{"paper_id":"347caf5d-bf2f-4fec-b4ca-0533e92aa60e","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\nAdenomyosis – Facts and Questions 13th World\nCongress on Endometriosis, 2017 May 17–20, 2017\nVancouver, CAN Extended Abstracts\nNeis F, Rohloff N, Bühler K, DeWilde RL, Krentel H\nMechsner S, Neis KJ, Götte M, Kiesel L\nJ. Reproduktionsmed. Endokrinol 2018; 15 (5-6)\n253-269\n\n\n253\nAdenomyosis – Facts and Questions\n13th World Congress on Endometriosis, 2017\nMay 17–20, 2017 , Vancouver, CAN\nExtended Abstracts*\nmiRNA Regulation of Cell Function in Adenomyosis  \nand Endometriosis\nN. Rohloff, M. Götte, L. Kiesel\nDepartment of Gynaecology and Obstetrics, Albert-Schweitzer-Campus 1, University Hospital Münster\n „ Abstract\nmicroRNAs (miRNAs) play an important \nrole in benign and malignant diseases \nthrough post-transcriptional regulation \nof various proteins. Various miRNA-\ndysregulations have been shown in en-\ndometriosis and adenomyosis. Based on \ntheir function and technical properties, \nmiRNAs could potentially be promising \nbiomarkers and therapeutical targets in \nendometriosis and adenomyosis.\nIn endometriosis miRNA-145, miRNA-\n200b and miRNA-142-3p downregula-\ntions account for enhanced proliferation, \ninvasion and stem cell functions in en-\ndometriotic tissues through regulation \nof multiple pathways as NFKB, cyto-\nskeletal impairment, alteration of cellu-\nlar adhesions and stem cell factors.\nIn adenomyosis miR-10b is the most \npromising target. Dysregulation of vari-\nous genes and miRNAs have been found, \nbut detailed studies are still needed to \ndecode the pathways.\n „ Micro RNAs in Endo­\nmetriosis\nMicroRNAs (mi-RNAs) non-coding \nRNA molecules. As a small, singular \nstrand RNA molecule they target mRNA \nto inhibit protein expression through \ngene regulation (gene silencing) on a \npost-transcriptional level. The mRNA is \ndegraded or translation is inhibited [1].\nVarious studies demonstrate the impact \nof miRNAs on every aspect of the inva-\nsion, viability and proliferation in en-\ndometriosis. They affect inflammation, \napoptosis, cell cycle, angiogenesis and \nmuch more. MiRNAs are also investi-\ngated as potential biomarkers in endo-\nmetriosis and adenomyosis.\nmiRNAs as Serum Markers of \nEndometriosis – Current con­\nclusions\nBased on their function and technical \nproperties, miRNAs could potentially be \npromising biomarkers in endometriosis. \nFor large and reliable studies standardiz-\ned guidelines, sample types and collec-\ntion methods as well as reference genes \nare needed. For a solid estimation these \nstudies should be performed on a large \nand uniform patient collective. All of the \nfollowing miRNAs could be targets of \nsuch studies with the potential to revolu-\ntionize endometriosis diagnostics.\nImportant miRNAs for \n regulation of Endometriosis\nMiR-145 is commonly expressed in \nmesenchymal cells (e.g. fibroblasts \nand smooth muscle cells) and inhibits \nexpression of cytoskeletal elements as \nFASCIN-1, tight-junction and adhesion \nmolecule JAM-A and protease-inhibitor \n– resulting in decreased proteolysis, cell \nmobility and adhesion. It also reduces \nstem cell factors as SOX-2, MSI2 and \nOCT-4 leading to less proliferation and \nmotility. In endometriosis, lower levels \nof miRNA-145 have been detected, ac-\ncounting for increased proliferation and \nlesion invasiveness [2].\nAs the cell composition of those cell \ntypes is different in the three entities of \nendometriosis differences between the \nforms should be expected. Also, the \nmiRNA-145 levels differ and contribute \nto different invasiveness in the entities. \nIn studies miRNA-145 dysregulation and \ndecrease occur in more invasive and ag-\ngressive lesions [2–3].\nMiR-142-3p likely inhibits endometrio-\nsis by decreasing cell proliferation and \nenhancing apoptosis through NFKB by \nrepressing IL-6 ST. Through regulation \nof W ASL, Integrins as well as actin and \nvinculin in endometriosis, the building \nof spikes and focal adhesion formation \nis reduced, resulting in diminished inva-\nsiveness. miRNA-142-3p is reduced in \nendometriosis – possibly enhancing inva-\nsion and progress of the lesions through \ncytoskeletal changes, enhanced prolif-\neration, immunological responses, angio-\ngenesis and altered oestrogen levels [4].\nMiR-200b increases E-cadherin expres-\nsion through decreased ZEB-1 and ZEB \n2 levels resulting in decreased cell mo-\nbility, decreased declamping from the \ncell layer and diminished invasion. In \nendometriosis miRNA 200b expression \nis reduced, inducing lesion growth, en-\nhanced invasion and progression of the \ndisease [5].\n*Appraised by the Chairman, Prof. L. Kiesel, Münster\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\nFor personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.\n\nExtended Abstracts\n254\nThose miRNAs and many more may \nbe future targets for therapies and bio-\nmarker research.\n „ MiRNAs in Adenomyosis\nFor Adenomyosis few studies exist and \ndata concerning miRNA changes is rare.\nIn large transcription studies and micro-\narray studies several miRNA expressions \nwere dysregulated in ectopic endome-\ntrium in Adenomyosis versus normal \nendometrium [6–7] (Tab.1).\nExpression of miRNA 10b is downregu-\nlated most significantly in microarray and \nRT-PCR in endometrial tissue in adeno-\nmyosis compared to normal tissue and \neven less expressed in ectopic endome-\ntrium in adenomyosis. At the same time \ncell migration and invasion are increased \nin endometrium of adenomyosis patients \nand even more increased in ectopic en-\ndometrium of adenomyosis patients. In \nsummary, in adenomyosis invasion and \ncell migration of endometriotic cells are \nincreased, possibly due to severely de-\ncreased levels of miR-10b [6]. miR-10b \nregulates apoptosis and proliferation and \nis known to be dysregulated in various \ncancers [8] (Fig. 1).\nAlso, endometrial epithelial cells are tar-\ngets of miRNA regulation. As a poten-\ntial indicator of invasiveness or severity \nZEB1 is also known to be regulated by \nmiRNAs and to be dysregulated in ad-\nenomyosis. This indicates miRNA-dys-\nregulation. In deep infiltrating endome-\ntriosis as well as in adenomyosis ZEB1 \nwas expressed excessively. In normal \nendometrium ZEB1 was not expressed \nat all [9].\nAs in endometriosis, IL6-ST regulated \npathways seem to be involved.\nAs these few data show, research is still \ninsufficient regarding pathophysiology \nand regulation of adenomyosis in general \nand concerning miRNA in particular. If \nresults about regulation of endometriosis \ncan be applied for adenomyosis as well \nshould be validated, followed by adeno-\nmyosis specific factors and pathways.\nReferences:\n1. MacFarlane LA, Murphy PR. MicroRNA. Biogenesis, \nfunc tion and role in cancer. Curr Genomics 2010; 11: 537–\n61.\n2. Adammek M, Greve B, Kässens N, Schneider C, Brüg-\nge mann K, et al. MicroRNA miR-145 inhibits proliferation, \ninvasiveness, and stem cell phenotype of an in vitro endo-\nmetriosis model by targeting multiple cytoskeletal ele-\nments and pluripotency factors. Fertil Steril 2013; 99: \n1346–55.\n3. Saare M, Rekker K, Laisk-Podar T, Rahmioglu N, Zon-\nder van K, et al. Challenges in endometriosis miRNA stud-\nies - From tissue heterogeneity to disease specific miR-\nNAs. Biochim Biophys Acta 2017; 1863: 2282–92.\n4. Kästingschäfer CS, Schäfer SD, Kiesel L, Götte M. miR-\n142-3p is a novel regulator of cell viability and proinflam-\nmatory signalling in endometrial stroma cells. Repro-\nductive BioMedicine Online 2015; 30: 553–6.\n5. Eggers JC, Martino V, Reinbold R, Schafer SD, Kiesel L, et \nal. microRNA miR-200b affects proliferation, invasiveness \nand stemness of endometriotic cells by targeting ZEB1, \nZEB2 and KLF4. Reprod Biomed Online 2016; 32: 434–45.\n6. Guo Y, Lang X, Lu Z, Wang J, Li T, et al. MiR-10b Directly \nTargets ZEB1 and PIK3CA to curb adenomyotic epithelial \ncell invasiveness via upregulation of E-Cadherin and inhi-\nbition of akt phosphorylation. Cell Physiol Biochem 2015; \n35: 2169–80.\n7. Herndon CN, Aghajanova L, Balayan S, Erikson D, Bar-\nragan F, et al. Global transcriptome abnormalities of the \neutopic endometrium from women with adenomyosis. \nReproductive Sciences 2016; 23: 1289–303.\n8. Chen H, Fan Y, Xu W, Chen J, Xu C, et al. miR-10b In-\nhibits apoptosis and promotes proliferation and invasion \nof endometrial cancer cells via targeting HOXB3. Cancer \nBiother Radiopharm 2016; 31: 225–31.\n9. Furuya M, Masuda H, Hara K, Uchida H, Sato K, et al. \nZEB1 expression is a potential indicator of invasive endo-\nmetriosis. Acta Obstet Gynecol Scand 2017; 96: 1128–35.\nCorrespondence to:\nProf. Dr. med. Ludwig Kiesel\nDepartment of Gynaecology and \n Obstetrics\nUniversity Hospital Münster\nAlbert-Schweitzer-Campus 1,  \n48149 Münster\nGermany\ne-mail: l.kiesel@uni-muenster.de\nT able 1. Dysregulation of miRNAs in endometriosis. Mod. from [6, 7].\nDownregulated miRNAs \n[6] (sign. Microarray and \nqRT­PCR)\nUpregulated miRNAs [6] \n(sign. Microarray and qRT­\nPCR)\nDownregulated miRNAs \n[7]\nmiR-10b miR-143 miR-9-1\nmiR-371b-5p miR-513a miR-139\nmiR-92b-5p miR-466 miR-149\nmiR-30c miR-197\nmiR-326\nmiR-339\nFigure 1. miR-10 b in endometriosis after Guo et al 2015. Mod. from [5], open access (CC BY-NC).\n „ Relevancy to Practice\n – miRNAs can be future targets for \nindividualized therapies.\n – miRNAs may be valid candidates \nfor biomarkers in diagnosis of \nendometriosis and adenomyosis.\n – Adenomyosis and endometriosis \nhave different pathophysiologi-\ncal characteristics and need to be \nevaluated separately.\n – Standardized research is needed \nfor endometriosis and adenomy-\nosis, providing opportunities for \nresearchers.\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n255\nAdenomyosis – Possible Cause for Infertility in Women  \nwith Endometriosis?\nK. Bühler1, K. J. Neis1, F. Neis2\n1 Centre of Excellence for Endometriosis of the University Hospitals of Saarland – Frauenärzte am Staden, Saarbrücken;  \n2 Department of Obstetrics and Gynaecology, University of Tübingen\n „ Abstract\nAdenomyosis is a heterogeneous and \npoorly understood gynaecologic disease. \nMost frequently the major symptoms are \ntroublesome, heavy menstrual bleeding, \ndysmenorrhoea and sometimes a tender \nuterus. Since more women are tending to \ndelay their first pregnancy till their late \nthirties or early forties, adenomyosis has \nbecome more relevant in the context of \nsubfertility. In order to be able to answer \nthe question referred, a literature re-\nsearch was performed.\nAs possible causes for infertility in \nwomen with adenomyosis can be seen: \nintrauterine abnormalities, intensified \nuterine peristalsis and altered endome-\ntrial milieu. But, there is a lack of suf-\nficient data to show doubtless evidence \nthat adenomyosis alone is the cause of \nsubfertility. To improve fertility, surgi-\ncal treatment or/and reproductive medi-\ncine ± GnRH analogues pre-treatment \nare recommended. It is necessary to \nprovide a complete removal of all ad-\nenomyosis or to induce a reduction of \nthe inflammatory process by a GnRH \nagonist ( ultra-)long pre-treatment be-\nfore fertility enhancing procedures are \nstarted.\n „ Introduction\nAdenomyosis is a heterogeneous gy-\nnaecologic disease. It is a poorly un-\nderstood and so often called enigmatic \nand/or elusive due to the difficulties in \ndiagnosis and the lack of agreement con-\ncerning the definition. Most frequently \nthe major symptoms are troublesome, \nheavy menstrual bleeding, excruciating \ndysmenorrhoea and sometimes a tender \nuterus. But sometimes it can also be \nasymptomatic.\nAdenomyosis is a benign disease of the \nuterus characterised by an invasion of \nectopic endometrial glands and stroma \nwithin the myometrium producing a \ndiffusely enlarged uterus which micro-\nscopically exhibits ectopic, non-neo-\nplastic, endometrial glands and stroma \nsurrounded by the hypertrophic and hy-\nperplastic myometrium [1]. A first sci-\nentific description of adenomyosis was \ndone by C. Rokitansky in his publica-\ntion: “Über Uterusdrüsen-Neubildung” \nin 1860 [2].\nAdenomyosis is seen mostly in women \nat their late 4 th or 5 th life decade and so \nduring long time the problem adenomy-\nosis and fertility seemed not to be exist-\nent! Since more women are tending to \ndelay their first pregnancy till their late \nthirties or early forties, adenomyosis has \nbecome more relevant in the context of \nsubfertility. It is a welcome figure that \nin Germany in 2016 the number of new-\nborns re-approached the level reached in \n1996 but on the other side the number of \nmothers at the age of 40 years and more \nincreased since 2011 of 13.4% up to \nnearly 40,000 women [3]. When looking \nat ART treatment we have to realise that \nin 2016 every 5th woman treated by IVF \nwas at the age of ≥  40 years and 3.2% \neven at the age of ≥  44 years [4]. These \nfigures explain very well that adeno-\nmyosis has become an increasing prob-\nlem in fertility treatment although the \nincidence peak is about 5–10 years later \ncompared to endometriosis [5]. Never -\ntheless, endometriosis and adenomyosis \noften occur together in about 27% to \n49% and is significantly associated with \ndeep infiltrating endometriosis, parity, \ndysmenorrhea intensity and women’s \nage [6].\n „ Methods\nIn order to be able to answer the question \nreferred, a literature research was per -\nformed looking to the following items:\n – adenomyosis\n – fertility\n – endometriosis\n – surgery in patients with adenomyosis \n± endometriosis\n – medical treatment in patients with \n adenomyosis ± endometriosis.\n „ Adenomyosis in \n Patients with Fertility \n Disturbances\nIn animal studies it is quite easier to \nexamine the association between ad-\nenomyosis and fertility. In a population \nof captive baboons endometriosis was \nstrongly associated with the presence of \nadenomyosis with an OR of 31.5. Adeno-\nmyosis was associated with the presence \nof lifelong infertility (OR = 20.6), even \nif cases with coexisting endometriosis \nwere excluded (OR = 20.1) [7].\nIn human, long time, the only way to be \ncertain of adenomyosis is to examine the \nuterine tissue under the microscope after \nsurgery. Only with the possibility to diag-\nnose adenomyosis at the “living object” \nby ultrasound – US – and/or magnetic \nresonance imaging – MRI – the ques-\ntion of impact on fertility has emerged. \nBut there are conflicting results reported \nin the literature. One group reported in \nwomen with infertility and symptoms of \ndysmenorrhoea or menorrhagia that in \n54% adenomyosis could be detected by \nMRI. But finally, only 26 women were \nincluded in the study [8]. Puente et al. \n[9] diagnosed adenomyosis in women \nbefore starting an ART treatment or after \nrecurrent pregnancy loss by 3D-US. They \nfound signs for adenomyosis in 24.4%, \nsignificantly more often in women aged \n≥ 40, in 29.7% as compared to women \n< 40 years, 22%. The prevalence was \nalso significantly higher in those cases \nof recurrent pregnancy loss, 38.2 %, and \nprevious ART failure, 34.7%. Patients \nwith fibroids showed also adenomyosis \nin 18%. Among the patients with endo-\nmetriosis, 35.1% were also diagnosed \nwith adenomyosis. This is in contrast to \nthe group of Bazot et al. which reported \nthe coincidence of pelvic endometriosis \nand adenomyosis only in 27% (44/163 – \ndiagnostic by MRI) [10]. In a further \nstudy the same group demonstrated in \nwomen with dysmenorrhea, nonmen-\nstrual pelvic pain, dyspareunia, and pain \non defecation treated with laparoscopic \nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n256\ncolorectal resection only 4 women of \n22 – 18.2% – who wanted to conceive \nshowed also adenomyosis. 45.5% of the \nwomen got pregnant after the surgery, \nbut none of them with adenomyosis [11].\nKunz et al. looked in 227 infertile women \nabout the prevalence of adenomyosis, \ndiagnosed by MRI, and endometriosis \nand its impact on fertility. In 28% of \nthe women without endometriosis signs \nof adenomyosis were found in 28% of \nthe women and when in them there was \nan andrological reason of the infertili-\nty only in 9%. But in 160 women with \nproven endometriosis 79% showed also \nadenomyosis and in 30 women of them, \nyounger than 36 years and with fertile \npartners even in 90% adenomyosis could \nbe detected with MRI [12]. These differ-\nences are due to the different definitions \napplied.\nAs possible causes for infertility in wom-\nen with adenomyosis can be seen:\nIntrauterine abnormalities:\ndistortion of the uterine cavity, obstruc-\ntion of tubal ostium, interference with \nsperm & embryo\nUterine peristalsis:\ndysfunctional uterine hyperperistalsis, \nincreased intrauterine pressure, junc-\ntional zone hyperactivity → contractions \n(→ ectopic pregnancies ↑), disturbed \nuterotubal sperm transport\nAltered endometrial milieu:\nhigher macrophage density, more proin-\nflammatory cytokines, such as TNF-α or \nIL-1, reduction of progesterone receptor \nexpression\nVery often, a reduced endometrial re-\nceptivity is discussed also. So, Huang \net al. discussed if an abnormal expres-\nsion of oxytocin receptors in the uterine \njunctional zone may result in abnormal \nuterine contractile activity and reduces \nso fertility [13].\nThe group of the Instituto Valenciano de \nInfertilidad evaluated the endometrial \nreceptivity in patients with adenomyo-\nsis by two aspects: endometrial gene \nexpression and the model of oocyte \ndonation (OD) [14]. Endometrial sam-\nples were collected from six women in \nwhom ade nomyosis had been diagnosed \nby MRI and transvaginal US. There is \na similar endometrial gene expression \npattern in both the adenomyosis group \nand controls, and nonparametric tests \nrevealed 34 dysregulated genes in ad-\nenomyosis patients but none belonged \nto the group of window of implantation \ngenes. Pregnancy rates in OD did not \ndiffer among the three groups, control, \nwomen with endometrioma, women \nwith adenomyosis. However, miscar -\nriage was significantly higher in the ad-\nenomyosis group vs. the endometriosis \nand control groups and so, term preg-\nnancy rate was also significantly lower \nin the adenomyosis group compared \nwith others (Fig. 1).\n „ T reatment Options in \n Patients with Adenomyo­\nsis and Infertility\nSurgical treatment to improve \nfertility\nLimited data are available concerning \nthe efficacy of the different treatment \noptions of adenomyosis on fertility \noutcome and mostly the data are retro-\nspective evaluations or small case series \n[15]. As different surgical techniques \nare described: adenomyomectomy with \nunilateral salpingectomy, microsurgical \nadenomyomectomy, adenomyomectomy \nusing double or triple-flap method, or \ne. g. adenomyomectomy with continu-\nous horizontal mattress technique. Rocha \net al. reported in a recent review [16] a \npooled clinical pregnancy rate after sur -\ngical resection of adenomyosis of 38.8%, \nmostly achieved by ART, and a miscar -\nriage rate and live birth rate of 17.9% and \n30.4% respectively (Fig. 2).\nReproductive medicine to im­\nprove fertility\nOnce again, mostly retrospective stud-\nies are available. In the pooled analysis \nfrom Rocha et al. [16] the overall preg-\nnancy rate was 36.1%, live birth/ongoing \npregnancy rate 29.9% and miscarriage \nrate 25.9%. There is a significant differ -\nence in the outcome of IVF/ICSI treat-\nment cycles depending of the type of \nGnRH analogue used (Fig. 3). If the long \nagonist regimen was applied pregnancy \nand live birth rates were significantly \nincreased and the miscarriage rate sig-\nnificantly lower. This was also showed \nby a meta-analysis [17]. There was no \ndifference in ART outcome in women \nwith adenomyosis compared to women \nwithout adenomyosis when the long \ndown regulation protocol was used but \nwith the short protocol the results were \nsignificantly lower. And also looking at \nmiscarriage rates there was no difference \nwith the long downregulation but with \nthe short protocol when adenomyosis \nwas present.\nObviously, the myometrial thickness can \nserve as a marker for the ART treatment \noutcome. If in transvaginal US a myo-\nmetrial thickening of more than 2.50 cm \nwas seen at the day of hCG triggering the \nimplantation, clinical pregnancy, and live \nFigure 1. Cumulative pregnancy (CPR) and term pregnancy (TPR) rates after embryo transfer with donated \noocytes of women without adenomyosis. Mod. from [14].\n*significant difference\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n257\nbirth rates were significantly lower in the \nIVF-ET treatment with the short protocol \n[18].\nAlso, if frozen embryo transfer (FET) \nwas performed long downregulation \nwith GnRH agonist showed a beneficial \neffect: significantly higher ongoing preg-\nnancy/live birth rates [19, 20]. It seems \nthat GnRH-a treatment decreases the size \nand demarcation of adenomyotic lesions, \nas demonstrated by MRI [21], and treat-\nment has a positive effect on endometrial \nimplantations markers [22].\n „ Conclusion\nAdenomyosis represents a chronically \ninflammatory process yielding particu-\nlarly in early pregnancy loss. Concern-\ning a possibly reduced implantation the \npresent evidence is too poor and more \nstudies are needed to reach a definitive \nconclusion. Only if adenomyosis and \npelvic endometriosis occur together a \nclear fertility reduction is established. \nSo, there is a lack of sufficient data to \nshow doubtless evidence that adeno-\nmyosis alone is the cause of subfertility. \nIt seems that adenomyosis is the reason \nfor higher miscarriage rates and reduced \nfertility is more due to often concomitant \nendometriosis. But in both pathologies it \nis necessary in order to ameliorate fer -\ntility to provide a complete removal of \nall adenomyosis and/or endometriotic \nfoci or to induce a reduction of the in-\nflammatory process by a GnRH agonist \n(ultra-)long pre-treatment before fertility \nenhancing procedures are started.\nReferences:\n1. Bird CC, McElin TW, Manalo-Estrella P . The elusive ad-\nenomyosis of the uterus. Am J Obstet Gynecol 1972; 112: \n583–93.\n2. Rokitansky C. Über Uterusdrüsen-Neubildungen in \n Uterus- und Ovarial-Sarcomen. Zeitschrift der Kaiserlich \nKoenigl Gesellschaft der Aerzte zu Wien 1860; 37: 577–81.\n3. DeStatis. Continued increase in births in 2016. https://\nwww.destatis.de/EN/PressServices/Press/pr/2018/03/\nPE18_115_122.html. pressrelease no. 165. (last seen July \n26, 2018).\n4. Blumenauer V, Czeromin U, Fehr D, Fiedler K, Gnoth C, \nKrüssel JS, Kupka MS, Ott A, Tandler-Schneider A. D.I.R \nAnnual 2016 – The German IVF-Registry. J Reproduktions-\nmed Endokrinol 2017; 14: 272–305.\n5. Templeman C, Marshall SF, Ursin G, Horn-Ross PL, \nClarke CA, et al. Adenomyosis and endometriosis in the \nCalifornia Teachers Study. Fertil Steril 2008, 90: 415–24.\n6. Di Donato N, Montanari G, Benfenati A, Leonardi D, \nBertoldo V, et al. Prevalence of adenomyosis in women \nundergoing surgery for endometriosis. Eur J Obstet \nGynecol Reprod Biol 2014; 181: 289–93.\n7. Barrier BF, Malinowski MJ, Dick EJ Jr, Hubbard GB, \nBates GW. Adenomyosis in the baboon is associated with \nprimary infertility. Fertil Steril 2004; 82 (Suppl 3): 1091–4.\n8. de Souza NM, Brosens JJ, Schwieso JE, Paraschos T, \nWinston RM. The potential value of magnetic resonance \nimaging in infertility. Clin Radio 1995; 50: 75–9.\n9. Puente JM, Fabris A, Patel J, Patel A, Cerrillo M, \nRequena A, Garcia-Velasco JA. Adenomyosis in infertile \nwomen: prevalence and the role of 3D ultrasound as a \nmarker of severity of the disease. Reprod Biol Endocrinol \n2016; 14: 60.\n10. Bazot M, Darai E, Hourani R, Thomassin I, Cortez A, et \nal. Deep pelvic endometriosis: MR imaging for diagnosis \nand prediction of extension of disease. Radiology 2004; \n232: 379–89.\n11. Daraï E, Marpeau O, Thomassin I, Dubernard G, Bar-\nranger E, Bazot M. Fertility after laparoscopic colorectal \nresection for endometriosis: preliminary results. Fertil \nSteril 2005; 84: 945–50.\n12. Kunz G, Beil D, Huppert P , Noe M, Kissler S, Leyen-\ndecker G. Adenomyosis in endometriosis-prevalence and \nimpact on fertility. Evidence from magnetic resonance im-\naging. Hum Reprod 2005; 20: 2309–16.\n13. Huang M, Li X, Guo P , Yu Z, Xu Y, et al. The abnormal \nexpression of oxytocin receptors in the uterine junctional \nzone in women with endometriosis. Reprod Biol \nEndocrinol 2017; 15: 1.\n14. Martínez-Conejero JA, Morgan M, Montesinos M, \nFortuño S, Meseguer M, et al. Adenomyosis does not af-\nfect implantation, but is associated with miscarriage in \npatients undergoing oocyte donation. Fertil Steril 2011; 96: \n943–50.\n15. Devlieger R, D‘Hooghe T, Timmerman D. Uterine aden-\nomyosis in the infertility clinic. Human Reprod Update \n2003; 9: 139–47.\n16. Rocha TP , Andres MP , Borrelli GM, Abrão MS. Fertility-\nSparing treatment of adenomyosis in patients with in-\nfertility: A systematic review of current options. Reprod \nSci 2018; 25: 480–6.\n17. Bostels J. Adenomyosis and infertility: what evidence? \nMédecine la reproduction 2016; 18: 166–75.\nFigure 3. Pregnancy and live birth rates (%) after ART  treatment in women with adenomyosis. Mod. from [16].\nPR = pregnancy rate, LBR = live birth/ongoing pregnancy rate, all = overall, long = GnRH agonist regimen, \nshort = short GnRH agonist or GnRH antagonist regimen\n*significant difference\nFigure 2. Pregnancy and live birth rates (%) after surgical treatment of adenomyosis. Mod. from [16].\nPR = pregnancy rate, LBR = live birth rate, GnRHa = Gonadotropin Releasing Hormone agonist\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n258\n18. Youm HS, Choi YS, Han HD. In vitro fertilization and \nembryo transfer outcomes in relation to myometrial thick-\nness. J Assist Reprod Genet 2011; 28: 1135–40.\n19. Niu Z, Chen Q, Sun Y, Feng Y. Long-term pituitary \ndown regulation before frozen embryo transfer could im-\nprove pregnancy outcomes in women with adenomyosis. \nGynecol Endocrinol 2013; 29: 1026–30.\n20. Guo S, Zhang D, Niu Z, Sun Y, Feng Y. Pregnancy out-\ncomes and neonatal outcomes after pituitary down-regu-\nlation in patients with adenomyosis receiving IVF/ICSI and \nFET: results of a retrospective cohort study. Int J Clin Exp \nMed 2016; 9: 14313–20.\n21. Imaoka I, Ascher SM, Sugimura K, Takahashi K, Li H, et \nal. MR imaging of diffuse adenomyosis changes after \nGnRH analog therapy. J Magn Reson Imaging 2002; 15: \n285–90.\n22. Khan KN, Kitajima M, Hiraki K, Fujishita A, Nakashima \nM, Masuzaki H. Decreased expression of human heat \nshock protein 70 in the endometria and pathological le-\nsions of women with adenomyosis and uterine myoma \nafter GnRH agonist therapy. Eur J Obstet Gynecol Reprod \nBiol 2015; 187: 6–13.\nCorrespondence to:\nDr. Klaus Bühler\nCentre of Excellence for Endometriosis \nof the University Hospitals of Saarland \n– Frauenärzte am Staden, Saarbrücken\nBismarckstraße 39–41,  \n66121 Saarbrücken\nGermany\ne-mail: buehler.kf@t-online.de\nPathogenesis of Adenomyosis uteri (AM) – New Concepts\nS. Mechsner\nEndometriosis Centre Charité, Department of Gynecology, Charité Medical University Berlin, Germany\n „ Abstract\nAdenomyosis (AM) means the occur -\nrence of endometrial cells within the \nmyometrium. It could be present as a \ndiffuse superficial form or with deeper \ninfiltration. There are also focal forms, \nwhich are able to affect the adjacent or -\ngans such as the bladder or rectum. Over \nthe years the real prevalence of AM uteri \nhas been underestimated. However, the \nongoing better quality of ultrasounds and \nthe possibility of MRIs have demonstrat-\ned a high prevalence of AM in patients \nwith endometriosis (EM) especially in \npatients with infertility and ranked the \nprevalence between 80–91 % of all en-\ndometriosis patients.\nThis high prevalence may indicate the \npossible involvement of AM on the \npathogenesis of AM and EM-associated \ninfertility. Furthermore, some new data \nsuggest that AM might also have an im-\npact on miscarriages. Patients suffer from \nsevere dysmenorrhea, heavy menstrual \nbleeding, pelvic pain and dyspareunia.\nThe pathogenesis of AM still remains \nunclear. There is the idea of a peristaltic-\ndependent induction of microscopic tis-\nsue injury at the endometrial junctional \nzone (EMJZ), which in turn leads to the \ntranslocation of the basal endometrium \ninto the myometrium with the consecu-\ntive development of adenomyotic le-\nsions. This tissue injury might stimu-\nlate a process of tissue repair in which \nestrogen is locally produced, which in \nturn stimulates angiogenesis, prolifera-\ntion and a local OT synthesis. The local \nOT activated oxytocin receptors on the \nmyometrial smooth muscle cells cause \nmore hyperperistalsis. Subsequently, \nthe tissue injury increases and a vicious \ncircle is established. Microscopic find-\nings underlay this theory. Furthermore, \nultrastructural analysis of the junctional \nzone identifies stem cell like cells, which \nmight be involved in the pathogenesis of \nthis disease.\nThe adenomyotic-associated myome-\ntrial cells show an over expression of \nthe oxytocin receptor as well as changes \nin their architecture. Both might lead to \n dysperistalsis of the myometrial cells and \nthe reduced uterine blood flow, which \ncauses ischemic pain. The myometrial \ninnervation seems to be disturbed and \nthe deletion of sympathetic nerve fibers \nmight be a further factor in the functional \nchanges of the myometrium.\n „ Background\nAdenomyosis (AM) seems to be a fix \nlinked objective to endometriosis. How-\never, over the years the real prevalence \nof adenomyosis uteri has been underes-\ntimated. The ongoing better quality of \nultrasounds and the possibility of MRIs \nhave demonstrated a high prevalence of \nadenomyosis in patients with endome-\ntriosis, especially in those with infertility \n[1]. This prevalence is currently ranked \nbetween 80–91% of all endometriosis \npatients.\nThe high prevalence may indicate the \npossible involvement of AM on a range \nof endometriosis related symptoms like \ndysmenorrhoea and heavy menstrual \nbleeding, pelvic pain and dyspareunia \n[2]. But furthermore, there seems to be \na direct link to the pathogenesis of AM \nand EM-associated infertility and some \nnew data suggests that AM could be an \nimpact on miscarriages. AM is of great \nunderestimated clinical importance.\nAM means the occurrence of endometrial \ncells within the myometrium. It could be \npresent as a diffuse superficial form char-\nacterised by a thicker junctional zone or \nwith deeper infiltration. In these cases, \nthe complete myometrial wall would be \nthicker and both uterine walls are more \nasymmetric to each other. If the infiltra-\ntion affects both sides, there will be an \noverall enlargement of the uterus. There \nare also focal forms, which are able to \naffect the adjacent organs such the blad-\nder or lead to retrocervical endometriosis \nwith bowel affection [3] (Fig. 1).\nIt is very important development for cli-\nnicians to focus on AM, especially when \ndescriptions on the ultrasonographic \nfeatures of uterine changes are becoming \nmore and more popular [4]. However, all \nthese visible changes have already shown \na disturbed uterus. It is a shame that we \nhave no possibility to recognize uterine \nchanges before irreversible damage has \noccurred. AM is a hard topic and the \nbrilliant review of Yen [5] was summa-\nrised at the end: “The mechanisms and \npathogenesis of AM and its clinical im-\npacts are still far from being understood. \nConsequently, it is difficult to diagnose \nAM at an early stage.“\nThis is what we have to focus on to ana-\nlyse in the near future. All these features \nneed time for development and the be-\nginning of these changes has not yet been \ndefined. Maybe it is linked to the pri-\nmary dysmenorrhoea, which over 90% \nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n259\nof endometriosis patients have reported \n(Leyen decker). There are also hints of \npresence of adenomyosis in adolescents \nwith severe dysmenorrhoea [6–9]. We \nknow that dysmenorrhoea is associated \nwith a disturbed pattern of contractili-\nty and this might be the beginning of \nthe tissue injury and ongoing changes. \nMaybe AM is more undetectable in its \nearly stages, but already present. In or -\nder to investigate this in more detail, we \nexamined 38 adolescent patients with \nsevere dysmenorrhoea for the early signs \nof adenomyosis such as the halo phe-\nnomenon, inhomogenous myometrium \nand asymmetry of the uterine walls and \nfound changes in 91% of the cases [un-\npublished data, Abesadze et al., in prep].\n „ Pathogenesis – Changes \nof the Junctional Zone \n(JZ)\nHowever, so far, we have no idea of the \npathogenesis of adenomyosis and as long \nas this remains to be unclear the innova-\ntive therapeutic approaches to fight this \ndisease are missing. The current leading \nidea of the pathogenesis of AM in uteri \nof reproductive aged women is the tis-\nsue injury and repair concept postulated \nby Leyendecker. What does this mean.: \nThe uteri of patients with adenomyosis \nexhibit hyperperistalsis [10]. This is \nlinked with a peristaltic-dependent in-\nduction of microscopic tissue injury at \nthe endometrial junctional zone (EMJZ), \nwhich in turn leads to the translocation \nof the basal endometrium into the myo-\nmetrium with consecutive development \nof adenomyotic lesions. This tissue in-\njury might stimulate a process of tissue \nrepair mechanisms in which oestrogen is \nlocally produced, this in turn stimulates \nangiogenesis, proliferation and a local \noxytocin (OT) synthesis. The local OT \nactivated oxytocin receptors on the myo-\nmetrial smooth muscle cells cause more \nhyperperistalsis. Subsequently, more tis-\nsue injury occurs and a vicious circle is \nestablished [11]. In agreement with this, \nfurther ongoing studies have analysed \nthe border between the endometrium and \nmyometrium in patients with and without \nAM and confirmed the concept of dis-\nrupture of the JZ. The endo-myometrial \nborder in patients with fibroids is very \nsmooth, whereas the endo-myometrial \nborder in patients with AM is disruptured \n[12, 13]. Interestingly, other than these \nmorphological changes, there is also an \nupregulation of smooth muscle actin pre-\nsent in the basal endometrial layer of pa-\ntients with AM. This is a strong hint for \na fibroblast to myofibroblast transition in \nthe JZ [14]. Myofibroblasts are known to \nsecrete Collagen 1, an important factor \nfor fibrosis, which is also upregulated in \nthe adenomyotic uteri [14–16]. So, fibro-\nblast to myofibroblast transdifferentia-\ntion (FMT) seems to be an important part \nof the process, which might be activated \nby tissue injury. Ongoing platelet aggre-\ngation seems to induce EMT and FMT in \na adenomyosis mice model [15].\nThe junctional zone was also analysed by \nultrastructural investigations and showed \na range of changes which are also in line \nwith mechanical alternations. For exam-\nple, normally the nucleus of non-adeno-\nmyosis patients is very smooth, whereas \nthe nucleus of patients with adenomyo-\nsis is irregular with invaginations. This \ncould be a result of mechanical altera-\ntion due to the strong contractions in \nthis area [13]. Transelectric microscopy \ngives a deep insight into the composition \nof the epithelial and stromal cells of the \njunctional zone. In uteri of adenomyosis \npatients the arrangement of these cells \nis interrupted by the myometrial cells. \nFurthermore, in non-adenomyotic uteri \nthe orientation of the myometrial smooth \nmuscle cells of the inner myometrium is \nparallel to each other, but in adenomyotic \nuteri the myometrial cells have no clear \norientation as they are directed in diverse \nalignments. Interestingly, there was a so \nfar undescribed cell population present \nin patients with and without AM. These \ncells are electro-lucent and mitochon-\ndria – and ribosome rich because these \nare characteristics from stem cell-like \ncells, which are called pale cells. These \ncells are mostly localised on the basal \nof the glands and are sometimes also \nconcentric to the lumen of the gland. \nPale cells have no desmosomes and are \npartially detached from the surrounding \ncells. A total detachment of these cells \nwas only observable in patients with \nadenomyosis and interestingly the cell \n bodies of the neighbouring cells seem \nto drift apart from each other, with the \nfinding of a thin basal cellular inter-\ndigitations. In a rare number of patients, \na micro-perforation of the basement \nmembrane was found with the building \nof pseudo-pods and even a cytoplasmic \nmigration. The migration of these cells \nwas only seen in AM specimens. So pale \ncells might also be involved in pathogen-\nesis of AM (Fig. 2). There seems to be \nsome so far unknown factors (perhaps \nthe severe peristaltic) which lead in turn \nto an activation of these cells with the in-\nduction of migration. Translocated pale \ncells might be able to develop into AM \nor endometriosis [13].\n „ Changes of the \n Adenomyotic Lesions\nThe adenomyotic lesions also show a \nrange of morphological changes: In AM \nlesions there are not only isolated isles \nof endometrial and stromal cells, but also \nsmooth muscle like cells present. These \ncells are located within the stromal cells, \nbut are also surrounded by the lesions. \nFigure 1. Adenomyosis uteri. Mod. from [3].\nA: Diffuse forms of adenomyosis uteri: a) superficial and b) deep; B: focal forms with bladder or bowel \naffection; C: clinical presentation of deep infiltration diffuse adenomyosis; D: clinical presentation of focal \nretrocervical adenomyosis with bowel infiltration\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n260\nThe adjacent myometrium seems to be \nvery compact with a changed architec-\ntural arrangement of the myometrium \nin comparison to the unaffected myo-\nmetrium. Similar to the junctional zone \nsmooth muscle metaplasia seems to be \npresent in this area, resulting in a com-\npact packed myometrium around the \nlesions. These myometrial cells show a \nmoderate to strong oxytocin and vaso-\npressin receptor (OTR/VPR) expres-\nsion. The adenomyotic stromal cells are \nmostly OTR negative with the exception \nof some single cells, which fuse with the \nsurrounding smooth muscle cells of the \nmyometrium. Using the antibody against \nsm-Actin, this spindle like cell popula-\ntion has been characterized as smooth \nmuscle cells, which are in direct contact \nwith the adenomyotic stroma cells. OTR \nand VPR are known as being very im-\nportant uterotonic peptides and may play \na crucial role in the dispersalist of AM. \nIn comparison to the unaffected myome-\ntrium there seems to be an overexpres-\nsion of the OTR in myometrial cells \nsurrounding the adenomyotic stroma and \nepithelium, however it might be possible \nthat the OTR-overexpression is due to \nthe compact morphology of the myome-\ntrial cells.\nOTR expression is present in the normal \nendometrium of patients with and with-\nout AM with cyclical changes especially \nin the functional layer. In AM lesions \nthere is only a weak expression of OTR \nin epithelial cells present, interestingly \nthe cells do not show a cyclic variation. \nOTR-expression in the AM lesion is \nsimilar to the expression described for \nthe basal layer of the endometrium [12]. \nVPR is also expressed in all layers of the \nmyometrium of the non-pregnant uterus. \nInterestingly, an immunoreactive staining \nin the smooth muscle cells of the blood \nvessels is also present.  In contrast to the \nOTR expression there is no VPR expres-\nsion in endometrial epithelial cells. In \nadenomyotic epithelial and stromal cells \nthere are no VPR expression detectable. \nIn contrast, the smooth muscle cells of \nthe myometrium and blood vessels do \nshow a moderate to strong VPR expres-\nsion. So both receptor systems might be \ninvolved in hyperperistalsis.\n „ Pathogenesis of Hyper­\nperistalsis and Dysmenor­\nrhoea\nMyometrial hyperactivity and reduced \nuterine blood flow causes ischemic pain. \nThis is a well-established phenomenon \nin women with primary dysmenorrhoea, \nmeaning women have a painful menstrua-\ntion starting with their first period [17]. \nOxytocin, Vasopressin as well as prosta-\nglandin (PG) F2a are involved in causing \nmyometrial contractility. Peptides like \nVasopressin, Endothelin, noradrenaline \nand endoperoxides might contribute to \nthe vasoconstriction. However, the rela-\ntionship between adenomyosis and dys-\nmenorrhoea needs to be clarified. There \nis still little knowledge about the patho-\nphysiology of adenomyosis-associated \ndysmenorrhoea. Recently it has been \ndemonstrated that the uteri from patients \nwith adenomyosis and endometriosis \nshow hyper- and dysperistalsis [18–20]. \nThe physiological role of OT and VP \nin non-pregnant uteri has not been fully \nunderstood. There is a body of evidence, \nthat these peptides play an essential role \nin uterine contractility and dysmenor -\nrhoea. The changed architectural myo-\nmetrial composition might be the cause \nof the ongoing hyper- and dysperistalisis, \nsometimes also with insufficient contrac-\ntion resulting in high menstrual bleeding.\n „ Changes in the Uterine \n Innervation of AM\nOne of the main topic of the last few \nyears was the question: Are there chang-\nes in the uterine innervation of patients \nwith AM and does this have an impact \non the pathogenesis? A systematic inves-\ntigation regarding the innervation of uteri \nwith AM was performed: full thickness \nspecimens after a hysterectomy were \nselected and the innervation in all layers \nwere investigated separately. Four differ-\nent kinds of pan marker for myelinated \nand unmyelinated nerve fibers (NF) \nwere used. No significant difference was \nfound between patients with and without \nAM. There were nearly no nerve fibers \nin the functional layer, only single ones. \nMore NF were detected in the basal and \njunctional layer and nearly 4 NF per mm² \nin the myometrium. The adenomyotic le-\nsions were also rarely innervated [21].\nIn order to understand the pathophysiol-\nogy and the pain mechanisms in more \ndetail the adenomyosis associated nerve \nfibers had to be characterised. In general, \nwe were interested in the correlation of \nsympathetic and sensory nerve fibers, be-\ncause these two nerve fiber systems seem \nto have a crucial role in chronic inflam-\nmatory diseases. For this, different nerve \nfiber markers were used to distinguish \nbetween sensory and sympathetic nerve \nfibers. Interestingly in adenomyotic \nmyo metria  there were a reduced num-\nber of sympathetic nerve fibers observed \n[21]. Changes in the sympathetic uter -\nine innervation are a known phenom-\nenon physiologically during cycle and \npregnancy. There seems to be hormone \ndependent changes present in the myo-\nmetrium of rodents. In the estrogen rich \nphase, the sympathetic nerve fibers de-\ncrease, and remodel in the estrogen-poor \nphases [22, 23]. This is also observed in \nFigure 2. Concept of adenomyosis and endometriosis pathogenesis. Reprint from [13] with permission from \nElsevier.\nJ Reproduktionsmed Endokrinol_Online 2018; 15 (5–6)\n\nExtended Abstracts\n261\nhumans with ongoing pregnancy, with \nthe lowest level at term. Maybe this has \nan influence on the contractility and make \nthe uterus calm with ongoing pregnancy. \nBut so far there is no data available about \nthe biological reason for this.\nBut the question is what happens in ad-\nenomyosis, what is the reason for the \nreduced number of sympathetic nerve \nfibers in AM? If the higher estrogen \nexpression is involved in this process, \nthen maybe the aromatase overexpres-\nsion with local estrogen synthesis is the \ntrigger for the disturbed remodelling of \nsympathetic nerve fibers in adenomyotic \nuteri. Perhaps this also has a functional \neffect on adenomyosis associated dys-\nmenorrhea and infertility with disorder \nin the contraction pattern with dysperi-\nstalsis.\n „ Conclusion\nThere seems to be evidence for a micro-\ntrauma associated pathway involved in \nthe pathogenesis of AM like fibroblast \nto myofibroblast transdifferentiation, \nespecially in the area of the JZ. Activa-\ntion of pale cells might be involved in the \npathogenesis of EM/AM. The translocat-\ned pale cells could have the potential to \ndevelop into fully differentiated lesions \nincluding stromal, epithelial as well as \nsmooth muscle cells.\nChanges of the architectural morphol-\nogy of the myometrium might be a \nreason for the dys-and hyperperistalsis. \nThe Oxytocin as well as the Vasopressin \nreceptor system might be involved here \nas well.  OTR is expressed in epithelial \nand smooth muscle cells in adenomyosis \nuteri. Oxytocin mediates the induction \nof PGF2α synthesis in epithelial cells, \nwhich mediates pain and oxytocin in-\nduces smooth muscle contraction. The \nchange in the myometrial architecture \namplifies the dys- and hyperperistalsis of \nthe myometrial cells. The selective inhi-\nbition of this receptors system might be \na promising new treatment option for en-\ndometriosis-associated dysmenorrhoea \nand cyclic pelvic pain, especially for \nwomen who want to become pregnant. \nThe disturbed remodeling of sympathetic \nNF might be another functional problem \nin the coordination of the myometrial \nacitivity. Altogether adenomyosis seems \nto be a disorder which causes defects in \nthe coordination of uterine contractions.\nReferences:\n1. Kunz G, Beil D, Huppert P , Noe M, Kissler S, Leyen-\ndecker G. Adenomyosis in endometriosis--prevalence and \nimpact on fertility. Evidence from magnetic resonance im-\naging. Hum Reprod 2005; 20: 2309–16.\n2. Parker JD, Leondires M, Sinaii N, Premkumar A, Nie-\nman LK, Stratton P . Persistence of dysmenorrhea and \nnonmenstrual pain after optimal endometriosis surgery \nmay indicate adenomyosis. Fertil Steril 2006; 86: 711–5.\n3. Keckstein J. Hysteroscopy and adenomyosis. Contrib \nGynecol Obstet 2000; 20: 41–50.\n4. Dueholm M. Uterine adenomyosis and infertility, review \nof reproductive outcome after in vitro fertilization and sur-\ngery. Acta Obstet Gynecol Scand 2017; 96: 715–26.\n5. Yen CF, Huang SJ, Lee CL, Wang HS, Liao SK. Molecular \ncharacteristics of the endometrium in uterine adenomyo-\nsis and its biochemical microenvironment. Reprod Sci \n2017; 24: 1346–61.\n6. Itam SP , 2nd, Ayensu-Coker L, Sanchez J, Zurawin RK, \nDietrich JE. Adenomyosis in the adolescent population: A \ncase report and review of the literature. J Pediatr Adolesc \nGynecol 2009; 22: e146–147.\n7. Ryan GL, Stolpen A, Van Voorhis BJ. An unusual cause \nof adolescent dysmenorrhea. Obstet Gynecol 2006; 108: \n1017–22.\n8. Mansouri R, Santos XM, Bercaw-Pratt JL, Dietrich JE. \nRegression of adenomyosis on magnetic resonance imag-\ning after a course of hormonal suppression in adoles-\ncents: A case series. J Pediatr Adolesc Gynecol 2015; 28: \n437–40. \n9. Dietrich JE: An update on adenomyosis in the adoles-\ncent. Curr Opin Obstet Gynecol 2010; 22: 388–92.\n10. Leyendecker G, Kunz G, Kissler S, Wildt L. Adeno-\nmyosis and reproduction. Best Pract Res Clin Obstet \nGynaecol 2006; 20: 523–46.\n11. Leyendecker G, Wildt L, Mall G. The pathophysiology \nof endometriosis and adenomyosis: Tissue injury and re-\npair. Arch Gynecol Obstet 2009; 280: 529–38.\n12. Mechsner S, Grum B, Gericke C, Loddenkemper C, \nDudenhausen JW, Ebert AD. Possible roles of oxytocin \nreceptor and vasopressin-1alpha receptor in the patho-\nmechanism of dysperistalsis and dysmenorrhea in pa-\ntients with adenomyosis uteri. Fertil Steril 2010; 94: 2541–6.\n13. Ibrahim MG, Chiantera V, Frangini S, Younes S, Köhler \nC, Taube ET, Plendl J, Mechsner S. Ultramicro-trauma in \nthe endometrial-myometrial junctional zone and pale cell \nmigration in adenomyosis. Fertil Steril 2015; 104: 1475–83.\n14. Ibrahim MG, Sillem M, Plendl J, Chiantera V, Sehouli J, \nMechsner S. Myofibroblasts are evidence of chronic tis-\nsue microtrauma at the endometrial-myometrial junctional \nzone in uteri with adenomyosis. Reprod Sci 2017; 24: 1410–\n8. \n15. Liu L, Liu L, Yao HH, Zhu ZQ, Ning ZL, Huang Q. Stromal \nmyofibroblasts are associated with poor prognosis in sol-\nid cancers: A meta-analysis of published studies. PLoS \nOne 2016; 11: e0159947.\n16. Shen C, Jiang L, Shao H, You C, Zhang G, et al. Tar-\ngeted killing of myofibroblasts by biosurfactant di-rham-\nnolipid suggests a therapy against scar formation. Sci Rep \n2016; 6: 37553.\n17. Akerlund M, Andersson KE, Ingemarsson I. Effects of \nterbutaline on myometrial activity, uterine blood flow, and \nlower abdominal pain in women with primary dysmenor-\nrhoea. BJOG 1976; 83: 673–8.\n18. Leyendecker G, Kunz G, Wildt L, Beil D, Deininger H. \nUterine hyperperistalsis and dysperistalsis as dysfunc-\ntions of the mechanism of rapid sperm transport in pa-\ntients with endometriosis and infertility. Hum Reprod 1996; \n11: 1542–51.\n19. Kunz G, Beil D, Deiniger H, Einspanier A, Mall G, \nLeyen decker G. The uterine peristaltic pump. Normal and \nimpeded sperm transport within the female genital tract. \nAdv Exp Med Biol 1997; 424: 267–77.\n20. Bulletti C, De Ziegler D, Polli V, Del Ferro E, Palini S, \nFlamigni C. Characteristics of uterine contractility during \nmenses in women with mild to moderate endometriosis. \nFertil Steril 2002; 77: 1156–61.\n21. Barcena de Arellano ML, Arnold J, Lang H, Vercellino \nGF, Chiantera V, et al. Evidence of neurotrophic events \ndue to peritoneal endometriotic lesions. Cytokine 2013; 62: \n253–61.\n22. Zoubina EV, Mize AL, Alper RH, Smith PG. Acute and \nchronic estrogen supplementation decreases uterine \nsympathetic innervation in ovariectomized adult virgin \nrats. Histol Histopathol 2001; 16: 989–96.\n23. Zoubina EV, Fan Q, Smith PG. Variations in uterine in-\nnervation during the estrous cycle in rat. J Comp Neurol \n1998; 397: 561–71.\nCorrespondence to:\nProf. Dr. med. Sylvia Mechsner\nEndometriosis Centre Charité, Depart-\nment of Gynecology\nCharité Medical University Berlin\nHindenburgdamm 30, 12203 Berlin\nGermany\ne-mail: sylvia.mechsner@charite.de\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. Weder die Autoren, \nnoch die tragenden Gesellschaften noch der Verlag übernehmen irgendwelche Haftungsan-\nsprüche.\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\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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