{"paper_id":"ab6eb564-6ab9-4080-9d04-4c5ba0245eed","body_text":"Offizielles Organ:  AGRBM,  BRZ,  DVR,  DGA,  DGGEF ,  DGRM,  D·I·R,  EFA,  OEGRM,  SRBM/DGE\nKrause & Pachernegg  GmbH, Verlag für Medizin und Wirtschaft, A-3003 Gablitz\nJournal für\nReproduktionsmedizin \nund Endokrinologie\n– Journal of Reproductive Medicine and Endocrinology –\nAndrologie • Embryologie & Biologie • Endokrinologie • Ethik & Recht • Genetik \nGynäkologie • Kontrazeption • Psychosomatik • Reproduktionsmedizin • Urologie\nIndexed in EMBASE/Excerpta Medica/Scopus\nwww.kup.at/repromedizin\nOnline-Datenbank mit Autoren- und Stichwortsuche\nEndometriosis – Pathogenesis, Diagnosis, and\nTherapeutic Options for Clinical and Ambulatory Care\nSchweppe KW, Rabe T, Langhardt M, Woziwodzki J\nPetraglia F, Kiesel L\nJ. Reproduktionsmed. Endokrinol 2013; 10 (Sonderheft\n1), 102-119\n\n\n20.-21. März 2026\nUniversitätsmedizin Mainz\nENDOKRINOLOGIE & FERTILITÄT\nFÜR KLINIK & PRAXIS\nWeitere Informationen\n& Anmeldung unter\nEinladung zu unserer wissenschaftlichen Veranstaltung Endo-Ferti-Forum\nBrücke(n) zwischen Unikliniken und Praxen an Rhein und Main(z)\n– die aus dem bisherigen Format „Ferti Forum“ ab 2026 hervorgeht –\nFreuen Sie sich auf spannende Vorträge und den lebendigen Austausch mit Kolleg:innen und Expert:innen aus Klinik und\nPraxis. Freitagabend laden wir Sie herzlich zu einem entspannten Empfang ein –\neine perfekte Gelegenheit, Kontakte zu knüpfen und den T ag genussvoll ausklingen zu lassen.\nWissenschaftliche Leitung: Univ.-Professorin Annette Hasenburg, Dr. Susanne Theis, Universitätsmedizin Mainz,\nSanitätsrat Dr. Werner Harlfinger, BVF Rheinland-Pfalz Dr. Rüdiger Gaase, BVF Hessen Dr. Klaus J. Doubek\nSchirmherrschaften: Prof. Nicole Sänger, Uniklinik Bonn, Prof. Jan-Steffen Krüssel, Uniklinik Düsseldorf,\nDr. Annette Bachmann, Uniklinik Frankfurt am Main, Prof. Christine Skala, Uniklinik Köln\n\n102 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\nEndometriosis – Pathogenesis, Diagnosis, and Thera-\npeutic Options for Clinical and Ambulatory Care*\nK.-W. Schweppe1, T. Rabe2 (DGGEF e.V.), M. Langhardt1, J. Woziwodzki1, F . Petraglia3 (EEL), L. Kiesel4 (SEF)\nIn the last few years, considerable progress has been made understanding endometriosis and developing diagnostic procedures and therapeutic options.\nSophisticated endoscopic instruments allow laparoscopic surgery even in progressed stages and deep infiltrating endometriosis of the bowel and bladder.\nThe introduction of GnRH analogues with add-back medication and the development of new progestins have widened the range of options for effective\nmedical therapy. Nevertheless new prospective studies have demonstrated in the last decade that the success is temporary and the recurrence rates are\nhigh even when the surgery was adequate. Often medical treatment is effective during the time of application only. This means that customised long-term\ntherapy concepts based on guidelines developed by medical societies play a central role in the alleviation of pain, the reduction of recurrence rates, the\navoidance of repeat operations and the improvement of the patients’ quality of life. J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1): 102–\n19.\nKey words: endometriosis, pathogenesis, diagnosis, surgical treatment, medical treatment\n* A previous German version has been published in J Reproduktionsmed Endokrinol 2011; 8 (3): 180–94. The extended German version is published in: Rabe T. et al. “Seminar\nin Gynäkologischer Endokrinologie”, 2012 (further information: thomas_rabe@yahoo.de).\nReceived: May 21, 2012; accepted: June 21, 2012\nFrom the 1Endometriosezentrum Ammerland; the 2Universitäts-Frauenklinik Heidelberg; the 3Department of Pediatrics, Obstetrics and Reproductive Medicine, University of Sienna;\nand the 4Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe, Universitätsklinikum Münster\nCorrespondence:  Prof. Dr. med. Dr. h.c. K.-W. Schweppe, Endometriosezentrum Ammerland, Frauenklinik, Klinikzentrum Westerstede, Akademisches L ehrkrankenhaus der\nUniversität Göttingen, D-26655 Westerstede, Lange Straße 38; e-mail: Schweppe@Ammerland-Klinik.de\n   Definition\nEndometriosis is the occurrence of en-\ndometrial stroma and glands (often also\nwith muscle cells) outside the physi-\nological location, i.e. outside the uterine\ncavity. Morphologically, the disease can\nalso mimic other differentiations of the\nMullerian epithelium, e.g. tuboid (endo-\nsalpingiosis), isthmus-like and cervicoid\nmanifestations. The presence of cyto-\ngenic stroma alone is called stromatosis.\nIf the uterine muscles are affected dif-\nfusely or focally, this is called adeno-\nmyosis and adenomyoma respectively.\nDuring the reproductive phase, endo-\nmetriosis must be considered a chronic\ndisease. All treatment methods currently\nrecommended – surgical removal, me-\ndicinal suppression of ovarian function\nor a combination of surgical and medici-\nnal methods – have high recurrence rates\nranging between 20 and 80 after 5 years,\ndepending on stage [1].\nDepending on the pain symptoms, the\npatient’s performance at work, her sex\nlife and her quality of life are compro-\nmised in various ways. Depending on\nstage, her fertility is certainly reduced\nmechanically and perhaps also function-\nally, although there is a scientific contro-\nversy about the causes.\n   Epidemiology\nAlongside myomas, endometriosis is\none of the most common benign prolif-\nerative diseases affecting women in the\nreproductive years. According to epide-\nmiological data, there are approx. 0.25\nnew cases per 1000 woman years, corre-\nsponding to a frequency of 7.5% among\nthe female population or 1.5 million en-\ndometriosis patients in Germany and\nabout 40.000 new cases per year. As\nthere are no exact data about the fre-\nquency in the population, our estimate\nbased on prevalence rates is that 10–15%\nof the women aged between 15 and 50\nyears are affected by endometriosis. The\ndisease is one of the main causes of ab-\ndominal pain and infertility [2].\nAmong 1\nst degree relatives, the preva-\nlence is increased 6 to 9-fold [3], sug-\ngesting a genetic factor. Scientists re-\ncently identified 2 modified regions on\nchromosomes 7 and 1 as the first reliable\nevidence for DNA changes leading to\nthe development of this disease affecting\nan estimated 176 million women world-\nwide [4]. However, epigenetic factors\nmust also be considered; e.g., DNA me-\nthylations and histomodifications can\nexplain the progesterone resistance of\nthe implants and the overexpression of\nthe estrogen receptor beta [5].\nClinical observations showed that ex-\ntended duration and increased frequency\nof menstrual bleeding as well as sponta-\nneous and induced abortions especially\namong young women increase the risk\nof endometriosis [6].\nEndometriosis is a proliferative disease\ninvading the tissue of the affected organ\nstructures, but the risk of malignancy is\nlow. According to literature, it is far be-\nlow 1% [7]. More than 75% of the carci-\nnomas are located in the ovaries, and his-\ntological examination shows that > 90%\nof them are endometrioid adenocarcino-\nmas, while clear-cell adenocarcinomas\nare rare (Fig. 1).\nEven though women with endometriosis\nare not generally at a higher cancer risk\n[8], an association has been described\nbetween endometriosis and certain ma-\nlignomas, e.g. endocrine tumours, ova-\nrian cancer, renal cell carcinoma, brain\ntumours, malignant melanoma, non-\nHodgkin-lymphoma and breast cancer\n[9, 10]. For example, the standardised\nincidence ratio (SIR) has been reported\nas 1.38 for endocrine tumours, 1.37 for\novarian carcinomas and 1.08 for breast\ncancer. The SIR could be even higher for\nwomen with primary infertility, endo-\nmetriosis and one of the malignomas\nmentioned [11]. Molecular biology and\nFor personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH.\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 103\nmorphological findings have led to a\nnew concept of the morphogenesis of\nmalignant forms of endometriosis [12],\nas shown in Figure 2.\n   Etiology and Pathogenesis\nDespite more than 100 years of exten-\nsive research, the cause of endometriosis\nis unknown, and the pathophysiology is\nunderstood only partially. It is still un-\nclear why endometriosis may cause\nsymptoms in some women, while others\nhave no complaints although they have\nbeen diagnosed with the disease. There\nare also data suggesting that endo-\nmetriosis is just an epiphenomenon and\nthat the causes of the abdominal pain are\nquite different [13].\nT ransplantation\nParticularly in English-speaking coun-\ntries, a theory proposed by Sampson\n(1927) [14] has been accepted. He pos-\ntulated that during menstruation, vital\nendometrium is transported backwards\nvia the Fallopian tubes into the small\npelvis and implants there. This concept\nhas been modified and supplemented by\nmodern studies. Some suggest that the\nmechanisms of apoptosis are disrupted\nin the small pelvis, while others refer to\nindications that the desquamated endo-\nmetrium has undergone pathological\nchange. The result is in both cases that\nthe endometrial cells survive in the pouch\nof Douglas with consecutive invasion,\nangiogenesis and the development of\nimplants which trigger chronic inflam-\nmation as a defence reaction (s. Fig. 3a\nand b).\nMetaplasia\nThe concept of “retrograde menstrua-\ntion” cannot explain the occurrence of\nendometrial lesions outside the abdo-\nmen whereas the theory of metaplasia\ncan. It postulates that cells can develop\nand differentiate in situ to become endo-\nmetrioid tissue structures based on the\ncomplex and complete information con-\ntained in the genome of each cell [15].\nInfectious influences, hormonal imbal-\nances or immunological disorders can\ninduce such metaplastic processes.\nStem cell Concept\nBy using surface markers, cells have\nbeen detected in menstrual blood which\nare specific for embryonic or adult stem\ncells. This has led to the modification of\nthe concept of retrograde menstruation\nto the effect that it is not desquamated\ndifferentiated endometrium which\nreaches the abdominal cavity but endo-\nmetrial stem cells which implant there\nand differentiate metaplastically into\nendometriosis (glands, stroma, muscle\ncells) [16]. This corresponds to a combi-\nnation of the transplantation and the\nmetaplasia theories. Antiangiogenesis is\nbeing discussed as a new therapy prin-\nciple since angiogenesis plays a role in\nthe implantation and progression of\nendometriosis similar to malignant\ntumours. Substances directed against\nFigure 1. (a):  Small-cell adenocarcinoma (CC) in the cyst wall of ovarian endometriosis [EM] (HE stain, magnification 12.5 ×); (b): Highly prismatic epithelium lining the endo-\nmetrial cyst of the ovary [EM]; next to it in the same ovary, a clear-cell adenomcarcinoma [CC] (HE stain, magnification 200 ×)\na                                                                b\nFigure 2. Hypothetical pathogenesis of malignant transformations in endometriosis. From [12]. Reprint with kind\npermission from Springer Science+Business Media.\n\n\n104 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\nFigure 3. Current concept of endometriosis development.(a): Endometriosis results either from retrograde menstruation or the vascular or lymphatic spread of endometrial cells or\nendometrial stem cells. Under the influence of immune cells, apoptosis occurs in the area of the ectopic colonies e.g. in the p eritoneum; (b): If this process is disrupted (e.g.\nproliferation stimulus or oxydative stress), instead of apoptosis, there is an invasion of the foci with activation of angiogenesis and formation of endometrial implants in the target\ntissue. From: Petraglia, Pinzauti a. Trosti, 2011, pers. communication; by courtesy of the author.\na                                                                b\nFigure 4. Cystic ovarian endometriosis with varying activity – ranging from inactive, resting to complex hyperplasia. (a): Cyst wall with clustered, dilated glands (HE, 12,5 ×);\n(b): Upon larger magnification, the same sample shows the resting epithelium of an endometrioma (HE, 200 ×); (c): Cyst wall with actively proliferating, epithelial lining (HE,\n12,5 ×); (d): The same sample in a larger magnification shows the highly prismatic, proliferative epithelium with secretion phenomena (HE, 200 ×); (e): Lining of the cyst wall\nin ovarian endometriosis with pronounced proliferation (HE, 40 ×); (f): The proliferative activity with areas of simple hyperplasia can also be seen in the cystically dilated glands\n(HE, 40 ×); (g): Complex hyperplasia of the epithelial lining in cystic ovarian endometriosis (HE, 40 ×); (h): The same sample with CD stain (CD-10, 40 ×).\ne                              f                                 g                              h\na                              b                                 c                              d\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 105\nVGEF (vascular epithelial growth fac-\ntor) were tested in vitro and in animal\nexperiments [17]. The genesis and de-\nvelopment of endometriosis implants\nwas suppressed by these substances.\nConcept of Tissue T rauma\nYears of investigations by Leyendecker’s\nworking group (1998) [18] have sug-\ngested that dysrhythmia and disruptions\nof the basalis and the inner layer of the\nmyometrium may cause tissue defects.\nThis leads to the entrainment of endome-\ntrial stem cells from the basalis into the\nperitoneum, where they differentiate\ninto endometriosis. On one hand, this\npathology of the uterine structures ex-\nplains the reduced fertility in endo-\nmetriosis caused by disruptions of nida-\ntion and sperm transport [19], on the\nother, dysrhythmic cramps and tissue\ntraumatisation cause pain. Microtrau-\nmas (irregular perimenstrual contrac-\ntions) and macrotraumas (iatrogenic in-\nterventions) induce estrogen-dependent,\nexcessive repair processes. The trauma\nand the repair process lead to pathologi-\ncal changes of the tissue structure and\ninnervation, which is why the theory is\ncalled tissue injury and repair (TIAR)\n[20].\nOrganic Manifestations\nEndometriosis is most commonly found\nin the small pelvis. It mainly affects the\nperitoneum of the ligaments, the uterus,\nthe pouch of Douglas and the bladder\n(small nodules) as well as frequently the\novaries (cystic form with morphological\nvariations as shown in Figure 4). While\nthe mesosalpinx and the Fallopian tubes\nare also frequent locations of endome-\ntrial foci, other locations such as the cer-\nvix and the vagina are rare. Among the\ncases of extragenital endometriosis, the\nmost frequent location is the rectum\n(deep infiltrating form), followed by the\nsigmoid and the colon. The appendix,\nthe bladder wall and the ureter as well as\nthe small intestine are less frequently\naffected. Extraabdominal manifestations\nsuch as the lung, pleura, CNS, skin or\nepisiotomy scars are rareties with the\nexception of C-section scars, on which\nlesions are more common. The frequen-\ncies stated in literature for the various\norgans vary widely depending on\nwhether pain or infertility patients with\nendometriosis are examined, which spe-\ncialisation the clinic has or whether ma-\nterial from biopsies is included.\nClassification\nVarious classification systems have been\nsuggested for the severity of endo-\nmetriosis and its impact on fertility. The\nmost common one is the rASRM (re-\nvised classification of the American\nSociety of Reproductive Medicine)\n(Tab. 1), which is based on a score and\nonly includes lesions visible intraopera-\ntively. The ENZIAN stages proposed\nby the SEF (Society for Research into\nEndometriosis) in 2005 [22] has added\ndeep infiltrating endometriosis to the\nrASRM classification [23]. To assess\nfertility, an Endometriosis Fertility In-\ndex (EFI) [24] has also been suggested.\nBoth the AAGL (American Association\nof Gynecological Laparoscopists) and\nthe European Endometriosis League\n(EEL) as well as the SEF are currently\ndeveloping modifications which also\naccount for the clinical situation, the\nprognosis and, in particular, pain symp-\ntoms.\n   Diagnosis\nDiagnostic Problems\nDifferential diagnosis is very difficult\nwhen a patient presents with pelvic pain,\ndysmenorrhea, dyspareunia or other\nnon-specific abdominal or back pain.\nThe biggest problem for a woman with\nthese symptoms is to obtain a proper di-\nagnostic work-up and a reliable diagno-\nsis. Since the symptoms can be so varied,\nthe first doctor the women tend to go to\nis their GP , a gastroenterologist, an inter-\nnal specialist, a urologist or other spe-\ncialist, but even gynaecologists often do\nnot immediately think of endometriosis.\nAs a result, there is often a significant\ndelay in making the diagnosis. For\nexample, in Germany, an average of\nT able 1. Staging of Endometriosis according to the revised ASRM Classification\n(American Society of Reproductive Medicine) [21]; Depending on their extent,\nendometrial lesions and adhesions are allocated points; the stage depends on the\ntotal score.\nEndometriosis < 1 cm 1–3 cm > 3 cm points\nPeritoneum superficial 1 2 3\ndeep 2 4 6\nRight ovary superficial 1 2 4\ndeep 2 16 20\nLeft ovary superficial 1 2 4\ndeep 2 16 20\nEndometriosis: sum total implants points\nPouch of Douglas obliter ation partial complete points\n44 0\nAdhesions 1/3 including* 2/3 including 2/3 including\nRight ovary filmy 1 2 4\ndense 4 8 16\nLeft ovary filmy 1 2 4\ndense 4 8 16\nRight tube filmy 1 2 4\ndense 4* 8* 16\nLeft tube filmy 1 2 4\ndense 4* 8* 16\nAdhesions: Sum total (incl. Douglas)\n*increase to 16 pts. if tubes occluded\nT otal rASRM points\n(implants adhesions)\nStage I 1–5 points\nStage II 6–15 points\nStage III 16–40 points\nStage IV > 40 points\n\n106 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\n6 years go by between the first symp-\ntoms and the correct diagnosis [25]. Ap-\nparently, contraception based on ovula-\ntion inhibitors mask endometriosis-re-\nlated symptoms but do not prevent endo-\nmetriosis from developing [26].\nEarly endometriosis has a higher meta-\nbolic activity, a higher rate of mitosis, a\nstronger immunological reaction with\nprostaglandin and a higher cytokine ex-\npression than more advanced stages\n[27]. Therefore, early endometriosis re-\nsponds better to hormone withdrawal\nthan more advanced stages. The recur-\nrence rate is lower and the recurrence-\nfree interval is longer. For this reason,\nearly diagnosis is all the more important!\nFor all these reasons, we call on all col-\nleagues to consider endometriosis as a\nserious possibility whenever a patient\n(whatever her age) presents with diffuse\npain or therapy-resistant abdominal\ncomplaints!\nNecessary Diagnostic Steps\nA thorough patient history and analysis of\nthe symptoms are mandatory, but this can\nonly raise a suspicion that endometriosis\nmight be present. Evaluating the intensity\nof pain using the V AS score (visual ana-\nlogue scale) in a pain diary can be helpful\nto objectify the complaints and estimate\nthe success of therapy, since long-term,\nchronic disease can often pose a strain\nboth on patients and doctors. In visible\nlocations (skin scars, vulva, vaginal por-\ntion, vaginal fornix), gynaecological in-\nspection can provide certainty, and in\nnodular forms in the rectovaginal septum\nand the pouch of Douglas, palpation may\ngive a clear indication. However, only\nhistology can provide absolute evidence.\nLaboratory parameters are not very help-\nful. CA 125 is not suitable for diagnosis\nor follow-up [28].\nImaging techniques only allow for the\nverification and exact measurement of\nthe disease but cannot be the basis for an\nexact differential diagnosis. In cases of\nperitoneal endometriosis, they are use-\nless. For ovarian endometriosis, for ex-\nample, vaginal sonography has a posi-\ntive predictive value of no more than 75\n[29]. In deep infiltrating endometriosis,\nMRI is helpful to identify an involve-\nment of the bladder, the rectum, the pel-\nvic wall and a compression of the ureter\n[30]. Exact information about the extent\nand infiltration depth of intestinal endo-\nmetriosis can be obtained from rectal\nultrasound up to approx. 15 cm abanally\n[31]. Experienced gynaecologists can\nuse vaginal ultrasound to examine deep\ninfiltrating endometriosis more sensi-\ntively and specifically than radiologists\nusing CT and MRI or gastroenterologists\nemploying coloscopy and rectal ultra-\nsound [32]. Even today, a laporoscopic\nbiopsy of macroscopically suspicious\ntissue is still the only reliable diagnostic\nmethod and must always be performed\nas the basis for customised therapy strat-\negies [33].\nHere are some arguments in favour of\nthe generous use of laparoscopy and\nbiopsy to work up a suspicion of endo-\nmetriosis:\n– There are no pathognomonic symp-\ntoms of endometriosis. The symp-\ntoms can be multi-faceted and either\ncyclical or acyclical!\n– The severity of the disease and the se-\nverity of the subjective symptoms are\nnot correlated with each other. In-\nstead, the complaints vary with the lo-\ncation of the lesions.\n– Although a laparoscopy is invasive,\nfailure to carry it out often leads to the\nwrong diagnosis and therefore the\nwrong treatment. Only in 35% of cases\nis cyclical and/or acyclical pelvic pain\ncaused by endometriosis [34].\nAll attempts made so far to diagnose\nendometriosis in a less invasive way using\nbiochemical parameters, tumour markers\nor auto-antibodies in peripheral plasma\nare not clinically helpful because they re-\nquire too much laboratory work [35] and\nare not sensitive and specific enough.\nPractical Recommendation\nIn order to avoid overdiagnosis and re-\nduce the above-mentioned diagnostic\ndelay, the following practical approach\nis recommended: In view of the fre-\nquency of dysmenorrhea especially\namong young women, it is not useful to\nsubject every patient with dysmenorrhea\nand pelvic pain to invasive differential\ndiagnostics. If the gynaecological ex-\namination is normal, a combined oral\ncontraceptive should be prescribed for\n3–6 months as a symptomatic interven-\ntion (so-called COC test). If the symp-\ntoms do not improve even after increas-\ning the dosage or changing the proges-\ntin, a long-cycle application can be at-\ntempted based on the experience of the\nlast few years [36]. If there is still no im-\nprovement within 6–9 months, laparo-\nscopy must be performed for further\ndiagnosis (Fig. 5).\nFigure 5. Practical approach to work up dysmenorrhea and cyclic abdominal pain.\n\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 107\nIn this way, unnecessary laparoscopy\ncan be avoided and the diagnostic delay\nkept to a maximum of 1–2 years.\nTherapy-resistant or recurrent “inflam-\nmatory adnexal diseases” and chronic\npelvic pain must also be worked up\nlaparoscopically since endometriosis is\nthe underlying disease in a third of these\ncases [34] (Fig. 6). There is a large vari-\nety of macroscopic manifestations, rang-\ning from small lesions to cysts or even\ntumorous nodules (Fig. 7). Figure 7 is a\nmacroscopic and Figure 8 a microscopic\nillustration of the clinical case of an “ap-\npendicitis” with the differential diagno-\nsis “salpingitis” [37].\nAdequate diagnostic pelviscopy requires\nthe exact description of the location and\nseverity of endometriosis; there are also\ncalls for an assessment of the growth\ntype and the degree of activity as well as\nfor the histological examination of tissue\nsamples [10]. In a typical case, the histo-\nlogical diagnosis of endometriosis is\nbased on evidence of ectopic endome-\ntrial glands and stroma. The glands are\nmostly inactive or proliferative; in very\nrare cases, they are secretorily trans-\nformed or hyperplastic, but the histo-\nlogical pattern does not necessarily cor-\nrelate with the functional condition of\nthe endometrium [38]. The endometrial\nstroma is similar to the normal stroma\nof the inactive or proliferative endo-\nmetrium; occasionally, a smooth muscle\nmetaplasia of the stroma is found. In\nmany cases, the cytogenic stroma is only\nvery narrow and exclusively found\nperiglandularly. The term “atypical\nendometriosis” is used for cytologically\natypical forms, but also for endometrial\nhyperplasia (simple or complex) in\nendometrial lesions [39].\nEndometriosis may often be masked\nby peritoneal changes such as whitish\nthickening, colourless bubbles, flame-\nshaped changes, hypervascularisation,\ndefects or fibrosis (Fig. 9a–f). If these\natypical cases are not worked up histo-\nlogically, the patient has been subjected\nto an invasive but inadequate diagnosis.\nEndoscopy is often inadequate in cases\nof deeply infiltrating, retroperitoneal\nendometriosis. Vaginal and rectal palpa-\ntion combined with vaginal sonography\nare the key examination methods in this\ncase. However, for adequate interdisci-\nplinary surgical planning purposes, it is\ncrucial to know the exact extent of the\ndisease. For this reason, further exami-\nnations are helpful when the patient is\naffected by deeply infiltrating endo-\nmetriosis (Tab. 2) even in cases where\nthe exact extent of the disease can only\nbe identified intraoperatively.\n“ Active – Inactive” – A Relevant\nCriterion?\nElectron microscopy of endometrial foci\nallows an assessment of the degree of\nproliferation, differentiation and hor-\nmonal modulation. Since these sophisti-\ncated examination methods are too ex-\npensive for clinical routine, simple mac-\nroscopic criteria such as growth type and\nimplant colour have been included in the\nrevised classification by the American\nSociety of Reproductive Medicine\n(1997) [21].\nThe macroscopic appearance of the dis-\nease depends not just on the growth type\nand the hormone dependency of the im-\nplant.  Natural ageing and reactive in-\nflammatory processes also influence the\nprogression and regression of these foci.\nFor these reasons, the appearance at the\ntime of the diagnostic pelviscopy is just\nFigure 6. Share of endometriosis as a cause of chronic abdominal pain. Mod. from [34].\nFigure 7. Endoscopic appearance of endometriosis. (a): fresh peritoneal endometrial lesion on the pelvic perito-\nneum with distinctly visible vessels (Rimbach/Saarlouis); (b): Older, nodular peritoneal endometriosis in the area of\nthe lig. sacrouterinum (Rimbach/Saarlouis); (c): Endometriosis in the area of the tube wall with peritubal adhesions\n(Rimbach/Saarlouis); (d): Conglomerate of appendix and tube in endometriosis: The infundibulum and the inflamed\nappendix stick together, mixed with vesicular, partially bloody endometriosis (Endo).\na                                         b\nc                                         d\n\n108 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\na snapshot of a complicated, multifacto-\nrial, dynamic process.\nMicroscopically, the diversity of the im-\nplants is even greater than macroscopi-\ncally. The important factors are the vary-\ning degrees of differentiation, variable\nhormone dependency (cyclicality, re-\nceptor status), variable or absent prolif-\nerative activity (mitosis index, prolifera-\ntion marker), concomitant inflammation\nand degenerative processes [40].\nStudies on steroid hormone receptors\nand proliferation markers [41] show that\nmedicinal treatment is particularly effec-\ntive for fresh implants, while older foci\nmust be removed surgically or may pos-\nsibly not require any therapy at all be-\ncause they are not actually the cause of\nthe patient’s complaints.\nFindings from molecular biology [42]\nsupport the view that endometriosis and\nhealthy endometrium are different kinds\nof tissue. Defective enzyme systems in\nthe ectopic foci, e.g. 17 β-steroid dehy-\ndrogenase type 2, lead to autonomous\nestrogen production and acyclical, con-\ntinuous proliferation.\nThese findings also have practical con-\nsequence for medicinal therapy con-\ncepts. Low levels or the complete lack of\nprogesterone receptors in implants and\ndisruptions of the intracellular progest-\nerone metabolism (so-called progester-\none block) explain the inadequate effect\nof a progestin therapy against endo-\nmetriosis (Fig. 10). Activated enzyme\nsystems which are blocked in the eutopic\nendometrium such as aromatase facili-\ntate local estrogen production, locally\namplifying the proliferation of the ec-\ntopic focus and also the inflammatory\nreaction via the effect on the prostaglan-\ndin metabolism (Fig. 11). In view of\ncontradictory data, it is not clear whether\naromatase is activated in the endometrial\nlesion itself as first suggested by Noble\net al. [43] or whether the endometrial le-\nsions show no aromatase activity them-\nselves but the cells of the affected organs\nexpress the enzyme [44].\nThe answer to this question has no clini-\ncal consequences, and the use of aro-\nmatase inhibitors is at the experimental\nstage with some positive case reports but\nno valid and convincing studies.\nFigure 8. Microscopic image of endocrinically active endometriosis of the appendix (E = intramural endometrial\nfocus; M = mucous membrane of the appendix). (a): highly differentiated, proliferative endometrial foci (HE stain,\n200 ×); (b): highly positive estrogen receptors (ERp, brown stain, 200 l).\nFigure 9. Various types of peritoneal endometriosis. (a): vesicular form (V); (b): nodular (N) und plaque-type growth\n(Pl); (c): flat, fibrotic form (F); (d): clear vesicles, no bleeding (B); (e): blood-containing vesicles with flame-shaped\ninflammation (E); (f): brown, grey residual blood with delicate adhesions (A).\nc                                         d\ne                                         f\na                                         b\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 109\nOnce all the information mentioned\nabove is available, based on the woman’s\nage, her family planning and her com-\nplaints, a symptomatic, a conservative,\norgan-sparing or an aggressive resective\ntherapy or a combination of these mea-\nsures can be discussed and agreed upon\nwith the patient.\n   Surgical T reatment Strate-\ngies\nDifferential diagnosis require invasive\nlaparoscopy, if possible with a biopsy.\nConsequently, surgical measures are at\nthe centre of primary treatment. The ob-\nvious choice is that a surgical interven-\ntion should directly follow on from the\ndiagnostic laparoscopy under the same\nanaesthesia (single-stage procedure); if\nthere is a risk of extensive resection, a\ntwo-stage procedure can certainly be ac-\ncepted if it is preferred by the patient be-\ncause she wants to receive more differ-\nentiated advice. The ablative procedures\ninclude all surgical techniques removing\npathological changes to the organs\n(endometrial lesion, endometrial cyst\n[Fig. 12 a–d], scars and adhesions) and\npreserving healthy organ parts (conser-\nvative ablative therapy) or removing the\naffected organs in toto (radical ablative\ntherapy).\nAntiestrogenic or antiinflammatory sub-\nstances are suitable for a drug-based\ntherapy. The former lead to a suppres-\nsion of the ovarian estrogen synthesis of\nvarying duration and intensity. This can\nbe achieved temporarily by various\ndrugs (GnRH agonists, GnRH antago-\nnists, antigonadotropins, progestins,\ncombined oral contraceptives) or perma-\nnently through surgical ovariectomy.\nAnti-inflammatory and analgetic pros-\ntaglandin synthesis inhibitors have also\nproven effective. COX-2 inhibitors caus-\nally interfere with the metabolism of the\nareas of endometriosis. Due to cardiac\nside-effects, these substances have been\nwithdrawn from the market with some\nexceptions and not been approved for\nendometriosis therapy.\nThe third treatment option consists of\nsymptomatic measures which may range\nfrom complementary medicine to physi-\ncal applications and balneotherapeutic\nmeasures with a relaxing, cramp-releas-\ning and perfusion-promoting effect.\nThese options also include homeopathy,\nT able 2. Special Diagnostic Procedures for Deep Infiltrating Endometriosis Based\non the Guidelines of the German Society for Gynecology and Obstetrics. From\n[29].\nMethod Diagnostic Finding\nColoscopy Exclusion of primary bowel diseases*, stenosis, external\npressure\nMRI Involvement of the bladder wall, stenosis of the ureter,\nuterine adenomyosis\nRectal ultrasound Involvement of the intestinal wall, depth of invasion, extent\nof the tumor\nColon barium enema Involvement of higher bowel sections, stenosis\nRenal ultrasound Ureteral congestion, hydronephrosis\nIntravenous pyelogram Ureteral involvement, stenosis of the ureter\nCytoscopy Bladder failure\n* only useful for intestinal bleeding and/or women > 35\nFigure 11. Vicious circle in the endometrial focus maintains the proliferation and inflammatory reaction: (1) local\nestrogen is produced by aromatase activation; (2) estrogens stimulate prostaglandin synthesis via the activation of\nthe COX-2 enzyme; (3) Prostaglandin E-2 again stimulates aromatase. Whether the aromatase is activated in the\nendometrial lesion itself or in the surrounding tissue (fat, peritoneum) is controversial.\nFigure 10. Estrogen metabolism in endometrial lesions: Defective 17-beta-steroid-dehydrogenase type 2. This\nmeans that the bioactive estradiol cannot be converted into the less active estron. In the normal endometrium,\nprogesterone activates this 17-beta-HSD Type 2 and has an antiproliferative effect; this mechanism is disrupted in\nendometrial lesions (so-called progesterone block).\n\n\n110 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\nTCM and other therapies which can be\nused successfully especially for chronic\npain patients.\nPrinciples of Surgical T reatment\nMinimally invasive surgical techniques\nhave become standard today. Various\nendoscopic techniques of destroying or\nremoving endometrial lesions are used.\nComparative studies have shown that\nthese different techniques – mono- or\nbipolar coagulation, heat application,\nvaporisation or excision – are equivalent\nas long as the foci are completely re-\nmoved. However, the cycle phase does\nhave an influence on the relapse rate:\nWhen peritoneal endometriosis was\nendoscopically removed premenstrually,\nthe relapse rate after 2 years was twice as\nhigh (15%) than when the intervention\nhad been carried out postmenstrually. It\nis assumed that this is due to peritoneal\ndefects caused by the operation which\nhad not healed by the time of the subse-\nquent menstruation [45].\nTherapy Goals: Pain Removal\nand/or Pregnancy\nThe hardest facts on the therapeutic\nvalue of endoscopic intervention for\npain patients – also for low-grade endo-\nmetriosis – have been produced by the\nstudies of Sutton et al. [46]. In a prospec-\ntive, double-blind (fake operation!) ap-\nproach, it was shown that the pain symp-\ntoms had improved after 6 months in\n63% of the patients in the therapy group\nwhile only 23% of the women in the pla-\ncebo operation group reported pain re-\nlief. However, this also means that one\nthird of the women experienced no pain\nrelief as a result of the operation and that\nadjuvant drug therapies are crucial to\nimprove the results and reduced the re-\nlapse rates.\nThe effectiveness of the surgical therapy\nfor endometriosis can conveniently be\ncompared looking at the subgroup of in-\nfertile patients since pregnancy is a more\nobjective treatment goal than pain relief.\nWhen used appropriately, the different\nlaparoscopic resection and coagulation\ntechniques lead to results which are\ncomparable or even superior to those of\nmicrosurgical laparatomy [47]. How-\never, these older studies are open to criti-\ncism for lack of randomisation and retro-\nspective analysis. Only two studies have\nbeen carried out in a prospective and\nrandomised way and yielded controver-\nsial results. According to a Canadian\nmulticenter study [48], surgery for en-\ndometriosis improves the pregnancy\nrates significantly compared with purely\ndiagnostic laparoscopy (31% vs 18%),\nbut this was not confirmed by an Italian\ngroup [49] (20 vs 22%). More recent\npublications are no better in terms of\nmethodology since it is difficult to estab-\nlish a control arm with placebo surgery\nboth for infertile and pain patients. An-\nother problem is surgeon quality. It is an\nopen question whether the published\ndata, which originate from centres, can\nalso be achieved in routine care. How-\never, the type of endoscopic removal\ndoes not seem to play a role [50]. More\nrecent data suggest that secondary dam-\nage such as adhesions are more relevant\nthan the area of endometriosis itself.\nMaruyama et al. [51] report on 41.8%\npregnancies within 18 months of surgi-\ncal removal for endometriosis without\nadhesions and only 13.27% for endo-\nmetriosis with adhesions on both adn-\nexa.\nCustomised Surgical Concepts\nBased on the woman’s personal situation\nand her symptoms,   customised treat-\nment strategy must be developed which\naccounts for not only the acute pathol-\nogy but also the chronicity of the disease\nand is specific for the different forms of\nendometriosis. Peritoneal endometriosis\nis a particular challenge for the surgeon\nsince its appearance can vary; the sur-\ngeon needs to know and recognise even\natypical manifestations (see above). Fur-\nthermore, the diffuse spread of endome-\ntrial lesions and their growth even under\nadhesions requires a subtle and patient\napproach. The risk of an incomplete op-\neration is high; many recurrences are\nprobably due to persistent active foci.\nIn a case of suspected ovarian endo-\nmetrosis, if there is an indication for sur-\ngery due to complaints and in order to\ninvestigate an unclear adnexal enlarge-\nment, the need for a histological diagno-\nsis is controversial, since old hemor-\nrhagic corpus luteum cysts or follicular\ncysts have the macroscopic appearance\nof a typical “chocolat cyst” in a quarter\nof all cases. However, functional cysts\nrequire neither surgical nor drug therapy.\nThe most efficient method is the com-\nplete excision of the endometrioma\nwhile sparing the healthy residual ovary.\nSurgical experience is crucial as, by con-\ntrast with other benign ovarian cysts, it\ncannot be avoided that some healthy tis-\nsue is also removed and the follicular\nreserve reduced while resecting endo-\nmetrial cysts. There have been reports\nabout falling AMH levels, reduced fertil-\nity – also in IVF programmes – and, in\nFigure 12. Endometrial cyst in the area of the ovary. (a): Left-sided endometrial cyst of the ovary with adhesions\nand concomitant reactive inflammation; (b): Ultrasound view of an endometrial cyst: homogeneous, low internal\necho (bleeding) and thickened cyst wall; cap-shaped residual ovary on right picture margin (Elsässer, Heidelberg);\n(c): Extensive, endocrinically inactive endometrial cyst of the ovary with bleeding (HE, 25,5 ×); (d): Florid, endo-\ncrinically active endometrial cyst of the ovary within the hyperplastic cyst wall (HE, 40 ×).\na                                         b\nc                                         d\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 111\nextreme cases, premature menopause.\nThere are contradictory data about pre-\noperative treatment with GnRH ago-\nnists, whereas postoperative treatment\nreduces the risk of recurrence [52]. Deep\ninfiltrating endometriosis (DIE) in-\ncludes forms of endometriosis which\ngrow tumourously below the perito-\nneum.\nEndometriosis often affects the septum\nrectovaginale, the parametrium, para-\nrectal tissue, the rectum (Fig. 13, 14) and\nthe sigma, but also higher intestinal sec-\ntions as well as the pelvic wall with con-\nsecutive involvement of the ureter. Due\nto their high proportion of fibrous tissue\nand muscle cells, these nodular growths\nshow a poor response to drugs. The im-\nplants stay vital and start to progress\nsoon after the cessation of the medica-\ntion. For this reason, surgery is predomi-\nnant in the treatment of these manifesta-\ntions; permanent medication is an option\nonly in exceptional cases. If there are\nno symptoms, intestinal endometriosis\nwhich can be easily controlled and does\nnot result in stenosis can be treated ob-\nservantly; active therapy is only indi-\ncated in these cases if there are symp-\ntoms or progression.\nThe goal of therapy is the complete exci-\nsion of the endometrial foci and their\nsecondary lesions while preserving or-\ngan function. In the case of small nod-\nules, the defect on the bladder or the in-\ntestine can be closed primarily; in exten-\nsive deep infiltrating cases, the affected\nintestinal segment must be resected and\nintestinal continuity restored by anasto-\nmosis. If the ureter is affected, this often\nmeans a psoas hitch reimplantation.\nEven in cases of advanced intestinal\nendometriosis, complete removal can be\nachieved by careful preparation in the\nmuscularis without opening the lumen.\nA musculo-muscular and sero-muscular\ntwo-layer suture is possible so that a\nresection with anastomosis can often be\navoided [53].\nThese operations are normally carried\nout by laparotomy; however, there are\nmore and more reports about endoscopic\ntechniques, showing that with adequate\ntraining and an interdisciplinary ap-\nproach, even partial intestinal resections\nand Stabler-type anastomoses can be\nperformed endoscopically [54]. In terms\nof therapy success and quality of life, the\nFigure 13. Deeply infiltrating endometriosis: surgical site. (a): Fibrotic tumour infiltrating the rectum; (b): Resec-\ntion with good safety margin, saving the posterior wall of the rectum and the mesorectum.\na                                         b\nFigure 14. Deeply infiltrating endometriosis: macroscopic view of the resected part of the rectum (a) and micro-\nscopic image (b), showing that even in such an extensive case, the mucosa of the rectum can be intact and colo-\nscopy cannot be used to confirm the diagnosis.\nFigure 15. Adenomyosis uteri interna. (a): In the sonographic cross-section, the inhomogeneous appearance of the\nmyometrium can be seen with a poorly delineated area of adenomyosis (unlike myomas); (b): Doppler sonography\nshows the increased perfusion in the area of adenomyosis (US images: Elsässer, Heidelberg); (c): The endometrial\nfocus visible within the uterine muscles (HE, 12,5 ×); (d): With a higher magnification, the glands and the cytogenic\nstroma can be clearly discerned (HE, 40 ×)\na                                         b\nc                                         d\n\n112 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\nroute of access is irrelevant as long as the\nlesion has been removed adequately, as\nshown by a recent prospective random-\nised study [55].\nIf the wall of the uterus is also involved,\ne.g. in cases of retrocervical endometrio-\nsis, or if there is concomitant uterine ad-\nenomyosis (Fig. 15), physicians should\ndiscuss with the patient whether to per-\nform a hysterectomy as the only way to\nremove the endometriosis completely so\nthat the risk of recurrence would be\ngreatly reduced.\nThere is a controversy about whether\npreoperative drug treatment is useful in\ncases of intestinal and bladder involve-\nment. The arguments in favour are that\nthe surgical trauma is reduced and that\nshorter operating times, less blood loss,\nand pelviscopy rather than laparotomy\nare possible; the arguments against are\nthat the preparation of the more fibrosed\ntissue is more difficult and there is a risk\nof missing small, regressive, non-pal-\npable implants and of reduced circula-\ntion in the operating area, possibly lead-\ning to healing disorders and insufficient\nanastomosis. Whether the success rates\nand relapse rates are improved by the\npreoperative use of e.g. GnRH agonists\nas a depot is unknown because of a lack\nof follow-up data.\nThese carefully chosen customised treat-\nment options avoid surgical overtherapy\nand are tuned to the type of endometrio-\nsis and progression risk. On the other\nhand, the surgeon is required to make a\nsubstantial diagnostic effort and be very\nknowledgeable about the different thera-\npeutic options: surgery, drugs and a\ncombination of both. Based on current\nknowledge, this is the only way to re-\nmove or alleviate the symptoms and se-\nquelae of this disease, which has a ten-\ndency to recur (Fig. 16). It should be\nnoted that there is still a lack of compre-\nhensive controlled studies, and the long-\nterm value of the exclusively surgical\ntreatment of a pain patient is just as over-\nrated [56] as the improvement of fertility\nin a fertility patient [57].\n   Drug Therapy\nBasic research has shown in vitro and in\nvivo that various immunological, in-\nflammatory, paracrine and endocrine\nfactors are relevant for the progression\nof endometriosis. Although some inter-\nesting therapeutic concepts can be de-\nrived from them (Fig. 17), they have so\nfar only been tested experimentally in\nvitro or in animal studies. The existing\ndrug treatments which are still used in\npractice rest on two pillars: (1.) Suppres-\nsion of ovarian function and (2.) reduc-\ntion of the reactive concomitant infec-\ntion. The clinically tested substances are,\non one hand, steroid hormones inter-\nfering with the negative feedback of the\nhypothalamic-pituitary-ovarian axis but\nwhere these hormones or their metabo-\nlites do not develop any estrogenic prop-\nerties (progestins, selective progestin-\nreceptor modulators) and, on the other,\nsubstances such as GnRH analogues\n(agonists and antagonists) which directly\nblock the release of gonadotropin at the\npituitary level. Pain through endometro-\nsis can be influenced by PG synthesis\nFigure 16. Combined treatment principle for endoscopically and histologically confirmed endometriosis, which\nneeds to be adapted to the individual case.\nFigure 17. Concept for the pathogenesis of endometriosis and the corresponding therapeutic strategies, which are\npartly used in practice, partly experimental or hypothetical. From Petraglia, Pinzauti a. Trosti 2011, pers. communi-\ncation; by courtesy of the author.\nER-βα: estrogen receptor- α; PR-A B: progesterone receptor A and B; NSAIDs: non-steroidal anti-inflammatory\ndrugs; SPRM: selective progesterone receptor modulators.\n\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 113\ninhibitors. Whether these merely sup-\npress the inflammatory reaction in the\ninvolved tissue or directly influence the\nendometrial lesions themselves is the\nsubject of current research, since COX-2\nexpression was found in all three forms\nof endometriosis [58].\nAs endometrosis is a chronically recur-\nring and systemic disease, neither a tem-\nporary drug-based nor a surgical therapy\ncan protect the patient from recurrence\nunless castration or chronic medication\nlead to permanent estrogen withdrawal.\nThis is a crucial fact when it comes to\nadvising the patient and setting up a\ntherapy plan. As a result, repeated inter-\nmittent or long-lasting continuous drug\ntherapies are often required: The ques-\ntion is not just whether a substance is\neffective in terms of leading to endo-\nmetriosis regression and pain relief but\nalso how it is tolerated and whether the\nindividual side-effects are acceptable.\nProgestin T reatment\nFor decades, low-dosed progestins have\nbeen used successfully in clinically rou-\ntine – alone or in combination with low-\ndosed estrogens, even though the scien-\ntific data about specific mechanisms of\naction of progestins for endometriosis\nare still patchy. In contrast with their sta-\ntus in uterine endometrium, specific\nenzyme systems are blocked (e.g. 17 β-\nHSD Type 2) or activated (e.g. aroma-\ntase) in endometrial lesions, the proges-\ntin receptor concentrations are low and\nprogestins reduce the synthesis of pro-\ngestin receptors so that long-term therapy\nfurther reduces the sensitivity of the im-\nplants to the therapeutic substance. This\nis described as a so-called progesterone\nblock in ectopic foci (Fig. 10). Earlier\nanimal experiments also suggest that\nthere is no direct effect of progestins on\nthe implant. In castrated animals with\nendometriosis, progestin alone did not\nlead to disease regression; there was a\npersistence of vital implants [59].\nThe choice of substance depends on sub-\njective tolerance, while dosage is based\non the biological effect on the endo-\nmetrium (transformation dose). How-\never, since the continuous administra-\ntion of progestins leads to low estrogen\nlevels, this frequently results in spotting\nor breakthrough bleeding, whereupon\nthe dosage is often increased or estrogen\nis added. What is clear is that the endo-\nmetriosis-related symptoms can be sup-\npressed in up to 80% of the cases, but the\nrecurrence rate after discontinuing the\nmedication is high.\nMechanism of Action of Progestins\nPhysiologically, progestins oppose es-\ntrogens. There is a large number of sub-\nstances which are eigher derivatives of\nprogesterone (medroxyprogesterone\nacetate, dydrogesterone etc.) or or C-19-\nnortestosterone (norethisterone, lyn-\nestrenol, desogestrel etc.). They differ\nby their active profile and intensity of\naction on the metabolism of various or-\ngan systems. They all cause the secre-\ntory transformation of the estrogen-pre-\ntreated endometrium, but their biologi-\ncal activity varies so that adequate trans-\nformation requires different amounts of\nactive substance (Fig. 18).\nIn addition to the progestinic effects, all\nsynthetic progestins also have other ef-\nfects which can be explained by their\nstructural similarity with other steroids;\nfor example, progesterone derivatives\nhave estrogenic effects and nortestoster-\nFigure 18. Biological activity of various progestins based on the transformation dose and the dosages used to treat\nendometriosis.\nFigure 19. Possible mechanisms of action of progestins for endometriosis.\n\n\n114 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\none derivatives have androgenic effects.\nProgestins reduce the frequency and in-\ncrease the amplitude of the GnRH pulse,\nthereby suppressing the release of gona-\ndotropin, which leads to an anovulatory\nsituation with low peripheral estrogen\nand progestin levels. Their mechanism\nof action for endometriosis is complex.\nApart from the negative feedback effect\non the centrally controlled estrogen pro-\nduction of the ovaries, progestins are\nalso assumed to lead to the suppression\nof the concomitant local intraperitoneal\ninflammation (Fig. 19) and of the result-\ning pain. They reduce the increased\nnumber and activity of macrophages in\nthe pouch of Douglas fluid [60].\nUnder the influence of estrogen, the in-\ncrease of TNF-alpha in the pouch of\nDouglas fluid stimulates the nuclear fac-\ntor Kappa-β and increases various inter-\nleukins as inflammation mediators [61].\nProgestins also interfere suppressively\nwith this metabolic pathway. In addition,\ndirect changes are assumed to occur in\nthe endometrial implant similar to those\nleading to the secretory transformation\nand decidualisation of the endometrium.\nMorphological [37] and in-vitro studies\n[42] suggest that this assumption is in-\ncorrect. This would explain clinical find-\nings showing that there was still micro-\nscopic evidence of vital endometrial\nlesions after 6 months of treatment with\n5 mg/day of lynestrenol in all cases at the\ntime of surgical removal [62]. The histo-\nlogical changes under progestin therapy\nand the precise mechanism of action is\nstill not clear after years of experience\nwith this therapy.\nResults of T reatment for Endo-\nmetriosis\nLow-dose oral progestins (5–20 mg/day)\nhave been described as effective for\nsymptoms of endometriosis. The re-\nported subjective success rates vary be-\ntween 60 and 94%. Due to short follow-\nup periods, there are not many meaning-\nful data about the rate of recurrence;\nhowever, in the long term, they are above\n50% [63].\nAs nearly all progestins used for endo-\nmetriosis treatment have been withdrawn\nfrom the market in Germany (e.g. lyn-\nestrenol, medrogestone, norethisterone\nacetate) and the use of estrogen-proges-\ntin combinations (oral contraceptives) is\nin line with the guidelines but off-label,\nthe newly approved dienogest in a dos-\nage of 2 mg/d has become particularly\nimportant. Under this treatment, the sub-\njective symptoms of endometriosis im-\nprove significantly even though break-\nthrough bleeding is frequent [64].\nThe estrogen receptor concentrations in\nthe uterine endometrium only return to\nthe level of the normal secretion phase\nafter three months of dienogest treat-\nment, and delayed maturation as well as\nthe appearance of a late proliferation\nphase were seen histologically. Exami-\nnations of endometrial lesions showed a\nvery disparate rate of regression under\nprogestin therapy, confirming that the\nreaction may vary greatly, apparently\ndepending on the varying receptor ex-\npression in ectopic foci. Prospective ran-\ndomised studies with dienogest 2 mg/d\ncompared with leuprorelin [65] showed\nthe same effectiveness in treating the\nsymptoms and a clear superiority com-\npared to placebo (Fig. 20) [66]. Preg-\nnancy rates after treatment with medro-\nxyprogesterone acetate, lynestrenol,\nnorethisterone acetate or dienogest vary\nbetween 5 and 90% on account of differ-\nent selection criteria in the study groups\nand therefore do not allow a scientifi-\ncally proven statement.\nOther routes of application have also\nbeen tested successfully. Depot medro-\nxyprogesterone acetate (100–200 mg)\neffectively suppresses subjective endo-\nmetriosis symptoms, but the suppressive\neffect may last for months or even years,\nso it is only recommended for older pa-\ntients who do not wish to have children\n[67].\nThe intravaginal continuous progestin-\nestrogen application in a three-weekly\nrhythm or the continuous application of\nthe progestin over two years as a subcu-\ntaneous implant are also theoretically\nsuitable for symptomatic therapy and\nhave been used successfully in some\ncases [68]. However, there is a lack of\nsystematic prospective studies, and the\ndirect effect on the endometrial lesions is\nunknown. Furthermore, progestins can\nbe locally applied by an intrauterine sys-\ntem releasing 20 µg levonorgestrel daily.\nThe suppression of the endometrium, the\nreduction of apoptotic processes as well\nas antiinflammatory effects have been\nshown [69].\nEndometriosis-related complaints in\ncases of adenomyosis or rectovaginal\nendometriosis such as dysmenorrhea or\ndyspareunia are reduced. Apart from\nhigh local progestin concentrations in\nutero, the low systemic concentrations\nof levonorgestrel also seem to play a\nrole. This is the explanation given for the\npositive effects on peritoneal forms of\nendometriosis [70], and the ovulation in-\nhibition in 85% of the users – at least in\nthe first few months after the introduc-\ntion of the system – is also evidence of\nsystemic effects. An advantage is that the\nsystem remains in place for 5 years,\nalthough the effect on endometriotic\ncomplaints seems to subside after 12–18\nFigure 20. Effectiveness of 2 mg dienogest vs. placebo for dysmenorrhea and abdominal pain using the visual ana-\nlogue scale (mm, mean scores). Mod. from [66] with permission from Elsevier publishers.\n\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 115\nmonths. The disadvantage is that spot-\nting and breakthrough bleeding still\noccurs in the first 6 months before the\nsystem reaches its full effects. In terms\nof clinical practice, it should be noted\nthat all these useful applications are off-\nlabel applications in Germany.\nGnRH Analogue T reatment\nGnRH analogues are agonists and anta-\ngonists of the natural LH-RH. They act\ndirectly on the pituitary-hypothalamic\nsystem. While the antagonists are used in\noncology and reproductive medicine,\nGnRH agonists have become widespread\nin endometriosis treatment despite their\ninitial stimulation effect. Regression and\natrophy of the endometrial lesions with-\nout relevant metabolic side-effects is\nachieved by reversible medicinal ova-\nrian suppression caused by desensitising\nthe pituitary (Fig. 21). There is no differ-\nence between the substances used in\nterms of the subjective and objective\nsuccess rates [71]. Because of improved\ncompliance and reliable suppression, de-\npot preparations are preferred in prac-\ntice. The side-effects are mainly hypo-\nestrogenic and comparable with meno-\npausal complaints. The treatment period\nis limited to 6 months despite good toler-\nability because the hypoestrogenic situa-\ntion causes a reversible bone deminerali-\nsation by 4–6% on average with big\nvariations, similar to the lactation pe-\nriod. In order to reduce demineralisation\nwithout minimising the therapeutic ef-\nfect, a so-called “add back” therapy [72]\nwith low-dosed estrogens or progestins\nhas been introduced. If the add-back\ndosage is too high or in the case of cycli-\ncal application, the therapeutic effect of\nthe GnRH agonists is obviously reduced\nor suspended.\nCompared with progestins, GnRH ana-\nlogues are more effective in achieving a\nregression of the endometrial implants\nas confirmed by prospective randomised\nstudies [73]. They are at least as effective\nin reducing the symptoms, as corrobo-\nrated by a comprehensive Cochrane\nanalysis [74]. It is important to note that\nthe much-used inexpensive combined\noral contraceptives are inferior to GnRH\nin terms of their effectiveness [75]. The\ndifferent commercially available GnRH\nagonists are similarly effective in terms\nof pain reduction and endometriosis re-\ngression, as confirmed by a review by\nShaw et al. [76]. However, after 6 months\nof therapy, 50% of the patients still have\nresidual scarry lesions containing vital\nendometrial glands and stroma [37, 77].\nThis explains why endometriosis which\npersists after this potent treatment can\nbecome symptomatic again, and a recur-\nrence is merely a question of time.\nAntiinflammatory T reatment\nIn order to prevent the development of a\nchronic pain syndrome, pain therapy\nconcepts should be integrated directly\ninto the treatment plan. The synthesis of\nCOX-2 in normal endometrium, endo-\nmetriosis and adenomyosis has been de-\nscribed [78], and women with endo-\nmetriosis overexpress this enzyme. This\nexplains its high concentrations in endo-\nmetrial lesions and pouch of Douglas\nfluid [79]. Apart from proliferative and\ninflammatory effects, specific prosta-\nglandins cause vasoconstriction, is-\nchemia, cell necrosis, spasms and tissue\npain. Non-steroidal antiinflammatory\ndrugs (Aspirin\n®, Ibuprofen ®, V oltaren®)\ninhibit the activity of cyclooxygenase\nnon-specifically, thus reducing the syn-\nthesis of prostaglandin. This explains\ntheir varying clinical success in cases of\nendometriosis-related abdominal pain\n[80]. The specific COX-2 inhibitors de-\nveloped some years ago block the intra-\ncellular COX-2 activity and have fewer\ngastrointestinal side-effects. So far, they\nhave not been approved for endometrio-\nsis, and their use should first be investi-\ngated in studies as no data are available\nabout possible teratogenic effects [81].\nSince all drugs except Etoricoxib\n(Arcoxia\n®) have been taken from the\nmarket due to cardiac side-effects, prac-\ntitioners will have to make do with non-\nselective preparations for the time being.\nIf no adequate pain relief can be achieved\nby these substances in combination with\ncombined oral contraceptives or pro-\ngestins, additional retarded opioids of\nWHO stages I and II must be used. The\ndrug-based pain therapy should be ac-\ncompanied by pain coping seminars.\nPhysical therapy like baths, local ther-\nmal treatment and relaxation exercises\nare useful complements. These methods\nshould aim to prevent pain from becom-\ning the focal point in the patient’s life.\n   Practical Recommenda-\ntions\nPain Patients\nAlthough the surgical removal of endo-\nmetriosis is the primary treatment, de-\npending on stage, location and type of\nthe disease, the rate of recurrence within\n5 years after endoscopic surgery ranges\nbetween 25 and 70%. Surgeon quality\nand the timing of the intervention within\nthe menstrual cycle contribute to this\nproblem [45]. The adjuvant use of\nGnRH agonists reduces the rate of recur-\nrence and prolongs the recurrence-free\ninterval significantly [82].\nA treatment period of only 3 months can\nbe equally effective in terms of pain re-\nFigure 21. Mechanisms of action of GnRH agonists: By desensitising the pituitary, a pseudomenopausal situation\nis created.\n\n\n116 J Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1)\nEndometriosis\nduction, but the recurrence-free interval\nis significantly longer if the suppression\nphase lasts 6 months.\nThe clinical benefit of an additional drug\ntherapy can be significant especially in\npatients with pain due to active perito-\nneal endometriosis. Although the use of\noral contraceptives in the treatment of\nendometriotic complaints is widespread,\na prospective randomised study [83] has\nshown that their postoperative use is not\nas effective as the adminstration of\nGnRH agonists. On the other hand, oral\ncontraceptives are less expensive and\nhave a different side-effect spectrum.\nThe additive use of these drugs should\nbe considered after adjuvant treatment in\norder to further prolong the recurrence-\nfree interval.\nPossibilities of Long-T erm\nT reatment\nExtensive and/or progressive cases as\nwell as deeply infiltrating forms of endo-\nmetriosis are often problematic. In these\ncases, even primary intervention is often\ntechnically difficult and confronts the\nsurgeon with many problems. This is all\nthe more true in cases of recurrence.\nSince substantial fibrosis and myohyper-\nplasia lead to tumorous changes, exten-\nsive resection is necessary but fraught\nwith the problem of incomplete removal\nand the risk of intra- and postoperative\ncomplications. In order to achieve an\nimprovement of the symptoms of this\ntype of endometriosis, various forms of\ntreatment such as oral contraceptives,\nprogestins, GnRH analogues as depot\ndrugs, physical therapy or homeopathy\nas well as the intrauterine release of pro-\ngestins can be attempted permanently or\nintermittently alongside surgical re-\nmoval while taking the chronicity of the\ndisease into account (Fig. 22). A particu-\nlar advantage of GnRH analogues is the\npossibility to reduce side-effects through\nadd-back medication, which explains\ntheir increasing importance as a very ef-\nfective long-term treatment [85]. A pro-\ngressive reduction of the pain symptoms\nhas been achieved by the long-term ad-\nministration of dienogest over a period\nof 15 months [86].\nRecurrence\nIf the patient has recurrent complaints\nand/or a recurrence is diagnosed, she can\nbe offered another surgical intervention\nor another course of drug treatment or a\ncombination of both (Fig. 23). Since\nendometriosis is a chronic disease, a\ntherapeutic approach must be discussed\nwith the patient which is acceptable for\nher, has the least possible side-effects, is\ncost-efficient and, in particular, is what\nthe patient herself asks for after having\nbeen appropriately informed. Although\nrepeat operations cannot always be\navoided, it is absolutely paramount to\nchoose a medicinal treatment concept\nafter such an operation. The spectrum of\npossible drug therapies has been listed\nabove. Progestins as permanent medica-\ntion or continuous oral contraceptives\nare often used primarily as a symptom-\natic treatment in view of the costs. If this\nis not sufficient, GnRH agonists are ef-\nfective even when used repeatedly in\ncases of recurrence. Combined with add-\nback medication, they also have few\nside-effects.\nAnother option is the titration of the\n“therapeutic estrogen window” in which\nlow-dosed GnRH analogues are used\n[87]. A still further possibility is to carry\nout intermittent 3-monthly treatment epi-\nsodes with a GnRH agonist and a low-\ndose continuous combined estrogen/\nprogestin add-back medication. This is\nan inexpensive and well-tolerated treat-\nFigure 23. General principle of therapy for recurrent endometriosis. An individual therapy plan must be discussed\nand defined with each patient.\nFigure 22. Results of various long-term treatments for recurrent endometriosis. Mod. from [84].\n\n\nEndometriosis\nJ Reproduktionsmed Endokrinol 2013; 10 (Special Issue 1) 117\nment form. Whether these long-term\ntherapies can be discontinued after 2–3\nyears of freedom from symptoms and\nfollowed with a long-cycle oral contra-\nceptive is still unclear.\nRecommendations for Cases\nof Infertility Caused by Endo-\nmetriosis\nThe management of infertile patients\nsuffering from chronic recurrent endo-\nmetriosis is discussed controversially. In\nsevere cases with excessive endometrio-\nsis, organic damage and adhesions lead\nto mechanical infertility; in mild or mod-\nerate endometriosis, however, the dis-\nease can be associated with functional\ninfertility or it can be an irrelevant addi-\ntional finding. Drug-based therapies\nalone will not improve fertility. A few\nyears ago, a Chochrane analysis clearly\nshowed that the suppression of the ova-\nrian function by minimal or mild endo-\nmetriosis does not influence the infertil-\nity [88]. It should be borne in mind that\nthis statement is based on studies with\nlow case numbers. There is a lack of in-\nternational multicenter studies which\nwould produce sufficient case numbers\nand result in scientifically robust find-\nings.\nDown-regulation with GnRH agonists\nprior to the stimulation phase in IVF pro-\ntocols prevents the premature LH peak,\nleads to more oocytes and improves\npregnancy rates compared with therapy\nprotocols in which no GnRH agonist was\nused [89]. The positive effect of GnRH\nagonists used up to 6 months before an\nIVF cycle irrespective of the stage of\nendometriosis (ultra-long protocol)\nneeds to be discussed carefully on a case\nby case basis. Especially in older pa-\ntients, prolonged suppression cannot be\na useful therapy option since the subse-\nquent stimulation can be compromised\nin view of the age-related low ovarian\nreserve [90]. The same is true for women\nwho have been operated for ovarian\nendometriomas repeatedly or bilaterally.\nSo far, there is no consensus in the litera-\nture about how long the GnRH medica-\ntion should be carried out in the ultra-\nlong protocol.\nIn the case of low-grade peritoneal endo-\nmetriosis – especially if macroscopic\nand microscopic aspects suggest that the\nimplants are inactive – the endometriosis\nshould not be a factor determining the\ninfertility treatment. Once other infertil-\nity factors have been excluded or treated\nsuccessfully and the stimulation of the\novaries does not lead to pregnancy after\n6–12 cycles, the endometriosis can be\naccepted as the cause of infertility and\nshould be treated as such. In this situa-\ntion, the endoscopic excision or vapori-\nsation of all lesions is recommended\nsince this has resulted in improved preg-\nnancy rates in at least one prospective\nrandomised study [48].\nIn advanced stages, endoscopic surgery\nmust be performed to resect the implants\nand cysts, and the reproductive organs\nmust be repaired microsurgically as far\nas possible. If extensive adhesiolysis is\nnecessary, if the surgical intervention is\nincomplete and insufficient or if a repeat\noperation is required, assisted reproduc-\ntion offers the best chance of achieving\npregnancy if GnRH agonists are used in\nthe ultra-long protocol. Treatment with\nGnRH analogues alone after surgical in-\ntervention for endometriosis does not\nimprove the chances of achieving preg-\nnancy.\n   Conclusion/Relevancy to\nPr\nactice\nThis review of the surgical and medici-\nnal therapies suggests recommendations\nbased on scientific literature and Ger-\nman as well as European (ESHRE)\nguidelines. On the one hand, surgical ex-\ncellence is required in order to ad-\nequately perform the often difficult in-\nterventions for endometriosis endo-\nscopically but also to recognise the lim-\nits of surgery. Even well-trained and ex-\nperienced surgeons are sometimes only\npartially successful, and recurrence may\nrequire adequate medication, possibly\nover prolonged periods. For this reason,\nprecise knowledge of the different\nmechanisms of action and side-effects of\nthe available drugs is required in order to\nuse them in a targeted way, sometimes in\ncombination. While non-steroidal anti-\ninflammatory drugs, oral contraceptives\nand many progestins have proven worth-\nwhile empirically in the treatment of\npain, GnRH agonists with add-back\nmedication are currently the standard\ntreatment to effect regression of active\nendometriosis. New progestins in an ap-\npropriate dosage are an equivalent, inex-\npensive option with a different side-ef-\nfect spectrum.\nThe patient must always be comprehen-\nsively informed and involved in the deci-\nsion-making process about the most\nsuitable therapy. Merely applying the\nguidelines in a standardised way would\nnot be a responsible medical approach.\nAs the network of certified endometrio-\nsis centres is growing in Germany, Aus-\ntria and Switzerland [91], doctors should\nnot be afraid to consult their experienced\ncolleagues in particularly difficult cases\nor refer patients to specialised centres in\norder to develop a customised and effec-\ntive treatment strategy.\n   Conflicts of Interest\nIn the last three years, the corresponding\nauthor has worked as a speaker for the\ncompanies BayerHealthCare, Solvay and\nTakeda\nThomas Rabe: has held talks for\nJenapharm receiving payment and travel\nexpenses.\nMona Langhardt: no conflict of interest\nJörg Woziwodzki: no conflict of interest\nLudwig Kiesel: has held talks for\nBayerHealthCare receiving payment\nand travel expenses.\nFelice Petraglia: no conflict of interest.\nReferences:\n1. Waller KG, Shaw RW. 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Postoperative administra-\ntion of monophasic combined oral contraceptives after laparo-\nscopic treatment of ovarian endometriomas: a prospective,\nrandomised trial. Am J Obstet Gynecol 2000; 183: 588–92.\n84. Schweppe KW. Long-term continuous, intermittent and re-\ncurrent treatment of endometriosis. 7\nth International Sympo-\nsium on GnRH-Analogous in Cancer and Human Reproduction.\nGynecol Endocrinol 2003; 17 (Suppl 1): 28.\n85. Pierce S, Gazvani ChBM, Farquharson RG. Long-term use of\ngonadotropin-releasing hormone analogs and hormone replace-\nment therapy in the management of endometriosis: a random-\nized trial with a 6-year follow-up. Fertil Steril 2000;74: 964–8.\n86. Seitz C, Gerlinger C, Faustmann T, Strowitzki, T. Safety of\ndienogest in the long term treatment of endometriosis. Fertil\nSteril 2009; 92: 107.\n87. Uemura T, Shirasu K, Katagiri N. Low-dose GnRH agonist\ntherapy for the management of endometriosis. J Obstet\nGynaecol Res 1999; 25: 295–301.\n88. Hughes E, Brown J, Collins J, Farquhar C, Fedorkow DM,\nVandekerckhove P . Ovulation suppression for endometriosis.\nCochrane Database Syst Rev 2007; CD000155.\n89. Rickes D, Nickel I, Kropf S. Increased p regnancy rates after\nultra long postoperative therapy with gonadotropin-releasing\nhormone analogs in patients with endometriosis. Fertil Steril\n2002; 78: 757–62.\n90. Rickes D, Weiß M, Nickel I. Ovarielle Ansprechbarkeit auf\nrekombinante Gonadotropine nach ultralanger „Downregula-\ntion“ mit GnRH-Analoga. Zentralbl Gynäkol 2003; 125: 306.\n91. Schweppe KW, Eber AD, Kiesel L. Endometriosezentren in\nDeutschland. Der Gynäkologe 2010; 43: 233–40.\n\nHaftungsausschluss\nDie in unseren Webseiten publizierten Informationen richten sich ausschließlich an geprüfte \nund autorisierte medizinische Berufsgruppen und entbinden nicht von der ärztlichen Sorg-\nfaltspflicht sowie von einer ausführlichen Patientenaufklärung über therapeutische Optionen \nund deren Wirkungen bzw. Nebenwirkungen. 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Die entsprechenden Angaben werden von den \nAutoren mit der größten Sorgfalt recherchiert und zusammengestellt. Die angegebenen Do-\nsierungen sind im Einzelfall anhand der Fachinformationen zu überprüfen. Weder die  Autoren, \nnoch die tragenden Gesellschaften noch der Verlag übernehmen irgendwelche Haftungs-\nansprüche.\nBitte beachten Sie auch diese Seiten:\nImpressum Disclaimers & Copyright Datenschutzerklärung\nMitteilungen aus der Redaktion\ne-Journal-Abo\nBeziehen Sie die elektronischen Ausgaben dieser Zeitschrift hier.\nDie Lieferung umfasst 4–5 Ausgaben pro Jahr zzgl. allfälliger Sonderhefte.\nUnsere e-Journale stehen als PDF-Datei zur Verfügung und sind auf den meisten der markt-\nüblichen e-Book-Readern, Tablets sowie auf iPad funktionsfähig.\n Bestellung e-Journal-Abo\nBesuchen Sie unsere Rubrik\n Medizintechnik-Produkte\nInControl 1050 \nLabotect GmbH\nAspirator 3 \nLabotect GmbH\nPhilips Azurion:  \nInnovative Bildgebungslösung\nNeues CRT -D Implantat  \nIntica 7 HF-T QP von Biotronik\nArtis pheno \nSiemens Healthcare Diagnostics GmbH","source_license":"CC0","license_restricted":false}