest group and the COCP group. Dyspareunia \nscores in cases of postoperative endometriosis implants showed 6 studies with lower dyspareunia scores in the dienogest group than the COCP \ngroup, while 3 other articles showed higher dyspareunia scores in the dienogest group than in the COCP group. Assessment of the risk of bias \nin the meta‑analysis of the therapeutic effectiveness of the Egger regression test shows nonsignificant results which proves no tendency for \npublication bias (t = 1.111; df = 7.00; P = 0.303).\nConclusion: Dienogest is an effective pain treatment and it is effective for a subgroup of patients with endometriosis and pelvic pain. It is well \ntolerated as a pain treatment in adenomyosis patients without complications of severe uterine enlargement or severe anemia.\nKeywords: Combined oral contraceptive pill, deep endometriosis, dienogest\nAddress for correspondence: Dr. Indra Adi Susianto, \nDepartment of Obstetric Gynecology, Anugerah Women and Children \nHospital, Kalisari Baru No 7, Semarang, Central Java, Indonesia. \nE‑mail: indraadisusianto@unika.ac.id\nAccess this article online\nQuick Response Code:\nWebsite:  \nhttps://journals.lww.com/gmit\nDOI:  \n10.4103/gmit.GMIT‑D‑24‑00021\nThis is an open access article distributed under the terms of the Creative Commons \nAttribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is \npermissible to download and share the work provided it is properly cited. The work \ncannot be changed in any way or used commercially without permission from the journal.\nFor reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com\nHow to cite this article: Susianto IA, Susilaningsih N, Hidayat ST, \nRachmawati B. Dienogest therapy against the combined oral contraceptive \npill in deep infiltrating endometriosis cases: A systematic review and meta‑\nanalysis. Gynecol Minim Invasive Ther 0;0:0.\nDienogest Therapy Against the Combined Oral Contraceptive \nPill in Deep Infiltrating Endometriosis Cases: A Systematic \nReview and Meta-Analysis\nIndra Adi Susianto1,2,3*, Neni Susilaningsih4, Syarief Taufik Hidayat5, Banundari Rachmawati1,6\n1Department of Doctoral Research Degree Medical Faculty Diponegoro University, Semarang, 2Department of Obstetric Gynecology, Anugerah Women and Children \nHospital, 3Department of Obstetric Gynecology, Faculty of Medicine, Soegijapranta Catholic University, Departments of 4Anatomy Histology and 6Clinical Pathology, Faculty \nof Medicine, Diponegoro University, 5Department of Endocrinology‑Fertility, Faculty of Medicine, Diponegoro University and Kariadi Hospital, Semarang, Indonesia\nGynecology and Minimally Invasive Therapy XX (2025) XX‑XX\nArticle History: \nSubmitted: 27‑Aug‑2024 \nRevised: 27‑Nov‑2024  \nAccepted: 03‑Feb‑2025  \nPublished: 28‑Nov‑2025\n2\n3\n5\n5\n8\n8\nPage 4 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 4 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n2\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nmentioned on the article as an international terminology for \nendometriosis. [8,9]\nIn this case, supportive medical treatment is a necessity \nto improve women’s quality of life. 70% of women suffer \nfrom lower abdominal quadrant pain accompanied by severe \ndysmenorrhea, dysuria, dyspareunia, and even dyschezia \nand 48% found an endometrium such as tissue extending \nthe peritoneal surface that invades adjacent structure and \ndisruption of normal anatomy in patients with recurrent pelvic \npain with infertility.[1,10]\nThere are many medical treatments recommended to \neliminate chronic pelvic pain for DE lesions. The combined \noral contraceptive pill  (COCP) can be well tolerated \nsince the metabolic effect is low and it is usually used to \nsuppress ovulation and reduce menstrual blood flow in \nendometriosis. Apart from that, injectable therapy in the \nform of anti‑gonadotropin analog hormone (GnRH‑A) can \nalso be given but it triggers pharmacological menopause by \nsuppressing ovulation and reducing ovarian steroidogenesis \nand its use in the long term will have a risk of decreasing bone \nmineral density.[1,11]\nTo treat the symptoms related to DE, the administration of \nprogestin preparations, in fact, can inhibit ovulation, so it can \nreduce the levels of estrogen serum resulting in endometrial \natrophy. Furthermore, although they occur, they can reduce \nthe levels of peritoneal inflammation. In addition, although \nprogestins, such as desogestrel and medroxyprogesterone \nacetate can cause some androgen‑related side effects; \nnewer‑generation progestins, such as dienogest which \nis a fourth‑generation semisynthetic selective progestin, \nare well tolerated and it has the pharmacological features \nof semisynthetic selective progestins. Inside dienogest \nis 19‑nortestosterone, which has greater specificity in \nbinding to progesterone receptors and it offers effects on \nendometriotic lesions, with little androgenic, estrogenic, \nglucocorticoid, or mineralocorticoid activity. [5,12,13] Recently, \nthe efficacy of dienogest  (Visanne) in the management \nof endometriosis has been demonstrated. Dienogest is \na synthetic progestin, a 19‑nortestosterone derivative, \nwith good oral bioavailability and high selectivity for \nprogesterone receptors. [14‑16]\nIt has anti‑ovulatory, antiproliferative, and inhibitory effects. \nDienogest has proven to be able to inhibit nerve growth \nfactor expression induced by tumor necrosis factor‑alpha or \ninterleukin beta, a key mediator in generating pain associated \nwith endometriosis to inhibit nerve growth factor expressions \ninduced by tumor necrosis factor‑alpha or interleukin \nbeta, a key mediator in generating pain associated with \nendometriosis.[14,15]\nThe previous study has reported that dienogest not only holds \ndown the ovulation and gives the effect of antiproliferative, \nbut also inhibits the secretion of cytokines in endometrial \nstromal cells, leading to a reduction in pain associated with \nDE and adenomyosis. Lina el taha et al. mentioned that 70 \nwomen with endometriosis‑associated chronic pelvic pain, \ndysmenorrhea, or both for > 6 months were randomized to be \ngiven either dienogest (Visanne) 2 mg/day or COCP (Yasmin, \n0.03  mg ethinyl estradiol and 3 mg drospirenone) for \n24 weeks.[17,18]\nThis study aims to assess the latest evidence of the clinical \neffectiveness of supportive medical treatment using the \nselected medication dienogest compared to contraceptive \npills to control severe dysmenorrhea, dysuria, dyspareunia, \nand even dyschezia.\nMaterIals  and  Methods\nThis study is using a systematical review and meta‑analysis \nconducted in accordance with the Preferred Reporting Items \nfor Systematic Reviews and Meta‑Analyses (PRISMA) \nguidelines and based on the Cochrane Handbook for \nSystematic Reviews of Interventions that involve postsurgery \nadult patients of reproductive age with a laparoscopic surgery \nfollowed with medical therapies for the management of \nendometriosis‑related pain to cure the pelvic pain related \nto endometriosis, dysmenorrhea score, dyschezia score, \nand dyspareunia score from various races. This systematic \nstudy and meta‑analysis are registered with the ID: \nCRD42023173130 on October 27, 2023.\nThis systematic review is prepared under the recommendations \nof the Extension Statement and shown in Figure 1 . As this \nis a systematic review and meta‑analysis; therefore, formal \nethical approval is not required.\nResearch strategy\nA comprehensive search in five electronic databases had been \ndone from 2021 to 2023: PubMed, SCOPUS, Web of Science, \nCochrane Central Register of Controlled Trials (CENTRAL), \nand Google Scholar. Besides that, clinical‑registered \nresearch is conducted (http://clinicaltrial.gov) for a trial \nthat is potentially unpublished. Combinations of different \nkeywords have been used as follows: (“Endometriosis \nOR “Deep Infiltrating Endometriosis” OR “Severe \nEndometrioma” OR “DIE”), (“Laparoscopy Dissection” \nOR (“Laparoscopy Radical Exaction” OR Laparoscopy \nDeep Infiltrating Saver”) OR (“Gonadotrophin Releasing \nHormone”) OR “(GnRH Analog”) OR (“dienogest”) \nOR (“Visanne”) OR (“Nelandoz’) OR “kontrasepsi \nhormonal kombinasi OR (“continuous combined oral \ncontraceptive pill (CCOCP)”/”COCP”) that not only \nfrom Europe sample but also Turkey, Iran, Brazil, and \n9\nPage 5 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 5 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n3\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nIndonesia. The limitation of this research is that the author \ndid not mention the surgery that had been performed on \nall participants before their treatments after eliminating \nthe duplication, a recording is done which is taken from \nEndNote 20, iOS version continued with the infiltration of \ncomplete text from the study which is potentially fulfilling \nthe requirements.\nInclusion and exclusion criteria\nWe include a random controlled trial (RCT) which is conducted \naccording to these criteria: (1) a study involving postsurgery \nadult patients of reproductive age with a laparoscopically \ndocumented diagnosis of DIE;  (2) a study assessing the \nefficacy of any of the following medical therapies for the \nmanagement of endometriosis‑related pain: Combined \nhormonal contraceptives and dienogest; and (3) a study \nreporting these results: Changes on the total score of pelvic \npain related toendometriosis, dysmenorrhea score, dyschezia \nscore, and dyspareunia score and various races.\nData extraction and efficacy size\nFrom 9143 researchers, 9 independent researchers take the \ndata of this study, then, input the data, and every argument \nis solved by discussion. The domain for the data extraction \ninvolves the characteristics from the research summary \nattached, characteristics of the baseline population studied, \ndomains of risk of bias, and study outcomes. The measurement \nof the study result being attached is: (1) dysmenorrhea pain, \ndyschezia, and dyspareunia 6 months after surgery, assessed \nwith a 10 cm visual analog scale (V AS).\nRisk of bias assessment\nTwo independent reviewers (authors 2 and 4) assess \nthe RCT quality completing the requirements using the \ntables of quality risk assessment provided by Cochrane’s \ncompliance with systematic reviews of interventions. \nCochrane risks in bias assessment include the following \ndomains: sequence generation (selection bias), concealment \nof sequence allocation (selection bias), participants and \npersonnel blinding (performance bias), outcome assessment \nblinding (detection bias), incomplete outcome data (attrition \nbias), selective reporting of results (reporting bias), and other \npotential sources of bias. Assessments are categorized as “Low \nrisk,” “High risk,” or “Unclear risk bias.”\nresults\nResults of literature research\nThere are 33.907 studies about the treatment of endometriosis \nand adenomyosis after surgery coming from Cochran (17.400 \nstudies), PubMed (1426 studies), and Scopus study (587 \nstudies); but only 9143 studies are found in the online \nbibliography matching into the screening searching result. \nFrom that number, 143 are complete texts, with 96 eligible \nFigure 1: Shows the PRISMA graph. Network plot describing direct evidence between interventions\n2\n6\nPage 6 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 6 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n4\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nRCTs that all participants received medication after \nlaparoscopy surgery. However, after sorting them out, there \nare only 9 studies (1363 patients) included in this systematic \nreview and meta‑analysis of this network. All participants \nare divided into 2 groups with double‑blind control trials \nreceiving medication either dienogest or COCCP.\nAssessment of the risk of bias from the articles used \nin the meta -analysis of the effectiveness of dienogest \ntherapy versus contraceptive pills in cases of postsurgical \nendometriosis implants\nAssessments of the risk of bias in the studies included \nin the systematic review and meta‑analysis of dienogest \ntherapy against the CCOCP in the case of postintrasurgery \nendometriosis cases are shown in Table 1.\nThere are 9 articles related to the effectiveness of dienogest \ntherapy against contraceptive pills in cases of postoperative \nendometriosis implants. In Table 1, it can be seen that from \nthe 9 articles, 3 articles are found with a high risk of bias; \nthey are: Antonio Maiorana 2022, BilgehanSaglikGokmen \n2023, and Tolga Karacan 2020. This is because the three \nstudies are not clinical trials but observational studies. In \nTable 1, it also appears that there are 2 studies by Cihan Kaya \n2021 and Purwanto 2021 whose risk of bias is categorized as \nunclear. This is due to not providing information regarding the \nrandomization and concealment methods of the random order \nof allocation to research groups. Apart from that, blinding is not \ncarried out in these two studies. Next, there are 4 articles which \nhave a low risk of bias; they are: GelarehNiakan 2021, Lina El \nTaha 2021, Ticiana A. A. Miraa 2021, and Yutaka Osuga 2017.\nMeta-analysis of the effectiveness of dienogest therapy \nagainst contraceptive pills in cases of postoperative \nendometriosis implants\nDysmenorrhea score\nThe comparison of dysmenorrhea score in the group of \ndienogest with the group of combined oral contraceptives is \nshown in Table 2.\nWe can see from the table that there are 9 studies used in the \nmeta‑analysis of the effectiveness of dienogest therapy against \ncontraceptive pills in cases of postoperative endometriosis \nimplants. The dysmenorrhea score of those 6 studies (Antonio \nMaiorana 2022, BilgehanSaglikGokmen 2023, Cihan Kaya \n2021, Lina El Taha 2021, Purwanto 2021 dan Ticiana A. \nA. Miraa 2021) in the dienogest group is lower than that \nin the COCP group. In the other 3 articles (GelarehNiakan \n2021, Tolga Karacan 2020 dan Yutaka Osuga 2017), the \ndysmenorrhea score in the dienogest group is higher than it is \nin the COCP group.\nMeta‑analysis was carried out using a random effect model \nbecause the data are heterogeneous (Q = 63,655, df = 8; \nI2 = 87,432). Based on the data, it is revealed that 7 studies \nshow significant differences of dysmenorrhea scores in the \ndienogest group compared with the COCP group, except for \n2 studies (Lina El Taha 2021 dan Ticiana A. A. Miraa 2021) \ndue to the range of 95% interval of trust covers number 1. \nOverall, the whole dysmenorrheas score in the dienogest \ngroup is significantly lower than the COCP group with a mean \ndifference of −0,473 ± 0.109 (P < 0.001).\nTable 1: Characteristics of study data\nAuthor Design Population Treatment \n(dosage)\nControl (dosage) Number of \nPatients\nAge \n(average)\nOutcome \nvariable\nAntonio Maiorana \net al. 2023\nObservasional Study Adult with \nendometriosis\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n128 31,6 Post‑treatment \nV AS score \nBilgehan Saglik \nGokmen et al. 2023\nProspective \nObservasional Study\nPremenopausal \nwomen with \nendometriosis\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n200 41,5 Post‑treatment \nV AS score\nCihan Kaya et al. \n2021\nOpen Label‑RCT Women with pelvic \npain\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n171 40 Post‑treatment \nV AS score\nGelareh Niaken \net al. 2021\nOpen Label‑RCT Women with \nsymptomatic \nendometriosis\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n115 29,7 Post‑treatment \nV AS score\nLina El Taha et al. \n2021\nDouble blind‑RCT Adult with \nendometriosis\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n127 36,9 Post‑treatment \nV AS score\nJoko Purwanto \net al. 2020\nOpen Label‑RCT Women with pelvic \npain\nDienogest \nvs COCP\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n204 44,6 Post‑treatment \nV AS score\nTriciaana AA Miraa \net al., 2020\nDouble blind‑RCT women with \nendometriosis\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n126 46,5 Post‑treatment \nV AS score\nTolga Karacan \net al., 2020\nRetrospective Cohort Infertil women \nwith endometriosis\nDienogest \n2mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n154 32,8 Post‑treatment \nV AS score\nYutaka Osaga et al., \n2017\nDouble blind‑RCT Patient with \nendometriosis\nDienogest \n2 mg\nCOCP (EE 35 µg plus \nnorethisterone 1 mg)\n138 32,1 Post‑treatment \nV AS score\n1\n2\n2\nPage 7 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 7 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n5\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nDyschezia score\nThe comparison of dyschezia score in the dienogest group and \nthe combined oral contraceptive group is shown in Table 3.\nTable 3 shows the dyschezia scores from 9 studies used in \nthe meta‑analysis of the effectiveness of dienogest therapy \nversus contraceptive pills in cases of postoperative nometriosis \nimplants. There are 7 studies (Antonio Maiorana 2022, \nBilgehanSaglikGokmen 2023, Cihan Kaya 2021, Gelareh \nNiakan 2021 Purwanto 2021, TolgaKaracan 2020, and Yutaka \nOsuga 2017) with dyschezia scores in the dienogest group \nthat were lower than those in the COCP group. Meanwhile, \nin 2 other articles (Lina El Taha 2021 and Ticiana A. A. Miraa \n2021), the dyschezia score for the dienogest group was higher \nthan the COCP group.\nMeta‑analysis was carried out with a random effect model \nbecause the data are heterogeneous (Q = 41,278; df = 8; \nI2 = 80,619). Based on the data, it is known that 7 studies \nshow that the difference in dyschezia scores between the \ndienogest group and the COCP group is significant, except \nfor 2 articles (Cihan Kaya 2021 and Lina El Taha 2021) \nbecause the 95% confidence interval range covers the number \n1. Overall, the dyschezia score in the dienogest group was \nsignificantly lower than the COCP group with a mean \ndifference of −0.314 ± 0.089 (P < 0.001).\nTable 2: Dysmenorrhea Score in the Dienogest group and combined oral contraceptive group\nStudy name Dienogest COCP Difference\nMean±SD n Mean±SD n Mean±SD\nAntonio Maiorana 2022 6,24±4,23 128 8,3±2,53 128 ‑2,0±0,44\nBilgehan Saglik Gokmen 2023 3,8±2,70 200 6,9±19,12 200 ‑3,1±1,37\nCihan Kaya 2021 4,9±4,10 171 6,7±3,30 171 ‑1,8±0,40\nGelareh Niakan 2021 4,8±0,80 115 4,5±1,20 115 +0,3±0,13\nLina El Taha 2021 5,5±3,10 127 6,1±3,40 127 ‑0,6±0,41\nPurwanto 2021 4,6±0,80 204 4,9±0,80 204 ‑0,3±0,08\nTiciana A.A. Miraa 2021 1,8±x2,95 126 1,9±0,86 126 ‑0,2±0,27\nTolga Karacan 2020 9,0±3,90 154 6,0±1,70 154 +3,0±0,34\nYutaka Osuga 2017 5,9±1,70 138 4,4±1,10 138 +1,5±0,17\nTable 3: Dyschezia score in Dienogest group and combined oral contraceptive group\nStudy name Dienogest COCP Difference\nMean±SD n Mean±SD n Mean±SD\nAntonio Maiorana 2022 2,9±4,09 128 3,8±4,02 128 ‑0,9±0,51\nBilgehan Saglik Gokmen 2023 3,7±3,10 200 4,4±1,30 200 ‑0,7±0,24\nCihan Kaya 2021 1,1±2,80 171 1,3±2,20 171 ‑0,2±0,27\nGelareh Niakan 2021 7,0±3,0 115 10±3,30 115 ‑3,0±0,42\nLina El Taha 2021 3,8±3,50 127 3,4±3,70 127 0,4±0,45\nPurwanto 2021 4,6±0,80 204 4,9±0,80 204 ‑0,3±0,08\nTiciana A.A. Miraa 2021 4,8±4,09 126 3,7±3,98 126 1,1±0,51\nTolga Karacan 2020 5,0±2,10 154 5,0±1,30 154 ‑0,0±0,20\nYutaka Osuga 2017 4,5±2,80 138 5,9±20,00 138 ‑1,4±0,29\nTable 4: Dyspareunia Score in the Dienogest group with the combined oral contraceptive group is shown in table 4\nStudy name Dienogest COCP Difference\nMean±SD n Mean±SD n Mean±SD\nAntonio Maiorana 2022 6,0±3,89 128 5,8±3,87 128 +0,2±0,49\nBilgehan Saglik Gokmen 2023 3,4±1,80 200 5,2±3,80 200 ‑1,8±0,30\nCihan Kaya 2021 1,8±3,00 171 0,4±1,30 171 +1,4±0,25\nGelareh Niakan 2021 6,0±2,20 115 7,0±2,50 115 ‑1,0±0,31\nLina El Taha 2021 6,1±2,20 127 5,9±2,90 127 +0,2±0,32\nPurwanto 2021 4,9±0,80 204 4,9±0,80 204 0,0±0,08\nTiciana A.A. Miraa 2021 1,8±2,95 126 1,3±2,77 126 +0,5±0,36\nTolga Karacan 2020 5,0±1,60 154 7,0±1,84 154 ‑2,0±0,20\nYutaka Osuga 2017 3,4±2,80 138 4,5±2,90 138 ‑1,1±0,34\n1\n4\n4\n4\nPage 8 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 8 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n6\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nDyspareunia score\nA comparison of the dyspareunia score in the dienogest \ngroup with the combined oral contraceptive group is shown \nin Table 4.\nTable 4 shows the dyspareunia score from 9 studies used in the \nmeta‑analysis of the effectiveness of dienogest therapy versus \ncontraceptive pills in cases of postoperative endometriosis \nimplants. There are 6 studies (Bilgehan Saglik Gokmen 2023, \n2021, GelarehNiakan 2021, Purwanto 2021, TolgaKaracan \n2020, and Yutaka Osuga 2017) of dyspareunia, in which \nthe dienogest group’s score is lower than that of the COCP \ngroup. Meanwhile, in 3 other articles (Antonio Maiorana \n2022, Cihan Kaya and Lina El Taha 2021), the dyspareunia \nscore for the dienogest group is higher than the COCP group.\nThe results of the meta‑analysis comparing dyspareunia \nscores in the dienogest group with the COCP group are \nshown here, it is found that the meta‑analysis is carried \nout with a random effect model because the data are \nheterogeneous (Q = 79.295; df = 8; I2 = 89.991). Based on \nthe data, it is known that 6 articles show that the difference \nin dyspareunia scores between the dienogest group and the \nCOCP group is significant, except for 3 articles (Antonio \nMaiorana 2022, Lina El Taha 2021 and Ticiana A. A. Miraa \n2021) because the 95% confidence interval range covers the \nnumber 1. Overall, the dyspareunia score in the dienogest \ngroup is significantly lower than in the COCP group with a \nmean difference of‑0.384 ± 0.045 ( P < 0.001).\nBased on the results of the meta‑analysis, it can be seen that \nthe dysmenorrhea, dyschezia, and dyspareunia scores in the \ndienogest group are significantly lower than those in the \nCOCP group.\nRisk of publication bias\nIn the funnel plot, in Figure 2, it can be seen that the data are \nnot symmetrical due to the research with the results providing \na larger size of effect than other studies, but the results of \nthe analysis using the Egger regression test show results that \nare not significant. This proves that there is no potential for \npublication bias ( t = 1.111; df = 7.00;  P = 0.303).\nQuality of evidence\nThe quality of evidence from the meta‑analysis of the \neffectiveness of dienogest therapy against contraceptive \npills in cases of post‑surgical endometriosis implants is all \nmoderate.\ndIscussIon\nDue to the negative impacts caused by endometriosis \nsurgery in the form of ovarium damage and the decrease of \nfertility level, continuous medical treatment is mandatory \nas postsurgical supporting therapy to prevent recurrence \nand chronic pelvic pain. Combined contraceptive pills, \nsuch as medroxyprogesterone acetate or norethisterone, \nare used as the medical treatment and known as long‑term \nendometriosis treatment, which is cheap, effective, and can be \nwell‑tolerated.[17,19‑21] Another study compares the dienogest \nand the progestin norethindrone acetate (NETA) derivative \n19‑nortestosterone in women with endometriosis and it is \nfound as a statistically significant difference in reducing the \nmean of dysmenorrhea scores favoring the dienogest group. \nHence, there is no significant improvement in quality‑of‑life \nscores or sexual function scores. [3,8]\nThe results from those 9 studies have evaluated long‑term use \nof dienogest up to 52–53 weeks and reported that dienogest \nclinically improves pelvic pain in patients with previous \nlaparoscopy surgery‑related symptoms with a reduction in \nV AS scores but most patients suffer for abnormal menstrual \nbleeding as a side effect for dienogest.\nIn 6 studies conducted by Antonio Maiorana 2022, Bilgehan \nSaglik Gokmen 2023, Cihan Kaya 2021, Lina El Taha \n2021, Purwanto 2021, and Ticiana A. A. Miraa 2021 on \nthe therapeutic effect and the safety of dienogest 2 mg/day \nintake evaluated in 956 women using endometriosis‑related \nV AS scores, it can be concluded that the decrease in the \nmean of V AS score is well tolerated with few side effects \nin favor of dienogest over combined contraceptive pills \nafter 24 weeks of treatment. Overall, from the results of \nthe study population and comparing them with 96 previous \nliteratures, we observe significant differences in pain‑related \nsymptom scores of DIEin patients who revived dienogest \nthan the COCP. And also, there is a significant difference \nin pain reduction in dysmenorrhea, dyspareunia, dyschezia, \nand pelvic pain scores in the dienogest group than the \nCOCP group due to the effect of dienogest that reduce the \nsecretion of inflammatory cytokines or reduce endometrial \nfoci by suppressing the ovulation hormone despite the risk \nof abnormality. [6,15,17]\nFigure 2: Funnel plot diagram to assess publication bias in meta‑analysis \nof the effectiveness of dienogest therapy versus contraceptive pills in \npost‑surgical cases of susuka endometriosis\n1\n1\nPage 9 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 9 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n7\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nEndometriosis is an estrogen‑dependent disease known to \nbe effective in controlling the symptoms of endometriosis \npatients, especially chronic pelvic pain symptoms. There \nare several hormonal drug options, such as GnRH agonists, \nlow‑dose oral contraceptives, and levonorgestrel intrauterine \nsystems, but there are limitations to the duration of GnRH \nagonist treatment due to adverse effects associated with low \nestrogen symptoms.[21,22] Low‑dose oral contraceptives should \nbe administered with caution in patients aged 40 years or \nolder due to the risk of thrombosis, and the levonorgestrel \nintrauterine system has abnormal bleeding problems, and the \nrisk of pelvic inflammatory disease. [23‑25] Dienogest proved \nthat it improves pain relief in patients with endometriosis, \nespecially for patients seeking fertility preservation, across \na wide range of ages, and demonstrated safety assuming \nthat appropriate consideration is given to irregular uterine \nbleeding and anemia. [26‑29] However, the results of this study \nare limited to 16 weeks of treatment, and data regarding \nlonger treatment periods are needed. [17,19,24,27,29]\nconclusIon\nThese nine studies emphasize that dienogest is an effective \ntreatment for pain symptoms caused by adenomyosis under \ndouble‑blind, placebo‑controlled conditions. Due to reports \nof the risk of irregular heavy uterine bleeding and anemia \nassociated with dienogest, endometriosis patients with \nsevere uterine enlargement and severe anemia are excluded \nfrom the study. These 9 studies also show that dienogest is \nwell tolerated despite a high incidence of irregular genital \nbleeding. Dienogest is effective for the subgroup of patients \nwith endometriosis and pelvic pain and is well tolerated \nas a symptomatic treatment of pain in DE patients, not \naccompanied by complications of severe uterine enlargement \nor severe anemia.\nAcknowledgments\nThe authors thank all who support this systematic review \nand meta‑analysis.\nAuthor contributions\nConceptualization, methodology, writing original draft \npreparation, review, and editing by IA, NS, ST, and BR. \nData validation and analysis by IA. All authors have read \nand agreed to the final version of the manuscript.\nData availability statement\nAll data generated or analyzed during this study are included \nin this published article.\nFinancial support and sponsorship\nNil.\nConflicts of interest\nThere are no conflicts of interest.\nreferences\n1. Khan S, Lee CL. Treating deep endometriosis in infertile patients \nbefore assisted reproductive technology. Gynecol Minim Invasive Ther \n2021;10:197‑202.\n2. Lee CL, Khoo BP, Huang KG. From radical hysterectomy to radical \nsurgery for deep endometriosis. Gynecol Minim Invasive Ther \n2023;12:1‑3.\n3. Yang L, Bu G, Zhao J, La X, Ma C. Comparison of 3D and \n2D laparoscopy: Initial experience of perioperative outcomes \nand clinical assessment. J Gynecol Obstet Hum Reprod \n2024;53:102754.\n4. Potapov O, Kosiukhno S, Kalashnikov O, Marino MV , Todurov I, \nKomorowski AL. Comparison of 2D versus 3D in the basic single \nincision laparoscopy training. A  randomized controlled trial. \nChirurgia (Bucur) 2022;117:69‑80.\n5. Zhan S, Zhu Z, Yu H, Xia Y , Zhu Y , Wu F, et al . Comparison of \ntherapeutic effects between conventional 2D laparoscopy and 3D \nlaparoscopy in the treatment of colorectal cancer: A  systematic review \nand meta‑analysis. Am Surg 2024;90:3102‑12.\n6. Zhao B, Lv W, Mei D, Luo R, Bao S, Huang B, et al. Comparison of \nshort‑term surgical outcome between 3D and 2D laparoscopy surgery \nfor gastrointestinal cancer: A  systematic review and meta‑analysis. \nLangenbecks Arch Surg 2020;405:1‑12.\n7. Lee CL, Desai T, Huang KG. The role of three‑dimensional laparoscopy \nin gynecology: Time to revise our perspective? Gynecol Minim Invasive \nTher 2024;13:1‑3.\n8. International Working Group of AAGL, ESGE, ESHRE and WES, \nTomassetti C, Johnson NP, Petrozza J, Abrao MS, Einarsson JI, et al. An \ninternational terminology for endometriosis, 2021. Hum Reprod Open \n2021;2021:hoab029.\n9. Harada T, Taniguchi F, Guo SW, Choi YM, Biberoglu KO, Tsai SS, \net al. The Asian society of endometriosis and adenomyosis guidelines \nfor managing adenomyosis. Reprod Med Biol 2023;22:e12535.\n10. Mangeshikar A, Youssef Y , Sheth H, Mangeshikar P, Moawad G. \nTransvaginal natural orifice specimen extraction: A  10‑step approach \nfor laparoscopic excision of deep endometriosis infiltrating the \nrectosigmoid. Gynecol Minim Invasive Ther 2024;13:62‑3.\n11. Kim SE, Lim HH, Lee DY , Choi D. The long‑term effect of dienogest on \nbone mineral density after surgical treatment of endometrioma. Reprod \nSci 2021;28:1556‑62.\n12. Niakan G, Rokhgireh S, Ebrahimpour M, Mehdizadeh Kashi A. \nComparing the effect of dienogest and OCPS on pain and quality \nof life in women with endometriosis: A  randomized, double‑blind, \nplacebo‑controlled trial. Arch Iran Med 2021;24:670‑7.\n13. Angioni S, Cofelice V , Pontis A, Tinelli R, Socolov R. New trends \nof progestins treatment of endometriosis. Gynecol Endocrinol \n2014;30:769‑73.\n14. Lee DY , Park HG, Yoon BK, Choi D. Effects of different \nadd‑back regimens on hypoestrogenic problems by postoperative \ngonadotropin‑releasing hormone agonist treatment in endometriosis. \nObstet Gynecol Sci 2016;59:32‑8.\n15. Saglik Gokmen B, Topbas Selcuki NF, Aydın A, Yalcin Bahat P, Akça A. \nEffects of dienogest therapy on endometriosis‑related dysmenorrhea, \ndyspareunia, and endometrioma size. Cureus 2023;15:e34162.\n16. Caruso S, Iraci M, Cianci S, Vitale SG, Fava V , Cianci A. Effects of \nlong‑term treatment with Dienogest on the quality of life and sexual \nfunction of women affected by endometriosis‑associated pelvic pain. \nJ Pain Res 2019;12:2371‑8.\n17. Hudelist G, Pashkunova D, Darici E, Rath A, Mitrowitz J, Dauser B,  \net al. Pain, gastrointestinal function and fertility outcomes of modified \nnerve‑vessel sparing segmental and full thickness discoid resection for \ndeep colorectal endometriosis – A prospective cohort study. Acta Obstet \nGynecol Scand 2023;102:1347‑58.\n18. Mehdizadeh Kashi A, Niakan G, Ebrahimpour M, Allahqoli L, \nHassanlouei B, Gitas G, et al. A  randomized, double‑blind, \nplacebo‑controlled pilot study of the comparative effects of dienogest \nand the combined oral contraceptive pill in women with endometriosis. \nInt J Gynaecol Obstet 2022;156:124‑32.\n19. Mabrouk M, Paradisi R, Arena A, Del Forno S, Matteucci C, Zannoni \n3\n7\n10\nPage 10 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 10 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\n\n\nSusianto, et al.: Dienogest therapy against the COCP in DIE\n8\nGynecology and Minimally Invasive Therapy ¦ Month 2025 ¦ V olume XX ¦ Issue XX\nL, et al . Short‑term histopathological effects of dienogest therapy on \novarian endometriomas: In vivo , nonrandomized, controlled trial. \nGynecol Endocrinol 2018;34:399 403.\n20. Osuga Y , Hayashi K, Kanda S. Evaluation of the efficacy, safety, \nand clinically recommended dose of dienogest in the treatment of \nprimary dysmenorrhea: A  randomized, double‑blind, multicenter, \nplacebo‑controlled study. Fertil Steril 2020;113:167‑75.\n21. Bellelis P, Dias JA Jr., Podgaec S, Gonzales M, Baracat EC, Abrão MS. \nEpidemiological and clinical aspects of pelvic endometriosis – A case \nseries. Rev Assoc Med Bras (1992) 2010;56:467‑71.\n22. Riviello C, Cozzolino M, Pavone D. Regression of a large \nendometrioma after treatment with dienogest. JFIV Reprod Med \nGenet 2016;4:168‑9.\n23. The American College of Obstetricians and Gynecologists. Management \nof endometriosis. Obstet Gynecol Bull 2010;116:223‑36.\n24. Ek M, Roth B, Ekström P, Valentin L, Bengtsson M, Ohlsson B. Gastrointestinal \nsymptoms among endometriosis patients – A case‑cohort study. BMC \nWomens Health 2015;15:59.\n25. Ferrero S, Remorgida V , Venturini PL, Bizzarri N. Endometriosis: The \neffects of dienogest. BMJ Clin Evid 2015;06‑802.\n26. Tsai HW, Wang PH, Huang BS, Twu NF, Yen MS, Chen YJ. Low‑dose \nadd‑back therapy during postoperative GnRH agonist treatment. Taiwan \nJ Obstet Gynecol 2016;55:55‑9.\n27. Vercellini P, Somigliana E, Consonni D, Frattaruolo MP, De Giorgi O, \nFedele L. Surgical versus medical treatment for endometriosis‑associated \nsevere deep dyspareunia: I. Effect on pain during intercourse and patient \nsatisfaction. Hum Reprod 2012;27:3450‑9.\n28. Agarwal S, Fraser MA, Chen I, Singh SS. Dienogest for the treatment \nof deep endometriosis: Case report and literature review. J Obstet \nGynaecol Res 2015;41:309‑13.\n29. Lang J, Yu Q, Zhang S, Li H, Gude K, von Ludwig C, et al. Dienogest \nfor treatment of endometriosis in Chinese Women: A placebo‑controlled, \nrandomized, double‑blind phase 3 study. J Womens Health (Larchmt) \n2018;27:148‑55.\nPage 11 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654\nPage 11 of 11 - Integrity Submission\nSubmission ID\ntrn:oid:::28973:145533654","source_license":"CC0","license_restricted":false}