Hum. Reprod. Advance Access originally published online on June 24, 2005
Human Reproduction 2005 20(10):2698-2704; doi:10.1093/humrep/dei135
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ESHRE PAGE |
ESHRE guideline for the diagnosis and treatment of endometriosis
1 University of Oxford, Oxford, UK, 2 Karolinska Institutet, Stockholm, Sweden, 3 Clinique Universitaire Baudelocque, Paris, France, 4 Leuven University, Leuven, Belgium, 5 Maastricht University, Maastricht, The Netherlands, 6 Muenster University Hospital, Muenster, Germany, 7 Endometriose Foreningen, Denmark, 8 University of Cambridge, Cambridge, UK and 9 University College Hospital, London, UK
10 To whom correspondence should be addressed at: Nuffield Department of Obstetrics and Gynaecology, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK. E-mail: skennedy{at}molbiol.ox.ac.uk
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Abstract |
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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 references 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 laparoscopic 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 moderate–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 endometriosis 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 invaluable counselling, support and advice.
Key words: diagnosis/endometriosis/ESHRE guidelines/treatment
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Introduction |
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Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic, inflammatory 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 symptoms 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.
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Sources |
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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 Obstetricians and Gynaecologists.
- http://www.rcog.org.uk/guidelines.asp?PageID=106& GuidelineID.
- Guideline on the diagnosis and treatment of endometriosis, 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.
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Recommendations |
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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.
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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 investigation is best answered with observational data.
Recommendations were based on, and linked to, the supporting evidence, or, where necessary, the informal consensus of the working 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.
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Localization and appearance of endometriosis |
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 TopAbstractIntroductionSourcesRecommendations Localization and appearance of... SymptomsClinical signsDiagnosisAssisted reproduction in...IVFCoping with disease...Patient support groupsReferences |
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The most commonly affected sites are the pelvic organs and peritoneum, 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 anatomy. Disease severity is assessed by simply describing the findings at surgery or quantitatively, using a classification system such as the one developed by the American Society for Reproductive Medicine (ASRM) (1997)
. There is no correlation between such systems and the type or severity of pain symptoms. 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 ovarian 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 ligaments, vagina, bowel, bladder or ureters. The depth of infiltration is related to the type and severity of symptoms (Koninckx et al., 1991; Porpora et al., 1999; Chapron et al., 2003a).
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Symptoms |
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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 disease. 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 dysmenorrhoea; 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.
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Clinical signs |
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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 ligaments or in the pouch of Douglas, and/or visible lesions are seen in the vagina or on the cervix. The findings may, however, be normal.
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Diagnosis |
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Histology
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Investigations
Ultrasound
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Magnetic resonance imaging
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Blood tests
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Investigations to assess disease extent
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Assessment of ovarian cysts
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Laparoscopy
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Empirical treatment of pain symptoms without a definitive diagnosis
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Treatment of endometriosis-associated pain in confirmed disease
Non-steroidal anti-inflammatory drugs
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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.
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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 recommendations.
Duration of GnRH agonist treatment
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Surgical treatment
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There are no data to justify hormonal treatment prior to surgery to improve the success of surgery (Muzii et al., 1996
).
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There are no data supporting the use of uterine suspension but, in certain cases, there may be a role for pre-sacral neurectomy (Soysal et al., 2003
).
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Post-operative treatment
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Hormone replacement therapy
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Treatment of endometriosis-associated infertility in confirmed disease
Treatment of endometriotic lesions
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The recommendation above is based upon a systematic review and meta-analysis of two, similar but contradictory RCTs comparing laparoscopic surgery (± adhesiolysis) with diagnostic laparoscopy alone. Nevertheless, some members of the working group questioned the strength of the evidence because: (i) small numbers were treated in one of the studies (Parazzini, 1999
); (ii) although in the other, larger study (Marcoux et al., 1997) there was a significantly higher monthly fecundity rate in the treated compared to the control group, patients were apparently not blinded to whether they were treated or not.
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Assisted reproduction in endometriosis Intrauterine insemination |
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IVF |
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The recommendation above is based on a systematic review but the working group noted that endometriosis does not adversely affect pregnancy rates in some large databases (e.g. SART and HFEA) (Templeton et al., 1996
).
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Coping with disease Complementary therapies |
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Patient support groups |
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Notes |
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* The manuscript was prepared by the first author; all other authors contributed 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).
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P. Vercellini, E. Somigliana, P. Vigano, A. Abbiati, G. Barbara, and P. G. Crosignani Surgery for endometriosis-associated infertility: a pragmatic approach Hum. Reprod., February 1, 2009; 24(2): 254 - 269. [Abstract] [Full Text] [PDF]
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 D. de Ziegler, B. Borghese, C. Chapron, and D. L. Olive Gonadotropin-Releasing Hormone Agonists for Endometriosis N. Engl. J. Med., December 25, 2008; 359(26): 2844 - 2845. [Full Text] [PDF]
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M. Creus, F. Fabregues, F. Carmona, M. del Pino, D. Manau, and J. Balasch Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility: a preliminary trial Hum. Reprod., August 1, 2008; 23(8): 1910 - 1916. [Abstract] [Full Text] [PDF]
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J.E. den Hartog, C.M.J.G. Lardenoije, J.L. Severens, J.A. Land, J.L.H. Evers, and A.G.H. Kessels Screening strategies for tubal factor subfertility Hum. Reprod., August 1, 2008; 23(8): 1840 - 1848. [Abstract] [Full Text] [PDF]
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A. Van Langendonckt, J. Donnez, S. Defrere, G. A.J. Dunselman, and P. G. Groothuis Antiangiogenic and vascular-disrupting agents in endometriosis: pitfalls and promises Mol. Hum. Reprod., May 1, 2008; 14(5): 259 - 268. [Abstract] [Full Text] [PDF]
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J.R.A. Sherwin, A.M. Sharkey, A. Mihalyi, P. Simsa, R.D. Catalano, and T.M. D'Hooghe Global gene analysis of late secretory phase, eutopic endometrium does not provide the basis for a minimally invasive test of endometriosis Hum. Reprod., May 1, 2008; 23(5): 1063 - 1068. [Abstract] [Full Text] [PDF]
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A. Melin, P. Sparen, and A. Bergqvist The risk of cancer and the role of parity among women with endometriosis Hum. Reprod., November 1, 2007; 22(11): 3021 - 3026. [Abstract] [Full Text] [PDF]
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C.A. Petta, M.S. Arruda, D.E. Zantut-Wittmann, and C.L. Benetti-Pinto Thyroid autoimmunity and thyroid dysfunction in women with endometriosis Hum. Reprod., October 1, 2007; 22(10): 2693 - 2697. [Abstract] [Full Text] [PDF]
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H. C. Bohler, C. Gercel-Taylor, B. A. Lessey, and D. D. Taylor Endometriosis Markers: Immunologic Alterations as Diagnostic Indicators for Endometriosis Reproductive Sciences, September 1, 2007; 14(6): 595 - 604. [Abstract] [PDF]
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J. Bosteels, B. Van Herendael, S. Weyers, and T. D'Hooghe The position of diagnostic laparoscopy in current fertility practice Hum. Reprod. Update, September 1, 2007; 13(5): 477 - 485. [Abstract] [Full Text] [PDF]
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F. Wieser, M. Cohen, A. Gaeddert, J. Yu, C. Burks-Wicks, S. L. Berga, and R. N. Taylor Evolution of medical treatment for endometriosis: back to the roots? Hum. Reprod. Update, September 1, 2007; 13(5): 487 - 499. [Abstract] [Full Text] [PDF]
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S. Simoens, L. Hummelshoj, and T. D'Hooghe Endometriosis: cost estimates and methodological perspective Hum. Reprod. Update, July 1, 2007; 13(4): 395 - 404. [Abstract] [Full Text] [PDF]
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R. Gonzalez-Ramos, J. Donnez, S. Defrere, I. Leclercq, J. Squifflet, J.-C. Lousse, and A. Van Langendonckt Nuclear factor-kappa B is constitutively activated in peritoneal endometriosis Mol. Hum. Reprod., July 1, 2007; 13(7): 503 - 509. [Abstract] [Full Text] [PDF]
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M. Oktem, I. Esinler, D. Eroglu, N. Haberal, N. Bayraktar, and H. B. Zeyneloglu High-dose atorvastatin causes regression of endometriotic implants: a rat model Hum. Reprod., May 1, 2007; 22(5): 1474 - 1480. [Abstract] [Full Text] [PDF]
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S. Matsuzaki, M. Canis, J.-L. Pouly, R. Botchorishvili, P.J. Dechelotte, and G. Mage Both GnRH agonist and continuous oral progestin treatments reduce the expression of the tyrosine kinase receptor B and mu-opioid receptor in deep infiltrating endometriosis Hum. Reprod., January 1, 2007; 22(1): 124 - 128. [Abstract] [Full Text] [PDF]
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T. D'Hooghe and L. Hummelshoj Multi-disciplinary centres/networks of excellence for endometriosis management and research: a proposal Hum. Reprod., November 1, 2006; 21(11): 2743 - 2748. [Abstract] [Full Text] [PDF]
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E.C. Haagen, R.P.M.G. Hermens, W.L.D.M. Nelen, D.D.M. Braat, R.P.T.M. Grol, and J.A.M. Kremer Subfertility guidelines in Europe: the quantity and quality of intrauterine insemination guidelines Hum. Reprod., August 1, 2006; 21(8): 2103 - 2109. [Abstract] [Full Text] [PDF]
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K. Koga, Y. Takemura, Y. Osuga, O. Yoshino, Y. Hirota, T. Hirata, C. Morimoto, M. Harada, T. Yano, and Y. Taketani Recurrence of ovarian endometrioma after laparoscopic excision Hum. Reprod., August 1, 2006; 21(8): 2171 - 2174. [Abstract] [Full Text] [PDF]
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P. Crosignani, D. Olive, A. Bergqvist, and A. Luciano Advances in the management of endometriosis: an update for clinicians Hum. Reprod. Update, March 1, 2006; 12(2): 179 - 189. [Abstract] [Full Text] [PDF]
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