Standards Used by a Clinical and Scientific Endometriosis Center for the Diagnosis and Therapy of Patients with Endometriosis

DOI https://doi.org/10.1055/a-0813-4411 Published online 28. 2. 2019 | Geburtsh Frauenheilk 2019; 79: 487–497 © Georg Thieme Verlag KG Stuttgart · New York | ISSN 0016 ‑5751 Correspondence Dr. Stefanie Burghaus Frauenklinik, Universitätsklinikum Erlangen Universitätsstraße 21 –23, 91054 Erlangen, Germany [email protected] Deutsche Version unter: https://doi.org/10.1055/a-0813-4411 Supporting Information: https://doi.org/10.1055/a-0813-4411

Endometriosis is one of the most common benign gynecolog- ical diseases. The extremely heterogeneous complex of symp- toms complicates the diagnosis and treatment of this disease. In most patients, there is a latency period of several years be- tween the first occurrence of symptoms and the definitive di- agnosis. This paper aims (1) to evaluate standards for the di- agnosis and treatment of patients with (symptoms suspicious for) endometriosis in terms of feasibility, and (2) to assess the potential use of data collected by a certified clinical and scien- tific endometriosis center to answer scientific questions. Stan- dards for outpatient consultations were developed for a spe- cial endometriosis outpatient clinic. Between January 2014 and December 2017, a total of 1715 outpatients with a suspi- cion of endometriosis presented to this special endometriosis outpatient clinic; the diagnosis and treatment of patients was carried out in accordance with the developed standards. Data of this patient cohort obtained from patient records created during outpatient consultations and from a questionnaire re- corded in an Oracle-based database was analyzed. The patient cohort was also compared with another patient cohort who had attended different outpatient clinics and had been diag- nosed intraoperatively with endometriosis. 41.8 % of patients examined during special outpatient consultations had surgery for suspicion or recurrence of endometriosis. Endometriosis was confirmed in 81.5 % of cases. Pain symptoms were the main indication for surgery in 70.1 % of cases compared to 45.1 % of cases in the comparison group. The structured ap- proach used in the special endometriosis outpatient clinic is a key aspect of the care provided by the certified clinical and scientific endometriosis center. It ensures that patients are di- agnosed and treated in accordance with guideline recommen- dations, that diagnosis and treatment comply with certifica- tion requirements, and that the collected data can be used to answer scientific questions. GebFra Science | Original Article 487Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 Published online: 2019-02-28

Endometriosis is associated with a range of different clinical symp- toms. The tentative diagnosis may be based on menstrual cycle- related pain, chronic pain or infertility, and the definitive diagnosis is then confirmed by diagnostic laparoscopy. However, endome- triosis may also be diagnosed as an incidental finding in asymp- tomatic patients. Around 25 –30 % of women between the ages of 25 and 35 years are affected by this disease [1, 2]. The preva- lence of endometriosis among sterile women is even higher, with a reported incidence of up to 50 % [3 – 5 ] .A c c o r d i n gt od a t af r o m the German Federal Statistical Office, 27 113 patients with endo- metriosis were hospitalized in Germany in 2016 and had conserva- tive or surgical treatment. Because of the very heterogeneous presentation of the disease, it is assumed that the number of pa- tients with non-surgically diagnosed endometriosis is significantly higher [6]. Although gynecological research is becoming incr easingly aware of endometriosis, it is still assumed that the average latency period between the first appearance of symptoms and the defini- tive diagnosis is around 10 years [7]. This delay does not just put patients under considerable psychological strain and reduces their quality of life, it also leads to higher healthcare costs due to fre- quent visits to different physicians and unnecessary or futile diag- nostic and therapeutic procedures and limits patients ʼ capacity to work [8 – 11]. Establishing a consistent structure for special endo- metriosis outpatient clinics is necessary to enable treating physi- cians to make comparable, efficient and specific diagnoses and promptly prescribe the appropriate therapeutic measures. To improve the quality of medical care, research, and teaching, a certification process for endometriosis centers was introduced by the Stiftung Endometriose-Forschung (SEF), the European En- dometriosis League and the self-help group Endometriose Vereini- gung Deutschland e. V. in 2006 [12]. It uses a phased approach and defines the requisite criteria for certification. According to the criteria, diagnosis and treatment must be carried out in ac- cordance with appropriate guidelines, the center must work to- gether with self-help groups, the patient ʼs medical history must be recorded, and the center must compile an annual report. The standards differentiate between 1. gynecological practices, 2. centers of reproductive medicine, 3. rehabilitation clinics, 4. centers with only one surgeon specialized in treating endome- triosis, and 5. hospitals and surgical day clinics, which can be certified as clin- ical or clinical and scientific endometriosis centers. Patients have also taken note of this new certification process. In a multicenter study, 2500 patients were asked what they knew about certified centers, and 43.8 % of respondents reported that they had deliberately contacted a certified center to obtain a diag- nosis and treatment [13]. This study aimed to evaluate the feasibility of the standards de- veloped for certified clinical and scientific endometriosis centers to diagnose and treat patients with (symptoms suspicious for) en- dometriosis and analyzed a patient cohort diagnosed with endo- metriosis to determine whether additional scientific questions need to be asked. A model for the organizational structure of spe- cial endometriosis outpatient clinics and for the necessary diag- nostic and therapeutic procedures is presented here, and aims to define professional clinical standards. Patients and Methods In 2006, a standardized special endometriosis outpatient clinic was set up in the Gynecology Department of the University Hospi- tal of Erlangen and certified as a highest-level endometriosis cen- ter. Outpatient clinics are held twice a week; they are staffed by specialists who have additional qualifications/have undergone ad- vanced training in endometriosis. Patients present to the clinic after a referral by their gynecologist or on their own initiative after ZUSAMMENFASSUNG Endometriose zählt zu den häufigsten gutartigen gynäkologi- schen Erkrankungen. Ein sehr heterogener Symptomkomplex erschwert die Diagnose und die Therapie der Erkrankung. Meist besteht eine mehrjährige Latenz zwischen dem erstmali- gen Auftreten von Symptomen und der Diagnosestellung. Ziel der vorliegenden Arbeit sind (1) die Überprüfung von definier- ten Standards für die Diagnostik und die Therapie von Patien- tinnen mit (Verdacht auf) Endometriose auf ihre Umsetzbarkeit und (2) eine mögliche Nutzung dieses zur Beantwortung von wissenschaftlichen Fragestellungen als Grundlage im zertifi- zierten klinischen und wissenschaftlichen Endometriosezen- trum. In der Spezialambulanz für Endometriose wurde ein Stan- dard für die Durchführung dieser Sprechstunde entwickelt. Im Rahmen dieser Spezialambulanz erfolgten 1715 ambulante Pa- tientenvorstellungen von Januar 2014 bis Dezember 2017, we- gen der (Verdachts-)Diagnose Endometriose, die nach diesem Standard diagnostiziert und behandelt wurden. Anhand der Dokumentation der Patientinnenakte und des Fragebogens in einer Oracle-basierten Datenbank wurde eine Analyse des aus dieser Sprechstunde hervorgehenden Patientenkollektivs durchgeführt. Zudem wurde ein Vergleich mit dem Patientin- nenkollektiv durchgeführt, das sich in anderen Spezialambu- lanzen vorgestellt hat und bei dem intraoperativ ebenfalls En- dometriose diagnostiziert wurde. 41,8 % der Patientinnen aus dieser Sprechstunde wurden bei Verdacht auf Endometriose oder dem Rezidiv einer Endometriose operiert. Eine Endomet- riose konnte bei 81,5 % bestätigt werden. Die Schmerzsympto- matik war in 70,1 % die Hauptindikation für die Operation, im Vergleichskollektiv war diese 45,1 %. Die vorgestellte Struktu- rierung einer Spezialambulanz für Endometriose als zentraler Bestandteil eines zertifizierten klinischen und wissenschaftli- chen Endometriosezentrums ermöglicht eine leitliniengerech- te Diagnostik und Therapie der Patientinnen mit Endometriose, die Erfüllung der Zertifizierungsvoraussetzungen und das Be- antworten von wissenschaftlichen Fragestellungen. 488 Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 GebFra Science | Original Article they have researched the options themselves. A diagnostic and therapeutic approach was developed, based on the most impor- tant symptoms of disease. The feasibility of the approach was ret- rospectively evaluated in this feasibility study. Standards for special outpatient endometriosis clinics within certified endometriosis centers Before the patient first presents to her physician, she is given a case-history questionnaire to complete which contains detailed questions about her general medical and gynecological history. The patient is additionally given a specific questionnaire with questions which focus on typical endometriosis-related com- plaints. In addition to the case-history questionnaire, the patient is given a further questionnaire with questions which aim to an- swer a number of scientific questions. During the subsequent in- depth talk with the treating physician, the patient ʼs individual an- swers are discussed and amplified. The patient ʼs history of symp- toms is recorded, with a special focus on symptoms typical for en- dometriosis ( ▶ Fig. 1). Particular importance is attached to the patientʼs report on the extent of pain she experiences, which she rates using a numeric analog scale with values between 1 and 10. After the completed questionnaires have been handed in, the first diagnostic procedure consists of a general gynecological ex- amination and ultrasound ( ▶ Fig. 2). Ultrasound by itself is not enough to make a diagnosis of endometriosis or exclude it. How- ever, ultrasound can be used to detect the presence of ovarian en- dometrial cysts (also known as an endometrioma), assess the con- dition of the uterus including indications for adenomyosis, detect adhesions in the inner genital region, and evaluate uterine motil- ity status and any thickening of the intestinal wall in cases where the intestines are also affected [14 – 16]. Renal ultrasound should be carried out in addition to gynecological ultrasound to exclude asymptomatic hydronephrosis caused by deep infiltrating endo- metriosis affecting the ureters. Symptom-based diagnostic procedures are carried out to in- vestigate endometriotic symptoms ( ▶ Fig. 3). Clinical examina- tions are of only limited use to diagnose deep infiltrating endome- triosis. For certain clinical conditions such as deep infiltrating en- dometriosis of the ureter with hydronephrosis, magnetic reso- nance imaging is required to determine the extent of disease. Magnetic resonance imaging (MRI) and transvaginal ultrasound are equivalent in terms of making a diagnosis. However, MRI is more sensitive for detecting endometriotic foci in the vagina and uterosacral ligaments [17]. When patients present with chronic pain of the lower abdomen, close cooperation with a gastroenter- ologist is recommended to investigate and exclude other possible causes such as food intolerances, chronic inflammatory bowel dis- Medical history General medical history: Symptom-based medical history:Menstrual history DysmenorrheaGravidity/parity Lower abdominal painPrevious therapies Dyschezia/ hematochezia Previous operations Dysuria/hematuria Medication (previous and current) DyspareuniaAdditional diagnoses SterilityAllergies AsymptomaticBody mass index Familial history Social history ▶ Fig. 1 Standards for taking the general and symptomatic gyne- cological history of patients with endometriosis or symptoms sus- picious for endometriosis. Basic diagnostic procedures Inspection/speculum examination Bimanual vaginal rectal palpation and Vaginal ultrasound Renal ultrasound Genitals/vagina Posterior vaginal fornix Uterus Bil. uterosacral lig. Bil. adnexa Parametria Pouch of Douglas Rectovaginal septum Uterus (signs of adenomyosis) Ovaries Intestines Bladder ▶ Fig. 2 Standards for basic diagnostic procedures for patients with (symptoms suspicious for) endometriosis. Bil. = bilateral. 489Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 ease or irritable bowel syndrome and to obtain a differential diag- nosis. The third and last step of the treatment algorithm consists of developing an individual, guideline-based and, where necessary, interdisciplinary treatment concept for the respective patient ( ▶ Fig. 4). The treatment of endometriosis rests on two pillars: surgery and conservative management [18 – 20]. The choice of t h e r a p yi sg u i d e db yt h ep a t i e n tʼs symptoms and the patient ʼs reasons for presenting to the outpatient clinic and by the time and type of diagnosis, i.e. whether it is a primary diagnosis or whether the patient is presenting with recurrence. The definitive diagnosis can only be obtained by histological examination. Surgi- cal removal of endometriotic foci is the gold standard to control symptoms [20 – 22]. When considering whether excision of endo- metrioma is indicated, the decision to opt for surgery must also take the subsequent reduction in ovarian reserve after repeat sur- gical excisions into account. Other indications for endoscopic therapy of recurrent endometriosis are pain resistant to therapy and organ destruction. If the patient ʼs main focus is not on the pain but on her wish to have children, then, depending on the pa- tientʼs age and ovarian reserve, after a primary diagnosis of endo- metriosis, the recommended approach in most cases is surgery to remove the endometriotic foci followed by a visit to a clinic for re- productive medicine. If the patient has rASRM stage I or II endo- metriosis, then ablation or excision of endometriotic foci can im- prove fertility [23]. A patient- and goal-oriented approach is es- sential to find an individual solution for the patient [24]. It is worth assessing whether the patient should participate in a study to help establish new therapeutic concepts [25, 26]. Medical hormone therapy should be prescribed postopera- tively as prophylaxis and long-term therapy to prevent the recur- rence of endometriosis [18, 27]. Treatment options include pro- gestogen therapies, oral contraceptives (off-label use) and GnRH analogs [18]. Presentation to an outpatient pain clinic can be an additional therapeutic option for patients with persistent postoperative pain [28]. Other postoperative therapeutic options include physiother- apy, nutrition counselling and rehabilitation as well as individual therapeutic approaches such as osteopathy and traditional Chi- nese medicine (TCM). In addition to surgical and medical thera- pies, the interdisciplinary concept also includes the integration of psychosomatic therapies for patients with chronic lower abdomi- nal pain and sterility. A multidisciplinary approach is useful for patients with chronic lower abdominal pain [29, 30]. The quality of life of affected pa- tients and their ability to cope with chronic pain on a day-to-day basis can be significantly improved by the integration of psycho- somatic care into their care plan, and this can ultimately also have a positive impact on treatment results [22, 31]. A follow-up examination at the special endometriosis outpa- tient clinic or by the patient ʼs regular gynecologist should be agreed upon with the patient to monitor the outcome of treat- ment. Descriptive analysis of treated patients This study analyzed patients with (symptoms suspicious for) en- dometriosis who presented to the special endometriosis outpa- tient clinic of the University Endometriosis Center Franken (UEF) between January 1, 2014 and December 31, 2016. Patients from this patient population who had surgery between January 1, 2014 and December 31, 2017 were selected for further analysis. The selected time period was extended by a further year to include those patients whose visit to the outpatient clinic resulted in an indication for surgery. Only patients who were operated in the Symptom-based diagnostic procedures (Diagnostic) laparoscopy Dysmenorrhea Dysuria Dyspareunia Dyschezia Sterility MRI if applicable Cystoscopy in pa- tients with chronic microhematuria and/or ultrasound- based suspicion of bladder infiltration if applicable MRI Coloscopy/ rectoscopy to exclude differ- ential diagnosis if applicable MRI if applicable Presentation to Gastroenterology Dept. to obtain differential diag- nosis, e.g. food intolerances Hysteroscopy Chromo- pertubation ▶ Fig. 3 Symptom-based diagnosis of patients with (symptoms suspicious for) endometriosis. MRI = magnetic resonance imaging. 490 Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 GebFra Science | Original Article Gynecology Department of Erlangen University Hospital were in- cluded. Patients in whom endometrial disease was detected during surgery carried out between January 1, 2014 and December 31, 2017 were also included in the study. These patients had present- ed to other medical facilities such as polyclinics, private medical consultations, preoperative outpatient clinics or special outpa- tient clinics for gynecological endocrinology and reproductive medicine for lower abdominal pain of unknown origin or sterility. Patient data consisting of the patient ʼs medical history and clinical and surgical data were recorded in an Oracle-based IEEP (International Endometriosis Evaluation Program) database. The IEEP database is a multicenter online documentation system which has been used since January 1, 2014 to record the medical history and clinical data of patients with endometriosis in Ger- many. By June 2018, the data of more than 8000 female patients treated in different centers all over Germany had been recorded in the database. Patients ʼ medical history and clinical examination findings are recorded using an electronic case report form (eCRF). In addition, every patient completes a questionnaire which pro- vides data for various scientific questions (Supplement). This is useful as it contributes to developing and improving established standards and provides data for current research projects [32]. Based on the IEEP database, a sub-analysis was done of pa- tients presenting to the special endometriosis outpatient clinic and to other outpatient clinics. The analysis included age at initial operation, age at menarche, cycle length, duration of menstrual flow, body mass index (BMI), use of oral contraceptives (at any time and currently), incidental or prevalent endometriosis, whether surgery was indicated, surgical procedure (minimally in- vasive/open surgery/intraoperative change of surgical procedure (from minimally invasive to open surgery), ASRM classification, deep infiltrating endometriosis, histological diagnosis, and whether a hysterectomy was carried out. Therapy Suspicion of endometriosis Recurrent endometriosis Surgical: Laparoscopy to con- firm diagnosis and excise endometriotic f o c i ;i fn e c e s s a r y ,i n - terdisciplinary proce- dure together with surgeon/urologist Surgical: Poss. re-laparoscopy (laparotomy) if organ damage is present (e.g., hydronephrosis) a n dt h e r ei sas u s p i - cion of deep infiltrat- ing endometriosis; if necessary, interdis- ciplinary procedure together with sur- geon/urologist Individual symptom-based therapy and hormone therapy after excluding organ damage (e.g., hydronephrosis), no diagnostic signs of deep infiltrating endometriosis (except uterine adenomyosis) and the exclusion of an endometrioma Hormone therapy (progestogen therapy, off-label use of oral contraceptives, GnRH analogs)/prophylaxis against recurrence Postoperative hormone therapy as prophylaxis against recurrence or reproductive medicine if the patient wishes to have a child Postoperative hormone therapy as prophylaxis against recurrence or reproductive medicine if the patient wishes to have a child Pain therapy (multimodal) Pain therapy (multimodal) Psychosomatic support Psychosomatic support Physiotherapy Physiotherapy Nutritional counseling Nutritional counseling Rehabilitation Rehabilitation Sexual counseling Sexual counseling Osteopathy Osteopathy TCM/acupuncture TCM/acupuncture Alternative/integrative therapies: Alternative/integrative therapies: Conservative: Conservative: ▶ Fig. 4 Treatment algorithm: interdisciplinary care of patients with (symptoms suspicious for) endometriosis. 491Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497

A total of 1245 patients with (symptoms suspicious for) endome- triosis presented to the special endometriosis outpatient clinic be- tween January 1, 2014 and December 31, 2016, with a total of 1715 visits to the outpatient clinic ( ▶ Fig. 5 a). 520 of these pa- tients underwent surgery in the period between January 1, 2014 and December 31, 2017. Endometriosis was additionally diag- nosed during surgery in a further 1375 patients in the period be- tween January 1, 2014 and December 31, 2017. The patient co- hort of operated patients from the special endometriosis out- patient clinic and from other outpatient clinics is described in ▶ Table 1 . All patients were treated in accordance with the diag- nostic and therapeutic concept established by the UEF. Indications for surgery This study evaluated the patients attending the special endome- triosis outpatient clinic who required surgery. More than one third of patients (41.8 %; n = 520) who presented to the special endo- metriosis outpatient clinic between 2014 and 2016 subsequently underwent surgery between 2014 and 2017 because of sus- pected endometriosis or recurrence of endometriosis ( ▶ Fig. 5 a). Endometriosis was confirmed intraoperatively in 424 (81.5 %) of the 520 patients during 478 operations. The main indication for surgery was pain (70.1 %; n = 302). Pri- mary or secondary sterility was cited as the indication for surgery in 22.3 % (n = 96) of patients. Only 7.7 % (n = 33) of patients were operated on for other reasons such as suspicious ovarian findings. The number of re-operations in this period, i.e. the number of pa- tients who underwent more than one operation, was 47 (9.8 %). Some of the repeat operations were carried out for recurrence of endometriosis. In other cases, repeat surgery was done because extensive intestinal endometriosis was found intraoperatively, and this finding required an interdisciplinary follow-up procedure with partial intestinal resection. Patient cohorts from other special outpatient clinics Between 2014 and 2017, 1853 operations were carried out at the Gynecology Department in 1744 patients with an intraoperative diagnosis of endometriosis. This results in a difference of 1320 pa- tients who had surgery but did not present to the special endome- triosis outpatient clinic preoperatively ( ▶ Fig. 5 b). This cohort, which amounts to 75.7 % of operated patients, consists of patients with an incidental finding of endometriosis during surgery for oth- Special endometriosis outpatient clinic n = 1245 V = 1715 Conservative n = 725 Yes n = 424 O = 478 Pain O = 302 Indications for surgery Diagnosis of endometriosis Diagnosis of endometriosis Sterility O=9 6 Other O=3 3 Not specified O=4 7 a b Pain O = 573 Indications for surgery Sterility O = 362 Other O = 336 Not specified O = 104 Conservative n=N .E . Yes n = 1320 O = 1375 Surgery n = 520 O = 580 No n=9 6 O = 102 Surgery n=N .E . No n=N .E . Other outpatient clinics: Polyclinic Private consultation Direct referral to pre- operative outpatient clinic Special outpatient clinic for reproductive medicine n=N .E . ▶ Fig. 5 Description of patients who underwent surgery or were treated conservatively from a the special endometriosis outpatient clinic, and b other outpatient clinics. n = number of patients, V = number of outpatient visits; O = number of surgeries, N. E. = not evaluable. 492 Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 GebFra Science | Original Article er causes and patients who presented to other medical facilities such as special outpatient clinics for reproductive medicine, pri- vate consultations, polyclinics or directly to the preoperative out- patient clinic because of sterility or lower abdominal pain. When evaluating the main indication for surgery, it turned out that pain was mentioned significantly less often (45.1%). Sterility (28.5 %) and other reasons (26.4 %) were the other main indica- tions for surgery and almost as important as pain. The percentage of procedures performed laparoscopically (96.9 %), the percentage of histological confirmations of endome- triosis (90.0 %) and the extent of endometriosis classified using the rASRM score were comparable with the percentages of the patients from the endometriosis outpatient clinic. Surgical procedure and intraoperative findings The overwhelming majority of surgical operations were carried out as laparoscopic procedures (95.9 %), although in ten cases the procedure had to change intraoperatively from laparoscopic surgery to laparotomy. Six of these ten operations were carried out as interdisciplinary procedures, and the reason for switching procedures was partial intestinal resection carried out in coopera- tion with another surgeon. In two cases, secondary laparotomy was performed for myoma enucleation and to remove a large myomatous uterus, respectively. The final two operations were carried out together with a urologist, with one patient under- going nephrectomy and one patient undergoing ureteric implan- tation for endometriosis. 63.1 % of cases had rASRM stage I –II disease. Histological con- firmation was obtained in 93.7 % of operations ( ▶ Table 2 ). Of the patients where no histological evaluation was carried out intra- operatively, 19 patients had an adenomatous uterus and hysterec- tomy was not carried out. Only two cases had macroscopic suspi- cion of endometriosis which was not confirmed histologically. The remaining cases where no histological investigation was carried out were two-stage surgeries. In these cases, extensive disease with deep infiltrating endometriosis was found during the first op- eration. The decision was then taken to discontinue surgery and to perform a second subsequent operation, during which the di- agnosis was confirmed and partial intestinal resection or partial ureteric resection was carried out. Hysterectomy was carried out in 10.6 % of recorded cases. Postoperative course After surgery, every patient was given a doctor ʼs letter with writ- ten therapeutic recommendations. The recommendations in- cluded the proposed time of the postoperative follow-up exami- nations and, depending on the case, recommendations for medi- cations to control symptoms and to prevent recurrence, or further procedures to be followed in cases with primary or secondary ste- rility. It was recommended that patients wishing to have children should attend a special outpatient clinic for reproductive medi- ▶ Table 1 Characteristics of patients with a diagnosis of endometriosis who underwent surgery. Parameter Special endometriosis outpatient clinic Other outpatient clinics Total n=4 2 4 n=1 3 2 0 n=1 7 4 4 Age at first surgery (years) 32.9 (7.8, 399)* 34.9 (8.3, 1242)* 34.4 (8.2, 1642)* Age at menarche (years) 12.9 (1.5, 398)* 13.0 (1.5, 1179)* 12.9 (1.5, 1577)* Cycle length at initial presentation (days) 28.7 (7.4, 229)* 28.0 (5.3, 686)* 28.2 (5.9, 915)* Duration of menstrual flow at initial presentation (days) 5.4 (1.6, 279)* 5.4 (1.9, 896)* 5.4 (1.8, 1175)* Body mass index at initial presentation (kg/m 2) 24.1 (5.0, 327)* 24.3 (5.1, 1060)* 24.3 (5.1, 1384)* Use of oral contraceptives (ever) at the time of the initial presentation 417 (100%) 1300 (100%) 1717 (100 %) ▪ yes 246 (59.0 %) 476 (36.6 %) 722 (42.1 %) ▪ no 6( 1 . 4 % ) 4 9( 3 . 8% ) 5 5( 3 . 2% ) ▪ unknown 165 (39.6 %) 775 (59.6 %) 940 (54.7 %) Use of oral contraceptives (currently) at the time of initial presentation 418 (100%) 1301 (100%) 1719 (100 %) ▪ yes 140 (33.5 %) 305 (23.4 %) 445 (25.9 %) ▪ no 272 (65.1 %) 951 (73.1 %) 1223 (71.0 %) ▪ unknown 6( 1 . 4 % ) 4 5( 3 . 5% ) 5 1( 3 . 0% ) Prevalent/incidental endometriosis at initial presentation 390 (100%) 1218 (100%) 1608 (100 %) ▪ prevalent 224 (57.4 %) 194 (15.9 %) 418 (26.0 %) ▪ incidental 166 (42.6 %) 1024 (84.1 %) 1250 (74.0 %) * Mean value (standard deviation, number of patients) 493Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 cine. Postoperative follow-up examinations were carried out ei- ther at the Gynecology Department or by doctors in private prac- tice. 16.0 % (n = 68) of patients from the special endometriosis outpatient clinic with confirmation of endometriosis who had undergone surgery returned to our clinic within one year for a (postoperative) follow-up examination. Most of these patients had undergone an interdisciplinary procedure in cooperation with a surgeon and urologist and required specific follow-up examina- tions.

Standards for the process to be used by a special endometriosis outpatient clinic were developed at a certified clinical and scien- tific endometriosis center. These standards cover the specific clin- ical steps required to obtain a diagnosis, decide on the appropri- ate therapy and collect data for scientific purposes. The standards are based on the international recommendation of the S2k guide- line “Diagnosis and Therapy of Endometriosis ” [20] and the Euro- pean Society of Human Reproduction and Embryology [33]. A re- view of the literature showed that no comparable standardized approach for special endometriosis outpatient clinics has been published to date. There have been a number of international at- tempts to standardize the management of endometriosis and to compare national therapy recommendations. Every patient with endometriosis should be able to access diagnostic procedures and treatment tailored to her needs in certified specialist centers [34]. Careful detailed investigation of the patient ʼsm e d i c a lh i s - tory can provide important information about the location of en- dometriotic foci which, taken together with the findings obtained during non-invasive diagnostic procedures, can confirm the suspi- cion of endometriosis [35, 36]. The patient ʼsm e d i c a lh i s t o r yt o - ▶ Table 2 Description of surgical approach used. Parameter Special endometriosis outpatient clinic Other outpatient clinics Total O=4 7 8 O=1 3 7 5 O=1 8 5 3 Indications for surgery 431 (100%) 1271 (100%) 1702 (100 %) ▪ pain 302 (70.07 %) 573 (45.1 %) 875 (51.4 %) ▪ sterility 96 (22.27 %) 362 (28.5 %) 458 (26.9 %) ▪ other 33 (7.66 %) 336 (26.4 %) 369 (21.7 %) Surgical approach 441 (100%) 1273 (100%) 1714 (100 %) ▪ minimally invasive 423 (95.9 %) 1233 (96.9 %) 1656 (96.6 %) ▪ laparotomy 4( 0 . 9 % ) 1 6( 1 . 3% ) 2 0( 1 . 1% ) ▪ change of procedure intraoperatively 10 (2.3 %) 16 (1.3 %) 26 (1.5 %) ▪ other 4 (0.9 %) 7 (0.5 %) 11 (0.6 %) ▪ unknown 0( 0 . 0 % ) 1( 0 . 1 % ) 1( 0 . 1 % ) rASRM 404 (100%) 1195 (100%) 1599 (100 %) ▪ stage 0 21 (5.2 %) 80 (6.7 %) 101 (6.3 %) ▪ stage I 143 (35.4 %) 564 (47.2 %) 707 (44.2 %) ▪ stage II 93 (23.0 %) 210 (17.6 %) 303 (18.9 %) ▪ stage III 53 (13.1 %) 146 (12.2 %) 199 (12.4 %) ▪ stage IV 82 (20.3 %) 132 (11.0 %) 214 (13.4 %) ▪ unknown 12 (3.0 %) 63 (5.3 %) 75 (4.7 %) Deep infiltrating endometriosis 442 (100%) 1275 (100%) 1717 (100 %) ▪ yes 327 (74.0 %) 779 (61.1 %) 1106 (64.4 %) ▪ no 112 (25.3 %) 471 (36.9 %) 583 (34.0 %) ▪ unknown 3( 0 . 7 % ) 2 5( 2 . 0% ) 2 8( 1 . 6% ) Histological confirmation 442 (100%) 1275 (100%) 1717 (100 %) ▪ yes 414 (93.7 %) 1147 (90.0 %) 1561 (90.9 %) ▪ no 28 (6.3 %) 125 (9.8%) 153 (8.9 %) ▪ unknown 0( 0 . 0 % ) 3( 0 . 2 % ) 3( 0 . 2 % ) Hysterectomy 445 (100%) 1279 (100%) 1724 (100 %) ▪ yes 47 (10.6 %) 153 (12.0 %) 200 (11.6 %) ▪ no 398 (89.4 %) 1126 (88.0 %) 1524 (88.4 %) O = number of operations; rASRM = classification of the American Society for Reproductive Medicine 494 Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 GebFra Science | Original Article gether with a gynecological examination have a combined sensi- tivity of around 80 % for diagnosing endometriosis, although only histological examination can provide the definitive confirmation of the diagnosis. There is a symptom-based prognostic model which can be used to improve the selection of patients requiring surgery. The selection accuracy for patients who had surgery with histological confirmation of endometriosis was higher for patients with rASRM stages III and IV. By comparison, the predictive accuracy was much poorer for lower-stage endometriosis (stage I and II) [37]. In our study, endometriosis was confirmed in more than 80 % of patients who underwent surgery. The extent of pain is not directly correlated with the location and extent of endometriosis [38, 39]. Our data were unable to confirm an increase in rASRM scores for patients with significant clinical symptoms (data not shown). Some specialist societies support primary conservative medi- cal treatment for women with mild to moderate lower abdominal pain who have regular ultrasound examinations [33, 40]. Howev- er, there are no data which have shown that this approach is supe- rior, and this approach should therefore only be agreed upon with patients on an individual basis. A review of the indications for surgery provides information about the patient cohort presenting to the special endometriosis outpatient clinic. Non-specific lower abdominal pain was associ- ated with endometriosis in up to half of all cases [35]. Our results showed that 70.1 % of surgical procedures performed in patients from the special endometriosis outpatient clinic and 45.1 % of op- erations carried out in patients from other outpatient clinics were performed because of pain. The low number of patients with ste- rility presenting to the special endometriosis outpatient clinic can be explained by the fact that patients with sterility usually first presented to the special outpatient clinic for gynecological endo- crinology and reproductive medicine at the University Center for Reproduction Franken (UEF) and did not initially present to the en- dometriosis center. In the patient cohort from other outpatient clinics, the relatively low number of patients where pain was the main indication for surgery was because, in the majority of these patients, surgery was indicated for other findings such as myo- matous uterus, ovarian cysts or sterility. Surgical procedures to diagnose and alleviate endometriosis play a very important role. In terms of diagnosing endometriosis, no imaging procedures used to date offer results which are as ac- curate as surgery [41], meaning that surgical procedures remain the gold standard for diagnosing endometriosis. However, be- cause of the possible negative consequences of this invasive ap- proach such as adhesions, loss of functional ovarian tissue or dam- age to internal organs, it is important that in cases with recurrent endometriosis the recommendation for surgery is based on strict and restrictive criteria [24, 42]. If stage rASRM I/II resectable en- dometriosis is found during surgical investigation for endometrio- sis, complete excision of endometriotic tissue should be done dur- ing the same procedure. Cases with rASRM stage III/IV endome- triosis require an individual approach according to the main ther- apy goals agreed upon with the patient prior to surgery (pain re- lief vs. pregnancy). During the surgical removal of endometriotic tissue in a patient with ovarian endometriosis it is important to consider the best way of preserving ovarian reserve in the long term, particularly when treating patients who wish to have chil- dren. Women below the age of 30 are reported to have a higher risk for repeat surgery for endometriosis [43]. The success of therapy in terms of improving pain symptoms is higher for the first opera- tion compared to subsequent operations. Abboth et al. reported a decrease in pain symptoms of 83 % in the first 6 months compared to 53 % after subsequent operations [21]. Experienced surgeons, guideline-based recommendations for follow-up treatment, and the integration of interdisciplinary therapy concepts should re- duce the rate of re-operations, although the well-known, dis- ease-specific rate of recurrence reported for endometriosis must be taken into account [44]. Even after carrying out complete exci- sion of endometriotic foci, recurrence rates of between 10 % and 55 % within the first 12 months after surgery have been reported [45]. To be able to deal appropriately with the above-mentioned cir- cumstances, it is proposed that patients with a history of disease should be cared for in endometriosis centers. This is also reflected by our figures. After presenting to the special endometriosis out- patient clinic, excisional surgery was carried out 49.2 % of all pa- tients. These patients were already known to have endometriosis, and surgery was performed because of therapy-resistant pain. The majority of patients presenting to the special endometriosis outpatient clinic had already been treated previously for endome- triosis, and this was also reflected in the percentage of patients taking oral contraceptives (59.1 %). By comparison, 89.9% of pa- tients from other outpatient clinics did not have a previous surgi- cal confirmation of endometriosis, and the percentage of them taking oral contraceptives as therapy was significantly lower (36.6 %). The quality criteria for surgery for patients from the spe- cial endometriosis outpatient clinic did not differ from that for pa- tients from other outpatient clinics. 96.6 % of procedures were carried out as minimally invasive procedures. Magnification provides better visualization of the peritoneum, making it easier to detect and excise endometriotic foci. The intraoperative histological confirmation of the suspected diagnosis was high (90.9 %). The majority of cases where surgical procedures did not provide histological confirmation of the sus- pected diagnosis had uterine adenomyosis. Nor routine proce- dure has been established to confirm uterine adenomyosis, mak- ing it difficult to confirm adenomyosis surgically. A large percent- age of cases in this patient population had deep infiltrating endo- metriosis, the majority of whom had uterine adenomyosis. When a center becomes a certified endometriosis center, its quality criteria must also include postoperative follow-up. At present, 16.0 % of patients who have a surgical procedure for en- dometriosis return to our clinic for their postoperative follow-up. Non-hospital-based gynecologists who cooperate with the endo- metriosis center by providing follow-up care for operated patients receive written therapy recommendations, thereby completing the postoperative care network. All operated patients who have no wish to have children and no contraindications should be of- fered prophylactic therapy against recurrence to reduce the recur- rence of typical endometriosis-related complaints and prevent the development of endometrioma [18, 46]. Patients who booked appointments with non-hospital-based gynecologists who are 495Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 part of the care network were not included in this data evaluation, which may explain the low number of postoperative follow-up ex- aminations carried out by the center. This study aimed to present the standards for the process fol- lowed by a special endometriosis outpatient clinic and to evaluate a specific patient cohort. The study has both strengths and weak- nesses. Setting up a special outpatient clinic and the correspond- ing data analysis is associated with higher costs for personnel and documentation and a greater ex penditure of time and requires additional resources in terms of more personnel. However, the majority of patients who received an intraoperative diagnosis of endometriosis previously presented to other outpatient clinics. Diagnosis and treatment at these other outpatient clinics are in accordance with the same accepted standards, but because of the inconsistency with which outpatient visits are coded, the data of patients who present to those outpatient clinics with a suspi- cion of endometriosis or recurrence of endometriosis and are managed conservatively or for whom the suspected endometrio- sis was not confirmed intraoperatively cannot be evaluated. More- over, the data does not yet show whether the patient presented to the outpatient clinic at the recommendation of her gynecologist, of an outpatient endometriosis clinic or on her own initiative. If this information were available, it could be used to develop a tar- geted process to attract more patients to the endometriosis out- patient clinic and focus more attention on the topic of endome- triosis. The strengths of the study include the high number of treated patients and the fact that use of a scientific questionnaire made it possible to analyze the characteristics of operated patients. The clinicʼs structure represents a marketing tool to recruit patients to the center and maintain a long-term relationship with patients. The standards for the special endometriosis outpatient clinic published here are also relevant for routine gynecological prac- tice. They ensure that the choice of therapy is patient-centered and goal-oriented. This was demonstrated by the high level of sensitivity for the indications for surgery. The concept presented in this study should serve as an example and can be implemented or adapted by other endometriosis centers according to their in- frastructure. As the recommendations for a standardized therapy algorithm for women with endometriosis are, in some cases, still inconsistent, the algorithm presented here aimed to fill this gap. Attending an outpatient clinic encourages a relationship of trust and creates a bond between the patient and the clinic where she is treated. Patients benefit from undergoing surgery at a certified center for endometriosis which follows standardized processes, with patients profiting from the clinical and scientific expertise and the quality-assured transparent structures and processes cre- ated during certification. Conflict of Interest The authors declare that they have no conflict of interest.

[1] Saha R, Kuja-Halkola R, Tornvall P et al. Reproductive and Lifestyle Fac- tors Associated with Endometriosis in a Large Cross-Sectional Population Sample. J Womens Health (Larchmt) 2017; 26: 152 –158 [2] Sar ıdoğ an E. Adolescent endometriosis. Eur J Obstet Gynecol Reprod Biol 2017; 209: 46 –49 [3] Mahmood TA, Templeton A. Prevalence and genesis of endometriosis. Hum Reprod 1991; 6: 544 –549 [4] Witz CA, Burns WN. Endometriosis and infertility: is there a cause and effect relationship? Gynecol Obstet Invest 2002; 53 (Suppl. 1): 2 –11 [5] Viganò P, Parazzini F, Somigliana E et al. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol 2004; 18: 177–200 [6] Buck Louis GM, Hediger ML, Peterson CM et al.; ENDO Study Working Group. Incidence of endometriosis by study population and diagnostic

the ENDO study. Fertil Steril 2011; 96: 360 –365 [7] 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 [8] Simoens S, Hummelshoj L, D ʼHooghe T. Endometriosis: cost estimates and methodological perspective. Hum Reprod Update 2007; 13: 395 – 404 [9] Nnoaham KE, Hummelshoj L, Webster P et al.; World Endometriosis Re- search Foundation Global Study of Women ʼs Health consortium. Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 2011; 96: 366 –373.e8 [10] Simoens S, Dunselman G, Dirksen C et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in re- ferral centres. H um Reprod 2012; 27: 1292 –1299 [11] Soliman AM, Surrey E, Bonafede M et al. Real-World Evaluation of Direct and Indirect Economic Burden Among Endometriosis Patients in the United States. Adv Ther 2018; 35: 408 –423 [12] Ebert AD, Ulrich U, Keckstein J et al.; Endometriosis Research Founda- tion, and the European Endometriosis League. Implementation of certi- fied endometriosis centers: 5-year experience in German-speaking Eu- rope. Gynecol Obstet Invest 2013; 76: 4 –9 [13] Thiel FC, Scharl A, Hildebrandt T et al. Financing of certified centers: a willingness-to-pay analysis. Arch Gynecol Obstet 2013; 287: 495 –509 [14] Hudelist G, Fritzer N, Staettner S et al. Uterine sliding sign: a simple sonographic predictor for presence of deep infiltrating endometriosis of the rectum. Ultrasound Obstet Gynecol 2013; 41: 692 –695 [15] Exacoustos C, Manganaro L, Zupi E. Imaging for the evaluation of endo- metriosis and adenomyosis. Best Pract Res Clin Obstet Gynaecol 2014; 28: 655 –681 [16] Van den Bosch T, Dueholm M, Leone FP et al. Terms, definitions and measurements to desc ribe sonog raphic features of myometrium and uterine masses: a consensus opinion from the Morphological Uterus Sonographic Assessment (MUSA) group. Ultrasound Obstet Gynecol 2015; 46: 284 –298 [17] Bazot M, Lafont C, Rouzier R et al. Diagnostic accuracy of physical exami- nation, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometrio- sis. Fertil Steril 2009; 92: 1825 –1833 [18] Lermann J, Hackl J, Burghaus S et al. Die medikamentöse Therapie der Patientin mit Endometriose. Frauenheilkunde up2date 2017; 11: 27 –41 [19] Renner SP, Lermann J, Burghaus S et al. Die operative Therapie der Endo- metriose. Frauenheilkunde up2date 2016; 10: 311 –330 [20] Ulrich U, Buchweitz O, Greb R et al.; German and Austrian Societies for Obstetrics and Gynecology. National German Guideline (S2k): Guideline for the Diagnosis and Treatment of Endometriosis: Long Version – AWMF Registry No. 015-045. Geburtsh Frauenheilk 2014; 74: 1104 –1118 496 Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497 GebFra Science | Original Article [21] Abbott J, Hawe J, Hunter D et al. Laparoscopic excision of endometriosis: a randomized, placebo-controlled trial. Fertil Steril 2004; 82: 878 –884 [22] Deguara CS, Pepas L, Davis C. Does minimally invasive surgery for endo- metriosis improve pelvic symptoms and quality of life? Curr Opin Obstet Gynecol 2012; 24: 241 –244 [23] Jacobson TZ, Duffy JM, Barlow D et al. Laparoscopic surgery for subfertil- ity associated with endometriosis. Cochrane Database Syst Rev 2010; (1): CD001398 [24] Singh SS, Suen MW. Surgery for endometriosis: beyond medical thera- pies. Fertil Steril 2017; 107: 549 –554 [25] Barra F, Ferrero S. mTor Inhibitors for the Treatment of Endometriosis. Geburtsh Frauenheilk 2018; 78: 283 –284 [26] Kacan T, Yildiz C, Baloglu Kacan S et al. Everolimus as an mTOR Inhibitor Suppresses Endometriotic Implants: an Experimental Rat Study. Ge- burtsh Frauenheilk 2017; 77: 66 –72 [27] Petraglia F, Hornung D, Seitz C et al. Reduced pelvic pain in women with endometriosis: efficacy of long-term dienogest treatment. Arch Gynecol Obstet 2012; 285: 167 –173 [28] Oladosu FA, Tu FF, Hellman KM. Nonsteroidal antiinflammatory drug re- sistance in dysmenorrhea: epidemiology, causes, and treatment. Am J Obstet Gynecol 2018; 218: 390 –400 [29] Butrick CW. Chronic pelvic pain: how many surgeries are enough? Clin Obstet Gynecol 2007; 50: 412 –424 [30] Lovrincevic M. Chronic pelvic pain in women of childbearing age. Curr Opin Anaesthesiol 2003; 16: 275 –280 [31] Siedentopf F, Tariverdian N, Rücke M et al. Immune status, psychosocial distress and reduced quality of life in infertile patients with endometrio- sis. Am J Reprod Immunol 2008; 60: 449 –461 [32] Burghaus S, Fehm T, Fasching PA et al. The International Endometriosis Evaluation Program (IEEP Study) – A Systematic Study for Physicians, Re- searchers and Patients. Geburtsh Frauenheilk 2016; 76: 875 –881 [33] Dunselman GA, Vermeulen N, Becker C et al.; European Society of Hu- man Reproduction and Embryology. ESHRE guideline: management of women with endometrios is. Hum Reprod 2014; 29: 400 –412 [34] Johnson NP , Hummelshoj L. Consensus on current management of en- dometriosis. Hum Reprod 2013; 28: 1552 –1568 [35] Fauconnier A, Chapron C. Endometriosis and pelvic pain: epidemiologi- cal evidence of the relationship and implications. Hum Reprod Update 2005; 11: 595 –606 [36] Vercellini P, Giudice LC, Evers JL et al. Reducing low-value care in endo- metriosis between limited evidence and unresolved issues: a proposal. Hum Reprod 2015; 30: 1996 –2004 [37] Nnoaham KE, Hummelshoj L, Kennedy SH et al.; World Endometriosis Research Foundation Women ʼs Health Symptom Survey Consortium. Developing symptom-based predictive models of endometriosis as a clinical screening tool: results from a multicenter study. Fertil Steril 2012; 98: 692 –701.e5 [38] Vercellini P, Trespidi L, De Giorgi O et al. Endometriosis and pelvic pain: relation to disease stage and localization. Fertil Steril 1996; 65: 299 –304 [39] Renner SP, Boosz AS, Burghaus S et al. Visual pain mapping in endome- triosis. Arch Gynecol Obstet 2012; 286: 687 –693 [40] Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. Fertil Steril 20 14; 101: 927 –935 [41] Nisenblat V, Bossuyt PM, Farquhar C et al. Imaging modalities for the non-invasive diagnosis of endometr iosis. Cochrane Database Syst Rev 2016; (2): CD009591 [42] Janssen EB, Rijkers AC, Hoppenbrouwers K et al. Prevalence of endome- triosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review. Hum Reprod Update 2013; 19: 570– 582 [43] Shakiba K, Bena JF, McGill KM et al. Surgical treatment of endometriosis: a 7-year follow-up on the requirement for further surgery. Obstet Gyne- col 2008; 111: 1285 –1292 [44] Renner SP , Rix S, Boosz A et al. Preoperative pain and recurrence risk in patients with peritoneal endometriosis. Gynecol Endocrinol 2010; 26: 230–235 [45] Vercellini P, Somigliana E, Viganò P et al. The effect of second-line sur- gery on reproductive performance of women with recurrent endome- triosis: a systematic review. Acta Obstet Gynecol Scand 2009; 88: 1074–1082 [46] Zorbas KA, Economopoulos KP, Vlahos NF. Continuous versus cyclic oral contraceptives for the treatment of endometriosis: a systematic review. Arch Gynecol Obstet 2015; 292: 37 –43 497Burghaus S et al. Standards Used by … Geburtsh Frauenheilk 2019; 79: 487 –497