Update on endometriosis

by Lone Hummelshoj*, Andrew Prentice** and Patrick Groothuis***

*      Endometriosis.org
**   University Dept of Obstetrics and Gynaecology, Rosie Hospital, Cambridge, UK
*** Research Institute Growth and Development, Dept of Obstetrics and Gynaecology, University Hospital Maastricht, The Netherlands

This article first appeared in Women's Health January 2006;2(1):53-56, and have been reproduced with the permission of Future Medicine, which retains copyright.
This article may not be reproduced without explicit permission.

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The World Endometriosis Society conducted the 9th World Congress on Endometriosis on 14 – 17 September 2005 in Maastricht, the Netherlands, where it attracted 660 delegates. The president of the congress was Professor Hans Evers, who had chosen his theme, “the patient as a partner”, to remind everyone that the persistent nature of endometriosis is such that physicians and patients will, more often than not, know each other for a very long time – and thus partnership and collaboration becomes essential in solving the puzzle of the illness. This partnership was very much in evidence throughout the congress, where representatives from national patients support groups in 15 countries participated in and contributed to the meeting.

The atmosphere of the meeting was an informal one, created to nurture discussion and ideas within 11 carefully selected seminars, which addressed everything from tangible molecular cell biology to intangible quality of life (QOL).

A lot of this is rooted in the fact that endometriosis is surrounded by taboos and myths, but it has also been acknowledged that for too many years patients, clinicians, and scientists have pursued the disease and illness separately – and subsequently never got too far. With the realisation, however, that all the stakeholders play a crucial part in solving the endometriosis puzzle, joint initiatives have emerged at local, regional, national, and international levels to move clinical expertise and research forward, and to improve overall quality of life for women with endometriosis. Thus, the 9th World Congress moved forward with its theme of “the patient as a partner”, by “kicking off” the congress, with a one day pre-congress course, which included 140 participants (three quarters clinicians and one quarter women with endometriosis), co-chaired by Axel Forman, Lone Hummelshoj, and Andrew Prentice. This course centred around “best practice in endometriosis”, where examples of joint physician/patient organisation initiatives from around the world were presented in the morning, followed by intense brainstorming in the afternoon, which lead to the conclusion that there is a greater need for:

1. Organising networks of specialist care
2. Prevention of endometriosis and implementation of self-help programmes
3. International awareness through better profiling of endometriosis
4. Utilising all the capabilities of support groups
5. Identifying and overcoming barriers, which have to be considered when women, especially adolescents, present with symptoms suggestive of endometriosis
6. Better diagnostic tools and more efficient treatments.

The main congress was divided into two “tracks” – one aimed at scientists and one aimed at clinicians. Although perhaps contradicting the partnership described before, this proved to be a good way of structuring a meeting, as was demonstrated by the highly interactive discussions in the sessions. For many years, investigators have attempted to elucidate the pathogenesis of endometriosis, but progress is slow and the demand for better options for diagnosis and treatment is rapidly increasing. In the past few years the focus in endometriosis research has started to shift from a strictly basic or clinical nature towards translational research. Investigators are exploring how the available knowledge can be applied to benefit the patient. This was one of the most apparent features of the 9th World Congress on Endometriosis. Next to substantial attention for the physiology and behaviour of eutopic and ectopic endometrium, the main focus was on finding new ways to improve the diagnosis and management of endometriosis.

The stage was set with sessions on the epidemiology and genetics of the disease, expertly moderated by Paolo Vercellini and Stephen Kennedy. Vercellini confirmed that the incidence has not increased in the last 30 years and remains at 2.37–2.49/1000/year, which equates to an approximate prevalence of 6-8%, and that the risk factors of developing endometriosis include:

• early age of menarche
• short menstrual cycles
• long duration of menstrual flow
• inverse relationship to parity
• family history of endometriosis.

If a genetic predisposition can be identified in women, who develop endometriosis, this could provide an important, and much greater, understanding of the aberrant cellular and molecular mechanisms involved in the aetiology and pathophysiology of endometriosis, and could potentially lead to better diagnostic methods and targeted treatments. Developments in this area may not be rapid but do generate hope for the future.

Stephen Kennedy and Sue Treloar used a positional-cloning approach to identify genomic regions which convey susceptibility. The linkage study included 1,176 families (931 from an Australian group and 245 from a UK group), each with at least two members - mainly affected sister pairs - with surgically diagnosed disease. The first report of significant linkage to a major locus for endometriosis on chromosome 10q26 was presented, and they promise us more at the next World Congress in 2008.

The only definitive way to diagnose endometriosis is through a laparoscopy with biopsy. Despite an overall sensitivity of 97% [2], it is an invasive procedure with a specificity of only 77%. Thus, new test of endometriosis biomarkers must be both sensitive and specific and should reflect pathophysiological change.

Linda Giudice, in her eloquent key note lecture, presented data from gene expression studies and showed selections of genes that are aberrantly expressed in endometrium from women with endometriosis. These markers are potential candidates for the diagnosis of endometriosis, or may be responsible for the observed subfertility in endometriosis patients. Results from several other studies using genomics, proteomics, and glycomic approaches to identify biomarkers for endometriosis were presented as well. The findings require further validation.

A new diagnostic test was introduced by Valeo Medical. This test is based on the detection of autoantibodies against Thomsen-Friedenreich (T) antigen (Gal beta1-3GalNAc) bearing proteins, which were identified by Grant Yeaman from Vanderbilt University (TN, USA). The sensitivity and specificity of the test are 80%, which means that improvements are still warranted.

An interesting marker was also presented by Daniela Hornung. These investigators showed that the expression of the blood borne marker CCR1 mRNA in peripheral blood leucocytes in women with endometriosis is significantly higher compared with women without the disease.

Another option for the noninvasive diagnosis of endometriosis is imaging. Endometriosis can be assessed by means of several imaging techniques, including transvaginal sonography (TVS), endorectal sonography (EUS), and MR imaging. Regina Beets-Tan convincingly showed that functional MR imaging offers a superior combination of 3D imaging with high spatial and temporal resolution, low observer dependency, no radiation exposure and no risk for iodinated contrast agents related adverse reactions such as nephrotoxicity. In combination with MR contrast agents, which are intravenously administered (dynamic contrast-enhanced MRI), dynamic changes in MR signal intensity in selected tissue volumes can be detected. Some of the new generation contrast agents can also be loaded with specific antibodies, which also allows targeted imaging.

Anne van Langendonckt performed gene expression analysis on endothelial cells isolated from endometriotic lesions in an attempt to identify specific antigens. Various genes were found to be up-regulated in blood vessels in ectopic endometrium. Their specificity is currently being validated. If proven specific, their applicability in targeted MRI will be investigated.

Whilst we await the perfect non-invasive diagnostic method, a poignant point was made by Michel Canis that listening to the patient describing her symptoms, also comes a long way in the clinical diagnostic process.

Yet again in the conference, we were reminded of the importance of the patient and also the importance of old fashioned clinical methods.

Perhaps more important than clinicians not listening is the lack of general awareness of endometriosis and its symptoms. These factors, combined with the lack of noninvasive diagnostic methods, means that the current diagnostic delay of the disease is an average of 8.3 years, according to new data collected by the Endometriosis All Party Parliamentary Group in the United Kingdom (n=7025 from 52 countries), which was presented by Lone Hummelshoj in the session on pain and quality of life. In addition to the diagnostic delay, 65% of women indicated that they had initially been mis-diagnosed with another condition. Only one third felt that the management of their endometriosis-related symptoms was effective, and less than 50% were satisfied that their endometriosis was under control.

• 78% of responders indicated that they lose an average of 5.3 days/month at work due to their symptoms, with 36% having had their job affected (n=2518), to the extent that:

o 41% have given up/lost job due to illness
o 37% have reduced their hours
o 23% have changed their jobs
o 6% are on disability benefits.

• 72% (n=5064) reported relationship problems, with:

o 10% saying that it caused a split
o 11% saying that it was difficult to look after their children
o 34% saying that it caused significant problems with their partner.

This data highlight areas that have a significant impact on patients’ quality of life, in particular in comparison to results from a North American survey from 1998 (n=4000) [3], where outcomes responses were (7 years apart, in a different study group, and with a different study design) worryingly similar.

It became clear that issues surrounding pain and quality of life in women with endometriosis have an impact not only on the affected individual but also on her family, and on society in general.

Furthermore, the poster, which got the first prize, was presented by Melissa Parker and Anne Sneddon. They found that approximately 50% of teenagers with severe dysmenorrhoea had endometriosis, confirming that it is a common condition in adolescents.

It was therefore also reassuring that basic research – despite a desperate lack of funding – has moved forward to the extent that it has.

With regard to the pathogenesis of endometriosis, it was shown that endometriosis induced in baboons shows many parallels to endometriosis in the humans, based on the behaviour of the lesions and the expression of proteins. This model is therefore very suitable for the pre-clinical evaluation of new drugs for the treatment of endometriosis.

The recent hype in stem cell research has also reached this meeting. Work was presented, which showed that a population of cells resides in the endometrium which has stem cell properties. It may be these properties that convey the tremendous plasticity to endometrial cells, which allows them to survive at ectopic locations.

It was shown that factors such as hypoxia and iron contribute to the early development of endometriosis. Such findings deserve further follow-up and could lead to new treatment modalities for endometriosis.

It is clear that continued, significant investment into basic research is essential in order to understand and solve the mechanisms of endometriosis.

From a clinical perspective, surgery remains a major, current treatment modality for endometriosis. The debates witnessed during the congress amongst the surgeons focused on whether or not to treat minimal and mild disease, whether or not to strip or destroy the walls of ovarian endometriomas, and how aggressive to be when operating on recto-vaginal disease. Whilst consensus was not reached on these issues, one clear message came through: only surgeons properly trained and experienced in laparoscopic surgery should be performing these operations, as surgery continues to carry significant risks that must be properly explained and understood by patients. Data presented by both Christel Meuleman and Ray Garry highlighted high success rates in pain, quality of life, sexual activity and cumulative fertility rates when surgery was carried out by multi-disciplinary teams in specialist tertiary referral centres.

The last session of the conference, chaired by Serdar Bulun discussed new emerging medical therapies for endometriosis. Iron chelators and inhibitors of NF-kB and leptin signalling were promoted as alternative modalities to intervene in the initial stages of endometriosis development.
Luca Fusi demonstrated that ectopic endometrium has very high sulfatase activity. Sulfatase converts the largest pool of oestrogens in the woman, oestrone-sulfate, into oestrone which is then converted into oestradiol by aromatase, which is also expressed in ectopic endometrium. The authors suggested that sulfatase inhibitors in combination with aromatase inhibitors for the treatment of deep invasive endometriosis may present an effective addition to current hormonal therapies.

Pulling it all together is not easy, but Andrew Prentice discussed the role of evidenced based medicine in creating a consensus for the management of endometriosis. It is clear that despite many clinical trials there is still a paucity of reliable clinical data that actually address the questions that are relevant today. Prentice also highlighted the danger in only accepting data from randomised controlled trials and suggested that endpoints to clinical trials should be directed at assessing improvements in the illness or quality of life rather than disease resolution alone.

It is clear that well conducted clinical research is still required and the potential movement towards world wide collaboration following discussions between the Endometriosis Special Interest Groups of the European Society for Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM) at the conference is a welcome move. Such collaboration in Europe has already been productive with the online publication of the ESHRE Guideline on the Diagnosis and Management of Endometriosis [1, 101], announced at the congress.

The 9th World Congress on Endometriosis brought together world leaders in the field of endometriosis to address a wide range of topics from molecular cell biology to quality of life. It was evident that there continues to be a worldwide lack of awareness of endometriosis amongst women and, more frighteningly, amongst non-specialist clinicians. There also remains a desperate need for non-invasive diagnostic techniques and perhaps by 2008, at the 10th World Congress on Endometriosis, the promise demonstrated at this congress may be delivered into clinical practice. Throughout the congress patients, clinicians and scientists shared their experience and research, participated in discussions, and put forward their ideas. A strong commitment amongst scientists to work towards solving the endometriosis puzzle was demonstrated, and exciting developments in genetics may open up new pathways of research, diagnosis and treatment. And, whilst we await further development in this particular field, potential new medical therapies for the treatment of endometriosis were presented and may become available in the future.

Public health initiatives must be undertaken to generate awareness of the high prevalence and impact of endometriosis across all societies and at all levels. In order to develop novel diagnostic techniques and effective therapeutic methods, significant commitment to investment into basic research is needed. It is evident that the scientists are committed to working on solving the endometriosis puzzle, but vital funding is still desperately lacking. The Endometriosis Special Interest Groups of ESHRE and ASRM will collaborate further on a global basis in order to enhance clinical research and to encourage the development of clinical networks linked to specialist centres to ensure that all women with endometriosis have access to the most appropriate treatment.

For more information on endometriosis for patients, clinicians and scientists please visit the global forum for news and information in endometriosis at www.endometriosis.org.

The 10th World Congress on Endometriosis takes place in Melbourne, Australia, on 11-14 March 2008.

• A lack of awareness of the symptoms of endometriosis results in an average diagnostic delay of over 8 years.

• Issues surrounding pain and quality of life in women with endometriosis have an impact not only on the affected individual but also on her family and on society in general.

• Significant investment is needed for basic research into non-invasive diagnostics and effective therapeutic modalities.

• Exciting developments in genetics may open up new pathways of research, diagnosis and treatment.
• Networks of specialist care centres are essential to ensure women have access to the most appropriate treatment.

• Clinicians welcome the ESHRE Guideline on the Diagnosis and Management of Endometriosis [1, 101]

1. Kennedy S, Bergqvist A, Chapron C, et al.: ESHRE guideline on the diagnosis and management of endometriosis. Human Reprod 20(10), 2698-2704 (2005).

2. Buchweitz O, Poel T, Diedrich K, et al.: The diagnostic dilemma of minimal and mild endometriosis under routine conditions. J Am Assoc Gynecol Laparosc 10(1), 85-9 (2003).

3. Sinaii N, Cleary SD, Ballweg ML, Nieman LK, Stratton P: High rates of autoimmune and endocrine disorders, fibromyalgia, chronic fatigue syndrome and atopic diseases among women with endometriosis: a survey analysis. Human Reprod 17(10), 2715-2724 (2002).

101. www.endometriosis.org/guidelines