{"paper_id":"282afa68-b265-4aa2-bc52-231f7295006c","body_text":"Offizielles Organ:  AGRBM,  BRZ,  DVR,  DGA,  DGGEF ,  DGRM,  D·I·R,  EFA,  OEGRM,  SRBM/DGE\nKrause & Pachernegg  GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz\nJournal für\nReproduktionsmedizin \nund Endokrinologie\n– Journal of Reproductive Medicine and Endocrinology –\nAndrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik \nGynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie\nIndexed in EMBASE/Excerpta Medica/Scopus\nwww.kup.at/repromedizin\nOnline-Datenbank mit Autoren- und Stichwortsuche\nHow to Diagnose and Treat Adenomyosis in Patients with\nEndometriosis\nKrentel H, DeWilde RL\nJ. Reproduktionsmed. Endokrinol 2018; 15 (5-6)\n262-269\n\n\n20.-21. März 2026\nUniversitätsmedizin Mainz\nENDOKRINOLOGIE & FERTILITÄT\nFÜR KLINIK & PRAXIS\nWeitere Informationen\n& Anmeldung unter\nEinladung zu unserer wissenschaftlichen Veranstaltung Endo-Ferti-Forum\nBrücke(n) zwischen Unikliniken und Praxen an Rhein und Main(z)\n– die aus dem bisherigen Format „Ferti Forum“ ab 2026 hervorgeht –\nFreuen Sie sich auf spannende Vorträge und den lebendigen Austausch mit Kolleg:innen und Expert:innen aus Klinik und\nPraxis. Freitagabend laden wir Sie herzlich zu einem entspannten Empfang ein –\neine perfekte Gelegenheit, Kontakte zu knüpfen und den T ag genussvoll ausklingen zu lassen.\nWissenschaftliche Leitung: Univ.-Professorin Annette Hasenburg, Dr. Susanne Theis, Universitätsmedizin Mainz,\nSanitätsrat Dr. Werner Harlfinger, BVF Rheinland-Pfalz Dr. Rüdiger Gaase, BVF Hessen Dr. Klaus J. Doubek\nSchirmherrschaften: Prof. Nicole Sänger, Uniklinik Bonn, Prof. Jan-Steffen Krüssel, Uniklinik Düsseldorf,\nDr. Annette Bachmann, Uniklinik Frankfurt am Main, Prof. Christine Skala, Uniklinik Köln\n\n262\nHow to Diagnose and T reat Adenomyosis  \nin Patients with Endometriosis\nH. Krentel1, RL. De Wilde2\n „ Introduction\nWhile peritoneal and deep infiltrating \nendometriosis play an important role \nin the international scientific literature, \nadenomyosis is still underrepresented, \nalthough it is a frecuent symptomatic \nuterine disease affecting the central \ngenital organ in premenopausal wom­\nen. An incidence of more than 30% of \nadenomy osis in hysterectomy specimens \nhas been detected by histopathological \nexamination [1], however the incidence \nin younger women with ongoing family \nplanning remains unknown. Less than \n5% of all patients with adenomyosis \nhave no symptoms. The most frecuent \nsymptom is dysmenorrhea followed by \nbleeding disorders, chronic pelvic pain \nand dyspareunia [2]. Different publica­\ntions also indicate that adenomyosis has \na negative impact on fertility, reporting \nreduced pregnancy and live birth rates \nand increased miscarriage rates after \nIVF in patients with adenomyosis [3–6]. \nIn recent literature reviews the relation \nof adenomyosis to the increased risk of \nobstetrical complications like preterm \nbirth, preterm premature rupture of mem­\nbranes, uterine rupture and uterine atony \nis discussed [7, 8]. At the same time it \nhas been reported in various publications \nthat medical and surgical treatment of \nadenomyosis may improve fertility [9, \n10], although a standard for the treatment \nof infertile women with adenomyosis \nhas not yet been established [11]. These \ndata show that adenomyosis has to be \nincluded in the diagnostic procedures in \npatients with endometriosis and specific \ntreatment options should be considered \nand discussed with the patients in case of \nadenomyosis [12].\n „ Methods\nPubMed search has been realized using \nthe keywords adenomyosis, hysteros­\ncopy, 2D transvaginal sonography, 3D \ntransvaginal sonography, doppler sono­\ngraphy, elastography, MR imaging and \nlaparoscopy, adenomyomectomy, infer ­\ntility, subfertility, focal adenomyosis, \ndiffuse adenomyosis, dienogest, gon­\nadotropin­releasing hormone agonists, \nlevonorgestrel­releasing intrauterine sys­\ntem, high­intensity focused ultrasound, \nuterine artery embolization\n „ Results and Discussion\n1. Diagnosis of Adenomyosis\nDifferent diagnostic tools like 2D and 3D \ntransvaginal ultrasound, doppler sono­\ngraphy, sonoelastography, MR imaging \nand diagnostic hysteroscopy and laparo­\nscopy with their specific findings play an \nimportant role in the diagnosis of adeno­\nmyosis [13]. Especially when combined \nwith clinical history and examination \n[14] [15] the imaging techniques offer \na good specificity and sensitivity in the \nhands of the skilled examiner. The dia­\ngnostic findings can change in relation \nto patients age, hormonal treatment and \nmenstrual cycle [16]. As dysmenorrhea \nis the most common symptom of adeno­\nmyosis, the disease should be assumed \nin case of persistent dysmenorrhea af­\nter laparoscopic resection of peritoneal \nor deep infiltrating endometriosis even \nwhen typical imaging findings are miss­\ning [17]. In case of deep infiltrating \nendometriosis the probability of simul­\ntaneous adenomyosis is almost 50%. In \nthis group the pain reduction by surgical \ntreatment of the deep infiltrating endo­\nmetriosis is less effective than in patients \nwithout adenomyosis [18]. However \na reliable standard in the diagnosis of \n adenomyosis so far does not exist.\nTransvaginal Ultrasound\nTransvaginal ultrasound is the most ac­\ncessible and cost­effective diagnostic \ntool. Typical sonographic features have \nbeen described in the last years: hetero­\ngeneous myometrium, hyperechoic or \nhypoechoic linear striation in the myo­\nmetrium, myometrial anechoic lacunae \nor cysts, subendometrial microcysts, \nasymmetrical myometrial thickening of \nthe uterine wall, globally uterine enlarge­\nment, the so called question mark sign, \nthickening of the junctional zone and hy­\nReceived: August 3, 2018; accepted: September 22, 2018 (responsible Editor: Prof. L. Kiesel, Münster)\nFrom the 1Clinic of Gynecology, Obstetrics and Gynecological Oncology, Bethesda Hospital, Duisburg, Germany, and the 2Clinic of Gynecology, Obstetrics and Gynecological \n Oncology, University Hospital for Gynecology, Pius-Hospital Oldenburg, Medical Campus University of Oldenburg, Germany\nCorrespondence: Harald Krentel, Clinic of Gynecology, Obstetrics, Gynecological Oncology & Senology, Bethesda Hospital, Heerstraße 219, 47053 Duisburg, Germany;  \ne-mail: krentel@cegpa.org\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\nFor personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.\nSince some years the uterus has become part of the discussion about treatment concepts in patients with peritoneal and deep infiltrating \nendometriosis, especially in subfertile women. Anyhow adenomyosis is still underdiagnosed and its impact on symptomatology in patients \nwith endometriosis, on subfertility especially in young premenopausal women and on the right choice of treatment approaches is still under-\nestimated. An age related incidence is not yet known. This might be related to the difficulties in diagnosing adenomyosis. Transvaginal ultra-\nsound and MR imaging have a high accuracy in the hands of the skilled examiner, but the global awareness on how to diagnose adenomy-\nosis has just begun. Pretherapeutical screening for adenomyosis allows the identification of subgroups and thus individualization of medi-\ncal and surgical treatment. In the following the actual not yet evidence based diagnostic and therapeutic options, especially in patients with \n adenomyosis and subfertility are reviewed and discussed. J Reproduktionsmed Endokrinol_Online 2018; 15 (5-6): 262–9.\nKey words: Adenomyosis, uterine endometriosis, infertility, dysmenorrhea, transvaginal ultrasound, adenomyomectomy,  \nfocal adenomyosis, diffuse adenomyosis, dienogest, gonadotropin-releasing hormone agonists,  \nlevonorgestrel-releasing intrauterine  system, high-intensity focused ultrasound, uterine artery embolization\n\nHow to Diagnose and T reat Adenomyosis in Patients with Endometriosis\n263\nperechoic myometrial areas [19–22]. In a \nrecent review Andres et al evaluated the \nliterature in the last 10 years in order to \ndetermine the accuracy of  transvaginal \nultrasound and its imaging features [23]. \nThe pooled sensitivity and specificity for \n2D transvaginal ultrasound was 83.8% \nand 63.9%. The feature heterogeneous \nmyometrium reached the highest pooled \nsensitivity with 86 %, while globular \nuterine enlargement was the most spe­\ncific sign. The combination with the \nfeature question mark sign increased the \naccuracy. In a similar review Bazot et al \nshowed comparable results pointing out \nthe high heterogenity between the in­\ncluded studies and the missing consensus \nin adenomyosis classification [24]. \nIn 2014 Dartmouth el al also reviewed \nthe literature and concluded that uter ­\nine asymmetry is not an accurate sign, \nbut myometrial cysts, linear myome­\ntrial stria tions, poor delineation of the JZ \nand a heterogenous myometrium define \nadeno myosis in transvaginal ultrasound \n[25]. Different publications show a high \nvariation in the most useful ultrasound \nfeatures changing between linear stria­\ntion, myometrial cysts, question mark \nsign, heterogenious myometrium and \nasymmetrical myometrial thickening \n[26–28]. However not only the most ac­\ncurate transvaginal ultrasound feature \nremains still uncertain, but also the most \nsensitive and specific combination of \nfeatures and thus the question of a pos­\nsible ultrasound score in the detection \nof adenomyosis. Dueholm stated that \nadenomyosis is likely in the presence of \nthree or more ultrasound signs [29]. In a \nnext step additional techniques can help \nto ensure the suggested diagnosis. \nIn the assessment of the junctional zone \nthe 3D transvaginal ultrasound seems to \nbe more accurate than the 2D technique \n[27]. In 86% of patients with adenomyo­\nsis Sharma et al detected an irregular \njunctional zone in 3D transvaginal ul­\ntrasound [30]. Luciano et al described \nJZ(max) > 8 mm, myometrial asymmetry \nand hypoechoic striation as most specific \nparameters in 3D transvaginal ultrasound. \nThe combination of two features reached \nan accuracy of 90% [31]. However the \nuse of 3D transvaginal ultrasound did not \nimprove the pooled overall accuracy in \nthe most recent review. Poor junctional \nzone definition showed the highest sensi­\ntivity (86.0%) and specificity (56.0%). In \nthe dif ferentiation between adenomyosis \nand myomas transvaginal ultrasound \nwith additional color Doppler reached a \nhigh accuracy (sensitivity 95.6%, speci­\nficity 93.4%) [23]. Leiomyomas showed \nperipheral vascularity in 89%, while \ncentral vascularity was found in 93 % of \nadeno myosis lesions in additional dop­\npler sonography [30]. Another tool in \norder to discriminate uterine lesions is \nsonoelastography measuring the specific \ntissue stiffness and color patterns [32, \n33]. In conclusion the transvaginal ultra­\nsound examination is a good diagnostic \ntool in order to determine adenomyosis. \nHowever its accuracy depends on ex­\namination criteria selection and the ex­\naminers experience. In 2015 the MUSA \n(Morphological Uterus Sonographic \nAssessment) group reported a consensus \nstatement on sonographic uterine fea­\ntures summarizing parameters and the \nuse of terminology [34].\nMR Imaging\nMR imaging offers an additional dia­\ngnostic approach in order to detect \n adenomyosis, to differentiate focal and \ndiffuse adenomyosis, to localize and \nmeasure affected uterine tissue prior to \nsurgical interventions and in order to \ndifferentiate adenomyosis from fibroids \n[35]. Focal or diffuse thickening of the \njunctional zone (JZ[max]) > 12 mm, a \nJZ(max) to myometrial thickness ratio \n> 40%, areas of myometrial low­signal­\nintensity and high­signal­intensity spots \nin the T2­weighted technique are the \ntypical findings [36, 37]. Stamatopoulos \net al described a sensitivity of 46.1% and \nspecificity of 99.2% of MRI in the diag­\nnosis of adenomyosis [38]. Bazot et al. \ncompared transvaginal ultrasound with \nmagnetic resonance imaging and report­\ned no difference in accuracy. In patients \nwith additional uterine myomas the sen­\nsitivity was higher in MR imaging [36].\nHysteroscopy and Laparoscopy\nThe role of hysteroscopy in adenomyosis \nhas been recently reviewed [39, 40]. Su­\nperficial endometrial openings, irregular \nendometrium, hypervascularization and \ncystic hemorrhagic lesions have been de­\nscribed as the main hysteroscopic find­\nings suspecting adenomyosis [22, 41, \n42]. The possibility to proof the diagno­\nsis by histopathologic examination after  \nhysteroscopic retrieval of subendometri­\nal adenomyotic tissue has been already \nreported in 1992 [43]. With modern of­\nfice hysteroscopy Dakhly et al showed an \nincreased specificity in the combination \nof transvaginal ultrasound and endomyo­\nmetrial biopsy [44]. \nProbable laparoscopic parameters in \nadenomyosis are uterine enlargement, a \npillowy resistance of the uterine wall, the \nblue sign and cystic subserous hemor ­\nrhagic lesions [22]. Jeng et al described \nthe laparoscopy­guided myometrial \nbiopsy as a valuable tool for obtain­\ning a definite diagnosis in patients with \nclinical suggestion of adenomyosis [45]. \nThe histologic proof of adenomyosis \ncan facilitate therapeutic decisions, es­\npecially in case of adenomyosis­related \nsubfertili ty. Additionally both minimally \ninvasive surgical approaches offer a \n variety of treatment options in patients \nwith adenomyosis.\nIn conclusion the diagnosis or exclusion \nof adenomyosis in patients with endo­\nmetriosis should be possible by the ex­\nperienced gynecologist. The individual \ncombination of different diagnostic tools \nincluding imaging techniques and mini­\nmally invasive surgical approaches offer \na high accuracy in the diagnosis of ad­\nenomyosis and in some cases even histo­\nlogical certainty. Thus adenomyosis can \nbe included in the respective individual \ntreatment concept.\n2. T reatment of Adenomyosis\nWhen adenomyosis has been diagnosed, \nthe reliability of the diagnostic methods, \nthe symptoms of the disease, the impact \non fertility and the respective treatment \noptions should be mentioned and dis­\ncussed with the patients. According to \nthe family planning the treatment options \nin patients with adenomyosis can be di­\nvided into two groups: patients with on­\ngoing family planning and patients with \ncompleted family planning. \nIn case of ongoing family planning the \npresence of adenomyosis represents a \nserious adverse factor. Recent data show \nthat medical or surgical treatment of ad­\nenomyosis can improve fertility. Thus \nin patients who wish to conceive in the \nfuture the treatment should be planned in \norder to improve symptoms and fertility, \npreserving the integrity of the uterus. An­\nother factor for choosing the treatment \nmethod is the age depending moment \nof diagnosis of adenomyosis. Better di­\nagnostic methods and global adenomyo­\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nHow to Diagnose and T reat Adenomyosis in Patients with Endometriosis\n264\nsis awareness recently allow an earlier \ndiagnose of the disease in very young \nwomen who still do not have actual wish \nof conception. In these cases a long­term \ntreatment with low complication rates \nand the aim to prevent a worsening of the \nuterine situation is required. Surgical so­\nlutions does not play an important role in \nthese patients as the adenomyotic lesions \nin most of these cases are minimal and \nalmost invisible by transvaginal ultra­\nsound and MR imaging and thus surgical \ntherapy planification is difficult. The use \nof low dose LNG­IUDs, which are es­\npecially designed for young nulliparous \npatients, could be an option. However \nthe effectiveness of these IUDs on ade­\nnomyosis related symptoms needs to be \nproven by prospective studies. \nIn many cases adenomyosis is just \n diagnosed in correlation with ongoing \ndiagnostic steps in infertility treatment. \nThus the inmediate improvement of the \nuterine situation is required. This aim \ncan be achieved by medical or surgical \ninterventions or a combination of both. \nProspective studies leading to an evi­\ndence based recommendation are miss­\ning so far. In a recent literature review \nDueholm gives an overview of minimal \ninvasive treatment options including \nmedical and surgical methods, high­\nlighting treatment strategies, but also \nthe lack of knowledge and the difficul­\nties in suggesting evidence­based treat­\nments [46]. However actual literature \nshows a variety of different medical and \nsurgical possibilities in the treatment of \nadenomyosis regarding both groups of \npatients.\na) Medical approach\nThe medical therapeutic options in \npatients with adenomyosis have been \nrecently reviewed by Vannuccini et al \n[47], Pontis et al [48] and Tsui et al \n[49]. Each conclude that the use of sup­\npressive hormonal treatment with high \ndose progestins, oral contraceptives, \nlevonorgestrel­IUDs, GnRH agonists, \naromatase inhibitors, selective estrogen \nreceptor modulator (SERMs) and se­\nlective progesteron receptor modulator \n(SPRM´s) are able to reduce symptoms \nby reduction of adenomyosis. However \neach therapy is related to specific side \neffects. Actually all medical approaches \nrepresent an off­label use as no medical \nsolution is licensed in the specific treat­\nment of adenomyosis. In daily practice \nand also in literature combinations of the \nabove mentioned medical treatment op­\ntions can be found.\nDienogest and other Progestins\nWhile the daily administration of 2 mg \nof dienogest in patients with peritoneal \nand deep infiltrating endometriosis is a \nstandard procedure, the use of dienogest \nin patients with adenomyosis can not \nbe adopted without further evaluation. \nThe package insert describes the pos­\nsibility of severe uterine bleedings in \npatients with adenomyosis while using \ndienogest. In 2012 Nagata el al described \nthat adenomyosis patients treated with \ndienogest have a higher risk of treatment \ndiscontinuation due to bleeding disor ­\nders, especially when they are of young \nage, have anemia before treatment and/or \nhave mildly supressed or unsuppressed \nestradiol after they started dienogest \ntreatment [50]. \nNishino et al described an acute mas­\nsive uterine bleeding under dienogest \ntreatment in a patient with adenomyosis \n[51]. However Hirata et al. showed that \ndienogest reduces adenomyosis­related \npelvic pain in 15 patients with treatment \nfor up to 24 weeks. But also in this pub­\nlication 5 patients experienced metror ­\nrhagia [52]. In two publications Osuga \net al reported the treatment of 130 and \n67 adenomyosis patients with dienogest \nfor 52 and 16 weeks. They described an \neffective pain reduction but also irregular \nuterine bleedings as most common ad­\nverse reaction. However they concluded \nthat the treatment was well­tolerated by \nmost of the patients [53, 54]. As possible \nmechanisms a reduction in proliferation, \nNGF expression and nerve fiber density \nhas been shown [55]. In another study the \nnumber of natural killer cells increased \nin glandular structures after treatment \nwith dienogest [56]. \nIn conclusion dieno gest seems to signif­\nicantly reduce pain in patients with aden­\nomyosis, while the impact of side effects \nlike bleeding disorders and depression \non the discontinuation of the treatment \nshould be evaluated in larger prospective \nand age­depending studies. Also other \nprogestins like MPA or norethisterone \nacetate can reduce pain in patients with \nadenomyosis, but are related to side ef­\nfects such as acne, edema and reduction \nof libido causing high withdrawal rates \n[57–59].\nCombined Oral Contraceptives (COCs)\nEspecially in the treatment of sympto­\nmatic endometriosis, the COC´s play an \nimportant role when Dienogest is not tol­\nerated by the patients. The combination \nof low dose estrogen with dienogest can \ncope with the progestin­related adverse \neffects. COC´s also may reduce adeno­\nmyosis­related pain, but lead to irregular \nbleedings in many cases [49, 60]. How­\never in case of adenomyosis the treatment \nwith COC´s does not represent a specific \napproach, but just one more possibility in \na non­evidence­based situation. Shaaban \net al compared low­dose oral contracep­\ntive with levonorgestrel­releasing intrau­\nterine system (LNG­IUS) and showed \nthat both approaches reduced symptoms \nafter six month. However LNG­IUS is \nmore effective in reducing pain and men­\nstrual blood loss [61].\nLevonorgestrel Intrauterine Device\nThe effectiveness of LNG­IUDs in the \ntreatment of adenomyosis related symp­\ntoms has been shown in various publica­\ntions [62–65]. LNG­IUDs are equal or \nsuperior in comparison with systemic \nprogestins or oral contraceptives. LNG­\nIUDs are used in young women with \nadenomyosis with ongoing family plan­\nning, in women with completed family \nplanning instead of hysterectomy [66], as \na maintenance therapy after adenomyosis \nsurgery [67] and in patients with fertility \ntreatment before assisted reproduction. \nIn a retrospective analyze Park et al de­\nscribed the treatment with LNG­IUS in \npatients with large uterine adenomyosis \nand heavy menstrual bleeding. In all pa­\ntients an improvement in dysmenorrhea \nand menstrual bleeding has been shown. \n10% of patients underwent premature \nLNG­IUS removal and 16.7% underwent \nsubsequent hysterectomy [68]. However \na high patient satisfaction of about 80% \nin women after 35 years has been shown \n[69]. In a prospective cohort study Li et \nal investigated changes in menstruation \npatterns and adverse effects in patients \nwith adenomyosis treated by LNG­\nIUD. During the follow­up period up \nto 60 month, the rate of amenorrea and \nshortened menstruation increased, while \nadverse effects decreased [70]. Lee et al \nshowed that there is a relationship be­\ntween treatment failure rate and uterine \nvolume in the use of LNG­IUDs [71]. \nThe incidence of spontaneous expul­\nsion of the IUS is higher in patients with \nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nHow to Diagnose and T reat Adenomyosis in Patients with Endometriosis\n265\nade nomyosis and/or uterine fibroids \nthan in normal uterus [72] and seems to \ndepend on the insertion technique [73] \nand the placement timing [74]. In the \npostsurgical situation Lin et al described \nthat the use of levonorgestrel­releasing \nintrauterine system after conservative \nsurgery and temporary administration \nof gonadotropin­releasing hormone in \npatients with adenomyosis, guaranteed a \ngreater reduction of dysmenorrhea in a \n24­month follow­up period than the con­\ntrol group without additional LNG­IUD \n[67]. Zhang et al reported the combina­\ntion of LNG­IUD with gonadotropin­\nreleasing hormone analogue as a effica­\ncious treatment alternative [75]. The role \nof levonorgestrel­releasing intrauterine \nsystems in the treatment of adolescent or \nvery young women with adenomyosis, \nespecially the use of low­dose IUD’s, \nhas to be investigated in the future. Low­\ndose IUD’s with 13.5 or 19.5 mg of \nlevonor gestrel are suitable in nulliparous \nwomen, but the approved non­contracep­\ntive effects of 52 mg IUD’s can not be \nestimated yet for this new generation of \nIUDs [76]. In daily practice of fertility \ntreatment the application of LNG­IUDs \nprior to assisted reproduction also plays \na role, which is not yet evaluated by re­\nspective studies.\nGonadotropin-Releasing Hormone \nAna logues\nGonadotropin­releasing hormone ago­\nnists also play an important role in the \ntreatment of adenomyosis. The appli­\ncation can be presurgical, postsurgical, \nprior to assisted reproductice techniques \nor as individual medical treatment ap­\nproach instead of other therapies. Tan et \nal analyzed the value of gonadotropin­\nreleasing hormone agonist pretreatment \nbefore adenomyomectomy and showed \nthat the pretreatment reduces peri­ and \npostoperative complications [77, 78]. \nThe combination of gonadotropin­\nreleasing hormone agonist application \nwith conservative surgery seems to re­\nsult in longer durable symptom­control \nand better reproductive outcomes in \nsymptomatic and subfertile patients with \nadenomyosis compared with gonadotro­\npin­releasing hormone treatment alone \n[9, 79, 80]. \nHowever Chong et al investigated \nthe long­term efficacy of adenomyo­\nmectomy with or without postoperative \ngonadotropin­releasing hormone agonist \nadministration and found no differences \nin symptom control in both groups [81]. \nIn infertile women with adenomyosis the \ntreatment with gonadotropin­releasing \nhormone agonist is indicated before \nfertility treatment in order to improve \nthe results [47, 82]. Tremellen treated \nfour patients with repeated unsuccess­\nful in vitro fertilisation with ultra­long \npituitary downregulation and reported \npregnancy in all cases [83]. Mijatovic \net al showed that adenomyosis had no \nadverse effects on IVF/ICSI outcomes \nin patients with endometriosis when pre­\ntreated with long­term downregulation \n[84]. Niu et al showed that in frozen em­\nbryo transfer the long­term GnRH ago­\nnist pretreatment increased pregnancy \noutcomes [85]. They compared 194 pa­\ntients with down­regulation and stimula­\ntion with 145 patients with stimulation \nonly. In a recent publication Dueholm et \nal describe actual clinical considerations \nin case of adenomyosis and assisted \nreproductive techniques [86]. In a case \nseries Mansouri et al demonstrated the \nefficacy of gonadotropin­releasing hor ­\nmone agonists in adolescents with re­\nfractory chronic pelvic pain, failed COC \ntherapy and positive MR imaging for \nadenomyosis. The treatment improved \nsymptoms and repeated MR imaging \nshowed regression of the lesions [87]. \nAkira et al described the maintenance of \ntherapeutic effects with low­dose long­\nterm gonadotropin­releasing hormone \nagonist therapy achieving a plasma es­\ntradiol level within the therapeutic win­\ndow [88].\nAromatase Inhibitors\nEstrogen, estrogen receptors and aro­\nmatase play a role in the pathogenesis \nof adenomyosis [89]. Thus the use of \naromatase inhibitors represents another \nattempt in the treatment of adenomyosis \nand its symptoms. Badawy et al showed \nthat aromatase inhibitors are as effective \nas gonadotropin­releasing hormone ago­\nnists in reducing adenomyoma volumen \nand improving symptoms. 32 patients \nwere randomly treated with letrozole \n(2.5 mg/d) or subcutaneous goserelin \nfor 12 weeks. Interestingly two patients \nbecame pregnant during treatment with \nletrozole [90]. Kimura et al reported a \ncase of simultaneous treatment of se­\nvere symptomatic adenomyosis with \nanastrozole and gonadotropin­releasing \nhormone agonist. They described a re­\nduction of uterine volumen by 60% after \neight weeks of treatment [91]. The syn­\nthesis of estrogen in adenomyotic tissues \nhas been shown in the early 90s [92]. Its \nrole for the pathogenesis of adenomyo­\nsis, treatment approaches and the relation \nto malignancy arising from adenomyosis \nhas to be shown in further investigations.\nSelective Progesterone Receptor Mo-\ndulator\nSelective progesterone receptor modu­\nlator also seem to be able to reduce \nsymptoms in patients with adenomyosis. \nHowever only very few publications on \nthis topic exist so far. In a single­center \nretrospective observational study Gracia \net al used a 12­week course of ulipristal \nacetate (UPA) on 41 patients with adeno­\nmyosis and uterine fibroids. In 90 % of \nthe patients amenorrhea was acheived \nand the pain was reduced [93]. Further \ninvestigations are needed to evaluate \nthe efficacy and safety of this approach, \nespecially in combination with fertility \ntreatment.\nSelective Oestrogen Receptor Modu-\nlator, Valproic Acid, Anti-platelets The-\nrapy\nThis group of medicaments represent \nan even more experimental approach \nthan the above mentioned. In a recent \nclinical trial Harada et al showed the \npain reducing effect of a novel selec­\ntive oestrogen receptor modulator (SR­\n16234) in patients with endometriosis \nand adenomyosis. Also total dysmenor­\nrhea score as a secondary endpoint of \nthe study was improved [94]. Liu et al \nshowed in a case series that valproic \nacid treatment for three month in pa­\ntients with confirmed adenomyosis led \nto a complete reso lution of dysmenor ­\nrhea and an average reduction of uterine \nsize by 26% [95, 96]. In animal models \nthe positive influence of valproic acid, \nepigallocatechin­3­gallate, resveratrol, \nleonurine and anti­platelet therapy on \nadenomyosis­related pain has been \nshown [97–101].\nSeveral medical treatment options exist \nin order to reduce adenomyosis related \nsymptoms. The most effective and safe \nmethod, without severe side effects seems \nto be the use of LNG­IUD’s. The posible \nrole of new low­dose IUDs should be in­\nvestigated. In combination with fertility \ntreatment the use of gonadotropin­releas­\ning hormone agonists prior to concep­\ntion or assisted reproductive techniques \nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nHow to Diagnose and T reat Adenomyosis in Patients with Endometriosis\n266\nseems to improve pregnancy rates. How­\never this literature review shows that data \nis limited and prospective, comparative \nstudies are needed in order to find out the \nevidence based way. So far the medical \ntreatment of adenomyosis especially in \npatients with ongoing family planning is \nan individual recommendation, while the \nsituation in patients with completed fam­\nily planning is based on a large number \nof publications, especially regarding the \nLNG­IUDs.\nb) Surgical Approach\nIf the family planning is completed  \nminimally invasive total or supracervi­\ncal hysterectomy can effectively treat \nbleeding disorders and dysmenorrhea \ncaused by adenomyosis [82]. The lapa­\nroscopic supracervical hysterectomy \nwith intraabdominal in­bag morcellation \nis a surgical method with a very low risk \nof complications [102, 103] and can be \neasily combined with laparoscopic resec­\ntion of peritoneal endometriosis. In case \nof simultaneous cervical or retrocervical \nadenomyosis or deep infiltrating endo­\nmetriosis of the retrocervical region or \nthe parametrium the total laparoscopic \nhysterectomy, laparoscopically assisted \nvaginal hysterectomy or vaginal hyster ­\nectomy is safe and feasible [104, 105]. \nThe global endometrial ablation offers a \nless invasive treatment option in patients \nwho want to preserve the uterus. Philip \net al. described the use of radiofrequency \nglobal endometrial ablation in 43 pa­\ntients with adenomyosis with a 36 month \nfollow up. The intervention was effective \nin the treatment of adenomyosis related \nsymptoms, but the efficacy in control­\nling bleeding decreased over time [106]. \nThe correlation between failure rate of \nendometrial ablation and adenomyosis \nhas been described in various publica­\ntions [107–110]. Thus Nakamura et al \ndescribed multiple endometrial abla­\ntions repeating the procedure three times \nachieving higher satisfaction rates in \ncontrolling adenomyosis related menor ­\nrhagia [111]. Ota et al recently reported \nthe combination of microwave endome­\ntrial ablation and postoperative dienogest \nadministration [112]. The combination \nof endometrial ablation and LNG­IUS, \nespecially the 13.5 and 19.5 mg versions \nshould be investigated in patients who \nwant to preserve the uterus and avoid \nside effects by hormonal treatment. If \npossible a reliable control of symptoms \nwith low complication rates and without \nsystemic hormonal side effects should be \nfirst choice in this group.\nHowever more women with adeno­\nmyosis wish to conceive a child in the \nfuture and hysterectomy is not the only \neffective therapy any longer [113]. If pa­\ntients want to preserve the uterus, desire \npreser vation or improvement of fertility \nthe surgical resection of focal or diffuse \nade nomyosis by hysteroscopy, laparo­\nscopy or open surgery also represents \nan individual approach. Focal subendo­\nmetrial or intramural cystic adeno myotic \nlesions and intracavitary polypoid ade­\nnomyoma can be resected by bipolar or \nmonopolar hysteroresectoscopy. New \ninstruments with lower diameter offer \na minimally invasive approach espe­\ncially in very young nulliparous women. \nThe hysteroscopic resection of submu­\ncous adenomyotic lesions improves \ndysmenor rhea and bleeding disorders \n[114–117]. The influence of these sur ­\ngical approaches on patients fertility \nrequires further investigatios. However \nit is crucial to avoid the postsurgical for­\nmation of intrauterine adhesions by IUD \napplication or temporary insertion of a \nFoley catheter. Laparoscopic or abdomi­\nnal surgery offer a variety of surgical \ntechniques in patients with adenomyosis. \nIn an actual review Younes et al analyzed \n27 studies including 1398 patients. Re­\nsection of adenomyotic lesions is effec­\ntive for symptom control and most prob­\nably for adenomyosis­related infertility. \nMore than 75 % of patients experience \nimprovement of symptoms. Pregnancy \nrates varied after surgery depending on \nthe method and the additional medical \ntreatment of adenomyosis [118]. Most of \nthe surgical interventions can be realized \nby laparoscopy. The minimally invasive \napproach permits the excision of subse­\nrous cystic lesions [119] and focal adeno­\nmyomas [120, 121]. Also laparoscopic \ntechniques for diffuse adenomyosis with \nuterine artery blocking and double­flap \nmethod have been described [122–124]. \nRecently Kwack et al compared the lapa­\nroscopic and open surgical approach in \n224 cases of uterine adenomyomectomy \nwith transient occlusion of the uterine \narteries [125]. They concluded that sur ­\ngery is effective to reduce symptoms re­\ngardless of the approach, but laparotomy \nseems to be more suitable for diffuse and \nlaparoscopy more suitable for focal ade­\nnomyosis. \nChong et al reported that laparoscopic or \nrobotic adenomyomectomy are feasible \nand safe methods in patients with adeno­\nmyosis. The postsurgical administration \nof gonadotropin­releasing hormone ago­\nnist cycles did not improve the surgical \nresult [81]. The surgical excision of the \nadenomyotic tissue helps to reduce dys­\nmenorrhea and menorrhagia. In relation \nto adenomyosis­associated subfertility \nKishi et al described age as a determinant \nin fertility outcomes. In a retrospective \ncohort study they analyzed pregnancy \nrates in 102 patients who underwent lapa­\nroscopic adenomyomectomy depending \non the patients age. Women < 39 years \nold showed a clinical pregnancy rate of \n41.3 % and women > 40 years only a \nrate of 3.7 % [126]. In 2017 Dueholm \net al reviewed the reproductive outcome \nof patients with adenomyosis after dif­\nferent surgical approaches and in vitro \nfertilization [9], describing the results of \ndifferent open and laparoscopic surgical \ntechniques. The authors underlined that \nsurgery might be helpful in matters of \nfertility, but the effect of surgery needs to \nbe proven in the future. They emphasized \nthe lack of controlled studies, the miss­\ning clear diagnostic criteria, the missing \nreliable information about the impact \nof adenomyosis in fertility, the missing \ncorrelation between fertility and stage \nor type of adenomyosis and the lack of \na severity classification of the disease. In \nan actual review Rocha et al described an \noverall clinical pregnancy rate of 18.2% \nafter surgical treatment of adenomyosis. \nThe additional postoperative treatment \nwith gonadotropin­releasing hormone \nagonists increased the rate up to 40 % \n[127]. In another recent review Tan et al \ndescribed a mean pregnancy rate of \n52.7% in patients after surgery for fo­\ncal adenomyosis and 34.1% in patients \nwith diffuse adenomyosis. Uterine rup­\nture was reported in no patient with focal \nadenomyosis, but 6.8 % of patients with \nsurgery for diffuse adenomyosis. The \nauthors concluded that the decision for \nsurgery should be individual considering \npatients with adenomyosis with medical \ntreatment failure and women with infer ­\ntility despite assisted reproductive tech­\nniques [128]. However complications \nshould be considered and further studies \nare needed in order to proof the safety \nand effectiveness of surgical methods in \npatients with adenomyosis [129], includ­\ning the posible affection by concomitant \nendometriosis [130] and the posible \nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nHow to Diagnose and T reat Adenomyosis in Patients with Endometriosis\n267\nbenefit of additional medical treatments \nprior to or after surgery.\nIf patients want to avoid surgery and/or \ndesire fertility preservation or improve­\nment different interventional methods \nexist and therefore are currently under \ndiscussion [131]. The high­intensity \nfocused ultrasound is an alternative \ntreatment method in focal and diffuse \nadenomyosis. High­intensity focused \nultrasound offers symptom relief and a \nlow rate of major and minor complica­\ntions considering the specific selection \ncriteria. Additionally patients showed \nhigh conception and live birth rates after \ntreatment [132, 133]. The safety and effi­\ncacy of the method has been evaluated in \nvarious publications  highlighting also its \ncost­effectiveness and improvement of \nfemale sexual fuction index [134–137]. \nIn a prospective study 54 of 68 patients \ntreated with high­intensity focused ul­\ntrasound got pregnant and 21 delivered \nhealthy babies. No uterine rupture oc­\ncured [138]. However the role of high­\nintensity focused ultrasound in patients \nwho wishes to get pregnant should be \nfurther investigated. \nHai et al also described the transcervi­\ncal radiofrequency ablation for sympto­\nmatic adenomyosis as a safe and effec­\ntive method. No serious complications \noccured, however two patients devel­\noped intrauterine adhesions [139]. Also \nuterine artery embolization can reduce \nsymptoms and improve quality of life in \npatients with symptomatic adenomyo­\nsis. In a recent meta­analysis de Bruijn \net al reported an overall improvement \nof symptoms in 83.1 % of the patients \n(872/1049) [140]. Liang et al described \nthe technique as an effective uterus­spar ­\ning option for women with adenomyosis­\nrelated symptoms. Clinical success was \nachieved in 89 % of the patients (117) \nwithout major complications [141]. The \nimpact of uterine artery embolization on \nfertility and pregancy requires has been \nrecently reviewed and requires further \nevaluation [142]. \nAn other non­surgical alternative in \nboth groups of patients is the use of a \nlevonorgestrel­IUD alone or the postsur ­\ngical application as described above. A \nconscious or often unconscious option, \ndue to failed diagnosis of adenomyosis, \nis the eschewal of any particular treat­\nment. In daily routine this seems to play \na certain role also in fertility treatment, \nas no general treatment recommendation \nexists and/or no importance is attached \nto the presence of adenomyosis, although \ncorresponding literature shows that the \npresence of adenomyosis reduces the \npregnancy and birth rates after in vitro \nfertilization [3–6]. Prospective studies \nare needed in order to show which way \nis the best to improve fertility in patients \nwith adeno myosis.\n „ Conclusion\nThe cited data shows a wide range of \ndifferent experimental attempts in order \nto treat adenomyosis. Recently every \nmethod seems possible but none is prov­\nen in relation to effectiveness, fertility \noutcome, reliability and side effects. As \nthe incidence of adenomyosis is much \nhigher and the population much younger \nthan we thought, and thus the impact on \nfertility considerable, a consensus on di­\nagnosis and treatment in adenomyosis is \nneeded.\nA condition for adequate treatment is the \ndiagnosis of the uterine disease adeno­\nmyosis in patients with endometriosis. \nThis can be achieved by a combination \nof clinical history, gynecological exami­\nnation transvaginal ultrasound and ad­\nditionally MR imaging when needed. As \na function of individual patients family \nplanning and the type of adenomyosis \ndifferent treatment options offer a wide \nrange of medical and surgical treatment \napproaches. Prospective studies are \nneeded in order to describe the best way \nfor our patients in the future.\n „ Conflict of interest\nThe author declares that there is no con­\nflict of interest regarding the publication \nof this paper.\nReferences\n1. Yeniel O, Cirpan T, Ulukus M, Ozbal A, Gundem G, et al. \nAdenomyosis: prevalence, riskfactors, symptoms and \nclinical findings. Clin Exp Obstet Gynecol 2007; 34: 163–7.\n2. Li X, Liu X, Guo SW. Clinical profiles of 710 premenopau-\nsal women with adenomyosis who underwent hysterecto-\nmy. J Obstet Gynaecol Res 2014; 40: 485–94.\n3. Younes G, Tulandi T. Effects of adenomyosis on in vitro \nfertilization treatment outcomes: a meta-analysis. Fertil \nSteril 2017;108: 483–90.\n4. Salim R, Riris S, Saab W, Abramov B, Khadum I, Serhal \nP . 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Efficacy of multiple microwave endome-\ntrial ablation technique for menorrhagia resulting from \nadenomyosis. J Obstet Gynaecol Res 2015; 41: 1769–72.\n112. Ota K, Takahashi T, Shiraishi S, Mizunuma H. Com-\nbination of microwave endometrial ablation and postoper-\native dienogest administration is effective for treating \nsymptomatic adenomyosis. J Obstet Gynecol Res 2018; \n1287–92.\n113. Li JJ, Chung JPW, Wang S, Li TC, Duan H. The inves-\ntigation and management of adenomyosis in women who \nwish to improve or preserve fertility. Biomed Res Int 2018; \n2018: 6832685.\n114. Pontrelli G, Bounous VE, Scarperi S, Minelli L, Di \nSpiezio Sardo A, Florio P . Rare case of giant cystic adeno-\nmyoma mimicking a uterine malformation, diagnosed and \ntreated by hysteroscopy. J Obstet Gynaecol Res 2015; 41: \n1300–4.\n115. Gordts S, Campo R, Brosens I. Hysteroscopic diagno-\nsis and excision of myometrial cystic adenomyosis. \nGynecol Surg 2014; 11: 273–8.\n116. 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Zhou M, Chen JY, Tang LD, Chen WZ, Wang ZB. Ultra-\nsound-guided high-intensity focused ultrasound ablation \nfor adenomyosis: the clinical experience of a single cent-\ner. Fertil Steril 2011; 95: 900–5.\n138. Zhou CY, Xu XJ, He J. Pregnancy outcomes ans \nsymptom improvement of patients with adenomyosis \ntreated with high intensity focused ultrasound ablation. \nZhonghua Fu Chan Ke Za Zhi 2016; 51: 845–9.\n139. Hai N, Hou Q, Ding X, Dong X, Jin M. Ultrasound-\nguided transcervical radiofrequency ablation for sympto-\nmatic uterine adenomyosis. Br J Radiol 2017; 90: 20160119.\n140. de Bruijn AM, Smink M, Lohle PNM, Huirne JAF, \nTwisk JWR, et al. Uterine artery embolization for the treat-\nment of adenomyosis: a systematic review and meta-\nanalysis. J Vasc Interv Radiol 2017; 28: 1629–42.\n141. Liang E, Brown B, Rachinsky M. A clinical audit on \nthe efficacy and safety of uterine artery embolization for \nsymptomatic adenomyosis: results in 117 women. Aust N \nZ J Obstet Gynaecol 2018; DOI: 10.1111/ajo. 12767.\n142. Keung JJ, Spies JB, Caridi TM. Uterine artery emboli-\nzation: a review of current concepts. Best Pract Res Clin \nObstet Gynaecol 2018; 46: 66–73.\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nHaftungsausschluss\nDie in unseren Webseiten publizierten Informationen richten sich ausschließlich an geprüfte \nund autorisierte medizinische Berufsgruppen und entbinden nicht von der ärztlichen Sorg-\nfaltspflicht sowie von einer ausführlichen Patientenaufklärung über therapeutische Optionen \nund deren Wirkungen bzw. Nebenwirkungen. Die entsprechenden Angaben werden von den \nAutoren mit der größten Sorgfalt recherchiert und zusammengestellt. Die angegebenen Do-\nsierungen sind im Einzelfall anhand der Fachinformationen zu überprüfen. 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Die entsprechenden Angaben werden von den \nAutoren mit der größten Sorgfalt recherchiert und zusammengestellt. Die angegebenen Do-\nsierungen sind im Einzelfall anhand der Fachinformationen zu überprüfen. Weder die  Autoren, \nnoch die tragenden Gesellschaften noch der Verlag übernehmen irgendwelche Haftungs-\nansprüche.\nBitte beachten Sie auch diese Seiten:\nImpressum Disclaimers & Copyright Datenschutzerklärung\nMitteilungen aus der Redaktion\ne-Journal-Abo\nBeziehen Sie die elektronischen Ausgaben dieser Zeitschrift hier.\nDie Lieferung umfasst 4–5 Ausgaben pro Jahr zzgl. allfälliger Sonderhefte.\nUnsere e-Journale stehen als PDF-Datei zur Verfügung und sind auf den meisten der markt-\nüblichen e-Book-Readern, Tablets sowie auf iPad funktionsfähig.\n Bestellung e-Journal-Abo\nBesuchen Sie unsere Rubrik\n Medizintechnik-Produkte\nInControl 1050 \nLabotect GmbH\nAspirator 3 \nLabotect GmbH\nPhilips Azurion:  \nInnovative Bildgebungslösung\nNeues CRT -D Implantat  \nIntica 7 HF-T QP von Biotronik\nArtis pheno \nSiemens Healthcare Diagnostics GmbH","source_license":"CC0","license_restricted":false}