{"paper_id":"b5e0c32e-761c-4b8e-90a0-9c16a7f63d85","body_text":"Pharmacological Treatment for Symptomatic\nAdenomyosis: A Systematic Review\nTratamento farmacológico para adenomiose\nsintomática: revisão sistemática\nCristina Laguna Benetti-Pinto 1 Ticiana Aparecida Alves de Mira 1 Daniela Angerame Yela 1\nCassia Raquel Teatin-Juliato 1 Luiz Gustavo Oliveira Brito 1\n1 Department of Obstetrics and Gynecology, School of Medical\nSciences, Universidade Estadual de Campinas, Campinas, SP , Brazil\nRev Bras Ginecol Obstet 2019;41:564 –574.\nAddress for correspondence Cristina Laguna Benetti-Pinto, MD, PhD,\nAlexander Fleming, 101, 13083-881, Cidade Universitária,\nCampinas, SP, Brazil (e-mail: laguna.unicamp@gmail.com).\nKeywords\n► adenomyosis\n► abnormal menstrual\nbleeding\n► pelvic pain\n► systematic review\n► medical treatment\nAbstract Objective To assess the ef ficacy of non-surgical treatment for adenomyosis.\nData Sources A search was performed by two authors in the Pubmed, Scopus, and\nScielo databases and in the grey literature from inception to March 2018, with no\nlanguage restriction.\nSelection of Studies We have included prospective randomized studies for treating\nsymptomatic women with adenomyosis (abnormal uterine bleeding and/or pelvic pain)\ndiagnosed by ultrasound or magnetic resonance imaging.\nData Collection Studies were primarily selected by title and abstract. The articles that\nwere eligible for inclusion were evaluated in their entirety, and their data was extracted\nfor further processing and analysis.\nData Synthesis From 567 retrieved records only 5 remained for analysis. The intervention\ngroups were: levonorgestrel intrauterine system (LNG-IUS)(n ¼ 2), dienogest (n ¼ 2), and\nletrozole (n ¼ 1). Levonorgestrel intrauterine system was effective to control bleeding\nwhen compared to hysterectomy or combined oral contraceptives (COCs). One study\nassessed chronic pelvic pain and reported that LNG-IUS was superior to COC to reduce\nsymptoms. Regarding dienogest, it was efficient to reduce pelvic pain when compared to\nplacebo or goserelin, but less effective to control bleeding than gonadotropin-releasing\nhormone (GnRH) analog. Letrozole was as efficient as GnRH analog to relieve dysmenorrhea\nand dyspareunia, but not for chronic pelvic pain. Reduction of uterine volume was seen with\naromatase inhibitors, GnRH analog, and LGN-IUD.\nConclusion Levonorgestrel intrauterine system and dienogest have signi ficantly\nimproved the control of bleeding and pelvic pain, respectively, in women with\nadenomyosis. However, there is insuf ficient data from the retrieved studies to endorse\neach medication for this disease. Further randomized control tests (RCTs) are needed to\naddress pharmacological treatment of adenomyosis.\nCristina Laguna Benetti-Pinto ’s ORCID is https://orcid.org/0000-\n0001-6198-5593.\nreceived\nMarch 12, 2019\naccepted\nJune 24, 2019\nDOI https://doi.org/\n10.1055/s-0039-1695737.\nISSN 0100-7203.\nCopyright © 2019 by Thieme Revinter\nPublicações Ltda, Rio de Janeiro, Brazil\nReview Article\nTHIEME\n564\nPublished online: 2019-09-23\n\nIntroduction\nAdenomyosis is a benign disorder in which basal endometrial\nglands and stroma are found in the myometrium with reactive\nhyperplasia of the surrounding smooth muscle myometrial\ncells.1–5 It is a complex, gynecological condition with unknown\nincidence and etiology. Clinical symptoms are related to pain\nand bleeding, and they include dysmenorrhea, abnormal\nuterine bleeding, chronic pelvic pain (CPP), dyspareunia, and\ninfertility; however, a third of women can be asymptomatic.\n6\nSymptoms typically are reported to develop between the ages\nof 40 and 50 years; however, this may reflect the fact that the\nusual moment for diagnosing adenomyosis has been after\nperforming a hysterectomy because of preoperative difficulty\nto establish the diagnosis. With improvement of diagnostic\nmethods, like magnetic resonance imaging (MRI) and high-\nquality transvaginal ultrasound (TVUS), early diagnosis can be\nmade with an accuracy of 80 to 90%.\n7–11\nNon-surgical treatment can be necessary or desirable for\nwomen who want to maintain the uterus for a future pregnan-\ncy, those with other comorbidities that pose a higher risk for\nsurgery, or even those who are close to menopause and would\nnot like to undergo a surgical procedure. There are systematic\nreviews about uterine artery embolization, fertility-sparing\ntreatment in patients with infertility, and local excision of\nadenomyosis.\n12–14 A published review about medical treat-\nment for adenomyosis has presented their data narratively,\nsince the author states that the aim was to discuss the medical\napproach to the management of adenomyosis symptoms, with\nno analysis of the risk of bias and methodological quality.\n15\nGiven the need for systematic reviews and quality assessment\nfor analyzing these data, we sought to perform a systematic\nreview of the effectiveness of non-surgical treatment for\nadenomyosis on uterine volume, pelvic pain, and menstrual\nbleeding, when compared with other surgical and non-surgical\ninterventions.\nMethods\nStudy Design, Data Search, Inclusion/Exclusion\nCriteria\nThe present review was recorded in the International Pro-\nspective Register of Systematic Reviews (PROSPERO)16 under\nthe number CRD42017057896 and was developed according\nto Preferred Reporting Items for Systematic Reviews and\nMeta-Analyses (PRISMA).\n17\nSearches in the databases included articles from the\nfollowing sources: Pubmed, Scopus, Scielo, and the grey\nResumo Objetivo: Avaliar a e ficácia de tratamento não cirúrgico para adenomiose.\nFontes de dados: U m ap e s q u i s af o ir e a l i z a d ap o rd o i sa u t o r e sn a sb a s e sd ed a d o s\nPubmed, Scopus, Scielo e na literatura cinzenta desde o início de cada base de dados\naté março de 2018, sem restrição de idioma.\nSeleção de estudos: Incluímos estudos prospectivos randomizados para tratamento\nde mulheres sintomáticas com adenomiose (sangramento uterino anormal e/ou dor\npélvica) diagnosticadas por ultrassonogra fia ou ressonância magnética.\nColeta de dados: Os estudos foram selecionados principalmente por título e resumo.\nOs artigos que preencheram os critérios de inclusão foram avaliados na íntegra, e seus\ndados foram extraídos para posterior processamento e análise.\nSíntese dos dados: De 567 registros recuperados, somente 5 permaneceram para\nanálise. Os grupos de intervenção foram: sistema intrauterino de levonorgestrel (SIU-LNG)\n(n ¼ 2), dienogest (n ¼ 2), e letrozol (n ¼ 1). O SIU-LNG foi efetivo no controle do\nsangramento quando comparado à histerectomia ou aos contraceptivos orais combinados\n(COCs). Um estudo avaliou a dor pélvica crônica e relatou que o SIU-LNG foi superior ao COC\npara reduzir os sintomas. Em relação ao dienogest, este foi eficiente em reduzir a dor pélvica\nquando comparado ao placebo ou à goserelina, mas foi menos e ficaz no controle do\nsangramento do que o análogo do hormônio liberador de gonadotropina (GnRH). O\nletrozol foi tão e ficiente quanto o análogo do GnRH para aliviar a dismenorreia e a\ndispareunia, mas não para a dor pélvica crônica. Redução do volume uterino foi observada\ncom inibidores de aromatase, análogo de GnRH, e SIU-LNG.\nConclusão: O SIU-LNG e dienogest apresentaram bons resultados para o controle de\nsangramento e dor pélvica, respectivamente, em mulheres com adenomiose. No\nentanto, não há dados su ficientes para endossar cada medicação para tratar essa\ndoença. Futuros estudos randomizados s ão necessários para avaliar o tratamento\nfarmacológico da adenomiose.\nPalavras-chave\n► adenomiose\n► sangramento\nmenstrual anormal\n► dor pélvica\n► revisão sistemática\n► tratamento médico\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al. 565\n\n\nliterature. Two authors (L. G. O. B. and T. A. A. M.) performed a\ndistinct search using the following strategic combination of\nkeywords: ( “medical treatment ” OR “clinical treatment ” OR\n“hormone treatment ” OR goserelin OR leuprolide OR GnRH OR\n“GnRH analog ” OR “GnRH antagonist ” OR progesterone OR\nDienogest OR desogestrel OR COC OR “oral contracept ” OR\n“non-surgical treatment ” OR levonorgestrel OR drug OR\nmedroxyprogesterone OR mifepristone OR sprm OR ulipristal\nOR progestin OR “combined oral contraceptive ” OR aromatase\nOR letrozole OR anastrozole (adenomyosis)) NOT (animals OR\nchildren). All articles inserted in these databases were in-\ncluded up to March 2018.\nWe have included in this review prospective randomized\nand non-randomized studies with symptomatic women with\nimage diagnosis (ultrasound [US] or MRI) suggestive of adeno-\nmyosis who were submitted to medical treatment versus any\nother comparator group. The main symptoms were: abnormal\nuterine bleeding, pain and/or changes in uterine volume.\nThere were no restrictions regarding the language. We have\nexcluded studies with no control group, with cross-sectional\nor case-control designs, case series, or retrospective studies.\nPrimary and Secondary Outcomes\nOur primary outcomes were: menstrual bleeding through\nany kind of measurements, like hemoglobin (Hb) by labora-\ntory test or number of pads/days by the number of protector\nchanges per day according to women ’s report; pelvic pain\nthrough the visual analogue scale (VAS); and reduction of\nuterine volume measured in milliliters or cubic centimeters\nby TVUS or MRI.\nQuality of life was the secondary outcome, which was\nmeasured by questionnaires such as the World Health Orga-\nnization Quality of Life (WHOQOL) short version or the\nMedical Outcomes Study (MOS).\nStudies were primarily selected by title and abstract by\nthe same authors that conducted the searches. Thus, articles\nthat presented the eligibility criteria were evaluated in their\nentirety, and their data was extracted for further processing\nand analysis. Possible disagreements were discussed with a\nthird author (C. L. B. P.) to obtain a consensus. The reviewers\nsought data that were not possible to obtain after reading the\nmanuscript after an e-mail sent to the authors.\nStatistical analysis\nWe tabulated mean difference (MD) and their standard\ndeviations (SDs) between pre and posttreatments and their\nconfidence intervals from continuous variables. In order to\nbuild forest plots, a mathematical calculation of error prop-\nagation was used, according to the author,\n18 to identify the\nSDs not described in some of the studies included in the\npresent review after unanswered contact with the authors,\nonce the publication did not mention these data. It was not\npossible to conduct a meta-analysis by the differences of the\nstudies heterogeneity of the studies regarding the proposed\ntreatments, because each study assessed a different treat-\nment with or without a different comparator, and a single\npaired comparison was not present in more than one study.\nAs the number of studies was scant, an indirect meta-\nanalysis was not considered either. Funnel plots (publication\nbias) were not elaborated due to the scant number of\nretrieved studies. The risk of bias in the studies was assessed\nusing the Cochrane bias risk assessment tool,\n19 which clas-\nsifies studies at risk of low, high, or unclear bias. The Grading\nof Recommendations Assessment, Development and Evalua-\ntion (GRADE) criteria 20 were used to build a summary of\nfindings (SOF) table to evaluate the quality of the evidence.\nResults\nStudy Selection and Characteristics\n►Figure 1 describes the flowchart regarding the studies that\ncomprise the present review. From 567 records that were\nretrieved in this search, 5 were removed due to duplication,\n562 were screened, and 11 were fully assessed for eligibility,\nbut only 5 remained in the final model.\n►Table 1 displays all\nselected studies that comprised 288 women; a total of 267\nwomen completed the treatment and were included in the\nfinal results. No studies have mentioned whether their\nresults were interpreted by intention-to-treat or per proto-\ncol analysis.\nIn summary, three from thefive studies were held in Egypt,\nfour presented a randomized controlled design,21–25 and one\nwas prospective, non-randomized.24 One study was placebo-\ncontrolled,25 and the others were pharmacological treatments\nversus surgery or other drugs for adenomyosis. Transvaginal\nultrasound diagnosis was present in all studies, and MRI was\nadded as an option toTVUS in two studies.21–24 The duration of\ntreatment varied from 4 weeks to 12 months. The intervention\nx comparator groups were: levonorgestrel intrauterine system\n(LNG-IUS) versus hysterectomy21; LNG-IUS versus combined\noral contraceptive (COC) 23; letrozole versus goserelin 22;\ndienogest versus triptorelin 24; dienogest versus placebo. 25\nSome side effects of using pharmacological treatment were\nmentioned in all studies except one.\n24 ►Figure 2 condenses all\nforest plots from the analyzed outcomes. From our planned\nprimary outcomes, almost all of them (4 of 5) were present.\nTreatment with LNG-IUS\nTwo studies have assessed the use of LNG-IUS 21,23 versus\nhysterectomy or combined oral contraceptive (COC), respec -\ntively. In the first study, the LNG-IUS was effective to control\nbleeding, with an improvement of hemoglobin levels, and\nreduction in the number of days with bleeding. In the second\nstudy, a reduction in the number of days with bleeding was\nobserved. Compared to the other medical treatment using COC,\nthe bleeding pattern was improved in both arms; in the case of\nLNG-IUS, the mean number of bleeding days per month\ndecreased from 9.81 /C6 1.82 days before recruitment to\n2.63 /C6 2.13 days after the 6\nth m o n t ho fi n s e r t i o n(p < 0.001).\nIn the COCs group, the number of bleeding days per month\nreduced from 9.97 /C6 1.52 days to 5.52 /C6 1.00 days (p < 0.001).\nPelvic pain was assessed in one study,\n23 and the LNG-IUS\nwas more efficient in the improvement of chronic pelvic pain\nthan COC (6.23 /C6 0.67–1.68 /C6 1.25 - p < 0 . 0 0 1 ) ,a sw e l la st h e\nreduction in uterine volume (10.23/C6 1.06 mL–7.63 /C6 0.49 mL,\np < 0.001).\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al.566\n\n\nOnly one study assessed improvement of quality of life, 21\nwith superior effects on psychological and social life with\nLNG-IUS when compared to hysterectomy. Women that used\nLNG-IUS presented adverse effects: headache (11.9%), breast\ntenderness (7.1%), acne (4.8%), and transient depressive\nepisode (2.4%).\nTreatment with an Aromatase Inhibitor (Letrozole)\nOnly one study 22 evaluated letrozole in the treatment of\nadenomyosis compared to the GnRH analog goserelin. Letro-\nzole was as ef ficient as goserelin to relieve dysmenorrhea\n(p ¼ 0.48) and dyspareunia ( p ¼ 0.70), but the CPP control\nwas statistically higher with goserelin ( p ¼ 0.04). Regarding\nthe control of bleeding and the reduction of uterine volume,\nboth medications presented similar response, but more side\neffects (hot flushes) were reported with goserelin (81.3%).\nTreatment with Gonadotropin-releasing Hormone\nAgonist (GnRH Analog: Goserelin or Triptorelin\nAcetate)\nTwo studies evaluated the use of GnRH analog: one compared\nto an aromatase inhibitor (goserelin X letrozole), 22 and the\nother compared to dienogest (triptorelin X dienogest). 24\nThe GnRH analog was more ef ficient than the aromatase\ninhibitor in controlling CPP ( p ¼ 0.04), but they were equally\nefficient in the control of dysmenorrhea and dyspareunia.\nWhen compared to dienogest, the GnRH analog was more\nefficient in controlling dysmenorrhea at 16 weeks (30.6/C6 18.4\nversus 0.0, p < 0.0001) but equally ef ficient at reducing dys-\npareunia and CPP . Regarding bleeding control, the GnRH\nanalog did not present a statistical difference when compared\nto letrozole; conversely, it was superior to dienogest. Finally,\nregarding the reduction of uterine volume, the GnRH analog\nand aromatase inhibitor were equivalents;\n18 however, when\ncompared with dienogest, the GnRH analog was more ef fi-\ncient.21 One study evaluated side effects, having reported hot\nflushes in 81.3% of women treated with GnRH analog. 22\nTreatment with dienogest\nTwo studies evaluated dienogest; one compared to GnRH\nanalog (triptorelin) 24 and the other compared to placebo. 25\nDienogest was ef ficient in both studies to reduce pain\ncomplaints (dysmenorrhea, dyspareunia, and CPP). When\ndienogest was compared to the GnRH analog (triptorelin),\nboth were similar to control dyspareunia (20.7 /C6 16.5 versus\n25.8 /C6 19.1, p ¼ 0.3899) and CPP (21.7 /C6 11.6 versus 24.5 /C6\n13.8, p-value ¼ 0.5076). There was a signi ficant difference in\nthe posttreatment dysmenorrhea between dienogest and\ntriptorelin at 16 weeks, when the GnRH analog presented\na better result (30.6 /C6 18.4 versus 0.0, p < 0.0001).\nFig. 1 Flow diagram describing the search and study inclusion processes.\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al. 567\n\n\nTable 1 Characteristics of the included prospective studies\nAuthor,\nYear\nCountry Study aim Diagnosis Sample Study\ndesign\nTreatment Follow-up Evaluation\nmethod\nPain -\nresults\nBleeding\nloss -\nresults\nUterine\nvolume -\nresults\nQuality of\nlife\nOther\nresults\nSide\neffects\nOzdegirmenci\net al (2011)\n21\nTurkey To compare\nLNG-IUS\nversus hys-\nterectomy\nUS and\nMRI\ncriteria\nN ¼ 86; 43 in\neach group\nProspective\nrandomized\nclinical trial\n(do not\nregister)\nLNG- IUS\n(final partici-\npants,\nn ¼ 43);\nHysterecto-\nmy ( final\nparticipants\nn ¼ 32)\n6a n d\n12 months\n1. Menstrual\nbleeding\n(number of\npads/day\nand hemo-\nglobin\nlevels)\n2. Quality of\nlife\n(WHOQOL-\nbrief)\nDid not\nassess\nLNG-IUS\nincreased\nthe Hb levels\nto compara-\nble levels\nwith hyster-\nectomy\nDid not\nassess\nBoth\ntreatments\nhave\nimproved\nhealth-\nrelated\nquality of\nlife, but\nLNG-IUS had\nas u p e r i o r\neffect on\npsychologi-\ncal and social\nlife\nLNG-IUS:\nheadache\n(11.9%),\nbreast\ntenderness\n(7.1%), acne\n(4.8%), a\ntransient\ndepressive\nepisode\n(2.4%).\nHysterecto-\nmies: 1\n(3.1%) post-\noperative\ninfection\nBadawy et al\n(2012)\n22\nEgypt To compare\naromatase\ninhibitor\n(Letrozole\n2.5 mg/d)\nversus GnRH\nanalog\n(goserelin\n3.6 mg)\nUS\ncriteria\nN ¼ 32 Prospective\nrandomized,\nnon-blind\ncontrolled\nclinical trial\n(retrospec-\ntively\nregistered)\nLetrozole\n2.5mg/d\n(final partici-\npants n ¼ 15)\nGoserelin\n3.6mg/\nmonth ( final\nparticipants\nn ¼ 16)\n4, 8, and\n12 weeks\n1. Pain\nPelvic\npain, dys-\nmenor-\nrhea, dys-\npareunia\n(VAS)\n2. Menstrual\nbleeding\nand sub-\nfertility\n(question-\nnaire, but\nit is not\nclear)\n3. Uterine\nvolume\n(TVUS)\nGoserelin\nwas more\neffective in\nrelieving\nchronic\npelvic pain\n(p ¼ 0.04)\nGoserelin\nwas so\nefficient\nthan\nletrozole in\nrelieving\nmenorrhagia\nand metror-\nrhagia\nReduction in\nuterine\nvolumes,\nwithout\ndifference\nbetween the\ntwo groups\nHot flashes\n(0% with\nletrozole,\n81,3% with\ngoserelin),\nPregnancy\n(n ¼ 2w i t h\nletrozole)\nShaaban et al\n(2015)\n23\nEgypt To compare\nLNG-IUS\nversus COC\nUS\ncriteria\nN ¼ 62; 31 in\neach group\nProspective\nrandomized\nclinical trial,\nregistered\nLNG-IUS\n(final partici-\npants\nn ¼ 29)\nCOC (35mcg\nof gesto-\ndene þ\n30 mcg of\nEE, 21/7)\n(final partici-\npants\nn ¼ 28)\n6 months 1. Pain (VAS)\n2. Menstrual\nbleeding\n(menstrual\ndiary,\npads/day),\n3. Uterine\nvolume\n(TVUS and\nDoppler)\nBoth treat-\nments\nreduced\npains,\nhowever, the\nreduction\nwas greater\nin the\nLNG-IUS\ngroup\nBoth treat-\nments\ndecreased\nthe number\nof bleeding\ndays,\nnumber of\nsanitary\npads per day,\nbut the\nreduction\nwas greater\nwith LNG-IUS\nBoth treat-\nments de-\ncreased the\nuterine\nvolume, but\nthe reduc-\ntion was\ngreater with\nLNG-IUS\nUterine\narteries and\nintramyome-\ntrial Doppler\nindices in-\ncrease in\nboth groups,\nbut the\nincreases\nwere greater\nwith LNG-IUS\nLNG-IUS:\nexpulsion\n(n ¼ 1)\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al.568\n\n\nTable 1 (Continued )\nAuthor,\nYear\nCountry Study aim Diagnosis Sample Study\ndesign\nTreatment Follow-up Evaluation\nmethod\nPain -\nresults\nBleeding\nloss -\nresults\nUterine\nvolume -\nresults\nQuality of\nlife\nOther\nresults\nSide\neffects\nFawzy and\nMesbah\n(2015)\n24\nEgypt To compare\ndienogest\nversus\ntriptorelin\nacetate\nUS\ncriteria\nN ¼ 41;\ndienogest\n(n ¼ 22);\ntriptorelin\nacetate\ninjection\n(n ¼ 19)\nProspective\nnon- ran-\ndomized\nclinical trial\n(did not\nregister)\nDienogest\n2mg/day\n(final partici-\npants\nn ¼ 19)\nTriptorelin\nacetate ( final\nparticipants\nn ¼ 18)\n16 weeks 1. Pain,\ndysme-\nnorrhea,\ndyspareu-\nnia and\nchronic\npelvic\npain (VAS)\n2. Menstrual\nbleeding\n(3 levels of\nsatisfied,\nblood cell\ncount,\nferritin)\n3. Uterine\nvolume\n(TVUS)\nBoth treat-\nments\nreduced\nchronic\npelvic pain\nand dyspar-\neunia.\nTriptorelin\nwas more\neffective in\nrelieving\ndysmenor-\nrhea\nTriptorelin\nwas more\neffective\nthan\ndienogest\n(100 and\n73.7%\nrespectively)\nin control-\nling men-\nstrual bleed-\ning. Both\ntreatments\nimproved Hb\nlevels and\nferritin\nTriptorelin\nwas more\neffective in\nthe reduc-\ntion of\nuterine\nvolume\nDid not\nassess\nOsuga et al\n(2017)\n25\nJapan To compare\ndienogest\nversus\nplacebo\nUS and\nMRI\ncriteria\nN ¼ 67 Randomized,\ndouble-blind,\nmulticenter,\nplacebo-con-\ntrolled phase\nIII study\nDienogest\n2mg/day ( fi-\nnal partici-\npants n ¼ 34\nPlacebo ( fi-\nnal partici-\npants n ¼\n33)\n16 weeks 1. Pain\nPelvic\npain (pain\nseverity\nscore in\norder to\naccess\nwork and\nanalgesics\nuse and\nVAS)\n2. Menstrual\nbleeding\nPatient\ndiary\nform,\nclassified\nby the\nnumber of\ndays and\nseverity of\nbleeding.\n3. Uterine\nvolume\n(US and\nMRI)\n4. Quality of\nlife (MOS\n36-item\nshort-\nform\nhealth\nsurvey)\nDienogest\nreduced pel-\nvic pain and\nother pain\nparameters\nDienogest\npresented a\nlower num-\nber of days\nwith bleed-\ning, and the\nmost was\nspotting or\nbreak-\nthrough, but\nthe numbers\nwere not\nstatistically\ncompared\nbetween the\ngroups\nUterine volu-\nmereduction\nin both\ngroups, but\nno differ-\nence be-\ntween them\nBodily pain\nreduction\n(the item of\nquality of\nlife)\nReduction of\nanalgesics\nu s es c o r ei n\nthe Dieno-\ngest group\nAnemia and\nmenstrual\nbleeding\n(placebo)\nand\nhot flash\n(dienogest)\nAbbreviations: COC, combined oral contraceptive; GnRH, gonadotropin-releasing hormone; LVG-IUS, levonorgestrel intrauterine system; MOS, Med ical Outcomes Study; MRI, magnetic resonance imaging; TVUS, transvaginal ultrasound; US, ultrasound; VAS, visual\nanalogue scale; WHOQOL, World Health Organization Quality of Life.\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al. 569\n\n\nAlthough bleeding control was reported by many women,\ndienogest maintained bleeding in 26.3% of women versus\nnone from the GnRH group. 24 Similarly, uterine volume was\nreduced according to 2 studies in women who used dieno-\ngest, but this reduction was lower than that obtained with\nthe study that used GnRH analog (278 /C6 162–151 /C6 117 ml –\np ¼ 0.01).24 One of these studies 25 reported hot flushes\n(5.3%) as a side effect of the dienogest.\nTreatment with Combined Oral Contraceptives\nOnly one study included one COC to treat adenomyosis, 23\ncontaining 75 mcg of gestodene þ 30 mcg of ethynylestradiol,\nthat was taken for 21 days with 7 days without the pills (21/7),\ncompared to LNG-IUS. The results showed a reduction of pain\n(6.55 /C6 0.68–3.90 /C6 0.54 - p < 0.001), decreased bleeding\n(numbers of days), and reduction of the uterine volume, but\nit was still less efficient that LNG-IUs for all evaluated param-\neters (pain - 6.23 /C6 0.67–1.68 /C6 1.25 - p < 0.001).\nRisk of Bias and Methodological Quality\n►Figure 3 discusses the risk of bias from the retrieved\nstudies. Osuga et al 25 presented the lowest risk of bias\nwhen analyzing all criteria from this table. Almost all studies\n(except Osuga et al) 25 presented an unclear risk of bias for\nallocation concealment and selective reporting. Blinding was\nonly possible in two studies (Osuga et al,25 and Ozdergimenci\net al 21). About the GRADE criteria ( ►Table 2 ), all variables\npresented a moderate certainty assessment, except menstru-\nal bleeding (number of pads/day), comparing LNG-IUS versus\nCOC for 6 months, that presented low certainty assessment.\nAll studies presented serious imprecision due to the small\nnumber of events. Despite being sponsored by the pharma-\nceutical industry, the side effects of the Osuga et al study\nwere reported, and, therefore, we do not consider that\npublication bias was low. Moreover, it was not possible to\nperform GRADE criteria for the study from Ozdergimenci\net al due to inconsistencies, inaccuracy, and poor data\ndescription (it would not fit all the criteria for analyzing it).\nDiscussion\nIn the present systematic review, we have shown that the\nstudied treatments (LNG-IUS, aromatase inhibitor [letrozole],\nGnRH agonist [goserelin and triptorelin], dienogest, and COC\n[75mcg of gestodene þ 30 mcg of ethinyl estradiol]), were\nefficient for the control of the two most common symptoms\nof adenomyosis: heavy menstrual bleeding and dysmenorrhea/\npelvic pain. Equally, regarding enlarged uterus, the treatments\nFig. 2 Forest plot for the comparisons of the non-surgical treatments in the reduction of uterine volume, chronic pelvic pain, and menstrual\nbleeding.\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al.570\n\n\npromoted a reduction in the uterine volume. However, the\nnumber of retrieved studies is low and, according to\nthe literature available up to this point, still not enough to\nendorse any of the analyzed treatments; the follow-up period of\nthese studies was not long enough to permit a conclusion on\nhow effective these treatments would be in the long term (only\nthe LNG-IUS study presented a 12-month follow-up, which can\nbe considered short to medium term). Unfortunately, we also\nnoticed a lack of studies investigating the quality of life as a\nprimary outcome; since most of the studies were concerned\nwith objective outcomes (reduction of uterine volume, and\nnumber of days with abnormal bleeding); however, subjective\nimprovement or patient satisfaction should also be consid-\nered.\n26,27 Moreover, the differences regarding intervention and\ncomparator groups did not allow us to perform metanalysis or\nsubgroup analysis.\nThe most frequent symptoms of adenomyosis are pelvic\npain and abnormal uterine bleeding. Dysmenorrhea is present\nin 50 to 93% of women, while abnormal bleeding is present in\n27 to 65%.\n28 Despite the different comparators, it seems that the\ndifferent pharmacological treatments evaluated, dienogest,\nCOC, GnRH analog (triptorelin and goserelin), letrozole, and\nLNG-IUS, were effective to reduce pelvic pain complaints and to\nreduce bleeding in women with adenomyosis. These results\nsuggest that hormonal treatment improves the symptoms. The\nstrengths of this review are: the inclusion of randomized\ncontrolled trials (RCTs) in a systematic review, and the quality\nassessment of these studies by the GRADE criteria. However, it\nis important to mention that our findings were limited by\ndifferences in the inclusion criteria of the studies, length of\nfollow-up periods, different comparators, different scales used\nto measure blood volume loss or pelvic pain severity, which do\nnot allow conclusions about delaying or avoiding surgical\nprocedures. We have found another review in which the\nauthors presented their data in a narrative format, citing the\ndifferent available treatments. Also, in this publication, it is\npossible to visualize the dif ficulty of comparing treatments,\nlimiting conclusions about pharmacological treatment.\n15\nTherefore, the present study is the first systematic review\nevaluating the results from the pharmacological treatment in\nadenomyosis, with the intention to promote standardization of\nthe methods and to fulfill gaps in the next prospective studies.\nWith the intention of standardizing future studies, in\nthe present systematic review , we included below some\nFig. 3 Risk of bias summary ⊖ ¼ high risk of bias; ? ¼ uncertain risk of bias; ⊕ ¼ low risk of bias.\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al. 571\n\n\nTable 2 Summary of findings table according to Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria\nCertainty assessment - Reduction in uterine volume (ml or cc) Patients Effects Certainty Importance\nStudy Study design Bias risk Inconsistency Indirectness Imprecision Other\nconsiderations\nGroup 1 Group 2 Relative\n(95% CI)\nAbsolute(95% CI)\nDienogest x Placebo (16 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 34 33 /C0 MD 10.4 higher\n(2.06 lower to 22.86 higher)\n⊕⊕⊕/C14 MODERATE\nLetrozole x GnRH analog (12 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 15 16 /C0 MD 20.6 higher\n(0.09 lower to 41.29 higher)\n⊕⊕⊕/C14 MODERATE\nDienogest X GnRH analog (16 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 19 18 /C0 MD 94 higher\n(35.68 lower to 223.68 higher)\n⊕⊕⊕/C14 MODERATE\nCertainty assessment – Chronic Pelvic Pain (VAS) Patients Effects Certainty Importance\nStudy Study design Bias risk Inconsistency Indirectness Imprecision Other\nconsiderations\nGroup 1 Group 2 Relative\n(95% CI)\nAbsolute(95% CI)\nDienogest x Placebo (16 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 34 33 /C0 MD 37.8 lower\n(49.1 lower to 26.5 lower)\n⊕⊕⊕/C14 MODERATE\nDienogest x GnRH analog (16 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 19 18 /C0 MD 5.3 lower\n(19.43 lower to 8.83 higher)\n⊕⊕⊕/C14 MODERATE\nCertainty assessment – Hemoglobin level (g/dL) Patients Effects Certainty Importance\nStudy Study design Bias risk Inconsistency Indirectness Imprecision Other\nconsiderations\nGroup 1 Group 2 Relative\n(95% CI)\nAbsolute(95% CI)\nDienogest x GnRH analog (16 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 19 18 /C0 MD 1.2 lower\n(2.46 lower to 0.06 higher)\n⊕⊕⊕/C14 MODERATE\nDienogest x Placebo (16 weeks)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nSerious a Undetected 34 33 /C0 MD 0.4 higher\n(0.13 lower to 0.93 higher)\n⊕⊕⊕/C14 MODERATE\nCertainty assessment – Menstrual bleeding (pad/day) Patients Effects Certainty Importance\nStudy Study design Bias risk Inconsistency Indirectness Imprecision Other\nconsiderations\nGroup 1 Group 2 Relative\n(95% CI)\nAbsolute(95% CI)\nLNG-IUS x COC (6 months)\n1 Randomized\ntrial\nNot\nserious\nNot\nserious\nNot\nserious\nVery serious a Undetected 31 31 /C0 MD 1.74 lower\n(2.42 lower to 1.06 lower)\n⊕⊕/C14/C14 LOW\nAbbreviations: CI, con fidence interval; COC, combined oral contraceptive; GnRH, gonadotropin-releasing hormone; LVG-IUS, levonorgestrel intrauterine system; MD, mean difference/ a; VAS, visual analogue scale.\nTotal sample size of fewer than 400 patients.\nRev Bras Ginecol Obstet Vol. 41 No. 9/2019\nPharmacological Treatment for Symptomatic Adenomyosis Benetti-Pinto et al.572\n\n\nsuggestions that could be considered important to be includ-\ned during any checklist for preparing a prospective study for\nwomen with symptomatic adenomyosis. More studies are\nneeded to allow comparisons, conclusions on long-term\nefficacy, and side effects that limit its use.\nDiagnosis\nTo use pelvic US (preferably transvaginal probe —TVUS and\n3DTVUS—when available) or MRI for the diagnosis of adeno-\nmyosis,28,29 describing the presence or absence of at least the\nfollowing criteria:\n globular uterus with regular contours (US or MRI);\n asymmetrical thickening of the myometrial walls (US or\nMRI);\n thickening of the junctional zone (JZ) /C21 12 mm (MRI or,\neventually, by US);\n greatest JZ thickness to total myometrium ratio > 40 to\n50% (US or MRI);\n foci of high signal intensity running alongside the endo-\nmetrium on T2 and sometimes also T1-weighted;\n images that persist on Fat-Sat (FS) (MRI);\n anechoic sub endometrial microcysts in the myometrium\n(around 2 –4 mm in diameter) (US);\n description of association or not with leiomyoma.\nUterine Volume\n To perform the same imaging technique used for diagno-\nsis, preferably at the same time that clinical complaints\nare re-evaluated, to correlate the results.\nSymptoms (Pain and Bleeding)\n There is no speci fic questionnaire for adenomyosis\n To evaluate pain-related symptoms: pelvic pain, dysme-\nnorrhea, and deep dyspareunia. The assessment criteria\nshould include the VAS. When possible, make daily con-\ntrol diaries for each type of pain and register the frequen-\ncy of pain.\n To evaluate bleeding symptoms through a scale with the\nnumber of days of bleeding and number of pads per 30-\nday (interval). We suggest using the Pictorial Blood As-\nsessment Chart (PBAC) and serum levels of hemoglobin\nand ferritin.\n Both symptoms (pain and bleeding) should be evaluated\nat the initial time before treatment, and every 4 months\n(120 days).\nSide Effects\n To describe in detail all possible and unpredictable side\neffects, especially when these were indicative of discon-\ntinuation of treatment, including the number of losses.\n To report cases of non-response to pharmacological\ntreatment.\nQuality of Life\n To use the 36-item short-form survey (SF-36) or the\nWHOQOL questionnaire.\nConclusion\nLevonorgestrel intrauterine system and dienogest presented\ngood results for controling bleeding and pelvic pain, respec -\ntively, versus their comparators. However, there is insufficient\ndata from the retrieved studies to endorse each medication for\nsymptomatic adenomyosis. Future RCTs comparing pharma-\ncological treatments for adenomyosis are needed to bolster the\navailable data.\nContributions\nAll the authors participated actively in the study, as\nfollows: Yela D. A., Benetti-Pinto C. L., and Brito L. G. O.\nwere responsible for writing the protocol and the final\nmanuscript. Teatin-Juliato C. R. and Mira T. A. A. collected\nthe data and conducted a review of the literature.\nConflicts of Interest\nThe authors have no con flicts of interest to declare.\nReferences\n1 Levy G, Dehaene A, Laurent N, et al. An update on adenomyosis.\nDiagn Interv Imaging 2013;94(01):3 –25. Doi: 10.1016/j.diii.2012.\n10.012\n2 Bazot M, Daraï E. Role of transvaginal sonography and magnetic\nresonance imaging in the diagnosis of uterine adenomyosis. Fertil\nSteril 2018;109(03):389–397. Doi: 10.1016/j.fertnstert.2018.01.024\n3 Azziz R. Adenomyosis: current perspectives. Obstet Gynecol Clin\nNorth Am 1989;16(01):221 –235\n4 Brosens JJ, Barker FG, de Souza NM. 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