2010 Annual Evidence Update on Endometriosis PDF Version

7/30/2019 2010 Annual Evidence Update on Endometriosis PDF Version

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NHS Evidence womens health

Endometriosis

Annual Evidence Update

March 2010

H Wills, C Demetriou, K May, S Kennedy, S Kirtley & S Hogg

Nuffield Department of Obstetrics and Gynaecology, University of Oxford.


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Contents

1. Introduction 3

2. Search methodology 4

3. Epidemiology and aetiology of endometriosis 5

4. The pathological characteristics of endometriosis 7

5. The clinical features and diagnosis of endometriosis 8

6. Non-surgical management of endometriosis-associated pain 11

7. Surgical management of endometriosis-associated pain 16

8. Management of endometriosis-associated subfertility 21

9. Resources 24


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1. Introduction

Stephen Kennedy, Clinical Reader/Head of Department, Nuffield Department of Obstetrics

& Gynaecology, University of Oxford, who is trustee of the World Endometriosis Research

Foundation.

This is the fourth Endometriosis Annual Evidence Update.

The purpose of the last Evidence Update in March 2009 was to summarise and update the

information contained in the guidelines produced by the Royal College of Obstetricians &

Gynaecologists in 2006 and the European Society for Human Reproduction & Embryology

(ESHRE) in 2005.

We have continued the same approach in the 2010 update. We provide a summary of the

ESHRE guideline (updated in 2008) to the investigation and management of endometriosis,

alongside our own search of data from high quality studies published in the last year. References

relating to new, clinically relevant studies are provided in the text.

We hope that, in time, this site will become the single portal for all health care professionals and

women with endometriosis who require high quality information as an aid to clinical decision-

making. We also hope that the information provided will improve standards of care throughout

the UK.

Lastly, it is important to mention that endometriosis was chosen as one of the first topics for the

Database of Uncertainties about the Effects of Treatments (DUETS). This on-line resource gives

priority to identifying and publishing unanswered questions about the effects of treatments which

have been asked by patients and clinicians, whilst noting therapeutic uncertainties identified

through systematic reviews, clinical guidelines, and other formal mechanisms. Uncertainties that

we have identified during our 2010 evidence update can be found listed in the DUETs page of

this AEU.


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2. Search methodology

The aim of the literature search for the 2010 annual evidence update was to update the search

carried out in 2009. Search strategies from the RCOG guideline and the ESHRE guideline were

again replicated and the databases searched included the Cochrane Database of Systematic

Reviews, Pubmed, OVID Embase and EBSCOHost CINAHL. Systematic reviews, meta-

analyses and randomised controlled trials (RCTs) were specifically targeted, using a combination

of the Pubmed Systematic Review 2 or more terms minimum difference filter, Pubmed RCT

CRD/Cochrane Highly Sensitive filter, Embase OVID Systematic Review SIGN Filter, Embase

OVID RCT SIGN Filter, CINAHL Systematic Review SIGN Filter and the CINAHL RCT SIGN

Filter. The search terms used included endometriosis; endometriomas; endometriosis/diagnosis;

endometriosis/drug therapy; endometriosis/complications; endometriosis/surgery and these were

combined with the limits English in language and restricted to March 2009 until

January/February 2010.

The abstracts of the identified papers were manually inspected to determine their relevance and

appropriateness for inclusion in this document. Articles included were good systematic reviews

and RCTs, and less robust studies where they were considered to illustrate a point of controversy

or indicate a possible future direction for the management of the condition. When a paper was to

be included, or where doubt existed over the appropriateness of the data, the full-text was

obtained.

The following summary document is based on the existing guidelines, which have been updated

where new evidence has become available. These data are cited. Readers are referred to the

RCOG guideline for the citation details of the older studies.


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3. Epidemiology and aetiology of endometriosis

It is difficult to define the epidemiology of endometriosis precisely because a surgical procedure

is required to make the diagnosis definitively. However, the following are best estimates:

Endometriosis affects 10-15% of all women in the reproductive years.

The incidence is 40-60% in women with dysmenorrhoea and 20-30% in those with subfertility.

Risk factors include a heavy menstrual load (due to short cycle length and long duration of

flow).

Current/recent use of the combined oral contraceptive (COC), smoking and exercise may be

protective.

The sisters and daughters of affected women are 6-9 times more likely to develop

endometriosis than women in the general population. A recent systematic review has analysed

the potential genetic associations with endometriosis. However, no firm conclusions could be

drawn. A large number of studies have considered putative genetic markers, and these may be

of future benefit in assessing the risk of disease development, or in understanding disease

pathogenesis (Montgomery et al., 2008).

Endometriosis is a considerable burden in terms of both direct and indirect healthcare costs,

and its affect on quality of life (Gao et. al., 2006).

A number of hypotheses have been proposed to explain the aetiology of endometriosis. The most

dominant theory is retrograde menstruation (the passage of viable endometrial cells along the

fallopian tubes into the pelvis at the time of menstruation).

However, retrograde menstruation occurs commonly in all women. A systematic review found

evidence supporting the retrograde menstruation theory. A significantly higher prevalence of

endometriotic lesions was found in the right subphrenic area. The authors explain this by the

fact that peritoneal fluid, which is transported clockwise, is trapped in the right hypochondrium

by the falciform ligament (Vercellini et al., 2007).

It is likely that aberrant function in related pathophysiological systems (e.g. immunity, cell

clearance, angiogenesis) is responsible for the implantation and subsequent growth of

endometrial cells in the peritoneal cavity.

The disease causes chronic inflammation, fibrosis, adhesions and ovarian cyst formation.

Endometriosis has been associated in the past with various malignancies (e.g. ovarian cancer,

breast cancer, melanoma and non-Hodgkins lymphoma). However, the data are inconclusive

and the risks, if they exist, may not be clinically relevant (Somigliana et al., 2006). Another

recent systematic review, however, looked at causality versus bias for interpreting data

demonstrating an association between endometriosis and ovarian cancer. The authors


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concluded that a causal relationship exists but the frequency of malignant transformation of

endometriotic lesions into ovarian cancer is similar to that of eutopic endometrium (Vigano et

al., 2007).

A systematic review of the effect of food intake on endometriosis and dysmenorrhoea revealed

that there are no clear data supporting dietary recommendations. Some studies suggested thatfish oil (n-3 oils) may reduce pain symptoms in endometriosis. The authors suggested further

studies on this issue (Fjerbaek and Knudsen, 2007).

References

2010 AEU References

Montgomery G., Nyholt D., et al. (2008) The search for genes contributing to endometriosis risk.

Hum Reprod Update. 14(5): 447-457.

2008 AEU References

Fjerbaek A., Knudsen U.B. (2007). Endometriosis, dysmenorrhea and diet - what is the

evidence? Eur.J.Obstet.Gynecol.Reprod.Biol. 132(2): 140-7. June 2007.

Vercellini P., Abbiati A., Vigano P., Somigliana E.D., Daguati R., Meroni F. & Crosignani P.G.

(2007). Asymmetry in distribution of diaphragmatic endometriotic lesions: evidence in favour of

the menstrual reflux theory. Hum.Reprod. 22(9): 2359-67. September 2007.

Vigano P., Somigliana E., Parazzini F. & Vercellini P. (2007). Bias versus causality: interpreting

recent evidence of association between endometriosis and ovarian cancer. Fertility and Sterility.88(3): 588-93. September 2007.

2007 AEU References

Gao X., Outley J., Botteman M., Spalding J., Simon J.A. & Pashos C.L. (2006). Economic

burden of endometriosis. Fertility & Sterility. 86(6): 1561-1572. December 2006.

Somigliana E., Vigano' P., Parazzini F., Stoppelli S., Giambattista E. & Vercellini P. (2006)

Association between endometriosis and cancer: A comprehensive review and a critical analysis

of clinical and epidemiological evidence. Gynecologic Oncology. 101(2): 331-341. May 2006.


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4. The pathological characteristics of endometriosis

Endometriosis is defined as the presence of endometrial-like tissue in sites outside the uterine

cavity, in so far as the lesions have many cellular and molecular characteristics in common with

eutopic endometrium.

The types of lesions seen are:

Superficial deposits on the peritoneal or ovarian surface with a typically blue-black powder-

burn appearance, but more subtle lesions are also recognised (e.g. petechial, vesicular,

polypoid, haemorrhagic or flame-like implants).

Small cysts on the peritoneal or ovarian surface containing old haemorrhage surrounded by

varying degrees of fibrosis.

Endometriomas (ovarian cysts), which contain thick, chocolate-like fluid; these are usually

stuck to the underlying peritoneal surface (ovarian fossa) and other structures (e.g. fallopiantube, bowel, uterus).

Deep nodules infiltrating more than 5 mm below the peritoneal surface that may penetrate or

adhere to other structures (e.g. bowel, bladder, ureters, vagina).

Recent work has identified nerve fibres within the endometrium of women with endometriosis,

which may lead to a better understanding of the disease process. The densities of nerve fibres,

staining positive for PGP9.5 (a neuronal marker), neuropeptide Y and vasoactive intestinal

polypeptide, were greater in the functional layer of women with endometriosis than women

without the disease. Preliminary results suggest nerve fibre density is reduced in women taking

hormonal therapy, as compared with those on no treatment, and the type of nerve fibres may also

change (Medina and Lebovic, 2009).

References

2010 AEU References

Medina M.G. & Lebovic D.I. (2009) Endometriosis-associated nerve fibers and pain. Acta

Obstet Gynecol Scand. 88(9): 968-975.


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5. The clinical features and diagnosis of endometriosis

The following symptoms have been associated with endometriosis:

Severe dysmenorrhoea (painful periods)

Deep dyspareunia (pain on intercourse)

Chronic non-menstrual pain

Pain at the time of ovulation

Dyschezia (pain on defaecation, especially at the time of menstruation)

Cyclical or perimenstrual symptoms, affecting the bowel or bladder, with or without abnormal

bleeding or pain

Subfertility (difficulty conceiving for more 12 months)

Chronic fatigue.

However, the predictive value of any one symptom or set of symptoms is uncertain because of

the overlap with other conditions, such as irritable bowel syndrome, interstitial cystitis, pelvic

inflammatory disease, fibromyalgia and musculoskeletal disorders (ASRM Practice Committee -

Pain, 2006.). The difficulties inherent in interpreting such symptoms contribute to the well-

recognised delay of up to 10 years between the onset of symptoms and a surgical diagnosis.

Endometriosis should be suspected in women of reproductive age who present with such

symptoms, especially if there is a cyclical component. A history and pelvic examination should

be performed. There is evidence to suggest that performing the examination during menstruationhelps to make the diagnosis, although many women are reluctant to be examined at that time.

The pelvic examination may be entirely normal, but features suggestive of endometriosis

include:

Generalised pelvic tenderness

Fixed, retroverted uterus (due to adhesions and/or deeply infiltrating disease)

Tender uterosacral ligaments (nodules may also be palpable)

Enlarged ovaries

Seeing lesions/nodules in the vagina or on the cervix.

The diagnosis may be suspected on clinical grounds but it can only be confirmed on visual

inspection of the peritoneal cavity at laparoscopy. Diagnostic laparoscopy remains the gold

standard for the diagnosis of endometriosis. A recent review considering the value of diagnostic

laparoscopy for a variety of conditions concluded that 78-84% of women undergoing


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laparoscopy for suspected endometriosis had the disease confirmed at surgery (Richardson,

2009).

Histological confirmation of at least one lesion represents ideal practice, although if an

endometrioma is greater than 4cms in diameter or deeply infiltrating disease is present, histology

should be obtained to exclude rare instances of malignancy.Disease severity should be assessed by documenting in detail the type, location and extent of all

lesions and adhesions found at surgery. Ideal practice is to record the findings on video or DVD

as well. Disease severity can be assessed quantitatively using a classification system such as the

one developed by the American Society for Reproductive Medicine (ASRM). However, there is

no correlation between such systems and the type or severity of pain symptoms.

Diagnostic laparoscopy is associated with an approximately 3% risk of minor complications,

such as nausea or shoulder-tip pain, and a risk of major complications, such as bowel perforation,

of between 0.6 to 1.8 per 1,000 procedures. Therefore, a non-invasive test would be clinically

useful.

The following tests have been used with varying degrees of success:

Serum CA-125 (a test for ovarian cancer) levels may be elevated in endometriosis but the test

has little diagnostic value and is not recommended.

Trans-vaginal ultrasound a useful tool to make and exclude the diagnosis of an ovarian

endometrioma, but it has limited value in diagnosing peritoneal disease. Two studies have

proposed different ways of performing ultrasound to detect deeply infiltrating endometriosis:

transvaginal tenderness guided ultrasound with 91% sensitivity and 89% specificity for

vaginal disease, and 74% sensitivity and 88% specificity for rectovaginal disease (Guerriero et.

al., 2008), and transrectal ultrasound in rectovaginal disease with a positive post-test prevalence

probability of 93% (Griffiths et. al., 2008). The authors advocating the use of transrectal

ultrasound concluded that pre-operative scanning for rectovaginal endometriosis strongly

predicts the need for extensive laparoscopic dissection and potential bowel resection.

Magnetic resonance imaging (MRI) there is insufficient evidence at present regarding its

diagnostic potential; however, MRI and other imaging modalities (e.g. transrectal ultrasound,

IVP, barium enema) may have a role in defining disease extent in deeply infiltrating

endometriosis.

The identification of nerve fibres may hold potential as a diagnostic test for endometriosis in the

future. One study has shown 100% sensitivity and specificity to detect endometriosis by tissue

biopsy (reviewed in Medina and Lebovic, 2009).

If a woman with symptoms suggestive of endometriosis wants treatment without a definitive

diagnosis, the options include counselling, analgesia and hormonal medication to reduce

menstrual flow (e.g. progestagens or COC). It is unclear whether the COC should be taken

conventionally, continuously or in a tricycle regimen in such circumstances.


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A gonadotrophin-releasing hormone (GnRH) agonist may be taken, although this is an expensive

option and concerns exist about the effects on bone mineral density (BMD). It is also argued that

establishing the correct diagnosis at laparoscopy before initiating therapy with significant short-

and long-term side effects is the preferred approach (ASRM Practice Committee - Pain, 2006).

References

2010 AEU References



Richardson W., Stefanidis D., et al. (2009) The role of diagnostic laparoscopy for chronic

abdominal conditions: an evidence-based review. Surg Endosc. 23(9): 2073-2077.

2009 AEU References

Griffiths A., Koutsouridou R., Vaughan S., Penketh R., Roberts S.A. & Torkington J.(2008)

Transrectal ultrasound and the diagnosis of rectovaginal endometriosis: a prospective

observational study. Acta Obstet Gynecol Scand. 2008; 87(4): 445-8.

Guerriero S., Ajossa S., Gerada M., Virgilio B., Angioni S. & Melis G.B. (2008) Diagnostic

value of transvaginal 'tenderness-guided' ultrasonography for the prediction of location of deep

endometriosis. Hum Reprod. 2008 Nov; 23(11): 2452-7. Epub 2008 Jul 29.

2007 AEU References

The Practice Committee of the American Society for Reproductive Medicine (2006). Treatment

of pelvic pain associated with endometriosis. Fertility & Sterility 2006 Nov; 86 (5 SUPPL. 1):

S18-27.


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6. Non-surgical management of endometriosis-associated pain

Endometriosis can be a chronic and debilitating disease, and few treatment options are entirely

satisfactory. A cure may be achievable but for many women the medical and surgical treatments

currently available have their limitations and symptoms often return after treatment.

Some women prefer not to take hormonal medication and are able to control their symptoms

with analgesics. Although non-steroidal inflammatory drugs (NSAIDs) may relieve

endometriosis-associated pain, there is too little evidence to assess their effectiveness. NSAIDs

have significant side-effects (e.g. 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. A Cochrane review found no significant difference between naproxen sodium

and placebo in providing adequate pain relief for endometriosis. However, the authors highlight

the paucity of evidence in this area, as only one trial was identified that could be included in this

review (Allen, 2009).

There is some evidence that high frequency TENS, acupuncture, vitamin B1 and magnesium

may help to relieve dysmenorrhoea, but there is limited evidence on such treatments in managing

endometriosis-associated pain. The role of Japanese acupuncture in managing such pain appears

to be limited. A 2008 study saw women randomly allocated to acupuncture or sham treatment for

an eight week treatment protocol. At four weeks, women in the acupuncture group had a

significantly greater decrease in pain scores compared with the sham group. However, this

difference was not sustained at eight weeks. Although both groups had a reduction in pain score

from baseline, the difference between sham and treatment groups was not significant (Wayne et

al., 2008).A Cochrane review considered the effectiveness and safety of Chinese Herbal Medicine (CHM)

in alleviating endometriosis-related pain. After laparoscopic surgery for endometriosis,

combined oral and enema administration of CHM has a comparable benefit to gestrinone but

with fewer observed side effects. Oral plus enema administration of CHM showed a greater

reduction in average pain scores than danazol and in the size of adnexal masses with fewer

adverse effects (Flower et al, 2009).

A systematic review of clinical and experimental data on the use of medicinal herbs in the

treatment of endometriosis illustrated the lack of evidence from clinical studies (Wieser et al.,

2007). However, the review highlighted the anti-inflammatory and pain-alleviating mechanismsof action of many herbal remedies and predicted that they might have a beneficial effect in

endometriosis symptoms, if tested in an appropriate manner.

The options for hormonal treatment include the COC, progestagens, androgenic drugs and GnRH

agonists; at appropriate doses, all suppress ovarian activity and menstruation. The levonorgestrel

intra-uterine system (LNG-IUS) also reduces endometriosis-associated pain (ESHRE 2007).


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The principal hormonal drugs studied COCs, danazol, gestrinone, medroxyprogesterone

acetate (MPA) and GnRH agonists are equally effective at relieving endometriosis-associated

pain when prescribed for 6 months but their side-effect and cost profiles differ. When used to

manage endometriosis-associated pain, intramuscular depot medroxyprogesterone acetate 150mg

can be given every three months. An RCT randomised one group of women to receive monthly

injections for 6 months, followed by 3 monthly injections, whilst the second group had 3

monthly injections throughout the treatment period. This trial found no statistically significant

difference in patient satisfaction between two different dosing schedules at various follow-up

periods (Cheewadhanaraks et al., 2009).

Implanon may also be an effective treatment for endometriosis related pain. Compared with

depot MPA, it demonstrated an equivalent improvement in pain scores over a 12 month study

period (Walch et al, 2009).

An RCT in women with endometriosis found dienogest (DNG) to be comparable with buserelin

acetate (BA) in reducing symptoms. DNG also resulted in less bone mineral density loss

compared with BA (Harada et al, 2009).

Maintaining women symptom free after successful treatment with GnRH agonists has also been

considered. Danazol and mid- or low-dose oral contraceptives were shown to maintain women

symptom free effectively for 12 months of treatment and prevent the recurrence of disease

(Kitawaki et al, 2008).

The use of aromatase inhibitors and their effect on pain in endometriosis was considered in a

systematic review. Seven studies (case reports and case series) all tended to show improvement

in pain scores, lesion size and quality of life in women using aromatase inhibitors. One RCT also

showed that aromastase inhibitors in conjunction with GnRH agonists improved pain scores, ascompared to GnRH agonists alone (Patwardhan et al, 2008).

Promising conclusions were found in a literature review regarding medical treatment for

rectovaginal disease, which was shown to have a beneficial effect on pain relief and lesion size,

as well as patient satisfaction and quality of life. Different forms of medical treatment appeared

effective, including GnRH analogues, danazol, the LNG-IUS and aromatase inhibitors

(Vercellini et al, 2009).

It is also important to bear in mind that:

medical treatment does not always provide complete pain relief and some patients fail to

respond at all.

symptom recurrence is common following medical treatment.

some side-effects limit long-term use and may produce poor compliance, e.g. androgenic side-

effects associated with danazol (Selak et al., 2007). GnRH agonist therapy may result in up to

6% BMD loss in the first 6 months and the loss may not always be entirely reversible.


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However, the concomitant use of add-back (oestrogen and progestagen) therapy protects

against BMD loss at the lumbar spine during treatment and for up to 6 months after treatment.

the COC and Depo-Provera can be used long term, but danazol and GnRH agonists are usually

restricted to 6 months; however, one study suggests 3 months with a GnRH agonist may be as

effective as 6 months in terms of pain relief. although the COC and GnRH agonist therapy appear to be equally effective, the published

studies are all small and no other treatments have been assessed as comparators (Davis et al.,

2007). Therefore, there is a clear need to evaluate fully the role of the COC in managing

symptoms associated with endometriosis.

A small double-blind, randomised, placebo-controlled trial has shown benefit in using a low dose

combined oral contraceptive pill (COCP) in reducing endometriosis-associated dysmenorrhoea

(Harada et al., 2008). The study is helpful because of the uncertainty that exists about the

effectiveness of the COCP in the treatment of endometriosis-associated pain (DUETS).

Another small double-blind, randomised, placebo-controlled trial found no benefit from using

Infliximab, an anti-TNF-alpha monoclonal antibody, to treat pain associated with deeply

infiltrating disease (Koninckx et al., 2008).

It is unclear whether hormonal treatment causes atrophy of endometriotic lesions, especially as

the natural history of the untreated disease is unknown. The available data suggest that MPA and

luteal phase dydrogesterone are ineffective, whereas gestrinone may be effective. The effects of

danazol and the GnRH agonist, triptorelin, are inconclusive.

References

2010 AEU References

Allen C., Hopewell S., Prentice A. & Gregory D. (2009) NSAIDs for Pain in Women with

Endometriosis. Cochrane Database of Systematic Reviews. 2009, Issue 2, Article No.

CD004753.

Cheewadhanaraks S., Peeyananjarassri K., et al. (2009) Interval of injections of intramuscular

depot medroxyprogesterone acetate in the long-term treatment of endometriosis-associated pain:

a randomized comparative trial. Gynecol Obstet Invest. 68(2): 116-121.

Flower A., Liu J.P., Chen S., Lewith G. & Little P. (2009) Chinese Herbal medicine forEndometriosis. Cochrane Database of Systematic Reviews. 2009, Issue 3, Article No.

CD006568.

Harada T., Momoeda M., et al. (2009) Dienogest is as effective as intranasal buserelin acetate for

the relief of pain symptoms associated with endometriosis. Fertility and Sterility. 91(3): 675-681.

Kitawaki J., Ishihara H., Kiyomizu M. & Honjo H. (2008) Maintenance therapy involving a

tapering dose of danazol or mid/low doses of oral contraceptive after gonadotropin-releasing


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hormone agonist treatment for endometriosis-associated pelvic pain. Fertility and Sterility. 89(6):

1831-1835.

Nawathe A., Patwardhan S., Yates D., Harrison G.R. & Khan K.S. (2008) Systematic review of

the effects of aromatase inhibitors on pain associated with endometriosis. BJOG. 115(7): 818-

822. June 2008.Vercellini P., Crosignani P., et al. (2009) Medical treatment for rectovaginal endometriosis: what

is the evidence? Hum Reprod. 24(10): 2504-2514.

Walch K., Unfried G., et al. (2009) Implanon versus medroxyprogesterone acetate: effects on

pain scores in patients with symptomatic endometriosis - a pilot study. Contraception. 79(1): 29-

34.

Wayne P., Kerr C., et al. (2008) Japanese-style acupuncture for endometriosis-related pelvic pain

in adolescents and young women: results of a randomized sham-controlled trial. J Pediatr

Adolesc Gynecol. 21(5): 247-257.

2009 AEU References

Harada T., Momoeda M., Taketani Y., Hoshiai H. & Terakawa N. (2008) Low-dose oral

contraceptive pill for dysmenorrhea associated with endometriosis: a placebo-controlled, double-

blind, randomized trial. Fertil Steril. 2008 Nov; 90(5): 1583-8. Epub 2007 Dec 27.

Koninckx P.R., Craessaerts M., Timmerman D., Cornillie F. & Kennedy S. (2008) Anti-TNF-

alpha treatment for deep endometriosis-associated pain: a randomized placebo-controlled trial.

Hum Reprod. 2008 Sep; 23(9): 2017-23. Epub 2008 Jun 12.

2008 AEU References

Davis L., Kennedy S., Moore J. & Prentice A. (2007). Modern combined oral contraceptives for

pain associated with endometriosis. Cochrane Database of Systematic Reviews. 2007, Issue 3,

Article No. CD001019.

ESHRE (2007) Guideline for the Diagnosis and Treatment of Endometriosis.

Selak V., Farquhar C., Prentice A. & Singla A. (2007). Danazol for pelvic pain associated with

endometriosis. Cochrane Database of Systematic Reviews. 2007, Issue 4, article No. CD000068.

Wieser F., Cohen M., Gaeddert A., Yu J., Burks-Wicks C., Berga S.L. & Taylor R.N. (2007)

Evolution of medical treatment for endometriosis: back to the roots? Hum.Reprod.Update. 13(5):

487-499.

2007 AEU References


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Abou Setta A.M., Al Inany H.G. & Farquhar C.M. (2006) Levonorgestrel releasing intrauterine

device for symptomatic endometriosis following surgery. Cochrane Database of Systematic

Reviews. 2006, Issue 4, Article No. CD005072.

Carpenter T.T. (2006) A systematic review to determine the effectiveness of medical therapies at

causing disease regression in endometriosis. Reviews in Gynaecological & Perinatal Practice2006 Sep; 6 (3-4).


of pelvic pain associated with endometriosis. Fertility & Sterility 2006 Nov; 86 (5 Suppl. 1):

S18-27.


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7. Surgical management of endometriosis-associated pain

A Cochrane review has shown that laparoscopic surgery gives greater improvement of

endometriosis-associated pelvic pain at 6 and 12 months after surgery, than diagnostic

laparoscopy alone. However, this finding should be applied with caution to women with severe

endometriosis as few women with severe disease were included in this review. No conclusions

regarding which specific laparoscopic surgical intervention is most effective could be drawn

(Jacobson et al, 2009).

Similarly, a systematic review considering laparoscopic management of endometriosis

demonstrated that laparoscopy is beneficial in treating endometriosis related pain at all stages of

the disease, although the best way to remove lesions (excision or ablation) is unknown.

Although laparoscopic uterosacral nerve ablation was not found to be a useful adjunct in the

treatment of endometriosis related pain, presacral neurectomy was found to be of benefit in some

patients (Yeung et al, 2009).

There has been continuing uncertainty about the best surgical treatment of ovarian

endometriomas to prevent cyst and symptom recurrence (DUETs), as well as its overall effect on

quality of life (DUETs).

A Cochrane review update is therefore helpful as it concluded that excisional surgery for

endometriomas provides a more favourable outcome than drainage and ablation with regard to

cyst recurrence and recurrence of pain symptoms (Hart et al., 2008). Laparoscopic excision of

the cyst wall was associated with a reduced recurrence rate of dysmenorrhoea (OR 0.15 CI 0.06-

0.38), dyspareunia (OR 0.08 CI 0.01-0.51) and non-menstrual pelvic pain (OR 0.10 CI 0.02-

0.56), a reduced cyst recurrence rate (OR 0.41 CI 0.18-0.93) and a reduced requirement forfurther surgery (OR 0.21 CI 0.05-0.79) than surgery to ablate the endometrioma.

In a recent trial, women were randomised to undergo immediate laparoscopic ovarian

cystectomy or a three step protocol, which involved endometrioma drainage, 3 months of

subsequent GnRH agonist therapy and a second laparoscopy for laser coagulation of the cyst

wall. Women who underwent the three step procedure showed a greater increase in anti-

Mllerian hormone level (an indicator of ovarian reserve) and a more significant increase in

antral follicle count than women undergoing the single step procedure. This may indicate that

ovarian function is better preserved following a three step surgical procedure, rather than the

traditional single step approach (Tsolakidis, 2009).

Another paper compared the use of bipolar diathermy with suturing to achieve haemostasis after

laparoscopic ovarian cystectomy. This found that suturing was associated with fewer post-

operative adhesions than diathermy at a second-look laparoscopy 60-90 days after initial

surgery (Pellicano et al, 2008).


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Other techniques of interest are the potential benefit of using mesna (a chemical mucolytic),

which appears to reduce operating time and perceived difficulty of operating, and a circular

excision technique for endometriotic cysts, which also seemed to improve ease of operating.

Finally, three trials have shown a benefit from the use of an adhesion barrier (Interceed, Adept or

Oxiplex) during surgery for endometriosis (Yeung et al, 2009).

The use of intra-operative, multi-modal analgesia (diclofenac sodium PR and repivacaine in

portal sites and sub-diaphragmatically) was found to reduce post-operative total hospital opioid

requirements significantly in women undergoing laparoscopic excision of endometriosis. No

difference in post-operative pain intensity between the two groups was demonstrated. A

reduction in post-operative opioid use with multi-modal intra-operative analgesia did not

translate into a reduction in post-op sedation, nausea and vomiting or hospital stay (Costello et

al, 2009).

The use of medical treatment in combination with surgery was also addressed in one review

(Yeung et al, 2009). The benefits of pre- and post-operative medical therapy are currently

unclear. Two trials compared pre- and post-operative medical therapy (GnRH agonists), and

found no difference in pain scores, although a reduction in r-ASRM scores in those women who

had pre-operative treatment. One trial also considered the use of the LNG-IUS post-operatively,

and found that it significantly improved pain scores compared to expectant management.

The recurrence of endometriosis after treatment is of great concern to patients and

gynaecologists alike. A recent review has attempted to quantify this risk, estimated to be 19%

over a 2 year period. However, the authors acknowledge that the studies use very different

definitions of recurrence, which makes it difficult to compare results. Several have attempted to

define risk factors for recurrence, with conflicting results (Guo, 2009).

In one RCT, women who had undergone laparoscopic excision of endometriomas were assigned

to no treatment or continuous/cyclical monophasic oral contraceptive pills (OCP) for 24 months.

Those women randomised to an OCP had reduced endometrioma recurrence rates compared to

those on no treatment (Seracchioli et al, 2008).

An additional study by the same authors, with similar methodology but greater sample size,

demonstrated that dysmenorrhoea scores were lowest for the continuous OCP users throughout

the 24 months. Although the reduction in dysmenorrhoea scores was not as great in cyclical OCP

users, they still had lower scores than untreated women by 18 and 24 months (Seracchioli,

2009a).

In women who had undergone conservative surgery for endometriosis, short term OCP use (6-

9.5 months) after surgery does not affect recurrence rates. However, use for 24-36 months does

appear to reduce the recurrence of endometriomas. One study indicated 6 months treatment was

sufficient to reduce dysmenorrhoea and chronic pelvic pain, although a second study did not

confirm this. Studies assessing long-term therapy showed a significant reduction in

dysmenorrhoea at 6 months for the continuous OCP group, and by 18 months for the cyclical


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OCP group. A second study also showed that 2 years continuous pill taking significantly reduced

dysmenorrhoea scores (Seracchioli, 2009b).

An RCT with five year follow-up concluded that adjuvant treatment with a GnRH agonist (for 3

months), following conservative surgery for Stage III-IV endometriosis, is not superior to

expectant management in terms of preventing symptom or cyst recurrence (Loverro et al, 2008).Raloxifene (a selective estrogen receptor modulator) use for 6 months post-operatively was

studied in women with pelvic pain and biopsy-confirmed endometriosis. However, there was no

evidence of treatment benefit. Furthermore, when compared with those taking placebo, the

raloxifene group had return of pain significantly earlier and underwent second surgery more

quickly (Stratton et al, 2008).

A small RCT also found that the use of pentoxifylline after conservative surgery for

endometriosis improved pain scores at 2 and 3 months follow-up compared to conservative

surgery only. The authors suggested prolonged use of pentoxifylline after conservative surgery

may improve long-term outcomes after surgical treatment (Kamencic et al, 2008).

The possible benefits of dietary intervention and medical treatments on the recurrence rates of

endometriomas after surgery were considered in one study. However, 6 months treatment with

GnRH agonists, OCP or dietary intervention (vitamins, minerals, salts, lactic ferments and fish

oil) did not affect the recurrence rate of endometriomas at 18 months follow-up (Sesti, 2009).

Uncertainty has always existed in the minds of clinicians and patients regarding the use of

hormone replacement therapy (HRT) following bilateral oophorectomy with or without a

hysterectomy for endometriosis. Unfortunately, the results of a recent Cochrane review add little

to the evidence base as only two small RCTs were identified, which suggested that HRT can

result in pain and disease recurrence (Al Kadri et al, 2009). However, the authors concluded thatthe evidence is not strong enough to advocate depriving severely symptomatic patients of HRT

and there is a need for more RCTs.

References

2010 AEU References

Costello M.F., Abbott J., Katz S., Vancaillie T. & Wilson S. (2009) A prospective, randomized,

double-blind, placebo-controlled trial of multimodal intraoperative analgesia for laparoscopic

excision of endometriosis. Fertility and Sterility. Epub 2009 April 24.

Guo S.W. (2009) Recurrence of endometriosis and its control. Hum Reprod Update. 15(4): 441-

461.

Jacobson T.Z., Duffy J.M., Barlow D., Koninckx P.R. & Garry R. (2009) Laparoscopic surgery

for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews. 2009,

Issue 4, Article No. CD001300.


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Pellicano M., Bramante S., et al. (2008) Ovarian endometrioma: postoperative adhesions

following bipolar coagulation and suture. Fertility and Sterility. 89(4): 796-799.

Seracchioli R., Mabrouk M., et al. (2008) Long-term cyclic and continuous oral contraceptive

therapy and endometrioma recurrence: a randomized controlled trial. Fertility and Sterility.

93(1): 52-56. Epub 2008 Oct 29.Seracchioli R., Mabrouk M., et al. (2009a) Long-term oral contraceptive pills and postoperative

pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled

trial. Fertility and Sterility. Epub 2009 May 12.

Seracchioli R., Mabrouk M., et al. (2009b) Post-operative use of oral contraceptive pills for

prevention of anatomical relapse or symptom-recurrence after conservative surgery for

endometriosis. Hum Reprod. 24(11): 2729-2735.

Sesti F., Capozzolo T., et al. (2009) Recurrence rate of endometrioma after laparoscopic

cystectomy: a comparative randomized trial between post-operative hormonal suppression

treatment or dietary therapy vs. placebo. Eur J Obstet Gynecol Reprod Biol. 147(1): 72-77.

Stratton P., Sinaii N., et al. (2008) Return of chronic pelvic pain from endometriosis after

raloxifene treatment: a randomized controlled trial. Obstet Gynecol. 111(1): 88-96.

Tsolakidis D., Pados G., et al. (2009) The impact on ovarian reserve after laparoscopic ovarian

cystectomy versus three-stage management in patients with endometriomas: a prospective

randomized study. Fertility and Sterility. Epub 2009 April 24.

Yeung P.P., Shwayder J. & Pasic R.P. (2009) Laparoscopic management of endometriosis:

comprehensive review of best evidence. J Minim.Invasive Gynecol. 16(3): 269-281.

2009 AEU References

Al Kadri H., Hassan S., Al-Fozan H.M. & Hajeer A. (2009) Hormone therapy for endometriosis

and surgical menopause. Cochrane Database of Systematic Reviews. 2009, Issue 1, Article No.

CD005997.

Hart R.J., Hickey M., Maouris P., Buckett W. & Garry R. (2008) Excisional surgery versus

ablative surgery for ovarian endometriomata. Cochrane Database of Systematic Reviews. 2008,

Issue 2, Article No. CD004992.

Kamencic H. & Thiel J.A. (2008) Pentoxifylline after conservative surgery for endometriosis: arandomized, controlled trial. J Minim Invasive Gynecol. 2008 Jan-Feb; 15(1): 62-6.

Loverro G., Carriero C., Rossi A.C., Putignano G., Nicolardi V. & Selvaggi L. (2008) A

randomized study comparing triptorelin or expectant management following conservative

laparoscopic surgery for symptomatic stage III-IV endometriosis.Eur J Obstet Gynecol Reprod

Biol. 136(2): 194-8. Epub 2006 Dec 18.


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2008 AEU References

Sesti F., Pietropolli A., Capozzolo T., Broccoli P., Pierangeli S., Bollea M.R. & Piccione E.

(2007). Hormonal suppression treatment or dietary therapy versus placebo in the control of

painful symptoms after conservative surgery for endometriosis stage III-IV. A randomizedcomparative trial. Fertility and Sterility. 88(6): 1541-7.

di Zerega G.S., Coad J. & Donnez J. (2007). Clinical evaluation of endometriosis and differential

response to surgical therapy with and without application of Oxiplex/AP* adhesion barrier gel.

Fertil.Steril. 87(3): 485-9.

2007 AEU References

Alborzi S., Ghotbi S., Parsanezhad ME., Dehbashi S., Alborzi S. & Alborzi M. (2007).

Pentoxifylline therapy after laparoscopic surgery for different stages of endometriosis: A

prospective, double-blind, randomized, placebo-controlled study. Journal of Minimally Invasive

Gynecology. 14(1): 54-8.

Latthe P.M., Proctor M.L., Farquhar C.M., Johnson N. & Khan K.S. (2007) Surgical interruption

of pelvic nerve pathways in dysmenorrhea: A systematic review of effectiveness. Acta

Obstetricia et Gynecologica Scandinavica. 86(1): 4-15.


of pelvic pain associated with endometriosis. Fertility & Sterility 2006 Nov; 86 (5 SUPPL. 1):

S18-27.


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8. Management of endometriosis-associated subfertility

A review article concluded that women with stage I-II endometriosis-associated infertility

benefit from laparoscopic treatment. Two studies demonstrated an increased pregnancy rate

amongst those who underwent surgical treatment compared with diagnostic laparoscopy alone

(Yeung et al, 2009).

Whether endometriosis adversely affects pregnancy rates in assisted reproduction has always

been controversial. Interestingly, therefore, a meta-analysis has shown that pregnancy rates

following controlled ovarian stimulation and intrauterine insemination (IUI) are significantly

lower in women with endometriosis compared to controls, but there are no significant differences

in women treated with IVF/ICSI (Kunz et al, 2008).

There has been continuing uncertainty about the best surgical treatment of ovarian

endometriomas to improve IVF outcomes (DUETs) and avoid damaging ovarian function

(DUETs) in infertile women.

A Cochrane review update concluded that excisional surgery for endometriomas provides a more

favourable outcome than drainage and ablation for spontaneous pregnancy (Hart et al, 2008), but

there is still insufficient evidence to determine the best treatment before IVF. However, a

systematic review and meta-analysis of 20 studies concluded that the available data show

surgical management of endometriomas has no effect on IVF pregnancy rates and ovarian

response to stimulation compared to no treatment (Tsoumpou et al, 2008).

The optimum technique for cyst removal has also been considered. A review article determined

that cyst excision compared with drainage had greater effects on pain and pregnancy outcomes.However, one study showed no difference in pregnancy rates following controlled ovarian

stimulation in women undergoing cystectomy rather than drainage (reviewed in Yeung et al,

2009).

There has also been uncertainty about the role of prolonged GnRH agonist treatment before IVF

(DUETs). A small RCT has added little to the evidence base by showing that 2 months treatment

before IVF produced a trend towards an increase in the implantation rate in women with Stage

III-IV disease (Ma et al, 2008).

An RCT with five year follow-up concluded that adjuvant treatment with a GnRH agonist,

following conservative surgery for Stage III-IV endometriosis had no effect on pregnancy rates(Loverro et al., 2008) and a small RCT suggested that combined laparoscopic surgery and

pentoxifylline therapy for endometriosis-associated infertility might improve pregnancy rates at

6 months follow-up (Creus et al, 2008). However, a systematic review concluded that there is

overall no evidence to support the use of pentoxifylline as a treatment for subfertility in women

with endometriosis, with no evidence of increased clinical pregnancy rates in women treated

with pentoxifylline compared with placebo (Lv, 2009).


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The potential benefit of second line surgery for women with recurrent endometriosis and a desire

for pregnancy has been assessed. Conception rates following second line surgery varied from 12

to 47%. Studies comparing primary surgery with repeat surgery found a reduced pregnancy rate

in women undergoing second line surgery. Overall, studies comparing only IVF or second line

surgery prior to IVF found no difference in pregnancy rates between each procedure (Vercellini

et al., 2009).

References

2010 AEU References

Lv D., Song H., Li Y., Clarke J. & Shi G. (2009) Pentoxifylline vs medical therapies for

subfertile women with endometriosis. Cochrane Database of Systematic Reviews. 2009, Issue 3,


Vercellini P., Somigliana E., et al. (2009) The effect of second-line surgery on reproductiveperformance of women with recurrent endometriosis: a systematic review. Acta Obstet Gynecol

Scand. 88(10): 1074-1082.

Yeung P., Shwayder J. & Pasic R.P. (2009) Laparoscopic management of endometriosis:


2009 AEU References

Creus M., Fbregues F., Carmona F., del Pino M., Manau D. & Balasch J. (2008) Combined

laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated

infertility: a preliminary trial. Hum Reprod. 23(8): 1910-6. Epub 2008 May 16.

Hart R.J., Hickey M., Maouris P. & Buckett W. (2008) Excisional surgery versus ablative

surgery for ovarian endometriomata. Cochrane Database of Systematic Reviews. 2008, Issue 2,


Kunz G. (2008) Treatment of women with endometriosis and subfertility: Results from a meta-

analysis. Geburtshilfe und Frauenheilkunde, 2008 Mar; 68 (3).

Loverro G., Carriero C., Rossi A.C., Putignano G., Nicolardi V. & Selvaggi L. (2008) A

randomized study comparing triptorelin or expectant management following conservative

laparoscopic surgery for symptomatic stage III-IV endometriosis. Eur J Obstet Gynecol ReprodBiol. 136(2): 194-8. Epub 2006 Dec 18.

Ma C., Qiao J., Liu P. & Chen G.. (2008) Ovarian suppression treatment prior to in-vitro

fertilization and embryo transfer in Chinese women with stage III or IV endometriosis. Int J

Gynaecol Obstet. 100(2): 167-70. Epub 2007 Nov 26.


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Tsoumpou I., Kyrgiou M., Gelbaya T.A. & Nardo L.G. (2008) The effect of surgical treatment

for endometrioma on in vitro fertilization outcomes: a systematic review and meta-analysis.

Fertil Steril. 92(1): 75-87.

2008 AEU References

Hughes E., Brown J., Collins J.J., Farquhar C., Fedorkow D.M. & Vandekerckhove P. (2007)

Ovulation suppression for endometriosis. Cochrane Database of Systematic Reviews. 2007, Issue

3, Article No. CD000155.

Pabuccu R., Onalan G. & Kaya C. (2007). GnRH agonist and antagonist protocols for stage I-II

endometriosis and endometrioma in in vitro fertilization/intracytoplasmic sperm injection cycles.

Fertil.Steril. 88(4): 832-9.

2007 AEU References

Gupta S., Agarwal A., Agarwal R. & Loret dM. (2006). Impact of ovarian endometrioma on

assisted reproduction outcomes. Reproductive Biomedicine Online. 13(3): 349-360.

The Practice Committee of the American Society for Reproductive Medicine (2006).

Endometriosis and infertility. Fertility & Sterility 2006 Nov; 86(5 SUPPL. 1): S156-60.


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9. Resources

2010 AEU References

Allen C., Hopewell S., Prentice A. & Gregory D. (2009) NSAIDs for Pain in Women withEndometriosis. Cochrane Database of Systematic Reviews. 2009, Issue 2, Article No.

CD004753.

Cheewadhanaraks S., Peeyananjarassri K., et al. (2009) Interval of injections of intramuscular

depot medroxyprogesterone acetate in the long-term treatment of endometriosis-associated pain:

a randomized comparative trial. Gynecol Obstet Invest. 68(2): 116-121.

Costello M.F., Abbott J., Katz S., Vancaillie T. & Wilson S. (2009) A prospective, randomized,

double-blind, placebo-controlled trial of multimodal intraoperative analgesia for laparoscopic

excision of endometriosis. Fertility and Sterility. Epub 2009 April 24.

Flower A., Liu J.P., Chen S., Lewith G. & Little P. (2009) Chinese Herbal medicine for

Endometriosis. Cochrane Database of Systematic Reviews. 2009, Issue 3, Article No.

CD006568.

Guo S.W. (2009) Recurrence of endometriosis and its control. Hum Reprod Update. 15(4): 441-

461.

Harada T., Momoeda M., et al. (2009) Dienogest is as effective as intranasal buserelin acetate for

the relief of pain symptoms associated with endometriosis. Fertility and Sterility. 91(3): 675-681.

Jacobson T.Z., Duffy J.M., Barlow D., Koninckx P.R. & Garry R. (2009) Laparoscopic surgery

for pelvic pain associated with endometriosis. Cochrane Database of Systematic Reviews. 2009,Issue 4, Article No. CD001300.

Kitawaki J., Ishihara H., Kiyomizu M. & Honjo H. (2008) Maintenance therapy involving a

tapering dose of danazol or mid/low doses of oral contraceptive after gonadotropin-releasing

hormone agonist treatment for endometriosis-associated pelvic pain. Fertility and Sterility. 89(6):

1831-1835.

Lv D., Song H., Li Y., Clarke J. & Shi G. (2009) Pentoxifylline vs medical therapies for

subfertile women with endometriosis. Cochrane Database of Systematic Reviews. 2009, Issue 3,




Montgomery G., Nyholt D., et al. (2008) The search for genes contributing to endometriosis risk.

Hum Reprod Update. 14(5): 447-457.


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Nawathe A., Patwardhan S., Yates D., Harrison G.R. & Khan K.S. (2008) Systematic review of

the effects of aromatase inhibitors on pain associated with endometriosis. BJOG. 115(7): 818-

822. June 2008.

Pellicano M., Bramante S., et al. (2008) Ovarian endometrioma: postoperative adhesions

following bipolar coagulation and suture. Fertility and Sterility. 89(4): 796-799.Richardson W., Stefanidis D., et al. (2009) The role of diagnostic laparoscopy for chronic

abdominal conditions: an evidence-based review. Surg Endosc. 23(9): 2073-2077.

Seracchioli R., Mabrouk M., et al. (2008) Long-term cyclic and continuous oral contraceptive

therapy and endometrioma recurrence: a randomized controlled trial. Fertility and Sterility.

93(1): 52-56. Epub 2008 Oct 29.

Seracchioli R., Mabrouk M., et al. (2009a) Long-term oral contraceptive pills and postoperative

pain management after laparoscopic excision of ovarian endometrioma: a randomized controlled

trial. Fertility and Sterility. Epub 2009 May 12.

Seracchioli R., Mabrouk M., et al. (2009b) Post-operative use of oral contraceptive pills for

prevention of anatomical relapse or symptom-recurrence after conservative surgery for

endometriosis. Hum Reprod. 24(11): 2729-2735.

Sesti F., Capozzolo T., et al. (2009) Recurrence rate of endometrioma after laparoscopic

cystectomy: a comparative randomized trial between post-operative hormonal suppression

treatment or dietary therapy vs. placebo. Eur J Obstet Gynecol Reprod Biol. 147(1): 72-77.

Stratton P., Sinaii N., et al. (2008) Return of chronic pelvic pain from endometriosis after

raloxifene treatment: a randomized controlled trial. Obstet Gynecol. 111(1): 88-96.

Tsolakidis D., Pados G., et al. (2009) The impact on ovarian reserve after laparoscopic ovariancystectomy versus three-stage management in patients with endometriomas: a prospective

randomized study. Fertility and Sterility. Epub 2009 April 24.

Vercellini P., Crosignani P., et al. (2009) Medical treatment for rectovaginal endometriosis: what

is the evidence? Hum Reprod. 24(10): 2504-2514.

Vercellini P., Somigliana E., et al. (2009) The effect of second-line surgery on reproductive

performance of women with recurrent endometriosis: a systematic review. Acta Obstet Gynecol

Scand. 88(10): 1074-1082.

Walch K., Unfried G., et al. (2009) Implanon versus medroxyprogesterone acetate: effects onpain scores in patients with symptomatic endometriosis - a pilot study. Contraception. 79(1): 29-

34.

Wayne P., Kerr C., et al. (2008) Japanese-style acupuncture for endometriosis-related pelvic pain

in adolescents and young women: results of a randomized sham-controlled trial. J Pediatr

Adolesc Gynecol. 21(5): 247-257.


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Yeung P., Shwayder J. & Pasic R.P. (2009) Laparoscopic management of endometriosis:


2010 Annual Evidence Update on Endometriosis PDF Version

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