World Endometriosis Society Newsletter

Firstly a somewhat belated but nevertheless sincere “Happy New Year” to all WES Members. I am sure that 2003 presents you with as many challenges as it does your WES Board Members.

The Society had a very successful Congress in February 2002 in San Diego, thanks to all the hard work of the two principal organisers, John Rock (immediate WES Past-President) and Robert Schenken – and their Committee Members.

The Congress certainly highlighted the scientific progress made in understanding the aetiology and pathogenesis of endometriosis, particularly at a molecular biological level. It was also clear that many controversies still exist in determining the most appropriate treatments for our patients and that there are few new therapies nearing the clinical market place. The support and infrastructure of the American Society for Reproductive Medicine was of paramount importance in underpinning the organisation and financial viability of this Congress. The WES sincerely thanks their President and Board for this assistance and for their donation to our funds from the small congress surplus.

What challenges does 2003 present to the Society? In brief many, however, the most pressing are to accrue enough funding to ensure viability of the Society to fund the production of regular Newsletters. To do this we need to increase membership and it is here that each one of your can be of assistance by encouraging your colleagues to join. Information on membership, costs and benefits appear elsewhere in this newsletter.

We would welcome local or national societies becoming affiliated to the WES which should help to increase awareness both of the WES but also of endometriosis to both physicians and patients.

In our new style newsletter you will see résumés/abstracts of various recent publications within the fields of epidemiology, basic research, medical and surgical treatments. These we hope will keep WES members informed on the most recent work and help direct changes to their own management plans. If you are aware of articles, either your own or published in your national or society journals concerning any aspect of endometriosis, please forward them to the address given.* We cannot promise to print all but at least we will have access to a wide spectrum of publications worldwide to select from.
Finally, please write and let me know if you have any other suggestions for the Newsletter, or how the WES may be able to assist you and your patients.

Best wishes,

Professor Robert Shaw

FORMATION OF HELLENIC ENDOMETRIOSIS SOCIETY

I was delighted as President of WES to be invited to speak at the 1st Panhellenic Congress on Endometriosis held on 22-23 November 2002 in Heraklion, Crete. It was a well organised, informative and highly successful meeting.

From this meeting was formed the HELLENIC ENDOMETRIOSIS SOCIETY with the following officers;

Chairman: E Koumantakis
Vice-Chairman: G Vlassis
General Secretary: I Matalliotakis
Treasurer: A Goumenou
Members: A Kalogezopoulos, D Panidis, E Deligeozoglu

The WES wish the Society every success and look forward to close co-operation in future events.

Professor Robert Shaw
President, WES

This is a new feature offered by the WES e-newsletter for the benefit of WES members. The articles listed below have been selected by WES Board members, acting as Associate Editors. Inevitably equally interesting articles may have been overlooked, so the WES membership is encouraged to inform the society of any they know of or have published themselves for possible inclusion in subsequent e-newsletters.

Board members have also commented on most of these articles. In some cases two members may have commented on the same article. General WES members are strongly encouraged to voice their own opinions and to open discussion through the e-newsletter’s new web Discussion link. This can also be used by members to ask questions of other members concerning any aspect of endometriosis. It is a way of maintaining contact between conferences and will, eventually, we hope prove to be an invaluable resource.

Comments on Selected Articles

Gurates et al: J Clin Endocrinol Metab 2002 September 4369-77. Both clinical and laboratory evidences indicate that endometriosis is dependent on estrogen for its development and evolution. Recent studies uncovered an autocrine mechanism which favored abnormal production of estrogen in endometriotic tissue. The fact that estrogen may be synthesized locally within endometriotic tissue, thereby contributing to its growth and development, is of a great relevance in endometriosis pathophysiology.

The paper of Gurates B published in the Journal of Clinical Endocrinology and Metabolism (J Clin Endocrinol Metab 87: 4369-77, 2002) extends previous studies from the same research group, and provide new clues as to the mechanisms underlying aromatase P450 (P450arom) increased expression in endometrioitic stromal cells vs normal endometrial cells. P450arom is the rate-limiting enzyme for the synthesis of estrogen and catalyses the conversion of C19 steroids to estrogens. Interestingly, the authors showed that Wilm’s tumor suppressor gene (WT1) inhibited cAMP- and steroidogenic factor-1 (SF-1)-induced P450arom promoter activity in endometriotic and endometrial stromal cells, and that WT1 levels were reduced in the endometriotic cells. In view of WT1 inhibitory effect on P450arom promoter, down-regulation of WT1 in endometriosis may contribute to the increased expression of P450arom in endometriotic tissue and consequently to abnormal production of estrogen. On the other hand, predominance of WT1 expression in endometrial cells as compared to endometriotic cells may represent a plausible mechanism by which estrogen production in normal endometrial tissue is suppressed.

The corresponding author for this study is S. Bulun, Department of Obstetrics and gynecology, University of Illinois at Chicago, 820 South Wood Street, M/C808, Chicago, Illinois 60612. Email : sbulun@uic.edu

Key points reported in this study include:

Modesitt et al. Obstet Gynecol 2002, Oct. 788-95. This is an epidemiological study with all the caveats necessary for epidemiological studies. It shows that women with endometriosis-associated cancers are typically premenopausal, have a high incidence of endometroid and clear cell histologies, and have early stage disease. Stage and gravidity independently predicted survival. Although in clinical practice this will not help you much, it is good that the relation between endometriosis and cancer receives new attention.

Akoum et al: J Clin Endocrinol Metab 2002 Dec 5785-92. Endometriosis is also commonly associated with intraperitoneal inflammation, but possible links between the immuno-inflammatory and endocrine changes observed in endometriosis women have been poorly understood. Chemokines such as RANTES whose concentrations were shown to be increased in the peritoneal cavity of patients with endometriosis may contribute to leukocyte recruitment and exacerbate thereby the immunoinflammatory process.

A recent study from Akoum et al (J Clin Endocrinol Metab 2002, 87: 5785-92) showed that estradiol (E2) and interleukin-1 (IL-1beta) exert a synergistic stimulatory action on RANTES (regulated upon activation, normal T cell expressed and secreted) expression by endometriotic cells. In fact, E2 alone had no detectable effect on RANTES protein secretion and mRNA synthesis, but, interestingly, it appeared to enhance IL-1-induced RANTES production. This study provides a new insight in the mechanisms of estrogen action in endometriosis, and a further evidence for a close relationship between immune and endocrine dysfunctions observed in this disease.The corresponding author for this study is A. Akoum, Hospital St. Francois Espinay, Center for Research, Laboratory for Endocrinology and Reproduction, 10 Rue Espinay, Local D0-711, Quebec City, PQ G1L 3L5, Canada. Email : ali.akoum@crsfa.ulaval.ca

Key points reported in this study include:

Akoum et al: RANTES expression in endometriotic tissue is not subject to cyclic variation. These findings reveal a new regulatory mechanism by which IL-1beta produced by activated macrophages, can in synergy with ovarian and locally produced E(2), lead to enhanced macrophages and T-lymphocyterecruitment, thereby exacerbating the local immunoinflammatory process. These findings provide further evidence of the close relationship between the endocrine and immunological changes observed in endometriosis.

Al-Fozan et al: Obstet Gynecol 2003, Jan 164-6. The notion of left lateral predisposition of endometriosis became fashionable some time ago and I am always amazed to read that left predisposition (60 %) is significantly different from right predisposition (40 %), supporting the theory that endometriosis originates from the regurgitated endometrial cells.The argument here is the presence of the sigmoid colon.But are we sure that the origin of ovarian endometriomas is regurgitated endometrial cells ? What about the metaplasia theory ? What about deep retroperitoneal lesions with ureteral stenosis ?And what if the left predisposition is due to a genetic or embryologic cause ? A good topic for discussion.

Al-Fozan & Tulandi reviewed the operative reports of 559 patients who underwent laparoscopic surgery for endometriosis. Data were collected on site of endometriotic implants and cysts in order to verify whether endometriosis and endometriomas are found more frequently in the left than in the right hemipelvis. Their results confirm a left lateral predisposition of the disease, as peritoneal implants, ovarian endometriotic cysts and adhesions were all significantly more frequent in the left than in the right hemipelvis.

The pathogenesis of ovarian endometriotic cysts is controversial. An endometrioma may be the result of either metaplasia of the coelomic epithelium covering the ovary or inversion and progressive invagination of the ovarian cortex after adhesion to the pelvic peritoneum caused by local implantation of endometrium regurgitated through the tubes. Investigating the anatomical distribution of endometriotic lesions may provide insights into the pathogenesis of the disease. If retrograde menstruation is the source of ectopic endometrium, the pattern of lesions should be determined mainly by gravity, proximity to the site of abdominal entry and anatomicophysiological variables, whereas if coelomic metaplasia is the cause of endometriosis, lesions should not be distributed in relation to factors influencing the spreading and implantation of endometrial cells in the pelvis.

According to the proponents of the metaplasia theory, endometriotic cysts derive from invagination and differentiation of coelomic epithelium into the ovarian cortex. This process, based on the metaplastic potential of pelvic mesothelium, is closely linked to the pathogenetic mechanism of epithelial ovarian tumours. However, if this is the case, no major asymmetry in the frequency distribution of left- and right-sided ovarian endometriomas should be expected. The same considerations apply to the theory suggesting that large endometriomas may develop as a result of secondary invasion of luteal cysts by ovarian surface endometriotic cells. In fact, according to the available evidence, ovulation occurs either equally on both sides or more frequently on the right but not the left side.

If instead retrograde menstruation is the origin of endometriotic lesions, Al-Fozan & Tulandi’s findings should be considered taking into account anatomic factors that may influence the distribution and implantation of regurgitated endometrial cells. Indeed, the two adnexal regions are different, the left one being “protected” by the sigmoid colon. Not only does this portion of the large bowel lean on the left tube and ovary but it is very often fixed to the pelvic brim by filmy adhesions which are so frequently observed as to be considered a paraphysiological finding. A microenvironment is established around the left adnexa, the boundaries of which are the pelvic side wall, the lateral aspect of the sigmoid and the left broad ligament. As a consequence, endometrial cells regurgitated through the left tube are less exposed to the peritoneal milieau, and this may facilitate adhesion, implantation, and growth.

The finding of a lateral asymmetry in the location of ovarian endometriotic cysts as well as peritoneal endometriotic implants is in line with epidemiological data suggesting that the major pathogenetic mechanism of peritoneal and ovarian endometriosis is not substantially different, and supports the menstrual reflux theory.

Duepree et al.: J Am Coll Surg 2002 Dec 794-8. A good series, but retrospective. The authors describe their series of 51 patients with deep endometriotic lesions. Bowel resection was necessary in 18 cases. We learn that 14.7 % of 51 women had rectal bleeding. Clear indications should be more extensively discussed when bowel resection is envisaged.

Duepree et al recently reported their experience in the management of deep pelvic endometriosis involving the rectosigmoid. This paper is interesting for several reasons.

Their experience appears realistic combining the expertise of gynecologists and
of colorectal surgeons. The authors treated 51 patients, including 26 superficial excisions, 18 segmental recto sigmoid resections, 5 disc excisions and 5 cases of other procedures such as small bowel resection and ileocolic resection. These procedures were decided according to the diameter of the nodule and to thickness of the bowel involvement. Conversion to laparotomy and hysterectomy were necessary in 7.8% and 14.9% respectively. The operating time was 187 minutes, ranging from 132 to 418 minutes. The complication rate was low, with 1 anastomotic leakage treated by temporary ileostomy and drainage.

This paper emphasizes that surgical excision of deep endometriosis is highly effective in the treatment of pain. But it also demonstrates the difficulties and the complications which may be encountered in the management of these patients.

Interestingly, using a paper from Donnez et al in 1997, the authors attributed to J Donnez the classification of rectovaginal endometriosis published by P Koninckx and D Martin in 1992. Physicians involved in endometriosis do know the big debate between these two experts from Belgium. But, from these colorectal surgeons point of view, this debate seems less important!!

The surgical technique used for colon resection is that used by colorectal surgeons. They use a small low incision in the left lower quadrant for the removal of the specimen and insertion of the anvil for a circular stapler anastomosis. Most colorectal surgeons would consider that this technique is safer than a transvaginal anastomosis and easier than the controversial trans anal technique previously proposed by Nezhat et al.

The authors did not report how often the vagina was opened to excise the disease in the posterior cul de sac. In the discussion they suggest that with improved experience laparoscopic colectomy may appear as a more attractive option to manage these patients.

These two points are essential. Today we have very little data to compare the debulking approach (no rectal procedure) with routine vaginal excision proposed by Donnez et al, the oncologic excision of rectal lesions without colon resection and uncommon vaginal excision

proposed by Koninckx et al and the routine rectal resection proposed by Possover et al. What is the best approach? We do know that reoperation is much more difficult and that it should be avoided but we do not know the best compromise between the risk of complications and the effect on pain.

Prospective studies with long-term follow up are required. Randomized trials are probably difficult to perform for such questions. But we do need prospective studies, with postoperative data collected by research nurses or physicians ‘blinded’ for the procedure. We also need long term follow up of these patients to assess the incidence of re-operation and the long term pain results. Do they need several surgical procedures, do they need repeat medical treatments, did they become pregnant with or without IVF?

Moreover, many “experts” would also like to know:

Would it be possible to organize a prospective survey on these questions or to collect the data already available in the departments responsible for managing these cases? Is this a realistic challenge for WES?

Address to which suggestions for the WES newsletter and references for articles for literature review should be sent is: gillianh@brunnet.net

Spring issue of the WES e-newsletter was prepared by Gillian Hobbs in conjunction with Familles PCO