1. ESHRE GUIDELINE for the diagnosis and management of endometriosis
Thomas M. D’Hooghe, M.D., Ph.D.
ESHRE SIG Endometriosis and Endometrium
Leuven (Belgium)
Postgraduate Course VWRG Leuven,
4th June 2010

2. LEARNING OBJECTIVES At the conclusion of this presentation,
participants should be able to:
1. Summarize the development, updating and level of evidence associated with clinical guidelines in general
2. Apply the ESHRE guidelines for clinical management of endometriosis in their own clinical practice
3. Explain why many clinical issues with respect to endometriosis management are still unresolved and require more and better research.
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3. Guideline Development Group
Gerard Dunselmann Maastricht University (NL) Chair
Working party
Andrew Prentice University of Cambridge (UK) Chair Working party
Charles Chapron Clinique Universitaire Baudelocque (F) Working party
Robert Greb Münster University Hospital (D) Working party
Thomas D’Hooghe Leuven University Hospital (B) Working party
Daniela Hornung UFK Lübeck (G) Working party
Lone Hummelshoj European Endometriosis Alliance (DK) Working party
Stephen Kennedy University of Oxford (UK) Working party
Ariel Revel University of Jerusalem (IS) Working party
Ertan Saridogan University College London (UK) Working party
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4. Recommendation: hierarchy of evidence
Level
Evidence 1a
Systematic review and meta-analysis of randomized controlled trials (RCTs) 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
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5. Recommendation: strength of evidence
Grade
Strength of evidence corresponding to each level of recommendation A
Requires at least one randomized controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation. (Evidence levels 1a, 1b) B
Requires the availability of well controlled clinical studies but no randomized clinical trials on the topic of recommendations. (Evidence levels 2a, 2b, 3) C
Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level 4)
GPP
Recommended best practice based on the clinical experience of the guideline development group
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6. Localization and appearance
Pelvic organs and peritoneum
Minimal to severe (ASRM classification 1996, FS 1997)
Presentation: peritoneal, ovarian, deep
Peritoneal: typical/subtle (red, white, clear)
Ovarian endometriotic cyst/endometrioma
Deeply infiltrative endo (DIE): > 5 mm
Adhesions  frozen pelvis
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7. Symptoms Variable presentation/often asymptomatic
Overlap with other conditions causing pain (IBS, PID, ..)
Delay between onset of symptoms and definitive diagnosis up to 12 years
Typical: severe dysmenorrhea, deep dyspareunia, CPP, cyclical pain associated with bowel or bladder
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8. Clinical signs Deeply infiltrating nodules are most reliably
detected when clinical examination is performed during menstruation (Koninckx et al., 1996).
Evidence
Level 3 C
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9. Diagnosis
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 C
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10. Diagnosis - histology
Positive histology confirms the diagnosis of endometriosis; negative histology does not exclude it. Whether histology should be obtained if peritoneal disease alone is at present controversial
Visual inspection is usually adequate but histological confirmation of at least one lesion is ideal.
In cases of ovarian endometrioma (>4 cm in diameter), and in deeply infiltrating disease, histology should be obtained to identify endometriosis and to exclude rare instances of malignancy.
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11. Diagnosis - histology
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).
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The management of severe/deeply infiltrating endometriosis is complex. Therefore, if disease of such severity is suspected or diagnosed, referral to a center with the necessary expertise to offer all available treatments in a multidisciplinary context, including advanced laparoscopic surgery and laparotomy, is strongly recommended.
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12. Investigations: ultrasound
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
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13. Investigations: MRI
At present, there is insufficient evidence to indicate that MRI is a useful test to diagnose or exclude endometriosis compared to laparoscopy.
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14. Investigations: blood tests
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 A
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15. Investigations – disease extent
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 intravenous pyelogram (IVP) and barium enema studies depending upon the individual circumstances, to map the extent of disease present, which may be multifocal.
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16. Assessment of ovarian cysts
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.
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17. Diagnosis - laparoscopy
Good surgical practice is to use an instrument such as a grasper, via a secondary port, to mobilize the pelvic organs and to palpate lesions which can help determine their nodularity.
It is also important 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.
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18. Diagnosis - laparoscopy
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 C
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19. PAIN – empirical w/o diagnosis
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.
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20. PAIN (confirmed disease) -NSAIDs
Non-steroidal anti inflammatory drugs (NSAIDs) may be effective in reducing endometriosis-associated pain (Kauppila et al, 1979; Kauppila et al, 1985; Ylikorkala et al, 1983)
Evidence
Level 1b A
It is important to note that NSAIDs have significant side effects, including gastric ulceration and an anti-ovulatory effect when taken mid-cycle. Other analgesics may be effective but there is insufficient evidence to make recommendations.
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21. PAIN -hormonal Tx
Suppression of ovarian function for 6 months reduces endometriosis-associated pain. The hormonal drugs investigated - COCs, Danazol, gestrinone, medroxyprogesterone acetate and GnRH agonists - are equally effective but their side-effect and cost profiles differ (Moore et al, 2004; Prentice et al, 2004a; Prentice et al, 2004b; Selak et al, 2004; Farquar et al, 2004).
Evidence
Level 1a A
There are pilot data suggesting that the aromatase inhibitor, letrozole, may be effective, though there are concerns about bone density loss (Ailawadi et al, 2004).
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22. PAIN– duration of GnRH-a Tx
Treatment for 3 months with a GnRH agonist may be as effective as 6 months in terms of pain relief (Hornstein et al., 1995).
Evidence
Level 1b A
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 1a A
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23. PAIN – hormonal Treatment
The levonorgestrel intrauterine device (LNG IUS) may be effective in reducing endometriosis-associated pain (Vercellini et al, 1999) but there is insufficient evidence to make recommendations.
Statement in publication adapted in 2006
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24. PAIN – hormonal treatment
The levonorgestrel intrauterine system (LNG IUS) reduces endometriosis-associated pain.
Evidence
Level 1a A
A systematic review identified two RCTs and three observational studies, all involving small numbers and a heterogeneous group of patients (Varma R et al, 2005). Nevertheless the evidence suggests that the LNG IUS reduces endometriosis-associated pain (Vercellini et al, 1999; Petta et al, 2005) with symptom control maintained over three years (Lockhat et al, 2005; Lockhat et al, 2004).
Statement in revised guidelines 2006
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25. PAIN – HRT
HRT is recommended after bilateral oophorectomy in young women given the overall health benefits and small risk of recurrent disease while taking HRT (Matorras et al, 2002).
The ideal regimen is unclear: adding a progestagen after hysterectomy is unnecessary but should protect against the unopposed action of estrogen on any residual disease. However, possible advantages of HRT should be balanced against increased risk of breast cancer!
Evidence
Level 4 C
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26. PAIN – surgical treatment
Ablation of endometriotic lesions plus laparoscopic uterine nerve ablation (LUNA) in minimal-moderate disease reduces endometriosis-associated pain at 6 months compared to diagnostic laparoscopy; the smallest effect is seen in patients with minimal disease (Jacobson et al, 2004a). However, there is no evidence that LUNA is a necessary component (Sutton et al, 2001), and LUNA by itself has no effect on dysmenorrhea associated with endometriosis (Vercellini et al, 2003).
Evidence
Level 1b A
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27. PAIN – surgical treatment
Pre-operative treatment
Although hormonal therapy prior to surgery improves rAFS scores, there is insufficient evidence of any effect on outcome measures such as pain relief (Yap et al, 2004).
Evidence
Level 1a A
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28. PAIN – surgical treatment
Post-operative treatment
Compared to surgery alone or surgery plus placebo, post-operative hormonal treatment does not produce a significant reduction in pain recurrence at 12 or 24 months, and has no effect on disease recurrence
(Yap et al, 2004).
Evidence
Level 1a A
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29. INFERTILITY – hormonal treatment
Suppression of ovarian function to improve fertility in minimal-mild endometriosis is not effective and should not be offered for this indication alone (Hughes et al, 2004). The published evidence does not comment on more severe disease.
Evidence
Level 1a A
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30. INFERTILITY – surgical treatment
Ablation of endometriotic lesions plus adhesiolysis to improve fertility in minimal-mild endometriosis is effective compared to diagnostic laparoscopy alone
(Jacobson et al, 2004b).
Evidence
Level 1a A
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31. INFERTILITY – surgical treatment
No RCT or meta-analyses are available to answer the question of whether surgical excision of moderate–severe endometriosis enhances pregnancy rates. Based upon three studies (Adamson et al., 1993; Guzick et al., 1997; Osuga et al., 2002) there seems to be a negative correlation between the stage of endometriosis and the spontaneous cumulative pregnancy rate after surgical removal of endometriosis, but statistical significance was only reached in one study (Osuga et al., 2002).
Evidence
Level 3 B
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32. INFERTILITY – surgical treatment
Laparoscopic cystectomy for ovarian endometriomas > 4 cm diameter improves fertility compared to drainage and coagulation (Chapron et al, 2002; Beretta et al, 1998).
Coagulation or laser vaporization of endometriomas without excision of the pseudocapsule is associated with a significantly increased risk of cyst recurrence (Vercellini et al, 2003; Hart et al, 2005)
Evidence
Level 1b A
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33. INFERTILITY – surgical treatment
Post-operative treatment
Compared to surgery alone or surgery plus placebo, post-operative hormonal treatment has no effect on pregnancy rates
(Yap, et al, 2004).
Evidence
Level 1a A
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34. INFERTILITY – ART: IUI
Treatment with intrauterine insemination (IUI) improves fertility in minimal–mild endometriosis.
IUI with ovarian stimulation is effective but the role of unstimulated IUI is uncertain (Tummon et al., 1997).
Evidence
Level 1b A
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35. INFERTILITY – ART: IVF
IVF is appropriate treatment especially if tubal function is compromised, if there is also male factor infertility, and/or other treatments have failed.
Evidence
Level 2b B
IVF pregnancy rates are lower in patients with endometriosis than in those with tubal infertility (Barnhart et al, 2002; Templeton A et al, 1996).
Evidence
Level 1a A
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)
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36. INFERTILITY – ART: COH for IVF
COH for IVF/ICSI is equally effective with both GnRH-a and GnRH antagonist protocols in terms of implantation and clinical pregnancy rates, but COH with GnRHa may be preferred because of the availability of more MII oocytes and embryos (Pabuccu et al, 2007).
Evidence
Level 1b B
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37. IVF and recurrence risk of endo
INFERTILITY – ART:
IVF and recurrence risk of endo
Risk for recurrence is no reason to withhold IVF therapy after surgery for endometriosis stage III or IV since cumulative endometriosis recurrence rates are not increased after ovarian hyperstimulation for IVF (D’Hooghe et al, 2006)
Evidence
Level 2a B
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38. INFERTILITY – ART: IVF
Laparoscopic ovarian cystectomy in patients with unilateral endometriomas between
3 and 6 cm in diameter before IVF/ICSI
can decrease ovarian response
without improving cycle outcome
(Demirol et al, 2006).
Evidence
Level 1b A
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39. INFERTILITY – ART: IVF
Treatment with a GnRH agonist for 3-6 months before IVF or ICSI should be considered in women with endometriosis as it increases the odds of clinical pregnancy fourfold. However, the authors of the Cochrane review stressed that the recommendation is based on only one properly randomized study and called for further research, particularly on the mechanism of action (Sallam, Garcia-Velasco et al., 2006).
Evidence
Level 1b A
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40. INFERTILITY – ART: IVF
Laparoscopic ovarian cystectomy can be considered if ovarian endometrioma ≥4 cm in diameter is present
-to confirm the diagnosis histologically
-to reduce the risk of infection
-to improve access to follicles
-to possibly improve ovarian response.
Counselling needed: risks of reduced ovarian function after surgery and the loss of the ovary.
The decision should be reconsidered if she has had previous ovarian surgery.
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41. EXTRAGENITAL ENDOMETRIOSIS
Appendicular endometriosis: appendectomy
Surgical treatment of bladder endometriosis: lesion excision + primary closure bladder.
Ureteral lesions: excision after ureteral stenting; if intrinsic lesions or significant obstruction: segmental excision with end-to-end anastomosis or reimplantation possibly necessary
Abdominal wall and perineal endometriosis: complete excision of nodule
Evidence
Level 3 B
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42. Adolescents: Laparoscopic evaluation of chronic pelvic pain
Laparoscopy should be considered in adolescents with CPP who do not respond to medical treatment (NSAIDs, OCPs) since endometriosis is very common under these circumstances.
(Goldstein et al, 1980; Vercellini et al, 1989; Reese et al, 1996; Laufer et al, 1997; Emmert et al, 1998; Hassan et al, 1999; Kontoravdis et al, 1999; Shin et al, 2005; Stavroulis et al, 2006)
Evidence
Level 3 B
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43. Adolescents: Laparoscopic Extent and appearance of endo
Minimal to mild endometriosis (rASRM classification) are the most common stages of disease in adolescents. Gynecologic surgeons should pay special attention to red, clear or white lesions which were reported to be more prevalent in adolescents as opposed to adults who have endometriosis.
(Goldstein et al, 1980; Vercellini et al, 1989; Davis et al, 1993; Reese et al, 1996; Laufer et al, 1997; Emmert et al, 1998; Hassan et al, 1999; Bai et al, 2002; Marsh and Laufer, 2005)
Evidence
Level 3 B
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44. Obstructive genital anomalies
Adolescents:
Obstructive genital anomalies
Menstrual flow obstruction such as Mullerian anomalies may cause early development of endometriosis in adolescents. Regression of the disease has been observed once surgical correction of the anomaly has been accomplished (Sanfilippo et al, 1986; Ugur et al, 1995; Hur et al, 2007).
Evidence
Level 3 B
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45. Coping with disease
There is evidence from two systematic reviews suggesting that high-frequency TENS, acupuncture, vitamin B1 and magnesium may help to relieve dysmenorrhea (Proctor and Murphy 2004; Proctor et al, 2004). One RCT has shown that vitamin E may relieve primary dysmenorrhea and reduce blood loss (Ziaei et al, 2005).
Whether such treatments are effective for endometriosis associated dysmenorroea and heavy bleeding is unknown.
Evidence
Level 4 C
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46. Coping with disease
Many women with endometriosis report that nutritional and complementary therapies such as homeopathy, reflexology, traditional Chinese medicine, herbal treatments, etc, do improve pain symptoms. While there is no evidence from RCTs in endometriosis to support these treatments, they should not be ruled out if the woman feels that they could be beneficial to her overall pain management and/or quality of life, or work in conjunction with more traditional therapies.
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Patient self-help groups can provide invaluable counselling, support and advice. The website provides a comprehensive list of all the self-help groups in the world.
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52. ESHRE guideline: user-friendly
Concise evidence based recommendations
Documentation of supporting recommendations
Full reference link
References linked to PubMed
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53. ESHRE guideline It is important to:
Maintain a good relationship with the woman
Involve the woman in all decisions
Be flexible in diagnostic and therapeutic thinking
Kennedy et al, Human Reprod 2005
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54. ESHRE guideline
"Treatment must be individualised, 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"
Kennedy et al, Human Reprod 2005
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55. ESHRE guideline "Patient self-help groups can provide invaluable
counselling, support and advice."
Kennedy et al, Human Reprod 2005
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56. ESHRE guideline: THE FUTURE
Clinicians will use or adapt it for local use
National organizations may adopt it
Dutch Society for Obstetrics and Gynaecology
Royal College for Obstetrics and Gynaecology
Japanese and Spanish translations (Turkish)
Brazil
Argentina
Consolidation of feedback from users
Regular ongoing review and modification
Annual (June ratification --> review --> October implementation)
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57. ESHRE Endo Guideline Status 2009
ESHRE Endometriosis Guideline rated as
BEST ESHRE Guideline based on objective criteria
(Human Reproduction, 2009)
: review of guideline
- eGLIA assessment of guideline quality
Guideline course for GDG members 4/2009
In collaboration with ESHRE SIG Quality in Repro Med
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