Endometriosis: Survey of Current Diagnostic and Therapeutic Options and Latest Research Work

! Endometriosis is one of the most frequent benign diseases in women of child-bearing age. The main symptoms are chronic upper abdominal pain and infertility. However, the aetiology and patho- genesis of endometriosis are as yet insufficiently clarified. Thus, therapy is mainly symptomatic with laparoscopic surgery being the gold stan- dard. The aim of drug therapy is to achieve a hy- po-oestrogenic condition. In cases of severe endo- metriosis and a desire to have children there is often an indication for assisted reproduction. The present article illustrates almost all current as- pects on the diagnosis of and therapy of endome- triosis. From the clinical viewpoint, emphasis is placed on the rare cases of deeply infiltrating en- dometriosis that are, however, accompanied with a high morbidity. Current therapeutic options in cases of infertility are also presented in more de- tail. Furthermore, special attention is paid to the latest research results from both clinical and basic research fields in order to demonstrate our cur- rent knowledge on the pathogenesis and, where possible, potentially related therapeutic options. Zusammenfassung ! Die Endometriose ist eine der häufigsten gutarti- gen Erkrankungen der Frau im reproduktions- fähigen Alter. Hauptsymptome sind chronische Unterbauchschmerzen und Infertilität. Ätiologie und Pathogenese der Endometriose sind jedoch bisher unzulänglich geklärt. Es erfolgt daher eine vornehmlich symptomatische Therapie, wobei die laparoskopische Entfernung als operativer „Goldstandard“ gilt. Ziel der medikamentösen Therapie ist das Erreichen eines hypoöstrogenen Zustands. Bei schwerer Endometriose und Kin- derwunsch ergibt sich häufig die Indikation für eine assistierte Reproduktion. Die vorliegende Ar- beit fasst alle aktuellen Aspekte zur Diagnostik und Therapie der Endometriose zusammen. Da- bei wird klinisch ein Schwerpunkt auch auf die zwar seltenere, jedoch mit hoher Morbidität ver- bundene tief infiltrierende Endometriose gesetzt. Auch zeitgemäße Therapieoptionen bei Infertili- tät werden näher dargestellt. Zudem wird ein Schwerpunkt auf neueste Forschungsansätze ge- legt, um sowohl Klinikern als auch Wissenschaft- lern aktuelle Erkenntnisse zur Pathogenese und ggf. daraus resultierenden Therapieoptionen dar- zustellen. Endometriosis: Survey of Current Diagnostic and Therapeutic Options and Latest Research Work Endometriose: Überblick über aktuelle Diagnostik- und Therapieoptionen und neueste Forschungsansätze Authors 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 Affiliations 1 Klinik für Frauenheilkunde, Geburtshilfe und Reproduktionsmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar 2 Institut für Klinisch-Experimentelle Chirurgie, Universität des Saarlandes, Homburg 3 Klinik für Gynäkologie und Geburtshilfe, Martin-Luther-Krankenhaus, Berlin Key words l" endometriosis l" infertility l" dyspareunia Schlüsselwörter l" Endometriose l" Infertilität l" Dyspareunie received 24. 5. 2013 revised 29. 6. 2014 accepted 30. 6. 2014

DOI http://dx.doi.org/ 10.1055/s-0034-1382884 Geburtsh Frauenheilk 2014; 74: 733–742 © Georg Thieme Verlag KG Stuttgart · New York · ISSN 0016‑5751 Correspondence PD Dr. Ingolf Juhasz-Böss Uniklinikum Saarland Frauenklinik Kirrbergerstraße 100 66424 Homburg/Saar Ingolf.Juhasz-Boess@ uniklinikum-saarland.de 733 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 Review Deutschsprachige Zusatzinformationen online abrufbar unter: www.thieme-connect.de/ ejournals/toc/gebfra strategies in some cases insufficient relief of the endometriosis- related complaints or disease recurrence can occur. The disease is thus also of economic relevance. Beside the medi- cal expenses, above all the patients ʼ inability to work is appreci- able [1, 5]. Repeated surgery, the in part chronic course as well as the delayed diagnostic confirmation after year-long symptoms and complaints results in a high medical expenditure [6]. The present article aims to give an actual survey of the diagnostic and therapeutic procedures as well as to present the latest re- search results on the subject of endometriosis. Aetiology of Endometriosis: Classic Theories and Latest Research Approaches ! Although endometriosis is one of the most investigated gynaeco- logical clinical entities, many aspects of the aetiology and patho- genesis of the disease have still not been completely clarified and thus represent a focus of current research on endometriosis. The classical theories on the development of endometriosis in- clude the “coelom metaplasia theory ” (according to Meyer) and the “theory of embryonic cell remains ” according to which the endometriosis lesions develop from tissue of embryonic origin, as well as the “theory of lymphovascular metastasis ”, which pro- poses that endometrial cells, similar to tumour cells, spread via lymphatic pathways or blood vessels and that in this way endo- metriosis lesions can develop in various positions in the body [7]. Today the most widely accepted theory on the development of endometriosis is, however, the “implantation theory ” accord- ing to Sampson [8]. This is based on the assumption that during menstruation, vital endometrium reaches the abdominal cavity from the uterus in a retrograde manner via the tubes. Favourable conditions there lead to implantation of tissue fragments on the peritoneum and thus to the development of endometriosis. How- ever, retrograde menstruations are certainly physiological and can be detected in up to 90 % of all women who undergo laparos- copy [9]. Thus there is no doubt that the development of endo- metriosis depends on many other pathogenic mechanisms, thus rendering it a typical multifactorial clinical entity. Numerous studies have in the meantime indicated that there is a genetic predisposition for endometriosis [10]. For this reason ge- nome-wide association studies are underway in order to identify the corresponding genetic factors. Although in the course of these studies 3 potential gene loci have already been found that are with the highest probability associated with the occurrence of endometriosis in Japanese and European women, it is still nec- essary to confirm such results in a larger number of cases and to correlate the obtained data with the various clinical subtypes of endometriosis [11]. In addition epigenetic studies are needed to clarify how certain environmental factors influence the disease. In this context, dioxins must be considered as potential disease- triggering environmental toxins [12]. Furthermore, certain com- ponents of foodstuffs such as, e.g., fatty acids and their deriva- tives, are being discussed as factors influencing the disease [13]. Various immunological aspects also play an important role in the pathogenesis of endometriosis, whereby the disease shows marked similarities with typical autoimmune diseases [14]. Thus, it was shown that in the course of endometriosis autoantibodies against endometrial antigens such as, e.g., transferrin or alpha 2- HS glycoprotein, are formed, and which can often in part be re- sponsible for the infertility frequently observed in endometriosis patients [15, 16]. Also concentration fluctuations of cytotoxic and activated lymphocytes peripheral blood during the menstrual cycle appear to play a certain role. The fluctuations of regulatory T cells detected during endometriosis can be attributed to a changed immune response [17]. Furthermore, endometriosis is characterised by a chronic inflammatory reaction with elevated concentrations of inflammatory cytokines in serum and the peri- toneal fluid [18]. Elevated numbers of macrophages, dendritic cells and natural killer cells are seen in the peritoneum which, for as yet insufficiently investigated reasons, are however not able to recognise and degrade the endometrium tissue scattered in the abdominal cavity [19]. This chronic inflammatory reaction, in turn, leads to an increased production and an inhibited degrada- tion of reactive oxygen species [20]. Accordingly, the administra- tion of substances with an antioxidative action could represent a meaningful supplement to the current therapeutic options. The basal parts of the endometrium contain endometrial stem cells and progenitor cells [21], which explains the high regenera- tion potential of this tissue. This is at present under discussion as a further cause for the occurrence of endometrium lesions. Thus, it is assumed that stem cells reach the abdominal cavity via retro- grade menstruation and under suitable conditions can then dif- ferentiate into endometriosis lesions [22]. This assumption is supported by the observation that the glandular cells of some en- dometriosis lesions are of monoclonal origin [22]. In addition, it is possible that also extrauterine, circulating stem and progenitor cells from bone marrow contribute appreciably to the formation of endometriosis lesions. Thus, it has been shown in a mouse model that not only glandular but also stromal cells from bone marrow cells can develop into endometriosis lesions [23]. Fur- thermore, up to 37 % of all endothelial cells in endometriosis le- sions are derived from circulating endothelial progenitor cells [24]. A major prerequisite for the long-term survival of endometriosis lesions is angiogenesis, i.e., the generation of new blood vessels [25]. Only in this way can the scattered endometrium tissue, which is initially ischaemic outside the uterus, be adequately supplied with oxygen and nutrients. For this reason, especially the early stages of endometriosis lesions exhibit a reddish colour- ation caused by a high density of blood vessels and vessel dilata- tions [26, 27]. Furthermore, in the past few years numerous an- giogenic growth factors have been identified – above all “vascular endothelial growth factor ” (VEGF) – which is produced and re- leased in increased amounts in endometriosis, and regulates the ingrowth of new blood vessels in endometriosis lesions [28]. In- terestingly, endometrium in the uterus of endometriosis patients already exhibits an elevated angiogenic activity which can favour the process of creation of new endometriosis lesions [29]. Endo- metriosis thus belongs to the group of angiogenic diseases along with rheumatoid arthritis, psoriasis, diabetic retinopathy as well as tumour growth and metastasis [29]. Accordingly in recent years increasing attention has been paid to analysing the control mechanisms that govern the formation of new blood vessels in endometriosis lesions, in order to identify new targets for a tar- geted, anti-angiogenic endometriosis therapy [30, 31]. In addi- tion, experimental in-vitro and in-vivo studies have already de- tected numerous members of various substance classes that exert an anti-angiogenic effect on endometriosis lesions. These include growth factor inhibitors, endogenous angiogenesis inhibitors, fu- magillin analogues, statins, cyclooxygenase 2 inhibitors, phyto- therapeutic agents, immune modulators as well as dopamine ag- onists [32]. Further clinical trials are needed to clarify to what ex- tent these active principles can be used for an anti-angiogenic 734 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 GebFra Science endometriosis therapy without causing severe side effects in the afflicted patients. Another area of current research focusses on the mechanisms that contribute to the pain symptomatic of endometriosis. Major contributing factors are considered to be long-term cyclic bleed- ing of the oestrogen-dependent endometriosis lesions with con- secutive inflammatory reactions as well as irritation and invasion of pelvic nerves [33]. Recent investigations, however, have shown that pain transmitting nerve fibres can grow together into endo- metriosis lesions [34], this is also designated as “neuroangiogen- esis” [35]. These nerve fibres in turn increase the pain sensation in the central nervous system [35]. If it were possible – as has al- ready been demonstrated in animal experiments [36] – to inhibit this process by targeted drug measures, we should be able in the future to develop appreciably more effective pain therapies hav- ing considerably fewer side effects than the conventional hor- mone treatment options. Summarising the current research results, we see that endome- triosis is a complex, multifactorial disease for which the aetiology and pathogenesis have not yet been completely clarified. The re- search findings of the past 10 years, however, do show that mo- lecular and cellular pathomechanisms which contribute to the development of the disease are increasingly being identified. This should provide the possibility in future to develop better tar- geted, new preventive and therapeutic treatment strategies. Diagnostic, Clinical Picture and Therapy for Endometriosis ! As recommended in the current guidelines and for the sake of better clarity, the differing manifestations of endometriosis are discussed separately although they often occur in combination [1]. First of all, the following aspects are valid for all manifesta- tions: Laparoscopy: Laparoscopy (LSC) is a central component in the di- agnosis of and therapy for endometriosis. Indication for LSC is: pain, organ changes and/or sterility. Surgical removal of the en- dometriosis lesions is considered to be the gold standard, on the one hand to control the symptoms and on the other hand for his- tological work-up [37]. It should be noted that asymptomatic en- dometriosis in a patient not desiring to have children does not re- quire any surgical or drug treatment [1]. Examination of the case history and the additional use of psychological questionnaires provide valuable information prior to the diagnostic/curative op- eration and can provide indications for the presence of an endo- metrial disease and thus support an optimal counselling for the symptomatic patient in the phase of decision-making for surgical clarification [4]. Localisation: Endometriosis preferentially attacks the lesser pelvis and here above all (in order of decreasing frequency) the pelvic peritoneum, the ovaries, the sacrouterine ligament, the rectovagi- nal septum as well as extragenital manifestations such as, e.g., the rectosigmoid or urinary bladder. Extraperitoneal manifestations are seldom [1]. Staging: In clinical routine endometriosis is subdivided according to its localisation into endometriosis genitalis externa and inter- na as well as extragenitalis [1]. Unfortunately endometriosis is not uniformly classified, furthermore the current staging is not satisfactory. The most widely used and most frequently used in reproduction medicine is the rASRM classification of the Ameri- can Society for Reproductive Medicine (ASRM) [38] ( l " Table 1 ). Retroperitoneal and deep infiltriating endometriosis are best de- scribed by means of the ENZIAN classification [39, 40] ( l" Fig. 1). However, the stage does not correlate with the degree of com- plaints, some afflicted women are even asymptomatic. Tumour marker CA-125: CA-125 is generally elevated in endome- triosis patients. However, this tumour marker has no differential diagnostic relevance. In clinical routine its determination is not recommended either for diagnosis or for course control [1]. Peritoneal endometriosis Morphology and symptoms In cases of peritoneal endometriosis a distinction is made be- tween pigmented (= typical) and not pigmented (= atypical) le- sions as well as between red, white and black lesions [26, 41] (l " Fig. 2). These lesions differ above all with regard to their activ- ity, fibrosis, age, etc. It is not clear to what extent the different forms correlate with specific symptoms of endometriosis [42]. Patients with preoperatively pronounced complaints have a higher risk of recurrence than patients with lower pain sensa- tions [43]. Diagnostics Peritoneal endometriosis cannot be detected by sonography. Standard procedure in the field of diagnosis of peritoneal endo- metriosis is laparoscopy [1]. Histological confirmation should al- so be attempted for peritoneal endometriosis as mentioned above [1]. Surgical and drug therapies The main objective is the laparoscopic removal of all peritoneal lesions by means of coagulation, vaporisation or excision [1]. It has not yet been clarified as yet which procedure is the most suit- able. In answer to this question there is only one randomised controlled trial and the Cochrane analysis published in 2014 [44, 45]. The aim of drug therapy is to achieve a hypo-oestrogenic status. Endometriosis implants can be regressively changed by means of Table 1 rASRM classification of endometriosis (modified from [38]). stage I (minimal): 1 –5; stage II (mild): 6 –15; stage III (moderate): 16 –40; stage IV (pronounced): > 40. Endometriosis 3c m Peritoneum superficial 1 2 4 deep 2 4 6 Ovaries R superficial 1 2 4 R deep 4 16 20 L superficial 1 2 4 L deep 4 16 20 Douglas obliteration partial complete 44 0 Adhesions ⅔ Ovaries R thin 1 2 4 R dense 4 8 16 L thin 1 2 4 L dense 4 8 16 Tubes R thin 1 2 4 R dense 4* 8* 16 L thin 1 2 4 L dense 4* 8* 16 * in cases of complete attack or, respectively, complete occlusion of the fimbria ends: 16 735 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 Review suppression of ovarian function. The drugs predominately used today are pure gestagens, gestagen-rich contraceptives, GnRH analogues and danazol. GnRH analogues are in such cases more effective than oral contraceptives or gestagens. A reduction of en- dometriosis-associated complaints can be achieved with all the mentioned substance classes, while GnRH analogues proved to be more effective for dysmenorrhoea and dyspareunia in some trials. Some of these drugs are associated with appreciable and, above all, different side effects. GnRHa should only be administered to- gether with the corresponding protective accompanying dugs (“add-back”) because of the consequences of a possible oestrogen deficiency [1]. With regard to the response to hormone therapy it seems that peritoneal endometriosis differs from ovarian and deep infiltrat- ing endometriosis. Duration of therapy with GnRH analogues amounts to 3 – 6 months. Although a 3-month therapy is equally effective the subsequent recurrence-free interval is then shorter [46]. Recent data from prospective studies have shown that dienogest as maintenance therapy after administration of GnRH can uphold the GnRH-induced effect for at least 12 months [47]. In 2 further RCCCTs equieffective actions of dienogest vs. GnRH analogues for endometriosis-associated pain were observed whereby with regard to clinical tolerance dienogest was better tolerated by the patients [48, 49]. Although frequently used in clinical routine there is no evidence for a positive effect of NSAR on endometriosis-specific complaints [50]. Ovarian endometriosis Diagnostics The ovaries are attacked in up to 50 % of all endometriosis pa- tients [1, 51]. Preoperative clarification is based on the clinical ex- Fig. 1 ENZIAN classification of deep infiltrating endometriosis (www.endometriose-sef.de/dateien/ ENZIAN_2013_web.pdf; © Keckstein). 736 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 GebFra Science amination. In the case of an ovarian endometrioma transvaginal sonography is suitable [51]. In cases of unclear ovarian space-fill- ing lesions histological clarification is always required. The differ- ential diagnosis, however, should take all ovarian findings into consideration and the results included in the operative proce- dures (especially LSC). Therapy The standard procedure is the laparoscopic removal of ovarian endometrioma [1]. In such cases the ovary-sparing extraction of the cyst bag is superior to thermal destruction [52]. Mere open- ing and lavage of the cyst bag as sole surgical intervention is not recommended due to the high rate of recurrences [53]. The recur- rence rate even after 2 operative interventions can still amount to 20.8 % and correlates above all with the duration of follow-up as well as the rASRM stage [54]. The exclusive use of drug therapy for ovarian endometrioma is not adequate and is not recommended [1]. Also postoperative GnRH analogues cannot compensate for an incomplete operation [55]. With regard to the recurrence rate data on the postoperative administration of a hormonal contraceptive are contradictory. Adenomyosis uteri Diagnostics In the diagnostic work-up besides gynaecological examinations the transvaginal sonography (TVS) above all and if necessary MRI are most suitable in such cases. TVS is of greater relevance in daily practice [56]. The sonographic criteria for making a diag- nosis are poorly delineated heterogeneous areas, in part, cystic intramural alterations, areas of changing echogenicity, irregular halo effects as well as a discrepancy between the anterior and posterior wall findings. Histological confirmation of adenomyo- sis is in most cases, however, only possible on hysterectomy sam- ples. Therapy Therapy is adapted to the patientʼs family planning wishes. When family planning has been completed hysterectomy (HE) repre- sents the most effective option. Here all common modalities of HE can be applied, but it must be taken into account that a possi- bly coexisting intraperitoneal endometriosis can usually not be managed by a purely vaginal procedure. A supracervical HE may also be envisioned but should not be performed in case of a con- current coexisting rectovaginal endometriosis. When planning an HE the operative procedure should be decided upon between surgeon and patient on a case by case basis [1]. For patients still desiring to have children or with a wish to retain their organs, the benefit of an operation has not been demon- strated. Interventional radiological procedures (e.g., embolisa- tion) or MRI-guided focussed ultrasound ablation are still in the experimental stage and should only be applied with the frame- work of clinical trials [1]. As alternatives to HE, gestagens, hormonal contraceptives and in- trauterine, local gestagen-releasing systems may be considered. The therapeutic effect is based on the induction of amenorrhoea. Contraceptives (monophasic formulations) and gestagens should therefore be taken continuously [1]. Deeply Infiltrating Endometriosis ! In comparison to peritoneal or ovarian endometriosis, still very little is known about deeply infiltrating endometriosis (DIE) although it is a clinically no lesser relevant form of the disease. In this form it is seen that endometriosis – similar to malignant diseases – can spread beyond organ borders and infiltrate various structures. The thus resulting space-filling lesions and in part in- vasive growth can lead to indurations and finally to the destruc- tion of functional mobile layers (e.g., between rectum and vagi- na) through to the occurrence of larger conglomerate tumours and in some cases even to disabling complaints. The fact that, in Germany, statistically an interval of 6 years must pass from the first manifestation of symptoms to the diagnosis of endometriosis is disturbing and may in part be due to frequent misinterpretations and a lack of experience with the deeply infil- trating variant of the disease (see l " Figs. 3 and 4)[ 1 ] . The mostly retroperitoneal growth of DIE is often not directly visible with laparoscopy – due either to the retroperitoneal posi- tion or complete Douglas obliteration – and thus it can hardly be defined in the common stage classifications (AFS/rASRM) [57]. DIE should thus additionally be described using the ENZIAN clas- sification (see l " Figs. 4 and 5) [40]. Frequently affected are the sacrouterine ligament, the parame- tria, the rectovaginal septum/fornix of the vagina, the rectosig- moid, the appendix, the urinary bladder and sometimes the ure- ter or also the small intestine. Symptoms The symptoms of DIE depend on the afflicted organs or, respec- tively, structures and vary between no complaints and disability and invalidisation due to severe pain. On the whole and as for en- dometriosis in general, there is no correlation between the ex- tent of the disease and the severity of the symptom spectrum. A small node in the rectovaginal septum can, for example, make in- tercourse so painful that it is no longer possible and turn defaeca- tion into a nightmare for the patients, whereas some other pa- tients with stenosed rectum and/or space filling tumours through to frozen pelvis experience no complaints at all. In general, the symptoms of DIE, beside the classical dysmenor- rhoea, do of course depend on the pattern of attack. Infiltration of the rectovaginal septum/fornix of the vagina or, respectively, the rectum often leads to dyspareunia and dyschezia, sometimes Fig. 2 Endometriosis attack of the peritoneum. Besides pigmented (= atypical) endometriosis lesions also typical, here, e.g., blister like unpig- mented lesions can be seen. 737 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 Review also to flatulence and tenesmus and can be accompanied by rec- tal passage of mucous or blood as well as changes in stool behav- iour through to paradox diarrhoea. DIE of the bladder or ureter can – beside hydronephrosis – cause dys- and haematuria. The lack of symptoms never excludes attack of the mentioned organs. Diagnostics The suspicion of DIE is based first of all on case history plus the clinical-gynaecological examination, where importance must be placed of an adequate deconvulation of the posterior fornix of the vagina in the speculum settings (see l " Fig. 3) and a rectal or rec- tovaginal palpation. Typically among the findings to be recorded – apart from pain trigger points – are visible endometriosis in the vagina, the rough nodular induration of the rectovaginal septum or the parametria/sacrouterine ligaments and, in some cases, uri- nary retention on sonography. With sufficient experience an in- filtration of the rectovaginal septum and the rectum can also be demonstrated by transvaginal sonography [51, 56]. The sono- graphic detection of bilateral endometrioma (especially in the sense of kissing ovaries) can be suggestive of DIE [58]. In the literature magnetic resonance imaging exhibits a high sen- sitivity for the diagnosis of FDI but is certainly dependent on the investigatorʼs experience or, respectively, knowledge of the dis- ease but only rarely does it lead to a change of the therapy [59, 60]. In cases of suspected intestinal involvement by DIE coloscopy is rarely useful since the endometrial infiltration usually stops at the mucosa so that the exclusion of intestinal attack is not possi- ble by rectoscopy. In such cases rectal endosonography is to be preferred [1, 59]. Coloscopy must only be used when it is neces- sary to exclude other differential diagnoses (e.g. colon cancer, di- verticulitis, chronic inflammatory bowel disease). DIE of the bladder can often be well visualised by sonography when the bladder is sufficiently full. In such cases, however, cystoscopy pri- or to surgery is reasonable in order to estimate the distance to the trigonum vesicae and the ureter orifices and, if necessary, to carry out thereby a splinting with a double J catheter. Therapy The therapy of choice for symptomatic DIE is resection with healthy margins [61 – 64]. The operations often include rectum resection (mostly en-bloc with the afflicted rectovaginal septum and the vagina), and partial resection of the sacrouterine liga- ment and parametria as well as parts of the bladder (see l " Figs. 4 to 7). Partial ureter resections with new implantation (e.g., psoas- hitch plasty) are much more rarely needed. Hysterectomy is not obligatory and is not wanted by the mostly young patients. The interventions can mostly be performed as laparoscopic or, if nec- essary vaginal-assisted procedures. Good cooperation between the various disciplines (gynaecology, surgery, urology) is a neces- sity and accordingly is required for the certification of specialised surgical centres by the Stiftung Endometrioseforschung, the Europäische Endometrioseliga and the Endometriose-Vereini- gung-Deutschland e. V. Fig. 3 Part of a DIE of the rectovaginal septum visible in the posterior fornix of the vagina. Fig. 4 Due to the almost exclusive retroperitoneal position the DIE of the rectovaginal septum and the rectum (rASRM I) is easily missed, see l " Fig. 5. Fig. 5 View from l" Fig. 4 with freely exposed retroperitoneal endome- triosis lesion (ENZIAN 2A, 2C). 738 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 GebFra Science Urinary retention – due to extrinsic or intrinsic DIE of the ureter – is the only acceptable absolute indication for surgery in the Ger- man-language guidelines since it is essential to prevent persist- ing damage to the kidneys [1]. An intestinal perforation or ileus due to stenosing DIE of the bowels can give rise to an urgent in- dication in a similar manner [65]. In the case of DIE diagnosed near to the ureter or its recent oper- ative management long-term biannual sonography of the kid- neys is recommended in order to recognise the potentially slowly but then also often asymptomatical development of urinary re- tention in a timely manner [1]. The decision for or against operative removal of DIE is – when as in most cases no absolute indication is given – made together with the patient on the basis of the symptoms and the level of suffering. In most cases an estimation of the extent by means of an at first purely diagnostic laparoscopy is helpful for both physi- cian and patient. In no case may the decision be made without sufficient counselling and time for consideration since extensive rehabilitating resection with participation of the bowels and/or bladder interventions do not guarantee either therapeutic suc- cess or freedom from de novo complaints resulting from surgery (late postoperative problems due to disorders of defaecation or to scar and adhesion complaints) [62, 66]. An appropriately high burden of suffering is a decisive prerequisite for rehabilitating operations. Critical in this context is always the wish for removal of an asymptomatic DIE merely on the basis of sterility. In the literature higher rates of not only spontaneous but also of IVF-induced pregnancies after complete resections in such cases can be found in the literature [67 – 69], however, the potential operative mor- bidity that is to be expected must be also be considered. In the worst case a previously complaint-free but infertile patient – in spite of unsuccessful IVF – may merely experience a marked de- terioration in her quality of life. Such scenarios must also be dis- cussed in detail with just those patients who are free of symp- toms. More recent data also even additionally question this im- provement in fertility, so that the guideline recommendations will probably have to be reassessed on this point [70]. Drug therapy is neither necessary as preparation nor as an adju- vant therapy after the surgical management of DIE. When, in spite of symptomatic DIE – initial or permanent – the decision against surgery is made, the classical hormone therapy options (monophasic oral contraceptives, gestagen monotherapy, levo- norgestrel IUP) can then be applied. An effect can only be ex- pected during the therapy so that a life-long continuation is a ne- cessity [1]. A malignant degeneration is rare but possible. DIE can typically develop into endometrioid or clear-cell adenocarcinomas in the pelvis without any clearly associated organs [71]. However, this risk is so low that an indication for treatment or surgery cannot be derived from this alone. Endometriosis and Sterility ! Pathophysiology of involuntary childlessness in cases of endometriosis There is a high coincidence between sterility and endometriosis [72], the reasons for this have not yet been clarified. It is esti- mated that 30 – 50 % of the women with endometriosis are infer- tile [73]. Mechanical factors due to adhesions of the adnexa with disorders of tube motility or, respectively, the ovum pick-up mechanism have been accepted as reasons for sterility. Further causes may involve disordered immunological dysregulation and also a change of the intra-abdominal milieu, due to cyto- kines, prostaglandins and macrophages. In an egg cell donation programme patients with endometriosis achieved similar preg- nancy rates as those women without endometriosis, however the pregnancy rates in case of transfer of embryos form women with endometriosis was markedly lower. This suggests a decrease in embryo quality in cases of endometriosis [74]. Fig. 6 a and ba DIE of the vesicocervical septum and bladder. b Cysto- scopic visualisation with intact urothelium over the finding. Fig. 7 Situation after local full wall excision of DIE of the bladder. 739 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 Review Drug therapy A hormone therapy for endometriosis can be performed with pure gestagens (e.g., dienogest, medroxyprogesterone acetate, levonorgestrel, chlormadinone acetate, cyproterone acetate and nomegestrol acetate), with monophasic oestrogen-gestagen combination formulations (especially taken in long cycles), as well as by means of GnRH analogues. In cases of low-degree en- dometriosis (AFS I and II), however, a metaanalysis of 16 random- ised and controlled studies did not reveal an improvement in fer- tility after drug treatment (GnRH analogues, gestagens) in com- parison to placebo or expectative procedure [75]. A postoperative drug therapy with GnRH agonists could not improve the sponta- neous pregnancy rates of sterility patients and is thus not recom- mended [55]. Operative therapy Just for patients desiring to have children and the suspicion of an endometrial disease surgical diagnosis and histological confirma- tion with simultaneous hysterectomy and chromopertubation of the Fallopian tubes represent the method of choice. In the course of this treatment if at all possible all endometriosis lesions should be surgically excised or thermally destroyed. Endometriosis cysts should be ablated with cyst bag in an organ-sparing manner. The rate of spontaneous pregnancies is in such cases also higher than for the excision endometriosis lesions in stages AFS I and II [52, 53, 76]. Assisted reproduction The measures of assisted reproduction in almost all stages of en- dometriosis seem to be more advantageous as compared with a non-surgical process. In cases of minimal endometriosis the probability of a pregnancy after a wait-and-see procedure for 6 months amounts to 28 % [77]. Several prospective controlled studies have shown a higher suc- cess rate under ovarian stimulation in combination with intra- uterine insemination [77]. For younger patients pregnancies oc- curred within the first cycle after operative management of en- dometriosis so that a maximum of 3 insemination treatments should be performed [78]. For endometriosis patients the success rate in the course of an in- vitro fertilisation is up to 50 % lower than for tubular sterility [79], furthermore, higher drug doses are needed for the markedly low- er responsiveness to gonadotropins [80]. On the basis of a large metaanalysis it has been shown that the implantation rate for en- dometriosis patients was markedly lower than that in the control group (12.72 vs. 18.08 %) [79]. In case of the recurrence of an ex- tensive endometriosis an assisted reproduction by means of in- vitro fertilisation is superior to renewed operative therapy with regard to the pregnancy rate [81]. In the case of advanced endo- metriosis AFS III and IV, a stimulation for IVF/ICSI in ultra-long protocol after surgical therapy for endometriosis leads to signifi- cantly higher pregnancy rates [82, 83]. In patients with endometriosis and the desire to have children surgical clarification and rehabilitation of endometriosis is con- sidered to be the gold standard. Depending on the degree of se- verity of the endometriosis, a cycle optimisation in combination with ovarian stimulation and accompanying intrauterine insemi- nation should be preferred although not more than 3 treatment cycles may be carried out. Patients with severe endometriosis should be treated as early as possible by means of IVF/ICSI, if necessary after stimulation in ul- tra-long protocol. Complementary Therapy, Rehabilitation and Follow-Up ! For chronic courses of endometriosis with the corresponding symptoms many women experience an alleviation of their com- plaints and an improvement in their quality of life through the use of complementary therapies such as, e.g., acupuncture, Chi- nese medicine, homeopathy, phytotherapy, osteopathy, physio- therapy etc. However, at present there are no randomised and controlled studies that confirm an evidence-based effect of these therapies [1]. The need for rehabilitation is often present after extensive surgi- cal interventions or in patients with chronic pain. The aim of rehabilitation should be the restoration of physical, mental and social well-being and should thus be generously offered to this patient collective. An important aspect is, however, also the con- frontation with the disease, which often has a chronic course and in part is accompanied by unavoidable restrictions and com- plaints. Afflicted women should be referred to regional and na- tional self-help organisations and self-help groups. The aftercare should be oriented on the symptoms. The patient ʼs quality of life is in the forefront of all efforts [1]. In the present article we have topically summarised many as- pects of endometriosis with reference to the most recent litera- ture. In particular the less common DIE, a form that is associated with a high morbidity, has been discussed in detail. Also sterility as well as the diagnostic and therapeutic consequences are spe- cifically summarised. Besides further important clinical aspects we have in the present article highlighted the most recent re- search results, in order to close the gap concerning actual re- search between scientists and clinicians. Conflict of Interest ! None.

1 Ulrich U, Buchweitz O, Greb R et al. Interdisciplinary S2k guidelines for the diagnosis and treatment of endometriosis: short version – AWMF Registry No. 015 – 045, August 2013. Geburtsh Frauenheilk 2013; 73: 890– 898 2 Burghaus S, Klingsiek P, Fasching PA et al. Risk factors for endometriosis in a German case – control study. Geburtsh Frauenheilk 2011; 71: 1073– 1079 3 Siedentopf F. Chronic pain syndromes in gynaecological practice: endo- metriosis and fibromyalgia. Geburtsh Frauenheilk 2012; 72: 1092 – 1098 4 Wölfler MM, Stadermann M, Rath W et al. Anamnestisches Screening bei symptomatischen Patientinnen mit und ohne Endometriose. Ge- burtsh Frauenheilk 2011; 71: 53 – 58 5 Oppelt P, Chavtal R, Haas D et al. Costs of in-patient treatment for endo- metriosis in Germany 2006: an analysis based on the G ‑DRG-Coding. Gynecol Endocrinol 2012; 28: 903 – 905 6 Hudelist G, Fritzer N, Thomas A et al. Diagnostic delay for endometriosis in Austria and Germany: causes and possible consequences. Hum Re- prod 2012; 27: 3412 – 3416 7 Sasson IE, Taylor HS. Stem cells and the pathogenesis of endometriosis. Ann N Y Acad Sci 2008; 1127: 106 – 115 8 Sampson JA. Peritoneal endometriosis due to menstrual dissemination of endometrial tissues into the peritoneal cavity. Am J Obstet Gynecol 1927; 14: 422 – 469 9 Halme J, Hammond MG, Hulka JF et al. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol 1984; 64: 151 – 154 740 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 GebFra Science 10 Augoulea A, Alexandrou A, Creatsa M et al. Pathogenesis of endometrio- sis: the role of genetics, inflammation and oxidative stress. Arch Gyne- col Obstet 2012; 286: 99 – 103 11 Rahmioglu N, Missmer SA, Montgomery GW et al. Insights into assessing the genetics of endometriosis. Curr Obstet Gynecol Rep 2012; 1: 124 – 137 12 Rier SE. The potential role of exposure to environmental toxicants in the pathophysiology of endometriosis. Ann N Y Acad Sci 2002; 955: 201– 212; discussion 230 – 232, 396– 406 13 Bellelis P, Podgaec S, Abrao MS. Environmental factors and endometrio- sis. Rev Assoc Med Bras 2011; 57: 448 – 452 14 Barrier BF. Immunology of endometriosis. Clin Obstet Gynecol 2010; 53: 397– 402 15 Mathur SP. Autoimmunity in endometriosis: relevance to infertility. Am J Reprod Immunol 2000; 44: 89 – 95 16 de Ziegler D, Borghese B, Chapron C. Endometriosis and infertility: pathophysiology and management. Lancet 2010; 376: 730 – 738 17 Slabe N, Meden-Vrtovec H, Verdenik I et al. Cytotoxic T-cells in peripher- al blood in women with endometriosis. Geburtsh Frauenheilk 2013; 73: 1042– 1048 18 May KE, Conduit-Hulbert SA, Villar J et al. Peripheral biomarkers of en- dometriosis: a systematic review. Hum Reprod Update 2010; 16: 651 – 674 19 Khoufache K, Michaud N, Harir N et al. Anomalies in the inflammatory response in endometriosis and possible consequences: a review. Minerva Endocrinol 2012; 37: 75 – 92 20 Alpay Z, Saed GM, Diamond MP. Female infertility and free radicals: po- tential role in adhesions and endometriosis. J Soc Gynecol Investig 2006; 13: 390 – 398 21 Gargett CE, Masuda H. Adult stem cells in the endometrium. Mol Hum Reprod 2010; 16: 818 – 834 22 Figueira PG, Abrao MS, Krikun G et al. Stem cells in endometrium and their role in the pathogenesis of endometriosis. Ann N Y Acad Sci 2011; 1221: 10 – 17 23 Du H, Taylor HS. Stem cells and reproduction. Curr Opin Obstet Gynecol 2010; 22: 235 – 241 24 Laschke MW, Giebels C, Menger MD. Vasculogenesis: a new piece of the endometriosis puzzle. Hum Reprod Update 2011; 17: 628 – 636 25 Groothuis PG, Nap AW, Winterhager E et al. Vascular development in endometriosis. Angiogenesis 2005; 8: 147 – 156 26 Nisolle M, Casanas-Roux F, Anaf V et al. Morphometric study of the stro- mal vascularization in peritoneal endometriosis. Fertil Steril 1993; 59: 681– 684 27 McLaren J. Vascular endothelial growth factor and endometriotic an- giogenesis. Hum Reprod Update 2000; 6: 45 – 55 28 Laschke MW, Menger MD. In vitro and in vivo approaches to study an- giogenesis in the pathophysiology and therapy of endometriosis. Hum Reprod Update 2007; 13: 331 – 342 29 Healy DL, Rogers PA, Hii L et al. Angiogenesis: a new theory for endome- triosis. Hum Reprod Update 1998; 4: 736 – 740 30 Laschke MW, Elitzsch A, Vollmar B et al. Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and plate- let-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic le- sions. Hum Reprod 2006; 21: 262 – 268 31 Feng D, Welker S, Korbel C et al. Protein kinase CK2 is a regulator of an- giogenesis in endometriotic lesions. Angiogenesis 2012; 15: 243 – 252 32 Laschke MW, Menger MD. Anti-angiogenic treatment strategies for the therapy of endometriosis. Hum Reprod Update 2012; 18: 682 – 702 33 Anaf V, Simon P, El Nakadi I et al. Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, perito- neal and ovarian endometriosis. Hum Reprod 2002; 17: 1895 – 1900 34 Alvarez P, Chen X, Hendrich J et al. Ectopic uterine tissue as a chronic pain generator. Neuroscience 2012; 225: 269 – 282 35 Asante A, Taylor RN. Endometriosis: the role of neuroangiogenesis. Annu Rev Physiol 2011; 73: 163 – 182 36 Novella-Maestre E, Herraiz S, Vila-Vives JM et al. Effect of antiangiogenic treatment on peritoneal endometriosis-associated nerve fibers. Fertil Steril 2012; 98: 1209 – 1217 37 Rimbach S, Ulrich U, Schweppe KW. Surgical therapy of endometriosis: challenges and controversies. Geburtsh Frauenheilk 2013; 73: 918 – 923 38 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67: 817 – 821 39 Haas D, Wurm P, Shamiyeh A et al. Efficacy of the revised Enzian classi- fication: a retrospective analysis. Does the revised Enzian classification solve the problem of duplicate classification in rASRM and Enzian? Arch Gynecol Obstet 2013; 287: 941 – 945 40 Tuttlies F, Keckstein J, Ulrich U et al. [ENZIAN-score, a classification of deep infiltrating endometriosis]. Zentralbl Gynakol 2005; 127: 275 – 281 41 Jansen RP, Russell P.Nonpigmented endometriosis: clinical, laparoscop- ic, and pathological definition. Am J Obstet Gynecol 1986; 155: 1154 – 1159 42 Harrison RF, Barry-Kinsella C. Efficacy of medroxyprogesterone treat- ment in infertile women with endometriosis: a prospective, random- ized, placebo-controlled study. Fertil Steril 2000; 74: 24 – 30 43 Renner SP, Rix S, Boosz A et al. Preoperative pain and recurrence risk in patients with peritoneal endometriosis. Gynecol Endocrinol 2010; 26: 230– 235 44 Healey M, Ang WC, Cheng C. Surgical treatment of endometriosis: a pro- spective randomized double-blinded trial comparing excision and ablation. Fertil Steril 2010; 94: 2536 – 2540 45 Duffy JM, Arambage K, Correa FJ et al. Laparoscopic surgery for endo- metriosis. Cochrane Database Syst Rev 2014; 4: CD011031 46 Hornstein MD, Yuzpe AA, Burry KA et al. Prospective randomized dou- ble-blind trial of 3 versus 6 months of nafarelin therapy for endome- triosis associated pelvic pain. Fertil Steril 1995; 63: 955 – 962 47 Kitawaki J, Kusuki I, Yamanaka K et al. Maintenance therapy with di- enogest following gonadotropin-releasing hormone agonist treatment for endometriosis-associated pelvic pain. Eur J Obstet Gynecol Reprod Biol 2011; 157: 212 – 216 48 Strowitzki T, Marr J, Gerlinger C et al. Detailed analysis of a randomized, multicenter, comparative trial of dienogest versus leuprolide acetate in endometriosis. Int J Gynaecol Obstet 2012; 117: 228 – 233 49 Harada T, Momoeda M, Taketani Y et al. Dienogest is as effective as in- tranasal buserelin acetate for the relief of pain symptoms associated with endometriosis – a randomized, double-blind, multicenter, con- trolled trial. Fertil Steril 2009; 91: 675 – 681 50 Allen C, Hopewell S, Prentice A et al. Nonsteroidal anti-inflammatory drugs for pain in women with endometriosis. Cochrane Database Syst Rev 2009; 2: CD004753 51 Hudelist G, Oberwinkler KH, Singer CF et al. Combination of transvaginal sonography and clinical examination for preoperative diagnosis of pel- vic endometriosis. Hum Reprod 2009; 24: 1018 – 1024 52 Hart RJ, Hickey M, Maouris P et al. Excisional surgery versus ablative surgery for ovarian endometriomata. Cochrane Database Syst Rev 2008; 2: CD004992 53 Alborzi S, Momtahan M, Parsanezhad ME et al. A prospective, random- ized study comparing laparoscopic ovarian cystectomy versus fenes- tration and coagulation in patients with endometriomas. Fertil Steril 2004; 82: 1633 – 1637 54 Kim ML, Kim JM, Seong SJ et al. Recurrence of ovarian endometrioma after second-line, conservative, laparoscopic cyst enucleation. Am J Obstet Gynecol 2014; 210: 216 e1 – 216 e6 55 Busacca M, Somigliana E, Bianchi S et al. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III – IV: a randomized controlled trial. Hum Reprod 2001; 16: 2399– 2402 56 Hudelist G, Keckstein J. [The use of transvaginal sonography (TVS) for preoperative diagnosis of pelvic endometriosis]. Praxis (Bern 1994) 2009; 98: 603 – 607 57 Khong SY, Bignardi T, Luscombe G et al. Is pouch of Douglas obliteration a marker of bowel endometriosis? J Minim Invasive Gynecol 2011; 18: 333– 337 58 Redwine DB. Ovarian endometriosis: a marker for more extensive pel- vic and intestinal disease. Fertil Steril 1999; 72: 310 – 315 59 Bazot M, Lafont C, Rouzier R et al. Diagnostic accuracy of physical ex- amination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endo- metriosis. Fertil Steril 2009; 92: 1825 – 1833 60 Saba L, Guerriero S, Sulis R et al. Learning curve in the detection of ovar- ian and deep endometriosis by using magnetic resonance: comparison with surgical results. Eur J Radiol 2011; 79: 237 – 244 61 Chopin N, Vieira M, Borghese B et al. Operative management of deeply infiltrating endometriosis: results on pelvic pain symptoms according to a surgical classification. J Minim Invasive Gynecol 2005; 12: 106 – 112 741 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 Review 62 Minelli L, Fanfani F, Fagotti A et al. Laparoscopic colorectal resection for bowel endometriosis: feasibility, complications, and clinical outcome. Arch Surg 2009; 144: 234 – 239; discussion 239 63 Haggag H, Solomayer E, Juhasz-Boss I. The treatment of rectal endome- triosis and the role of laparoscopic surgery. Curr Opin Obstet Gynecol 2011; 23: 278 – 282 64 Juhasz-Boss I, Lattrich C, Furst A et al. Severe endometriosis: laparo- scopic rectum resection. Arch Gynecol Obstet 2010; 281: 657 – 662 65 Decker D, Konig J, Wardelmann E et al. Terminal ileitis with sealed per- foration– a rare complication of intestinal endometriosis: case report and short review of the literature. Arch Gynecol Obstet 2004; 269: 294– 298 66 Possover M. Laparoscopic management of neural pelvic pain in women secondary to pelvic surgery. Fertil Steril 2009; 91: 2720 – 2725 67 Bianchi PH, Pereira RM, Zanatta A et al. Extensive excision of deep infil- trative endometriosis before in vitro fertilization significantly im- proves pregnancy rates. J Minim Invasive Gynecol 2009; 16: 174 – 180 68 Chapron C, Fritel X, Dubuisson JB. Fertility after laparoscopic manage- ment of deep endometriosis infiltrating the uterosacral ligaments. Hum Reprod 1999; 14: 329 – 332 69 Littman E, Giudice L, Lathi R et al. Role of laparoscopic treatment of en- dometriosis in patients with failed in vitro fertilization cycles. Fertil Steril 2005; 84: 1574 – 1578 70 Douay-Hauser N, Yazbeck C, Walker F et al. Infertile women with deep and intraperitoneal endometriosis: comparison of fertility outcome according to the extent of surgery. J Minim Invasive Gynecol 2011; 18: 622– 628 71 Ulrich U, Rhiem K, Kaminski M et al. Parametrial and rectovaginal ad- enocarcinoma arising from endometriosis. Int J Gynecol Cancer 2005; 15: 1206– 1209 72 Pritts EA, Taylor RN. An evidence-based evaluation of endometriosis- associated infertility. Endocrinol Metab Clin North Am 2003; 32: 653 – 667 73 Practice Committee of the American Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril 2006; 86 (5 Suppl. 1): S156 – S160 74 Simon C, Gutierrez A, Vidal A et al. Outcome of patients with endome- triosis in assisted reproduction: results from in-vitro fertilization and oocyte donation. Hum Reprod 1994; 9: 725 – 729 75 Hughes E, Brown J, Collins JJ et al. Ovulation suppression for endome- triosis. Cochrane Database Syst Rev 2007; 3: CD000155 76 Jacobson TZ, Duffy JM, Barlow D et al. Laparoscopic surgery for subfer- tility associated with endometriosis. Cochrane Database Syst Rev 2010; 1: CD001398 77 Tummon IS, Asher LJ, Martin JS et al. Randomized controlled trial of superovulation and insemination for infertility associated with mini- mal or mild endometriosis. Fertil Steril 1997; 68: 8 – 12 78 Greb R. Ovarielle Stimulation und intrauterine Insemination: Sinnvolle Therapie bei endometrioseassoziierter Sterilität? Gynak Endokrinol 2004; 2: 194 – 200 79 Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002; 77: 1148 – 1155 80 Mahutte NG, Arici A. Endometriosis and assisted reproductive technol- ogies: are outcomes affected? Curr Opin Obstet Gynecol 2001; 13: 275– 279 81 Pagidas K, Falcone T, Hemmings R et al. Comparison of reoperation for moderate (stage III) and severe (stage IV) endometriosis-related infer- tility with in vitro fertilization-embryo transfer. Fertil Steril 1996; 65: 791– 795 82 Rickes D, Nickel I, Kropf S et al. Increased pregnancy rates after ultralong postoperative therapy with gonadotropin-releasing hormone analogs in patients with endometriosis. Fertil Steril 2002; 78: 757 – 762 83 Sallam HN, Garcia-Velasco JA, Dias S et al. Long-term pituitary down- regulation before in vitro fertilization (IVF) for women with endome- triosis. Cochrane Database Syst Rev 2006; 1: CD004635 742 Juhasz-Böss I et al. Endometriosis: Survey of … Geburtsh Frauenheilk 2014; 74: 733 –742 GebFra Science