ESHRE子宫内膜异位症指南

2698 Published by Oxford University Press 2005 on behalf of the European Society of Human Reproduction and Embryology. Human Reproduction Vol.20, No.10 pp. 2698–2704, 2005 doi:10.1093/humrep/dei135 Advance Access publication June 24, 2005. ESHRE guideline for the diagnosis and treatment of endometriosis Stephen Kennedy1,10, Agneta Bergqvist2, Charles Chapron3, Thomas D’Hooghe4, Gerard Dunselman5, Robert Greb6, Lone Hummelshoj7, Andrew Prentice8 and Ertan Saridogan9 on behalf of the ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group* 1University of Oxford, Oxford, UK, 2Karolinska Institutet, Stockholm, Sweden, 3Clinique Universitaire Baudelocque, Paris, France, 4Leuven University, Leuven, Belgium, 5Maastricht University, Maastricht, The Netherlands, 6Muenster University Hospital, Muenster, Germany, 7Endometriose Foreningen, Denmark, 8University of Cambridge, Cambridge, UK and 9University College Hospital, London, UK 10To whom correspondence should be addressed at: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: Stephen.kennedy@obs-gyn.ox.ac.uk The objective was to develop recommendations for the diagnosis and treatment of endometriosis and its associated symptoms. A working group was convened comprised of practising gynaecologists and experts in evidence-based medicine from Europe, as well as an endometriosis self-help group representative. After reviewing existing evidence- based guidelines and systematic reviews, the expert panel met on three occasions for a day during which the guideline was developed and refined. Recommendations based solely on the clinical experience of the panel were avoided as much as possible. The entire ESHRE Special Interest Group for Endometriosis and Endometrium was given the opportunity to comment on the draft guideline, after which it was available for comment on the ESHRE website for 3 months. The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available at http://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant refer- ences and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the ‘gold standard’ investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparo- scopic uterine nerve ablation (LUNA) is necessary. In minimal–mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone. There is insufficient evidence available to determine whether surgical excision of mod- erate–severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endome- triosis than in those with tubal infertility. The management of severe/deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. Patient self-help groups can provide inval- uable counselling, support and advice. Key words: diagnosis/endometriosis/ESHRE guidelines/treatment *The manuscript was prepared by the first author; all other authors contrib- uted equally and are listed in alphabetical order. Guideline Development Group: Agneta Bergqvist, Karolinska Institutet, Stockholm (Chair), Charles Chapron, Clinique Universitaire Baudelocque, Paris (Working party), Gerard Dunselman, Maastricht University (Working party), Robert Greb, Muenster University Hospital (Working party), Thomas D’Hooghe, Leuven University (Vice-Chair), Lone Hummelshoj, Endometriose Foreningen, Denmark (Working party), Stephen Kennedy, University of Oxford (Report writer), Philippe Koninckx, Leuven University and University of Oxford (Contributor), Roberto Matorras, País Vasco University (Contributor), Michael Mueller, University of Berne (Contributor), Andrew Prentice, University of Cambridge (Working party), Ertan Saridogan, University College Hospital, London (Working party), Juan Garcia-Velasco, Instituto Valenciano de Infertilidad, Madrid (Contributor). by guest on M ay 22, 2012 http://hum rep.oxfordjournals.org/ D ow nloaded from Guideline for diagnosis and treatment of endometriosis 2699 Introduction Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic, inflam- matory reaction. The condition is predominantly found in women of reproductive age, from all ethnic and social groups. The associated symptoms can impact on general physical, mental and social well-being. Therefore, it is vital to take careful note of the woman’s complaints, and to give her time to express her concerns and anxieties as in other chronic diseases. Some women, however, have no symp- toms at all. Treatment must be individualized, taking the clinical problem in its entirety into account, including the impact of the disease and the effect of its treatment on quality of life. Pain symptoms may persist despite seemingly adequate medical and/or surgical treatment of the disease. In such circumstances, a multi-disciplinary approach involving a pain clinic and counselling should be considered early in the treatment plan. It is also important to involve the woman in all decisions; to be flexible in diagnostic and therapeutic thinking; to maintain a good relationship with the woman, and to seek advice where appropriate from more experienced colleagues or refer the woman to a centre with the necessary expertise to offer all available treatments in a multi-disciplinary context, including advanced laparoscopic surgery and laparotomy. Sources The guideline was commissioned by the ESHRE Special Interest Group (SIG) on Endometriosis and Endometrium, and developed by a working group. No systematic attempt was made to search the published literature independently of the following sources: • Clinical Evidence: the monthly, updated directory of evidence on the effects of clinical interventions, published by the BMJ Publishing Group (UK). http://www.clinicalevidence.com. • NICE Guideline on the assessment and treatment for people with fertility problems, produced by the National Institute for Clinical Evidence. • http://www.nice.org.uk/Docref.asp?d=106333. • Green Top Guideline on the investigation and management of endometriosis, produced by the Royal College of Obstetri- cians and Gynaecologists. http://www.rcog.org.uk/guidelines.asp?PageID=106& Guide- lineID. • Guideline on the diagnosis and treatment of endometrio- sis, produced by the Dutch Society of Obstetrics and Gynaecology. • http://www.nvog.nl/files/endometriose041026.pdf. • Consensus statement for the management of chronic pelvic pain and endometriosis, produced by a group of US gynaecologists. • http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd= Retrieve& db=PubMed&list_uids=12413979&dopt=Abstract. Recommendations The highest level of available evidence was used to form all the recommendations contained in this guideline. The evidence was graded using standard criteria shown in Table I. This scale, which was developed to apply to studies about the effectiveness of health-care interventions, is only a guide to the validity and relevance of evidence. Other questions may be more appropriately addressed by different study designs: for example, a question about the predictive power of an investiga- tion is best answered with observational data. Recommendations were based on, and linked to, the supporting evidence, or, where necessary, the informal consensus of the work- ing group. The strength of evidence corresponding to each level of recommendation is shown in Table II. Regarding diagnostic tests specifically, a recommendation based on the existence of a well-conducted systematic review was assessed as grade A. Localization and appearance of endometriosis The most commonly affected sites are the pelvic organs and peri- toneum, although other parts of the body such as the lungs are occasionally affected. The extent of the disease varies from a few, small lesions on otherwise normal pelvic organs to large, ovarian endometriotic cysts (endometriomas) and/or extensive fibrosis and adhesion formation causing marked distortion of pelvic anat- omy. Disease severity is assessed by simply describing the find- ings at surgery or quantitatively, using a classification system such as the one developed by the American Society for Repro- ductive Medicine (ASRM) (1997). There is no correlation between such systems and the type or severity of pain symptoms. Table I. Hierarchy of evidence Level Evidence 1a Systematic review and meta-analysis of randomized controlled trials (RCT) 1b At least one RCT 2a At least one well-designed controlled study without randomization 2b At least one other type of well-designed quasi-experimental study 3 Well-designed, non-experimental, descriptive studies, such as comparative studies, correlation studies or case studies 4 Expert committee reports or opinions and/or clinical experience of respected authorities Table II. Strength of evidence corresponding to each level of recommendation Grade Strength of evidence A Directly based on level 1 evidence B Directly based on level 2 evidence or extrapolated recommendation from level 1 evidence C Directly based on level 3 evidence or extrapolated recommendation from either level 1 or level 2 evidence D Directly based on level 4 evidence or extrapolated recommendation from either level 1, 2 or 3 evidence GPP Good practice point based upon the views of the Guideline Development Group by guest on M ay 22, 2012 http://hum rep.oxfordjournals.org/ D ow nloaded from S.Kennedy et al. 2700 Endometriosis typically appears as superficial ‘powder- burn’ or ‘gunshot’ lesions on the ovaries, serosal surfaces and peritoneum – black, dark-brown, or bluish puckered lesions, nodules or small cysts containing old haemorrhage surrounded by a variable extent of fibrosis. Atypical or ‘subtle’ lesions are also common, including red implants (petechial, vesicular, polypoid, haemorrhagic, red flame-like) and serous or clear vesicles. Other appearances include white plaques or scarring and yellow-brown peritoneal discoloration of the peritoneum. Endometriomas usually contain thick fluid like tar; such cysts are often densely adherent to the peritoneum of the ovar- ian fossa and the surrounding fibrosis may involve the tubes and bowel. Deeply infiltrating endometriotic nodules extend >5 mm beneath the peritoneum and may involve the uterosacral liga- ments, vagina, bowel, bladder or ureters. The depth of infiltra- tion is related to the type and severity of symptoms (Koninckx et al., 1991; Porpora et al., 1999; Chapron et al., 2003a). Symptoms Establishing the diagnosis of endometriosis on the basis of symptoms alone can be difficult because the presentation is so variable and there is considerable overlap with other conditions such as irritable bowel syndrome and pelvic inflammatory dis- ease. As a result there is often a delay of several years between symptom onset and a definitive diagnosis (Hadfield et al., 1996; Arruda et al., 2003; Husby et al., 2003). The following symptoms can be caused by endometriosis based on clinical and patient experience: severe dysmenor- rhoea; deep dyspareunia; chronic pelvic pain; ovulation pain; cyclical or perimenstrual symptoms (e.g. bowel or bladder associated) with or without abnormal bleeding; infertility; and chronic fatigue. However, the predictive value of any one symptom or set of symptoms remains uncertain as each of these symptoms can have other causes, and a significant proportion of affected women are asymptomatic. Clinical signs Finding pelvic tenderness, a fixed retroverted uterus, tender uterosacral ligaments or enlarged ovaries on examination is suggestive of endometriosis. The diagnosis is more certain if deeply infiltrating nodules are found on the uterosacral liga- ments or in the pouch of Douglas, and/or visible lesions are seen in the vagina or on the cervix. The findings may, how- ever, be normal. Diagnosis Histology Investigations Ultrasound Magnetic resonance imaging Blood tests Investigations to assess disease extent C Deeply infiltrating nodules are most reliably detected when clinical examination is performed during menstruation (Koninckx et al., 1996). Evidence level 3 C For a definitive diagnosis of endometriosis, visual inspection of the pelvis at laparoscopy is the ‘gold standard’ investigation, unless disease is visible in the vagina or elsewhere. Evidence level 3 GPP Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is present is controversial: visual inspection is usually adequate but histological confirmation of at least one lesion is ideal. In cases of ovarian endometrioma (>3 cm in diameter), and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy. GPP If the patient wants pain symptoms suggestive of endometriosis to be treated without a definitive diagnosis, then a therapeutic trial of a hormonal drug to reduce menstrual flow is appropriate (see ‘Empirical treatment’ section). GPP The management of severe/deeply infiltrating endometriosis is complex. Therefore, if disease of such severity is suspected or diagnosed, referral to a centre with the necessary expertise to offer all available treatments in a multi-disciplinary context, including advanced laparoscopic surgery and laparotomy, is strongly recommended. A Compared to laparoscopy, transvaginal ultrasound (TVS) has no value in diagnosing peritoneal endometriosis, but it is a useful tool both to make and to exclude the diagnosis of an ovarian endometrioma (Moore et al., 2002). TVS may have a role in the diagnosis of disease involving the bladder or rectum. Systematic review of diagnostic tests A Compared to laparoscopy, magnetic resonance imaging (MRI) has limited value as a diagnostic tool for endometriosis (Ang et al., submitted). Systematic review of diagnostic tests A Serum CA-125 levels may be elevated in endometriosis. However, compared to laparoscopy, measuring serum CA-125 levels has no value as a diagnostic tool (Mol et al., 1998). Systematic review of diagnostic tests GPP If there is clinical evidence of deeply infiltrating endometriosis, ureteral, bladder and bowel involvement should be assessed. Consideration should be given to performing MRI or ultrasound (transrectal and/or transvaginal and/or renal), with or without intravesical pressure (IVP) and barium enema studies depending upon the individual circumstances, to map the extent of disease present, which may be multi-focal. by guest on M ay 22, 2012 http://hum rep.oxfordjournals.org/ D ow nloaded from Guideline for diagnosis and treatment of endometriosis 2701 Assessment of ovarian cysts Laparoscopy Empirical treatment of pain symptoms without a definitive diagnosis Treatment of endometriosis-associated pain in confirmed disease Non-steroidal anti-inflammatory drugs It is important to note that NSAIDs have significant side- effects, including gastric ulceration and an anti-ovulatory effect when taken at mid-cycle. Other analgesics may be effective but there is insufficient evidence to make recommendations. Hormonal treatment The levonorgestrel intrauterine system (LNG-IUS) may be effective at reducing endometriosis-associated pain (Vercellini et al., 1999a), but there is insufficient evidence to make recom- mendations. Duration of GnRH agonist treatment Surgical treatment There are no data to justify hormonal treatment prior to surgery to improve the success of surgery (Muzii et al., 1996). There are no data supporting the use of uterine suspension but, in certain cases, there may be a role for pre-sacral neurec- tomy (Soysal et al., 2003). GPP Local guidelines for the management of suspected ovarian malignancy should be followed in cases of ovarian endometrioma. Ultrasound scanning ± serum CA-125 testing is usually used to try to identify rare instances of ovarian cancer; however, CA-125 levels can be elevated in the presence of endometriomas. GPP Good surgical practice is to document in detail the type, location and extent of all lesions and adhesions in the operative notes; ideal practice is to record the findings on video or DVD. GPP There is insufficient evidence to justify timing the laparoscopy at a specific time in the menstrual cycle, but it should not be performed during or within 3 months of hormonal treatment so as to avoid under-diagnosis. C All classification systems for endometriosis are subjective and correlate poorly with pain symptoms, but may be of value in infertility prognosis and management (Chapron et al., 2003b; D’Hooghe et al., 2003). Evidence level 3 C At laparoscopy, deeply infiltrating endometriosis may have the appearance of minimal disease, resulting in an underestimation of disease severity (Koninckx et al., 1994). Evidence level 3 GPP Empirical treatment for pain symptoms presumed to be due to endometriosis without a definitive diagnosis includes counselling, adequate analgesia, nutritional therapy, progestagens or the combined oral contraceptive (COC). It is unclear whether the COC should be taken conventionally, continuously or in a tricycle regimen. A GnRH agonist may be taken but this class of drug is more expensive, and associated with more side-effects and concerns about bone density. A Non-steroidal anti-inflammatory drugs (NSAID) may be effective in reducing endometriosis-associated pain (Kauppila et al., 1979; Ylikorkala and Viinikka, 1983; Kauppila and Ronnberg, 1985). Evidence level 1b A Suppression of ovarian function for 6 months reduces endometriosis-associated pain. The hormonal drugs investigated—COC, danazol, gestrinone, medroxyprogesterone acetate and GnRH agonists—are equally effective but their side-effects and cost profiles differ (Moore et al., 2004; Prentice et al., 2004a,b; Selak et al., 2004). Evidence level 1a A Treatment for 3 months with a GnRH agonist may be as effective as 6 months in terms of pain relief (Hornstein et al., 1995). Treatment for up to 2 years with combined estrogen progestagen ‘add-back’ appears to be effective and safe in terms of pain relief and bone density protection (Surrey and Hornstein, 2002). However, careful consideration should be given to the use of GnRH agonists in women who may not have reached their maximum bone density. Evidence level 1b GPP Depending upon the severity of disease found, ideal practice is to diagnose and remove endometriosis surgically at the same time, provided that pre-operative adequate consent has been obtained (Redwine and Wright, 2001; Abbott et al., 2003; Chapron et al., 2003b; Fed