Human Reproduction vol.7 no.3 pp.432-435, 1992

Endometriosis 1991: a discussion document

'To whom correspondence should be addressed

Introduction Our understanding of endometriosis is changing. Recent evidence has suggested that there are many visual presentations of the phenomenon of ectopic endometrium and that it can even be found in normal peritoneum (Vasquez et al., 1984; Jansen and Russell, 1986; Cornillie et al., 1990; Nisolle et al, 1990). In addition, the successful treatment of minor degrees of endometriosis does not appear to influence future fertility and the effect of drug therapy may only have a temporary impact on the extent of the disease as defined at laparoscopy (Evers, 1987; Thomas and Cooke, 1987). There are exciting recent developments in the medical and surgical treatment of endometriosis, including laser laparoscopy and GnRH agonists; because of the cost of the latter, however, clinicians must closely examine indications for their use. These dilemmas mean that many gynaecologists are confused as to what actually constitutes endometriosis, when, for how long and with what to treat it. Recently, the authors of this document met and had a wideranging and open discussion, over 2 days, of the current problems in endometriosis. This document is the result of those discussions and represents the consensus view of the group. Its purpose is not to be a statement of fact or an article of truth, rather it aims at highlighting the areas requiring clarification and gives the group's opinion on them, so that further debate can be stimulated. The areas discussed were: the definition of endometriosis, the pathophysiology of the disease, the use of local and distant markers to aid diagnosis and treatment, the rationale for medical therapy, the rationale for surgical therapy and, finally, the design of future clinical trials. The consensus view of the group for each of these areas is detailed below. 432

Definition of endometriosis Endometriosis is a disease affecting many women during their reproductive life. However, the mere presence of what is defined as endometriosis histologically cannot be equated per se to the presence of a disease. Endometriosis as a disease should be defined as 'the presence of ectopic endometrium, in association with evidence of cellular activity in the lesions and of progression, such as the formation of adhesions, or by its interference with normal physiological processes'. Pathophysiology Infertility Although endometriosis is often associated with infertility, it has never been proven that the implants themselves are the cause of sterility (Evers, 1989). Furthermore, there is no evidence that the simple medical or surgical elimination of the lesions improves fertility in these patients (Brosens et al., 1985). Therefore, endometriosis cannot be said to be a cause of infertility, unless there is mechanical disruption of oocyte retrieval and/or impairment of embryo transport in the tube (Mahmoud and Templeton, 1989). Therefore, besides the surgical removal of all mechanical obstacles created by the body's reaction to the presence of ectopic endometrium, in improving fertility, more attention should be placed on restoring a normal peritoneal milieu (Steinleitner et al., 1990). Pelvic pain Endometriosis is often associated with pelvic pain. The degree of pain, however, often does not reflect the extent of disease detectable at laparoscopy. Although the pain in endometriosis is often cyclical and associated with menstruation, it is not mediated through the mechanisms which have been described to explain functional dysmenorrhoea. There are many features of the inflammatory process detectable in pelvic endometriosis. It is possible that the local inflammatory process associated with active peritoneal lesions can cause pain and tenderness by the production of prostaglandins, kinins and other peptide factors. It is likely that the local production of prostaglandins can affect the sensitivity of sensory nerve fibres, resulting in a lower threshold for pain sensation. The psychological status of the woman can influence the perception of pain and it is difficult to know, in individual cases, whether the psychological disturbance precedes or aggravates the pain, or is the result of the chronic exposure to it. Although endometriosis may lead to the production of dense and filmy adhe' Oxford University Press

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A.Audebert, Bordeaux, France T.Backstrom, Uppsala, Sweden D.H.Barlow, Oxford, UK G.Benagiano', Rome, Italy I.Brosens, Lou vain, Belgium K.Biihler, Essen, Germany J.Donnez, Brussels, Belgium J.L.H.Evers, Maastricht, The Netherlands A.Pellicer, Valencia, Spain L.Mettler, Kiel, Germany L.Ronnberg, Oulu, Finland S.K.Smith, Cambridge, UK and E.J.Thomas, Southampton, UK

Endometriosis 1991

sions, these sequelae are not thought to have a role in the generation of pain, unless they prevent the normal distension of organs such as the bowel, ureter or bladder, or displace organs from their normal position so that partial obstruction of blood flow or function might occur. Treatment regimens have often produced relief of pain without affecting adhesion scores. It should be stressed that pain due to other causes may be incorrectly attributed to endometriosis and that gynaecologists must remain aware of other possibilities, such as the irritable bowel syndrome. Chocolate cysts

The use of markers for diagnosis In order to differentiate the para-physiological finding of ectopic endometrial cells from that of active lesions, various markers may have a role. To be useful as a screening tool for a given disease or disorder, a marker needs to have a high sensitivity; to be useful to follow-up the efficacy of treatment, it has to possess high specificity. Focal markers Focal markers are important to determine the activity of an individual lesion. Such markers may be found by immunohistochemical investigation of the lesions or determination in tissue homogenates. Examples are: labelled epitopes of OC-125, tissue levels of prostaglandin Ej, prostaglandin F 2a , leukotrienes, and steroid hormone receptors. Also, mitotic figures and the determination of the secretory products of glandular tissue may be helpful. The impact of the lesions on the local environment, namely the peritoneal fluid, could be used as a marker of activity (Halme et al., 1987; Hill and Anderson, 1989). The number and activity of peritoneal macrophages and the concentration of their products (e.g. tumour necrosis factor, leukotrienes and prostaglandins) in peritoneal fluid could also become useful markers. Other factors found in peritoneal fluid which may be helpful are: the concentration of leukocytes, C-reactive proteins, macroglobulins, plasminogens and plasminogen inhibitors. These local markers can appear either as a response to the disease in general, or to the lesions, or to retrograde menstruation. Serum markers Serum markers include the concentration of CA-125, antiendometrial antibodies and monocytes (Fraser et al., 1989; Telimaa et al., 1989; Kennedy et al., 1990). For CA-125, a

Rationale for medical therapy The main current indications for medical therapy are to decrease pain, improve fertility, inactivate the lesions, or stop the progression of the disease. Although the mechanisms are not fully understood, the use of current endocrine therapies undoubtedly decreases pain. It is possible that there is a large placebo effect, or that the therapeutic mechanism involves the suppression of menstrual cyclicity, rather than a direct effect on the disease. It is probable that, in the future, medical treatment may differ according to whether its goal is the elimination of the implant, the relief of pelvic pain or the achievement of pregnancy. Fertility Because there is no definite evidence that medical treatment of endometriosis per se improves fertility, there is no rationale for its use in asymptomatic disease in infertile women. This is especially true as current medications are potent inhibitors of fertility and can have significant side-effects. For this reason, these patients should be managed in the same way as those with unexplained infertility. Pain The use of medical therapy is definitely indicated for the reduction of pain in endometriosis, as long as the clinician can establish some causal relationship between the disease and the occurrence of pain. Elimination of the ectopic implant Placebo-controlled studies of medical therapy show an increase in the amount of visual disease in - 5 0 % of patients not treated medically, at 6 months follow-up. This does not occur in subjects on active treatment, where statistically significant regression can be documented. In these studies however, the second-look laparoscopy has been performed during the last week of treatment and it is now known that the impact of medical therapy is limited in time, being far less if the laparoscopy is delayed for some time. Presently available evidence does not justify keeping patients on long-term medical therapy for the purpose of stopping the progression of the disease, unless activity is demonstrated or symptoms are relieved. Indeed, a recommendation to infertile women to achieve pregnancy as fast as possible, may be just as good a treatment strategy. Long-term follow-up studies, however difficult in their metholodology, are needed to describe accurately the type of lesions, their evolution and the effect of medical therapy. Future directions A therapeutic strategy for the future should be directed at modifying the peritoneal environment, rather than at eliminating the implants. 433

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Chocolate cysts are recognized to be a common finding in women with endometriosis. Before 1920, the presence of blood-filled cavities was invariably attributed to processes such as ovarian haematoma, haemorraghic corpora lutea and ovarian tumours. The occurrence of these entities is rare, but should not be overlooked. The mechanism of cyst formation could include surface implantation of the endometrium with subsequent enclosure of the implant. Conversely, some ovarian lesions could result from Miillerian remnants. Finally, it is possible that the cysts could enlarge not only because of bleeding within the implants, but also by ovulation into the cyst from follicles in the surrounding cortex.

specificity has been calculated which allows its use as a marker to detect regression, progression and recurrence, once the diagnosis has been established. For the moment no effective screening markers exist.

A.Audebert et al.

The rationale of surgical therapy

Surgery If at all possible, surgery should not be radical, unless the patient is past the reproductive phase of her life. In this eventuality, removal of the ovaries at hysterectomy may be the proper procedure as there is evidence that it is associated with a lower rate of re-intervention. This recommendation must be weighed against the psychological damage caused to women who feel that castration is a negative experience in their lives. Operative laparoscopy Whenever feasible, operative laparoscopy should be preferred to laparotomy. Although there is no evidence of better results, there is widespread feeling that the risk of formation of postoperative adhesions is less after laparoscopy than laparotomy. In addition, operative laparoscopy is more convenient to the patient, the recovery is shorter and there may be considerable cost savings. As to the technique used, there is no evidence that laser vaporization, with its additional cost, is more effective in destroying lesions than electrocautery. It is axiomatic that only gynaecologists correctly trained in operative laparoscopy should be allowed to utilize this technology, under close monitoring.

Pelvic pain Trials should investigate the psychological profile of patients prior to their inclusion in therapeutic protocols, in order to allow proper comparison at the end of the study. The protocol should provide a clear methodology to prove a causal relationship between the symptom complex and endometriosis before the patient is included in these studies. The pre-treatment laparoscopy should detail the type and localization of the lesions so that this can be correlated with physical signs. All trials evaluating the effect of treatment on pelvic pain should be double-blind and randomized, although there are almost unsurmountable difficulties in the blinding when the drug has effects which are very obvious to both the clinician and the patient. If the study focuses on pain, a second-look laparoscopy is not essential. This will simplify the design, allow larger recruitment and ensure a better continuation. It may be more informative to perform any second-look laparoscopy 6—12 months after the end of treatment, as this will detail the recurrence of the disease and allow the eventual reappearance of symptoms to be compared with the visual assessment of endometriosis.

Combining medical and surgical therapy

Conclusions

There is no large body of evidence to support the hypothesis that combination of medical and surgical therapy improves the treatment of endometriosis. Pre-operative treatment may decrease the disease and thus make the operation easier, while post-operative therapy may prevent recurrence. Proper clinical trials are needed to answer this question.

This document has tried to highlight the current dilemmas in endometriosis. Responsible clinicians and research workers must not only address these difficult issues, but must also inform health and institutional authorities of existing problems. This should enable a rational introduction of new medical and surgical management strategies, the efficacy of which have been verified by valid clinical trials, in specific situations. It appears clearly from the document that new strategies are needed both in basic and in clinical research. To address these issues and—hopefully—agree on a set of recommendations, the group is planning to meet again during 1992.

The design of future clinical trials It seems clear from the many still unanswered questions concerning management of endometriosis that properly designed clinical trials are badly needed. The major goals of any future trial should be: improvement of fertility, elimination of pelvic pain and an evaluation of the impact of treatment upon the natural history of the disease. Fertility Practically all trials so far have been unable to show a measurable benefit of medical treatment in the infertile woman, although most studies were flawed by the small number of patients. For this reason there may be a small, but clinically relevant, impact of therapy upon fertility, which has been missed. 434

References Brosens,I.A.. Cornillie.F.. Koninckx.P. and Vasquez.G. (1985) Evolution of the revised American Fertility Society classification of endometriosis (letter). Fertil. Steril., 44, 714. Cornillie,F.. Oosterlynch.D.. Lauweryns.J.M. and Koninckx.P.R. (1990) Deeply infiltrating pelvic endometriosis: histology and clinical significance. Fertil. Steril.. 53. 978-985. Evers.E. (1989) The pregnancy rate of the no-treatment group in

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The criticism of the medical treatment of asymptomatic, mild endometriosis is equally valid for surgical therapy. Indeed, there is no justification today for surgical intervention in mild endometriosis, unless it can be demonstrated that ablation of active, haemorrhagic lesions may be more effective than medical inactivation in preventing their reactivation after cessation of treatment. There is however one condition requiring active surgical management: this is advanced endometriosis, especially if the ovary is also involved in the disease.

Therefore, future studies have to be large-scale, with randomized non-treated controls and have a prospective statistical validation incorporated. The end-points of such studies shall be infertility and pregnancy and not the impact of treatment on laparoscopic findings. It is vital that confounding factors such as age, duration of infertility and the condition of the male should be taken into account. Medical treatment in infertility can probably be < 6 months, which would have the benefit of shortening the follow-up time. Realistically, there should be a beneficial impact within a year of finishing the treatment, because it is difficult to see biologically how there can be causality between therapy and the occurrence of a pregnancy > 12 months later.

Endometriosis 1991

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randomized clinical trials of endometriosis therapy. Fertil. Steril., 52, 906-907. Evers,J.L.H. (1987) The second look laparoscopy for evaluation of the result of medical treatment of endometriosis should not be performed during ovarian suppression. Fertil. Steril., 47, 502-503. Fraser.I.S., McCarron.G. and Markham.R. (1989) Serum CA-125 levels in women with endometriosis. Aust. N.Z. J. Obstet. Gynaecol., 29, 416-420. Halme,J., Becker,S. and Haskill,S. (1987) Altered maturation and function of peritoneal macrophages: possible role in pathogenesis of endometriosis. Am. J. Obstet. Gynecol., 156, 783—788. Hill,J.A. and Anderson,D.J. (1989) Lymphocyte activity in the presence of peritoneal fluid from fertile women and infertile women with and without endometriosis. Am. J. Obstet. Gynecol., 161, 861-864. Jansen,R.P.S. and Russell,P. (1986) Nonpigmented endometriosis: clinical, laparoscopic, and pathologic definition. Am. J. Obstet. Gynecol., 155, 1154-1159. Kennedy,S.H., Starkey.P.M., Sargent,I.L., Hicks,B.R. and Barlow,D.H. (1990) Antiendometrial antibodies in endometriosis measured by an enzyme-linked immunosorbent assay before and after treatment with danazol and nafarelin. Obstet. Gynecol., 75, 914—918. Mahmood.T.A. and Templeton,A. (1989) The relationship between endometriosis and semen analysis: a review of 490 consecutive laparoscopies. Hum. Reprod., 4, 782—785. Nisolle,M., Paindaveine,B., Bourdon.A., Berliere.M., Casanas-Roux,F. and Donnez.J. (1990) Histological study of peritoneal endometriosis in infertile women. Fertil. Steril., 53, 984-988. Steinleitner.A., Lampert.H. and Lauredo.I.T. (1990) Heterologous transplantation of activated murine peritoneal macrophages inhibits gamete interaction in vivo: a paradigm for endometriosis-associated subfertility. Fertil. Steril., 54, 725-729. Telimaa.S., Kauppila.A., Ronnberg.L., Suikkari,A. and Seppala,M. (1989) Elevated serum levels of endometrial secretory protein PP14 in patients with advanced endometriosis. Am. J. Obstet. Gynecol., 161, 866-871. Thomas,E.J. and Cooke,I.D. (1987) Successful treatment of asymptomatic endometriosis: does it benefit infertile women? Br. Med. J., 294, 1117-1119. Vasquez.G., Cornillie.F. and Brosens,I.A. (1984) Peritoneal endometriosis: scanning electron microscopy and histology of minimal pelvic endometriotic lesions. Fertil. Steril., 42, 696—703. Received on October 31, 1991; accepted on November 4, 1991

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Endometriosis 1991: a discussion document.

Human Reproduction vol.7 no.3 pp.432-435, 1992 Endometriosis 1991: a discussion document 'To whom correspondence should be addressed Introduction O...
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