Update on Endometriosis

The challenge of endometriosis

Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic inflammatory reaction. The condition is predominantly found in women of reproductive age, from all ethnic and social groups. The associated symptoms can impact on general physical, mental and social wellbeing [1]. Endometriosis has proven elusive for scientists to get to the bottom of and clinicians to treat satisfactorily; and, most importantly, to have a profound impact on the lives of those affected by the illness.

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 very far. However, with the realization that all the stakeholders play a crucial role 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 QoL for women with endometriosis. Thus, the 9th World Congress moved forward with its theme, by beginning the congress with a 1-day precongress course, which included 140 participants (three-quarters clinicians and a quarter women with endometriosis), co-chaired by Axel Forman, Lone Hummelshoj and Andrew Prentice. This course centered around ‘best practice in endometriosis’, where examples of joint physician/patient organization initiatives from around the world were presented in the morning, followed by intense brainstorming in the afternoon, which led to the conclusion that there is a greater need for:

Key presentations

The main congress was divided into two tracks – one aimed at scientists and one 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 patients. This was one of the most apparent features of the 9th World Congress on Endometriosis. Next to substantial attention for the physiology and behavior of eutopic and ectopic endometrium, the main focus was on finding new ways to improve the diagnosis and management of endometriosis.

Epidemiology & genetics

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:

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 etiology 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 1176 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 more at the next World Congress in 2008.

Diagnosing endometriosis

The only definitive method of diagnosing 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, a new test of endometriosis biomarkers must be both sensitive and specific and should reflect pathophysiologic 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 the endometrium of 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 also presented. 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 antigen (Gal β1–3GalNAc)-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 demonstrated that the expression of the blood-borne marker chemokine receptor (CCR)1 mRNA in peripheral blood leukocytes 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 magnetic resonance imaging (MRI). Regina Beets-Tan convincingly demonstrated that functional MRI offers a superior combination of three-dimensional imaging with high spatial and temporal resolution, low observer dependency, no radiation exposure and no risk for iodinated contrast agent-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 for 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 upregulated in blood vessels in ectopic endometrium. Their specificity is currently being validated. If proven specific, their applicability in targeted MRI will be investigated.

While we await the perfect noninvasive 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.

The impact of endometriosis

Yet again at 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 non-nvasive 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 UK (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 misdiagnosed with another condition. Only a third felt that the management of their endometriosis-related symptoms was effective, and less than 50% were satisfied that their endometriosis was under control. A total of 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: 41% had given up or lost a job due to illness; 37% reduced their hours; 23% had changed their jobs; and 6% were receiving disability benefits. A total of 72% (n = 5064) reported relationship problems, with: 10% saying that it caused a separation; 11% saying that it was difficult to look after their children; and 34% saying that it caused significant problems with their partner.

These data highlight areas that have a significant impact on patients' QoL, in particular in comparison with 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 QoL 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 that received the first prize was presented by Melissa Parker and Anne Sneddon. They found that approximately 50% of teenagers with severe dysmenorrhea 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.

Basic research

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

The recent hype regarding stem cell research also reached this meeting. Work was presented, which showed that a population of cells resides in the endometrium that has stem-cell properties. It may be these properties that convey the tremendous plasticity of 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.

Clinical research

From a clinical perspective, surgery remains a major current treatment modality for endometriosis. The debates witnessed during the congress among the surgeons focused on whether to treat minimal and mild disease, whether to strip or destroy the walls of ovarian endometriomas, and how aggressive to be when operating on rectovaginal disease. While 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 to and understood by patients. Data presented by both Christel Meuleman and Ray Garry highlighted high success rates in pain, QoL, sexual activity and cumulative fertility rates when surgery was carried out by multidisciplinary 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 nuclear factor (NF)-κB 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 estrogens in women, estrone–sulfate, into estrone, which is then converted into estradiol by aromatase, 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.

Managing endometriosis

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 address the questions that are relevant today. Prentice also highlighted the danger in only accepting data from randomized, controlled trials and suggested that end points to clinical trials should be directed at assessing improvements in the illness or QoL rather than disease resolution alone.

It is clear that well-conducted clinical research is still required and the potential movement towards worldwide 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.

Summary

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 QoL. It was evident that there continues to be a worldwide lack of awareness of endometriosis among women and, more frighteningly, among nonspecialist clinicians. There also remains a desperate need for noninvasive 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 among 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. While we await further developments in this particular field, potential new medical therapies for the treatment of endometriosis were presented and may become available in the future.

Future perspective

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 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 encourage the development of clinical networks linked to specialist centers to ensure that all women with endometriosis have access to the most appropriate treatment.

Infomation resources

For more information on endometriosis for patients, clinicians and scientists should 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.