{"paper_id":"394fdfd4-8982-42b4-a8fe-59e32ff8b007","body_text":"Introduction, Definitions\nand Epidemiology\n!\nEndometriosis is one of the most frequent benign\ndiseases of the fertile woman and is defined as the\npresence of endometrium outside of the uterine\ncavity. The prevalence rates given in the literature\nvary widely. It is estimated that in Germany about\n40 000 new cases occur each year [1]. Risk factors\nfor endometriosis are, among others, the duration\nof period bleeding, length of the menstrual cycle,\nnumber of pregnancies, number of miscarriages\nand smoking status [2]. The pathogenesis of the\ndisease is even today not completely clarified.\nAlthough endometriosis is a benign disease, it\ncan spread to other organs through infiltrative\ngrowth and thus require extensive surgery. The\nmain symptoms of the disease are sterility and\nchronic pain [3, 4].\nCurrent therapeutic concepts are mainly aimed at\nsuppression of ovarian function and analgesia in\naddition to the operative management. For this\npurpose above all gestagen-rich contraceptives,\npure gestagen und GnRH analogues are em-\nployed. For pain therapy NSAR are used preferen-\ntially. In spite of the use of known therapeutic\nAbstract\n!\nEndometriosis is one of the most frequent benign\ndiseases in women of child-bearing age. The main\nsymptoms are chronic upper abdominal pain and\ninfertility. However, the aetiology and patho-\ngenesis of endometriosis are as yet insufficiently\nclarified. Thus, therapy is mainly symptomatic\nwith laparoscopic surgery being the gold stan-\ndard. The aim of drug therapy is to achieve a hy-\npo-oestrogenic condition. In cases of severe endo-\nmetriosis and a desire to have children there is\noften an indication for assisted reproduction. The\npresent article illustrates almost all current as-\npects on the diagnosis of and therapy of endome-\ntriosis. From the clinical viewpoint, emphasis is\nplaced on the rare cases of deeply infiltrating en-\ndometriosis that are, however, accompanied with\na high morbidity. Current therapeutic options in\ncases of infertility are also presented in more de-\ntail. Furthermore, special attention is paid to the\nlatest research results from both clinical and basic\nresearch fields in order to demonstrate our cur-\nrent knowledge on the pathogenesis and, where\npossible, potentially related therapeutic options.\nZusammenfassung\n!\nDie Endometriose ist eine der häufigsten gutarti-\ngen Erkrankungen der Frau im reproduktions-\nfähigen Alter. Hauptsymptome sind chronische\nUnterbauchschmerzen und Infertilität. Ätiologie\nund Pathogenese der Endometriose sind jedoch\nbisher unzulänglich geklärt. Es erfolgt daher eine\nvornehmlich symptomatische Therapie, wobei\ndie laparoskopische Entfernung als operativer\n„Goldstandard“ gilt. Ziel der medikamentösen\nTherapie ist das Erreichen eines hypoöstrogenen\nZustands. Bei schwerer Endometriose und Kin-\nderwunsch ergibt sich häufig die Indikation für\neine assistierte Reproduktion. Die vorliegende Ar-\nbeit fasst alle aktuellen Aspekte zur Diagnostik\nund Therapie der Endometriose zusammen. Da-\nbei wird klinisch ein Schwerpunkt auch auf die\nzwar seltenere, jedoch mit hoher Morbidität ver-\nbundene tief infiltrierende Endometriose gesetzt.\nAuch zeitgemäße Therapieoptionen bei Infertili-\ntät werden näher dargestellt. Zudem wird ein\nSchwerpunkt auf neueste Forschungsansätze ge-\nlegt, um sowohl Klinikern als auch Wissenschaft-\nlern aktuelle Erkenntnisse zur Pathogenese und\nggf. daraus resultierenden Therapieoptionen dar-\nzustellen.\nEndometriosis: Survey of Current Diagnostic and\nTherapeutic Options and Latest Research Work\nEndometriose: Überblick über aktuelle Diagnostik- und Therapieoptionen\nund neueste Forschungsansätze\nAuthors I. Juhasz-Böss 1, M. W. Laschke 2, F. Müller 3, P. Rosenbaum1,S .B a u m1,E .F .S o l o m a y e r1, U. Ulrich 3\nAffiliations 1 Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar\n2 Institut für Klinisch-Experimentelle Chirurgie, Universität des Saarlandes, Homburg\n3 Klinik für Gynäkologie und Geburtshilfe, Martin-Luther-Krankenhaus, Berlin\nKey words\nl\" endometriosis\nl\" infertility\nl\" dyspareunia\nSchlüsselwörter\nl\" Endometriose\nl\" Infertilität\nl\" Dyspareunie\nreceived 24. 5. 2013\nrevised 29. 6. 2014\naccepted 30. 6. 2014\nBibliography\nDOI http://dx.doi.org/\n10.1055/s-0034-1382884\nGeburtsh Frauenheilk 2014; 74:\n733–742 © Georg Thieme\nVerlag KG Stuttgart · New York ·\nISSN 0016‑5751\nCorrespondence\nPD Dr. Ingolf Juhasz-Böss\nUniklinikum Saarland\nFrauenklinik\nKirrbergerstraße 100\n66424 Homburg/Saar\nIngolf.Juhasz-Boess@\nuniklinikum-saarland.de\n733\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nReview\nDeutschsprachige\nZusatzinformationen\nonline abrufbar unter:\nwww.thieme-connect.de/\nejournals/toc/gebfra\n\n\nstrategies in some cases insufficient relief of the endometriosis-\nrelated complaints or disease recurrence can occur.\nThe disease is thus also of economic relevance. Beside the medi-\ncal expenses, above all the patients ʼ inability to work is appreci-\nable [1, 5]. Repeated surgery, the in part chronic course as well as\nthe delayed diagnostic confirmation after year-long symptoms\nand complaints results in a high medical expenditure [6].\nThe present article aims to give an actual survey of the diagnostic\nand therapeutic procedures as well as to present the latest re-\nsearch results on the subject of endometriosis.\nAetiology of Endometriosis: Classic Theories\nand Latest Research Approaches\n!\nAlthough endometriosis is one of the most investigated gynaeco-\nlogical clinical entities, many aspects of the aetiology and patho-\ngenesis of the disease have still not been completely clarified and\nthus represent a focus of current research on endometriosis.\nThe classical theories on the development of endometriosis in-\nclude the “coelom metaplasia theory ” (according to Meyer) and\nthe “theory of embryonic cell remains ” according to which the\nendometriosis lesions develop from tissue of embryonic origin,\nas well as the “theory of lymphovascular metastasis ”, which pro-\nposes that endometrial cells, similar to tumour cells, spread via\nlymphatic pathways or blood vessels and that in this way endo-\nmetriosis lesions can develop in various positions in the body\n[7]. Today the most widely accepted theory on the development\nof endometriosis is, however, the “implantation theory ” accord-\ning to Sampson [8]. This is based on the assumption that during\nmenstruation, vital endometrium reaches the abdominal cavity\nfrom the uterus in a retrograde manner via the tubes. Favourable\nconditions there lead to implantation of tissue fragments on the\nperitoneum and thus to the development of endometriosis. How-\never, retrograde menstruations are certainly physiological and\ncan be detected in up to 90 % of all women who undergo laparos-\ncopy [9]. Thus there is no doubt that the development of endo-\nmetriosis depends on many other pathogenic mechanisms, thus\nrendering it a typical multifactorial clinical entity.\nNumerous studies have in the meantime indicated that there is a\ngenetic predisposition for endometriosis [10]. For this reason ge-\nnome-wide association studies are underway in order to identify\nthe corresponding genetic factors. Although in the course of\nthese studies 3 potential gene loci have already been found that\nare with the highest probability associated with the occurrence\nof endometriosis in Japanese and European women, it is still nec-\nessary to confirm such results in a larger number of cases and to\ncorrelate the obtained data with the various clinical subtypes of\nendometriosis [11]. In addition epigenetic studies are needed to\nclarify how certain environmental factors influence the disease.\nIn this context, dioxins must be considered as potential disease-\ntriggering environmental toxins [12]. Furthermore, certain com-\nponents of foodstuffs such as, e.g., fatty acids and their deriva-\ntives, are being discussed as factors influencing the disease [13].\nVarious immunological aspects also play an important role in the\npathogenesis of endometriosis, whereby the disease shows\nmarked similarities with typical autoimmune diseases [14]. Thus,\nit was shown that in the course of endometriosis autoantibodies\nagainst endometrial antigens such as, e.g., transferrin or alpha 2-\nHS glycoprotein, are formed, and which can often in part be re-\nsponsible for the infertility frequently observed in endometriosis\npatients [15, 16]. Also concentration fluctuations of cytotoxic and\nactivated lymphocytes peripheral blood during the menstrual\ncycle appear to play a certain role. The fluctuations of regulatory\nT cells detected during endometriosis can be attributed to a\nchanged immune response [17]. Furthermore, endometriosis is\ncharacterised by a chronic inflammatory reaction with elevated\nconcentrations of inflammatory cytokines in serum and the peri-\ntoneal fluid [18]. Elevated numbers of macrophages, dendritic\ncells and natural killer cells are seen in the peritoneum which,\nfor as yet insufficiently investigated reasons, are however not able\nto recognise and degrade the endometrium tissue scattered in the\nabdominal cavity [19]. This chronic inflammatory reaction, in\nturn, leads to an increased production and an inhibited degrada-\ntion of reactive oxygen species [20]. Accordingly, the administra-\ntion of substances with an antioxidative action could represent a\nmeaningful supplement to the current therapeutic options.\nThe basal parts of the endometrium contain endometrial stem\ncells and progenitor cells [21], which explains the high regenera-\ntion potential of this tissue. This is at present under discussion as\na further cause for the occurrence of endometrium lesions. Thus,\nit is assumed that stem cells reach the abdominal cavity via retro-\ngrade menstruation and under suitable conditions can then dif-\nferentiate into endometriosis lesions [22]. This assumption is\nsupported by the observation that the glandular cells of some en-\ndometriosis lesions are of monoclonal origin [22]. In addition, it\nis possible that also extrauterine, circulating stem and progenitor\ncells from bone marrow contribute appreciably to the formation\nof endometriosis lesions. Thus, it has been shown in a mouse\nmodel that not only glandular but also stromal cells from bone\nmarrow cells can develop into endometriosis lesions [23]. Fur-\nthermore, up to 37 % of all endothelial cells in endometriosis le-\nsions are derived from circulating endothelial progenitor cells\n[24].\nA major prerequisite for the long-term survival of endometriosis\nlesions is angiogenesis, i.e., the generation of new blood vessels\n[25]. Only in this way can the scattered endometrium tissue,\nwhich is initially ischaemic outside the uterus, be adequately\nsupplied with oxygen and nutrients. For this reason, especially\nthe early stages of endometriosis lesions exhibit a reddish colour-\nation caused by a high density of blood vessels and vessel dilata-\ntions [26, 27]. Furthermore, in the past few years numerous an-\ngiogenic growth factors have been identified – above all “vascular\nendothelial growth factor ” (VEGF) – which is produced and re-\nleased in increased amounts in endometriosis, and regulates the\ningrowth of new blood vessels in endometriosis lesions [28]. In-\nterestingly, endometrium in the uterus of endometriosis patients\nalready exhibits an elevated angiogenic activity which can favour\nthe process of creation of new endometriosis lesions [29]. Endo-\nmetriosis thus belongs to the group of angiogenic diseases along\nwith rheumatoid arthritis, psoriasis, diabetic retinopathy as well\nas tumour growth and metastasis [29]. Accordingly in recent\nyears increasing attention has been paid to analysing the control\nmechanisms that govern the formation of new blood vessels in\nendometriosis lesions, in order to identify new targets for a tar-\ngeted, anti-angiogenic endometriosis therapy [30, 31]. In addi-\ntion, experimental in-vitro and in-vivo studies have already de-\ntected numerous members of various substance classes that exert\nan anti-angiogenic effect on endometriosis lesions. These include\ngrowth factor inhibitors, endogenous angiogenesis inhibitors, fu-\nmagillin analogues, statins, cyclooxygenase 2 inhibitors, phyto-\ntherapeutic agents, immune modulators as well as dopamine ag-\nonists [32]. Further clinical trials are needed to clarify to what ex-\ntent these active principles can be used for an anti-angiogenic\n734\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nGebFra Science\n\n\nendometriosis therapy without causing severe side effects in the\nafflicted patients.\nAnother area of current research focusses on the mechanisms\nthat contribute to the pain symptomatic of endometriosis. Major\ncontributing factors are considered to be long-term cyclic bleed-\ning of the oestrogen-dependent endometriosis lesions with con-\nsecutive inflammatory reactions as well as irritation and invasion\nof pelvic nerves [33]. Recent investigations, however, have shown\nthat pain transmitting nerve fibres can grow together into endo-\nmetriosis lesions [34], this is also designated as “neuroangiogen-\nesis” [35]. These nerve fibres in turn increase the pain sensation\nin the central nervous system [35]. If it were possible – as has al-\nready been demonstrated in animal experiments [36] – to inhibit\nthis process by targeted drug measures, we should be able in the\nfuture to develop appreciably more effective pain therapies hav-\ning considerably fewer side effects than the conventional hor-\nmone treatment options.\nSummarising the current research results, we see that endome-\ntriosis is a complex, multifactorial disease for which the aetiology\nand pathogenesis have not yet been completely clarified. The re-\nsearch findings of the past 10 years, however, do show that mo-\nlecular and cellular pathomechanisms which contribute to the\ndevelopment of the disease are increasingly being identified. This\nshould provide the possibility in future to develop better tar-\ngeted, new preventive and therapeutic treatment strategies.\nDiagnostic, Clinical Picture and Therapy\nfor Endometriosis\n!\nAs recommended in the current guidelines and for the sake of\nbetter clarity, the differing manifestations of endometriosis are\ndiscussed separately although they often occur in combination\n[1]. First of all, the following aspects are valid for all manifesta-\ntions:\nLaparoscopy: Laparoscopy (LSC) is a central component in the di-\nagnosis of and therapy for endometriosis. Indication for LSC is:\npain, organ changes and/or sterility. Surgical removal of the en-\ndometriosis lesions is considered to be the gold standard, on the\none hand to control the symptoms and on the other hand for his-\ntological work-up [37]. It should be noted that asymptomatic en-\ndometriosis in a patient not desiring to have children does not re-\nquire any surgical or drug treatment [1]. Examination of the case\nhistory and the additional use of psychological questionnaires\nprovide valuable information prior to the diagnostic/curative op-\neration and can provide indications for the presence of an endo-\nmetrial disease and thus support an optimal counselling for the\nsymptomatic patient in the phase of decision-making for surgical\nclarification [4].\nLocalisation: Endometriosis preferentially attacks the lesser pelvis\nand here above all (in order of decreasing frequency) the pelvic\nperitoneum, the ovaries, the sacrouterine ligament, the rectovagi-\nnal septum as well as extragenital manifestations such as, e.g., the\nrectosigmoid or urinary bladder. Extraperitoneal manifestations\nare seldom [1].\nStaging: In clinical routine endometriosis is subdivided according\nto its localisation into endometriosis genitalis externa and inter-\nna as well as extragenitalis [1]. Unfortunately endometriosis is\nnot uniformly classified, furthermore the current staging is not\nsatisfactory. The most widely used and most frequently used in\nreproduction medicine is the rASRM classification of the Ameri-\ncan Society for Reproductive Medicine (ASRM) [38] ( l\n\" Table 1 ).\nRetroperitoneal and deep infiltriating endometriosis are best de-\nscribed by means of the ENZIAN classification [39, 40] ( l\" Fig. 1).\nHowever, the stage does not correlate with the degree of com-\nplaints, some afflicted women are even asymptomatic.\nTumour marker CA-125: CA-125 is generally elevated in endome-\ntriosis patients. However, this tumour marker has no differential\ndiagnostic relevance. In clinical routine its determination is not\nrecommended either for diagnosis or for course control [1].\nPeritoneal endometriosis\nMorphology and symptoms\nIn cases of peritoneal endometriosis a distinction is made be-\ntween pigmented (= typical) and not pigmented (= atypical) le-\nsions as well as between red, white and black lesions [26, 41]\n(l\n\" Fig. 2). These lesions differ above all with regard to their activ-\nity, fibrosis, age, etc. It is not clear to what extent the different\nforms correlate with specific symptoms of endometriosis [42].\nPatients with preoperatively pronounced complaints have a\nhigher risk of recurrence than patients with lower pain sensa-\ntions [43].\nDiagnostics\nPeritoneal endometriosis cannot be detected by sonography.\nStandard procedure in the field of diagnosis of peritoneal endo-\nmetriosis is laparoscopy [1]. Histological confirmation should al-\nso be attempted for peritoneal endometriosis as mentioned\nabove [1].\nSurgical and drug therapies\nThe main objective is the laparoscopic removal of all peritoneal\nlesions by means of coagulation, vaporisation or excision [1]. It\nhas not yet been clarified as yet which procedure is the most suit-\nable. In answer to this question there is only one randomised\ncontrolled trial and the Cochrane analysis published in 2014 [44,\n45].\nThe aim of drug therapy is to achieve a hypo-oestrogenic status.\nEndometriosis implants can be regressively changed by means of\nTable 1 rASRM classification of endometriosis (modified from [38]). stage I\n(minimal): 1 –5; stage II (mild): 6 –15; stage III (moderate): 16 –40; stage IV\n(pronounced): > 40.\nEndometriosis < 1 cm 1 –3c m >3c m\nPeritoneum superficial 1 2 4\ndeep 2 4 6\nOvaries R superficial 1 2 4\nR deep 4 16 20\nL superficial 1 2 4\nL deep 4 16 20\nDouglas\nobliteration\npartial complete\n44 0\nAdhesions < ⅓⅓ – ⅔ > ⅔\nOvaries R thin 1 2 4\nR dense 4 8 16\nL thin 1 2 4\nL dense 4 8 16\nTubes R thin 1 2 4\nR dense 4* 8* 16\nL thin 1 2 4\nL dense 4* 8* 16\n* in cases of complete attack or, respectively, complete occlusion of the fimbria ends:\n16\n735\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nReview\n\n\nsuppression of ovarian function. The drugs predominately used\ntoday are pure gestagens, gestagen-rich contraceptives, GnRH\nanalogues and danazol. GnRH analogues are in such cases more\neffective than oral contraceptives or gestagens. A reduction of en-\ndometriosis-associated complaints can be achieved with all the\nmentioned substance classes, while GnRH analogues proved to\nbe more effective for dysmenorrhoea and dyspareunia in some\ntrials.\nSome of these drugs are associated with appreciable and, above\nall, different side effects. GnRHa should only be administered to-\ngether with the corresponding protective accompanying dugs\n(“add-back”) because of the consequences of a possible oestrogen\ndeficiency [1].\nWith regard to the response to hormone therapy it seems that\nperitoneal endometriosis differs from ovarian and deep infiltrat-\ning endometriosis. Duration of therapy with GnRH analogues\namounts to 3 – 6 months. Although a 3-month therapy is equally\neffective the subsequent recurrence-free interval is then shorter\n[46]. Recent data from prospective studies have shown that\ndienogest as maintenance therapy after administration of GnRH\ncan uphold the GnRH-induced effect for at least 12 months [47].\nIn 2 further RCCCTs equieffective actions of dienogest vs. GnRH\nanalogues for endometriosis-associated pain were observed\nwhereby with regard to clinical tolerance dienogest was better\ntolerated by the patients [48, 49]. Although frequently used in\nclinical routine there is no evidence for a positive effect of NSAR\non endometriosis-specific complaints [50].\nOvarian endometriosis\nDiagnostics\nThe ovaries are attacked in up to 50 % of all endometriosis pa-\ntients [1, 51]. Preoperative clarification is based on the clinical ex-\nFig. 1 ENZIAN classification of deep infiltrating\nendometriosis (www.endometriose-sef.de/dateien/\nENZIAN_2013_web.pdf; © Keckstein).\n736\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nGebFra Science\n\n\namination. In the case of an ovarian endometrioma transvaginal\nsonography is suitable [51]. In cases of unclear ovarian space-fill-\ning lesions histological clarification is always required. The differ-\nential diagnosis, however, should take all ovarian findings into\nconsideration and the results included in the operative proce-\ndures (especially LSC).\nTherapy\nThe standard procedure is the laparoscopic removal of ovarian\nendometrioma [1]. In such cases the ovary-sparing extraction of\nthe cyst bag is superior to thermal destruction [52]. Mere open-\ning and lavage of the cyst bag as sole surgical intervention is not\nrecommended due to the high rate of recurrences [53]. The recur-\nrence rate even after 2 operative interventions can still amount to\n20.8 % and correlates above all with the duration of follow-up as\nwell as the rASRM stage [54].\nThe exclusive use of drug therapy for ovarian endometrioma is\nnot adequate and is not recommended [1]. Also postoperative\nGnRH analogues cannot compensate for an incomplete operation\n[55]. With regard to the recurrence rate data on the postoperative\nadministration of a hormonal contraceptive are contradictory.\nAdenomyosis uteri\nDiagnostics\nIn the diagnostic work-up besides gynaecological examinations\nthe transvaginal sonography (TVS) above all and if necessary\nMRI are most suitable in such cases. TVS is of greater relevance\nin daily practice [56]. The sonographic criteria for making a diag-\nnosis are poorly delineated heterogeneous areas, in part, cystic\nintramural alterations, areas of changing echogenicity, irregular\nhalo effects as well as a discrepancy between the anterior and\nposterior wall findings. Histological confirmation of adenomyo-\nsis is in most cases, however, only possible on hysterectomy sam-\nples.\nTherapy\nTherapy is adapted to the patientʼs family planning wishes. When\nfamily planning has been completed hysterectomy (HE) repre-\nsents the most effective option. Here all common modalities of\nHE can be applied, but it must be taken into account that a possi-\nbly coexisting intraperitoneal endometriosis can usually not be\nmanaged by a purely vaginal procedure. A supracervical HE may\nalso be envisioned but should not be performed in case of a con-\ncurrent coexisting rectovaginal endometriosis. When planning\nan HE the operative procedure should be decided upon between\nsurgeon and patient on a case by case basis [1].\nFor patients still desiring to have children or with a wish to retain\ntheir organs, the benefit of an operation has not been demon-\nstrated. Interventional radiological procedures (e.g., embolisa-\ntion) or MRI-guided focussed ultrasound ablation are still in the\nexperimental stage and should only be applied with the frame-\nwork of clinical trials [1].\nAs alternatives to HE, gestagens, hormonal contraceptives and in-\ntrauterine, local gestagen-releasing systems may be considered.\nThe therapeutic effect is based on the induction of amenorrhoea.\nContraceptives (monophasic formulations) and gestagens should\ntherefore be taken continuously [1].\nDeeply Infiltrating Endometriosis\n!\nIn comparison to peritoneal or ovarian endometriosis, still very\nlittle is known about deeply infiltrating endometriosis (DIE)\nalthough it is a clinically no lesser relevant form of the disease.\nIn this form it is seen that endometriosis – similar to malignant\ndiseases – can spread beyond organ borders and infiltrate various\nstructures. The thus resulting space-filling lesions and in part in-\nvasive growth can lead to indurations and finally to the destruc-\ntion of functional mobile layers (e.g., between rectum and vagi-\nna) through to the occurrence of larger conglomerate tumours\nand in some cases even to disabling complaints.\nThe fact that, in Germany, statistically an interval of 6 years must\npass from the first manifestation of symptoms to the diagnosis of\nendometriosis is disturbing and may in part be due to frequent\nmisinterpretations and a lack of experience with the deeply infil-\ntrating variant of the disease (see l\n\" Figs. 3 and 4)[ 1 ] .\nThe mostly retroperitoneal growth of DIE is often not directly\nvisible with laparoscopy – due either to the retroperitoneal posi-\ntion or complete Douglas obliteration – and thus it can hardly be\ndefined in the common stage classifications (AFS/rASRM) [57].\nDIE should thus additionally be described using the ENZIAN clas-\nsification (see l\n\" Figs. 4 and 5) [40].\nFrequently affected are the sacrouterine ligament, the parame-\ntria, the rectovaginal septum/fornix of the vagina, the rectosig-\nmoid, the appendix, the urinary bladder and sometimes the ure-\nter or also the small intestine.\nSymptoms\nThe symptoms of DIE depend on the afflicted organs or, respec-\ntively, structures and vary between no complaints and disability\nand invalidisation due to severe pain. On the whole and as for en-\ndometriosis in general, there is no correlation between the ex-\ntent of the disease and the severity of the symptom spectrum. A\nsmall node in the rectovaginal septum can, for example, make in-\ntercourse so painful that it is no longer possible and turn defaeca-\ntion into a nightmare for the patients, whereas some other pa-\ntients with stenosed rectum and/or space filling tumours\nthrough to frozen pelvis experience no complaints at all.\nIn general, the symptoms of DIE, beside the classical dysmenor-\nrhoea, do of course depend on the pattern of attack. Infiltration\nof the rectovaginal septum/fornix of the vagina or, respectively,\nthe rectum often leads to dyspareunia and dyschezia, sometimes\nFig. 2 Endometriosis attack of the peritoneum. Besides pigmented\n(= atypical) endometriosis lesions also typical, here, e.g., blister like unpig-\nmented lesions can be seen.\n737\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nReview\n\n\nalso to flatulence and tenesmus and can be accompanied by rec-\ntal passage of mucous or blood as well as changes in stool behav-\niour through to paradox diarrhoea. DIE of the bladder or ureter\ncan – beside hydronephrosis – cause dys- and haematuria. The\nlack of symptoms never excludes attack of the mentioned organs.\nDiagnostics\nThe suspicion of DIE is based first of all on case history plus the\nclinical-gynaecological examination, where importance must be\nplaced of an adequate deconvulation of the posterior fornix of the\nvagina in the speculum settings (see l\n\" Fig. 3) and a rectal or rec-\ntovaginal palpation. Typically among the findings to be recorded\n– apart from pain trigger points – are visible endometriosis in the\nvagina, the rough nodular induration of the rectovaginal septum\nor the parametria/sacrouterine ligaments and, in some cases, uri-\nnary retention on sonography. With sufficient experience an in-\nfiltration of the rectovaginal septum and the rectum can also be\ndemonstrated by transvaginal sonography [51, 56]. The sono-\ngraphic detection of bilateral endometrioma (especially in the\nsense of kissing ovaries) can be suggestive of DIE [58].\nIn the literature magnetic resonance imaging exhibits a high sen-\nsitivity for the diagnosis of FDI but is certainly dependent on the\ninvestigatorʼs experience or, respectively, knowledge of the dis-\nease but only rarely does it lead to a change of the therapy [59,\n60]. In cases of suspected intestinal involvement by DIE coloscopy\nis rarely useful since the endometrial infiltration usually stops at\nthe mucosa so that the exclusion of intestinal attack is not possi-\nble by rectoscopy. In such cases rectal endosonography is to be\npreferred [1, 59]. Coloscopy must only be used when it is neces-\nsary to exclude other differential diagnoses (e.g. colon cancer, di-\nverticulitis, chronic inflammatory bowel disease). DIE of the\nbladder can often be well visualised by sonography when the\nbladder is sufficiently full. In such cases, however, cystoscopy pri-\nor to surgery is reasonable in order to estimate the distance to\nthe trigonum vesicae and the ureter orifices and, if necessary, to\ncarry out thereby a splinting with a double J catheter.\nTherapy\nThe therapy of choice for symptomatic DIE is resection with\nhealthy margins [61 – 64]. The operations often include rectum\nresection (mostly en-bloc with the afflicted rectovaginal septum\nand the vagina), and partial resection of the sacrouterine liga-\nment and parametria as well as parts of the bladder (see l\n\" Figs. 4\nto 7). Partial ureter resections with new implantation (e.g., psoas-\nhitch plasty) are much more rarely needed. Hysterectomy is not\nobligatory and is not wanted by the mostly young patients. The\ninterventions can mostly be performed as laparoscopic or, if nec-\nessary vaginal-assisted procedures. Good cooperation between\nthe various disciplines (gynaecology, surgery, urology) is a neces-\nsity and accordingly is required for the certification of specialised\nsurgical centres by the Stiftung Endometrioseforschung, the\nEuropäische Endometrioseliga and the Endometriose-Vereini-\ngung-Deutschland e. V.\nFig. 3 Part of a DIE of the rectovaginal septum visible in the posterior\nfornix of the vagina.\nFig. 4 Due to the almost exclusive retroperitoneal position the DIE of the\nrectovaginal septum and the rectum (rASRM I) is easily missed, see\nl\n\" Fig. 5.\nFig. 5 View from l\" Fig. 4 with freely exposed retroperitoneal endome-\ntriosis lesion (ENZIAN 2A, 2C).\n738\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nGebFra Science\n\n\nUrinary retention – due to extrinsic or intrinsic DIE of the ureter –\nis the only acceptable absolute indication for surgery in the Ger-\nman-language guidelines since it is essential to prevent persist-\ning damage to the kidneys [1]. An intestinal perforation or ileus\ndue to stenosing DIE of the bowels can give rise to an urgent in-\ndication in a similar manner [65].\nIn the case of DIE diagnosed near to the ureter or its recent oper-\native management long-term biannual sonography of the kid-\nneys is recommended in order to recognise the potentially slowly\nbut then also often asymptomatical development of urinary re-\ntention in a timely manner [1].\nThe decision for or against operative removal of DIE is – when as\nin most cases no absolute indication is given – made together\nwith the patient on the basis of the symptoms and the level of\nsuffering. In most cases an estimation of the extent by means of\nan at first purely diagnostic laparoscopy is helpful for both physi-\ncian and patient. In no case may the decision be made without\nsufficient counselling and time for consideration since extensive\nrehabilitating resection with participation of the bowels and/or\nbladder interventions do not guarantee either therapeutic suc-\ncess or freedom from de novo complaints resulting from surgery\n(late postoperative problems due to disorders of defaecation or to\nscar and adhesion complaints) [62, 66]. An appropriately high\nburden of suffering is a decisive prerequisite for rehabilitating\noperations.\nCritical in this context is always the wish for removal of an\nasymptomatic DIE merely on the basis of sterility. In the literature\nhigher rates of not only spontaneous but also of IVF-induced\npregnancies after complete resections in such cases can be found\nin the literature [67 – 69], however, the potential operative mor-\nbidity that is to be expected must be also be considered. In the\nworst case a previously complaint-free but infertile patient – in\nspite of unsuccessful IVF – may merely experience a marked de-\nterioration in her quality of life. Such scenarios must also be dis-\ncussed in detail with just those patients who are free of symp-\ntoms. More recent data also even additionally question this im-\nprovement in fertility, so that the guideline recommendations\nwill probably have to be reassessed on this point [70].\nDrug therapy is neither necessary as preparation nor as an adju-\nvant therapy after the surgical management of DIE. When, in\nspite of symptomatic DIE – initial or permanent – the decision\nagainst surgery is made, the classical hormone therapy options\n(monophasic oral contraceptives, gestagen monotherapy, levo-\nnorgestrel IUP) can then be applied. An effect can only be ex-\npected during the therapy so that a life-long continuation is a ne-\ncessity [1].\nA malignant degeneration is rare but possible. DIE can typically\ndevelop into endometrioid or clear-cell adenocarcinomas in the\npelvis without any clearly associated organs [71]. However, this\nrisk is so low that an indication for treatment or surgery cannot\nbe derived from this alone.\nEndometriosis and Sterility\n!\nPathophysiology of involuntary childlessness\nin cases of endometriosis\nThere is a high coincidence between sterility and endometriosis\n[72], the reasons for this have not yet been clarified. It is esti-\nmated that 30 – 50 % of the women with endometriosis are infer-\ntile [73]. Mechanical factors due to adhesions of the adnexa with\ndisorders of tube motility or, respectively, the ovum pick-up\nmechanism have been accepted as reasons for sterility. Further\ncauses may involve disordered immunological dysregulation\nand also a change of the intra-abdominal milieu, due to cyto-\nkines, prostaglandins and macrophages. In an egg cell donation\nprogramme patients with endometriosis achieved similar preg-\nnancy rates as those women without endometriosis, however\nthe pregnancy rates in case of transfer of embryos form women\nwith endometriosis was markedly lower. This suggests a decrease\nin embryo quality in cases of endometriosis [74].\nFig. 6 a and ba DIE of the vesicocervical septum and bladder. b Cysto-\nscopic visualisation with intact urothelium over the finding.\nFig. 7 Situation after local full wall excision of DIE of the bladder.\n739\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nReview\n\n\nDrug therapy\nA hormone therapy for endometriosis can be performed with\npure gestagens (e.g., dienogest, medroxyprogesterone acetate,\nlevonorgestrel, chlormadinone acetate, cyproterone acetate and\nnomegestrol acetate), with monophasic oestrogen-gestagen\ncombination formulations (especially taken in long cycles), as\nwell as by means of GnRH analogues. In cases of low-degree en-\ndometriosis (AFS I and II), however, a metaanalysis of 16 random-\nised and controlled studies did not reveal an improvement in fer-\ntility after drug treatment (GnRH analogues, gestagens) in com-\nparison to placebo or expectative procedure [75]. A postoperative\ndrug therapy with GnRH agonists could not improve the sponta-\nneous pregnancy rates of sterility patients and is thus not recom-\nmended [55].\nOperative therapy\nJust for patients desiring to have children and the suspicion of an\nendometrial disease surgical diagnosis and histological confirma-\ntion with simultaneous hysterectomy and chromopertubation of\nthe Fallopian tubes represent the method of choice. In the course\nof this treatment if at all possible all endometriosis lesions should\nbe surgically excised or thermally destroyed. Endometriosis cysts\nshould be ablated with cyst bag in an organ-sparing manner. The\nrate of spontaneous pregnancies is in such cases also higher than\nfor the excision endometriosis lesions in stages AFS I and II [52,\n53, 76].\nAssisted reproduction\nThe measures of assisted reproduction in almost all stages of en-\ndometriosis seem to be more advantageous as compared with a\nnon-surgical process. In cases of minimal endometriosis the\nprobability of a pregnancy after a wait-and-see procedure for 6\nmonths amounts to 28 % [77].\nSeveral prospective controlled studies have shown a higher suc-\ncess rate under ovarian stimulation in combination with intra-\nuterine insemination [77]. For younger patients pregnancies oc-\ncurred within the first cycle after operative management of en-\ndometriosis so that a maximum of 3 insemination treatments\nshould be performed [78].\nFor endometriosis patients the success rate in the course of an in-\nvitro fertilisation is up to 50 % lower than for tubular sterility [79],\nfurthermore, higher drug doses are needed for the markedly low-\ner responsiveness to gonadotropins [80]. On the basis of a large\nmetaanalysis it has been shown that the implantation rate for en-\ndometriosis patients was markedly lower than that in the control\ngroup (12.72 vs. 18.08 %) [79]. In case of the recurrence of an ex-\ntensive endometriosis an assisted reproduction by means of in-\nvitro fertilisation is superior to renewed operative therapy with\nregard to the pregnancy rate [81]. In the case of advanced endo-\nmetriosis AFS III and IV, a stimulation for IVF/ICSI in ultra-long\nprotocol after surgical therapy for endometriosis leads to signifi-\ncantly higher pregnancy rates [82, 83].\nIn patients with endometriosis and the desire to have children\nsurgical clarification and rehabilitation of endometriosis is con-\nsidered to be the gold standard. Depending on the degree of se-\nverity of the endometriosis, a cycle optimisation in combination\nwith ovarian stimulation and accompanying intrauterine insemi-\nnation should be preferred although not more than 3 treatment\ncycles may be carried out.\nPatients with severe endometriosis should be treated as early as\npossible by means of IVF/ICSI, if necessary after stimulation in ul-\ntra-long protocol.\nComplementary Therapy, Rehabilitation\nand Follow-Up\n!\nFor chronic courses of endometriosis with the corresponding\nsymptoms many women experience an alleviation of their com-\nplaints and an improvement in their quality of life through the\nuse of complementary therapies such as, e.g., acupuncture, Chi-\nnese medicine, homeopathy, phytotherapy, osteopathy, physio-\ntherapy etc. However, at present there are no randomised and\ncontrolled studies that confirm an evidence-based effect of these\ntherapies [1].\nThe need for rehabilitation is often present after extensive surgi-\ncal interventions or in patients with chronic pain. The aim of\nrehabilitation should be the restoration of physical, mental and\nsocial well-being and should thus be generously offered to this\npatient collective. An important aspect is, however, also the con-\nfrontation with the disease, which often has a chronic course and\nin part is accompanied by unavoidable restrictions and com-\nplaints. Afflicted women should be referred to regional and na-\ntional self-help organisations and self-help groups. The aftercare\nshould be oriented on the symptoms. The patient ʼs quality of life\nis in the forefront of all efforts [1].\nIn the present article we have topically summarised many as-\npects of endometriosis with reference to the most recent litera-\nture. In particular the less common DIE, a form that is associated\nwith a high morbidity, has been discussed in detail. Also sterility\nas well as the diagnostic and therapeutic consequences are spe-\ncifically summarised. Besides further important clinical aspects\nwe have in the present article highlighted the most recent re-\nsearch results, in order to close the gap concerning actual re-\nsearch between scientists and clinicians.\nConflict of Interest\n!\nNone.\nReferences\n1 Ulrich U, Buchweitz O, Greb R et al. Interdisciplinary S2k guidelines for\nthe diagnosis and treatment of endometriosis: short version – AWMF\nRegistry No. 015 – 045, August 2013. Geburtsh Frauenheilk 2013; 73:\n890– 898\n2 Burghaus S, Klingsiek P, Fasching PA et al. Risk factors for endometriosis\nin a German case – control study. Geburtsh Frauenheilk 2011; 71:\n1073– 1079\n3 Siedentopf F. Chronic pain syndromes in gynaecological practice: endo-\nmetriosis and fibromyalgia. Geburtsh Frauenheilk 2012; 72: 1092 –\n1098\n4 Wölfler MM, Stadermann M, Rath W et al. Anamnestisches Screening\nbei symptomatischen Patientinnen mit und ohne Endometriose. Ge-\nburtsh Frauenheilk 2011; 71: 53 – 58\n5 Oppelt P, Chavtal R, Haas D et al. 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Comparison of reoperation for\nmoderate (stage III) and severe (stage IV) endometriosis-related infer-\ntility with in vitro fertilization-embryo transfer. Fertil Steril 1996; 65:\n791– 795\n82 Rickes D, Nickel I, Kropf S et al. Increased pregnancy rates after ultralong\npostoperative therapy with gonadotropin-releasing hormone analogs\nin patients with endometriosis. Fertil Steril 2002; 78: 757 – 762\n83 Sallam HN, Garcia-Velasco JA, Dias S et al. Long-term pituitary down-\nregulation before in vitro fertilization (IVF) for women with endome-\ntriosis. Cochrane Database Syst Rev 2006; 1: CD004635\n742\nJuhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742\nGebFra Science","source_license":"public-domain-us","license_restricted":false}