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Endometriosis, 1995 — confusion or sense?
International Journal of Gynecology & Obstetrics 48 (1995) 149-155
Review article
Endometriosis, 1995- confusion or sense? E. J. Thomas ’ University of Southampton, Southampton University Hospital Trust, Southampton, UK
Received 12 September 1994;revision received 20 October 1994;accepted 26 October 1994
Abstract Objective: To review current understanding of endometriosis. Method: A review of etiology, pathogenesis,relationship with infertility, medical and surgical treatment. Results: It is likely that endometriosis occurs in most women at some stage in their reproductive years. Exposure to menstruation and estrogen are important etiologically. Current evidence suggeststhat implantation of menstrual endometrium is the commonest mechanismof pathogenesis.Clinical symptoms and signs are important in the diagnosis while laparoscopy remains the prime diagnostic technique. Treatment is not indicated for infertility but is for symptoms. Danazol and progestogensrepresent the best first-line therapy although gonadotropin-releasing hormone agonists are appropriate if economically justifiable. Both open and laparoscopic surgery are important especially in reconstructive work. The value of laser ablation in the treatment of infertility is unknown but it is effective in pain. The diseaseshould be regarded as a recurrent problem and treatment strategies designed appropriately. Conclusion: Endometriosis still represents an intellectual and therapeutic challenge but successful treatment is possible especially if it is individualized for each patient. Keywordr: Endometriosis; Pathogenesis; Infertility; Medical treatment; Surgery
1. Introduction Endometriosis was easier to understand 25 years ago when the diagnosis would only have been made by chance or because a laparotomy needed to be performed for a pelvic mass or severe symptoms. However the increasing use of laparoscopy has meant that access to the pelvis is much easier ’ Princess Anne Hospital, Coxford Road, Southampton SO16 SYA, UK, Tel.: +44 703 796044; Fax: +44 703 786933.
and is commoner in women with pelvic pain or who are asymptomatic, say in the investigation of infertility. It is becoming clear that endometriosis is a much more frequent and diverse phenomenon than was previously thought and may be physiological in menstruating women. Such information has created confusion about what constitutes endometriosis and when it requires treatment. This confusion has led to a division of opinion and there are now proponents of treating all endometriosis when it is diagnosed visually and others
0020-7292/95/$09.50 0 1995International Federation of Gynecology and Obstetrics SSDI 0020-7292(94)02277-6
150
E.J. Thomas/International Journal of Gynecology & Obstetrics 48 (1995) 149-155
who argue for a more selective approach. For the non-specialized gynecologist there are difficulties in deciding who to treat, when to treat and with what. This review highlights the main areas for discussion and the differing opinions that have been proposed. A simple framework for managing the disease, which should be relevant whatever level of health care is available, is described. 2. Deftition A literature review in 1985 [l] reported that endometriosis was diagnosed visually in 2.5% of laparoscopic sterilizations and between40 and 60% of laparoscopiesfor infertility. By 1992the incidence of the visual diagnosis of the diseasehad increased to 18% of laparoscopic sterilizations and in up to 80% of laparoscopies for infertility [2]. This does not represent a real increasein the incidence of the disease but rather an increase in the operator’s sensitivity to the diagnosis. It has also become clear that the manifestations of the disease are much more protean than the ‘powder burn’ spots or cysts that had been classically described. Jansen and Russel [3] reported that the diseasecould be found histologically in over 50% of clear vesicles, petechial and hemorrhagic areas,fibrous scarsand peritoneal defects. Furthermore there are reports that microscopic endometriosis could be found in up to 15% of normal peritoneal biopsies. In conclusion, it has become clear that the phenomenon is much more protean and ubiquitous than has ever been considered. Against this background it is difficult to be clear what constitutes endometriosis. A European consensusdocument [4] addressedthis and concluded that endometriosis per se is not a disease unless accompanied by signs of activity as defined by symptoms or local destruction. It is perhaps easier to think of two entities. The first is ectopic endometrium which can be defined as the presenceof tissue histologically similar to endometrium outside the uterine cavity and myometrium. This phenomenon is probably physiological and may be present in all menstruating women at somestagein their reproductive careers. The second is the disease, endometriosis, which is the presence of ectopic endometrium associated with symptoms or
local destruction or both. Whilst there is nothing formal about these definitions they do highlight the essential differences between the two phenomena. 3. Etiology Many factors have been postulated to be of etiological importance in endometriosis. Social class and personality have not been shown to be relevant except that women in higher social classes may delay childbearing longer and this may expose them to risk. Although differing incidences in racial groups have been reported there are so many confounding variables such as ease of accessto laparoscopy and timing of the investigation in differing countries, that no strong conclusions can be drawn. Three studies have reported a familial tendency to endometriosis. However care must be taken in interpreting this. It is likely that the diagnosis of endometriosis in one member of the family raises knowledge of the diseasewithin the family leading to an earlier recourse to medical help. The main etiological factors appear to be exposure to menstruation and estrogen. Goldman and Cramer [5] reported that endometriosis is more common in women with short menstrual cycles and longer menstruation. Vessey et al. [6], in a large longitudinal study, reported that the incidenceof endometriosis increasedwith age and that the oral contraceptive and pregnancy protected against the disease. This can be interpreted as aging leading to increasing exposure to menstruation and that the oral contraceptive and pregnancy would both decreasethat exposure. Goldman and Cramer [5] also reported that endometriosis was less common in smokers and in those with a low body mass index both of which would lead to a lower endogenous estrogen stimulation. The importance of these observations is that they emphasize how menstruation and estrogen are the two important etiological factors. It is not rational to recommend that women smoke cigarettes and becomeanorexic in order to avoid endometriosis. However, judicious use of the oral contraceptive and advice about early pregnancy may be valuable to women with a diagnosis made at a young age.
E.J. Thomas/International
Journal of Gynecology & Obstetrics 48 (1995) 149-155
4. Patbogenesis Endometriosis has been described as the disease of theories. There is compelling evidence that endometrium can be found in the veins and lymphatics draining the uterus suggesting that this may be one mechanism of dissemination especially to distant sites. Endometriosis can also occur through transplantation of endometrium at operation. However for most pelvic endometriosis the two main postulated mechanismsare through implantation of desquamated menstrual endometrium or mesothelial metaplasia either spontaneous or induced. Each mechanism has its proponents and it is possible to find endometriosis in males and in women without endometrium, so metaplasia is likely to occur. However there is evidence that endometriosis is very similar to endometrium in expression of growth factors [7], growth factor and steroid receptors [8-lo] and integrins [l l] in vivo. There is also considerable morphological similarity in endometriotic and endometrial stroma1and gland cultures in vitro and in the expression of epithelial antigens and intermediate filament proteins [ 12,131.Finally there are functional similarities in vitro between endometrium and endometriosis [ 13,141. Such similarities strongly suggestthat endometrium is the tissue of origin and thus that implantation is the main mechanism of pathogenesis. This is further supported by observations that peritoneal mesothelium does not express estrogen, progesterone or epidermal growth factor receptors [8,9], which would be vital for it to respond to an estrogenic signal. At the moment it appears that the etiological and experimental evidence supports the paradigm that most endometriosis results from the implantation of refluxed menstrual endometrium. The role of the immune system in allowing or aiding implantation is unclear. There are definite immune abnormalities reported in endometriosis [ 15,161. These include increases in endometrial autoantibodies, altered cell-mediated immunity, increasein important cytokines, and activation of lymphocytes and macrophages in the peritoneal fluid. However, there is considerable discussion
151
whether these are epiphenomenal or the result of the diseaserather than having a causal role and this still remains unresolved. 5. Natural history Three studies have reported the course of endometriosis if left either untreated or in a placebo arm [ 17-191. Overall they show that approximately 50% of endometriosis will either improve or remain the same over 6 months whilst there will be somedeterioration in the remainder. This deterioration is defined by an increase in the r-AFS [20] score but not necessarily by the appearance of symptoms.There is evidencethat the lesions in endometriosis have an evolution from active lesions which are vesicular and hemorrhagic to burnt out lesions represented by the ‘powder bum’ spots
WI. 6. Relationship with infertility Whilst there can be no doubt that endometriosis which damagesthe tubes and ovaries causesinfertility, there is no evidence that the successfultreatment of the diseasealone improves fertility [22]. As all medical treatments are contraceptive there is no indication for their use in infertility. There are still no properly designed studies of the surgical ablation of asymptomatic endometriosis in infertile women to determine whether this improves fertility. 7. Diagnosis The clinical presentation is still vital to the diagnosis of endometriosis. This is particularly important if it is acceptedthat some endometriosis may be found in many women, in which case it will occur coincidentally in some casesof pelvic pain. Attribution of causality will lead to inappropriate treatment in these women. The classic symptoms of endometriosis are cyclical pain and deep dyspareunia. The important signs are pelvic tenderness,nodules on the uterosacral ligaments, which are virtually diagnostic, and pelvic masses. The main diagnostic technique remains laparoscopy. Other techniques such as serum CA 125,im-
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Journal of Gynecology & Obstetrics 48 (1995) 149-155
munoscintigraphy with labelled ‘250C, magnetic resonanceimaging and ultrasound have not proved adequately sensitive or specific. Laparoscopy should be performed carefully with a good manipulator by an operator who is skilled in diagnosing the disease.Although there may be considerable clinical suspicion of endometriosis, the diagnosis should always be verified by laparoscopy before treatment is started, as the treatments are not without side effects and there can be considerable problems with women being labelled as having endometriosis when this may not be the case. 8. Indications for treatment As described before, infertility is not an indication to treat endometriosis. Symptomatic diseaseis the main indication. If the lesion is releasing inflammatory mediators that cause symptoms it should also be tender to touch in the same way that any acute inflammatory lesion is. Clinicians should be careful over attributing causality to a small amount of endometriosis where the symptom complex is not typical and the vaginal examination is normal. The role of perioperative medical treatment is unclear. Wheeler and Malinak [23] reported that some benefit accrued with postoperative medication but admitted the methodological flaws in their study. Otherwise there are no good methodological studies addressing the role of perioperative medication in open surgery. The recent developments in laparoscopic surgery have created new possibilities and recently Donnez et al. [24] showed that the combination of a GnRH agonist with laparoscopic cystectomy was beneficial. In conclusion, symptomatic endometriosis remains the main indication for treatment. 9. Medical treatment There are a number of potential medical treatments for endometriosis. The simplest are nonsteroidal antiinflammatory drugs (NSAIDs) taken during menstruation for dysmenorrhea. Good efticacy has been reported and these drugs have the benefit of few side effects in the short term and
they are not contraceptive. Progestogens have been popular in some countries for over 40 years. They decidualize the endometriosis leading to stromal edema,leukocyte infiltration and necrosis. There are a significant number of compounds available and they would all seemto have equivalent efficacy [25]. Their main side effects are edema, breast tenderness and poor bleeding control. Only a limited number of trials have beenperformed recently and in some countries their popularity has waned. Danazol (Danol; Sanoli, Guildford, UK) and gestrinone (Dimetriose; Roussel Laboratories, Uxbridge, UK) are complex drugs which are androgenic, progestogenic, antiestrogenic and antiprogestogenic. Although they are different compounds, it is logical to consider them together as they have similar mechanisms, the same efficacy and similar side effects [26,27]. Danazol has been the first-line medication in many countries. It is very effective but causes androgenic side effects. Gestrinone has equivalent efficacy (281 and tolerability and therefore the choice to use it instead of danazol should be based on economics although it is possible that the fact that it needsto be taken only every 3 days may be more acceptable to some women. The most recent additions to medical therapy are the GnRH agonists. These are analogs of native GnRH with a substitution at position 6 and often at 10 as well. Becausethey are metabolized more slowly than native GnRH and are much more potent, they act as a continual stimulation to the gonadotrophs in the anterior pituitary. This continual stimulation has the paradoxical effect of suppressing LH and FSH secretion so that the reproductive cycle is stopped. The subsequent hypoestrogenism leads to atrophy of the disease and healing. Their side effects are predictably hypoestrogenic with hot flushes, vaginal dryness and headaches [29]. Large randomized, comparative studies have shown them to be as effective as danazol and to have better tolerability [30-321. They would probably be the first-line treatment for endometriosis except that there is a substantial price differential betweenthem and danazol except for the nasal spray, nafarelin.
E. J. Thomas /International
Journal of Gynecology & Obstetrics 48 (1995) 149-155
10. Surgery The role of surgery in the treatment of endometriosis is well established. The timing of its use is a reflection of the personal preferenceof the practitioner, accessto modern laparoscopic techniques, the economics of the health care in that country, and the type of diseaseand presentation. Open laparotomy has been used for a long time both for conservative surgery and for hysterectomy with or without bilateral salpingo-oophorectomy. There are little new data published about open techniques except to address the role of oophorectomy at hysterectomy. Henderson and Studd [33] reported that the incidence of reoperation for continuing symptoms after hysterectomy was much less if the ovaries had been removed rather than conserved even if hormone replacement therapy was used. Clearly there is no defence for the wholesale removal of ovaries but the clinician needsto discussthis in detail with the woman and come to an agreed decision. Laparoscopic surgery for endometriosis has developed greatly in the last few years especially the use of the intraabdominal laser. Standard reconstructive laparoscopic surgery may lead to higher pregnancy rates than laparotomy [34]. Also the use of laser at laparotomy is equally effective as at laparoscopy [35] in subsequent pregnancy rates. The laser allows effective adhesiolysis without damaging adjacent tissue [36] and Sutton [37] has reported that adhesions are less likely to recur after laparoscopic surgery compared with laparotomy. In conclusion, laparoscopic surgery, in the right hands, with or without laser appears to be as effective as open surgery and probably better. The role of ablative laparoscopic surgery for pain is more controversial due to the lack of controlled studies. There are many uncontrolled studies claiming efficacy of this technique. One controlled study comparing laparoscopic laser ablation with sham operation has been performed and this shows no clear benefit at 3 months but a definite improvement in the laser group after 6 months (Sutton C, personal communication). The formal publication of these results is awaited with interest but if they are consistent then the amount
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of difference between the two groups at 6 months will determine whether it is economically justified to invest in an intraabdominal laser. Il. Treatment plans The next section provides a framework for the treatment of endometriosis for non-specialist clinicians. 11.1. Medical treatment
The first-line treatment for dysmenorrhea should be NSAIDs becausethey are cheap and can be used intermittently. If they are unsuccessful or if the problem is continuous pain or dyspareunia, then either progestogens or danazol should be used. There is clear evidence of intracellular degeneration in endometriosis after 2 months’ therapy [38] which is of such a degreethat it must lead to a change in cellular function and thus, symptoms. Therefore, if there is no change in symptoms after 3 months’ therapy both the diagnosis and treatment should be reviewed. If the clinician considers that the endometriosis was causal and not coincidental, then the medication should be changed to one which uses a different mechanism. The best of these would be the GnRH agonists which can also be used as a second-line therapy in patients who cannot tolerate other medications. The standard length of treatment is 6 months although that is not based on any well-conducted research. 11.2. Surgery
Laparoscopic ablation can be performed at diagnosis and is likely to be effective in women with symptomatic disease.However, as there is no evidencethat ablation improves fertility, there can be no justification for performing it in asymptomatic patients being investigated for infertility. Reconstructive surgery is clearly indicated in patients with pelvic damage wishing future fertility. Definitive surgery probably offers the best chance of cure of the problem although clearly this should only be undertaken after other avenueshave been explored and failed, and after considerable discussion with the patient about her future ambitions. The role of oophorectomy has already beendiscus-
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sed.One surgical strategy that could be considered in young women with resistant severediseaseis bilateral oophorectomy and the useof donor oocytes for future pregnancy. Such patients are rare and this management should only be considered at a tertiary referral center. 11.3. Recurrent disease
There is good evidence that medical therapy only suppressesthe diseaseand there is a clear recurrence rate of approximately 11% per annum [39]. In fact, if menstruation is a major causeof the diseasethen once this returns after either medical or surgical therapy there is a potential for recurrence. It is probably better to approach endometriosis as a chronic recurrent disease which can be managed with medication or conservative surgery but not cured. This is fairer to the patient and gives her realistic expectations. The problem with recurrence is knowing whether the treatment has failed or the diseasehas just inevitably returned. The return of symptoms within 6 months signals treatment failure and requires that a different strategy should be employed. The return of symptoms after 6 months signals that the disease has spontaneously recurred in spite of effective treatment and that the original treatment should be repeated. Further failure would require a change of treatment. In the end, the only treatment for severe, recurrent and resistant diseasemay well be a pelvic clearance. 12. Medical or surgical treatment Whether medical or surgical treatment is used is subject to many variables. Both are valid approaches for the initial treatment. Surgery will be more appropriate when there is tubal and ovarian damage,endometriotic cysts, diseaseat the end of the reproductive era, if there is other intercurrent gynecological disease or if medical therapy has failed. Medical treatment will be more appropriate in recurrent diseaseas repeated major surgical interventions are not easily justifiable. It may also be better in patients with normal pelvic anatomy as, unlessconsiderable skill is used, tubal and ovarian damage can occur as a result of the surgery thus creating more problems than it solves.
13. The patient The treatment should be individualized to each patient. Whether medical treatment or surgery is recommended will depend upon the absence or presenceof symptoms, the degree of the disease, the ageof the patient, her future fertility ambitions and her own feelings towards the disease and its implications. She therefore has a clear right to be involved in the decision-making as does her partner. Endometriosis is a complex diseasefor both doctor and patient and only by spending time and educating patients will a satisfactory service be provided. 14.
Conclusion
There has never been more knowledge about endometriosis currently, yet the causesof the disease and its rational treatment remain elusive. It still representsa major scientific and clinical challenge to clinicians, scientists and sufferers alike. References 111Thomas El. Investigations into the impact of gestrinone
upon the natural history of mild endometriosis and the relationship of that diseasewith infertility. University of Newcastle upon Tyne, 1987. PI Thomas EJ, Prentice A. The aetiology and pathogenesis of endometriosis. Reprod Med Rev 1992; 1: 21-36. [31 Jansen RP, Russel P. Nonpigmented endometriosis: clinical, laparoscopic and pathologic definition. Am J Obstet Gynecol 1986; 155: 1154-g. [41 Audebert A, Backstrom T, Barlow DH, et al. Endometriosis 1991:a discussion document. Hum Reprod 1992;7: 432-5. [51 Goldman MB, Cramer DW. The epidemiology of endometriosis. In: Chadha DR, Buttram VC, editors. Current concepts in endometriosis. New York: Liss, 1990: 15-31. 161Vessey MP, Villard-Mackintosh L, Painter R. Epidemiology of endometriosis in women attending family planning clinics. Br Med J 1993;306: 182-4. 171 Ferriani RA, Charnock-Jones DS, Prentice A, Thomas EJ, Smith SK. Immunohistochemical localization of fibroblast growth factors in normal human endometrium and endometriosis and the detection of their mRNA by polymerase chain reaction. Hum Reprod 1993; 8(l): 11-6. PI Prentice A, Randall B, Weddell A, et al. Epidermal growth factor receptor expression in normal endomet-
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Journal of Gynecology & Obstetrics 48 (1995) 149-155
rium and endometriosis: an immunohistochemical study. Br J Obstet Gynaecol 1992;99: 395-8. [9] Prentice A, Randall BJ, Weddell A, et al. Ovarian steroid receptor expression in endometriosis and in the two potential parent epithelia: endometrium and peritoneal mesothelium. Hum Reprod 1992; 7(9): 1318-25. [lo] Bergqvist A, Ljunberg 0, Skoog L. Immunohistochemical analysis of oestrogen and progesterone receptors in endometriotic tissue and endometrium. Hum Reprod 1993;8: 1915-22. [I I] Bridges JE, Prentice A, Roche W, Englefield P, Thomas EJ. The expression of integrin adhesion molecules in endometrium and endometriosis. Br J Obstet Gynaecol 1994; 101: 696-700. [I21 Matthews CJ, Redfem CPF, Hirst BH, Thomas EJ. Characterization of human purified epithelial and stromal cells from endometrium and endometriosis in tissue culture. Fertil Steril 1992; 57: 990-7. 1131 Ryan IP, Schriock ED, Taylor RN. Isolation, characterization and comparison of human endometrial and endometriosis cells in vitro. J Clin Endocrinol Metab 1994; 78(3): 642-9. [I41 Mellor SJ, Thomas EJ. The actions of oestradiol and epidermal growth factor in endometrial and endometriotic stroma in vitro. Fertil Steril 1994;62: 507-l 3. [ 151 Dmowski WP, Braun D, Gebel H. The immune systemin endometriosis. In: Thomas EJ, Rock J, editors. Modern approaches to endometriosis. Dordrecht: Kluwer, 1991: 97-111. (161 Hill JA. Immunology and endometriosis. Fertil Steril 1992;58(2): 262-4. [I71 Thomas EJ, Cooke ID. The impact of gestrinone upon the course of asymptomatic endometriosis. Br Med J 1987;294: 272-4. [18] Mahmood TA, Templeton A. The impact of treatment on the natural history of endometriosis. Hum Reprod 1990;5: 965-70. [I91 Telimaa S, Puolakka J, Ronnberg L, Kauppilla A. A placebo controlled comparison of danazol and high dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol 1987; I: 13-23. [20] American Fertility Society. Revised American Fertility Society classification of endometriosis: 1985.Fertil Steril 1985;43: 351-2. 1211 Redwine DB. Age-related evolution in color appearance of endometriosis. Fertil Steril 1987;48: 1062-3. 1221 Hughes EC, Fedorkow DM, Collins JA. A quantitative overview of controlled trials of endometriosis-associated infertility. Fertil Steril 1993; 59(5): 963-70. [23] Wheeler JM, Malinak LR. Combined medical and surgical therapy for endometriosis. In: Chadha DR, Buttram VC, editors. Current concepts in endometriosis. New York: Liss, 1990:281-8. [24] Donnez J, Nisolle M, Gillerot S, et al. Ovarian endometrial cysts - the role of gonadotrophin releasing
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hormone agonist and/or drainage. Fertil Steril 1994; 62(l): 63-6. 1251 Thomas EJ, Mettler L. Gestogensand anti-gestogensas treatment of endometriosis. In: Thomas EJ, Rock J, editors. Modem approaches to endometriosis. Dordrecht: Kluwer, 1991:221-38. [26] Barbieri RL. The use of danazol as a treatment of endometriosis. In: Thomas EJ, Rock J, editors. Modern approaches to endometriosis. Dordrecht: Kluwer. 1991: 239-55. [27] Worthington M, Irvine LM, Crook D, et al. A randomised comparative study of the metabolic effects of two regimensof gestrinone in the treatment of endometriosis. Fertil Steril 1993;59(3): 522-6. [28] Fedele L, Bianchi S, Viezzoli T, Arcaini L, Candiani GB. Gestrinone versus danazol in the treatment of endometriosis. Fertil Steril 1989; 51: 781-5. (291 Shaw RW. GnRH analogues in the treatment of endometriosis - rationale and efficacy. In: Thomas EJ, Rock J, editors. Modem approaches to endometriosis. Dordrecht: KIuwer, 1991:257-74. [30] Henzl MR. Corson SL, Moghissi K, et al. Administration of nasal nafarelin as compared with oral danazol for endometriosis. New Engl J Med 1988; 318: 485-9. [3l] Shaw RW, Zoladex Endometriosis Team. An open randomised study of the effect of goserelin depot and danazol in the treatment of endometriosis. Fertil Steril 1992;58(2): 265-72. [32] Wheeler JM, Knittle JD, Miller JD. Depot leuprolide versusdanazol in treatment of women with symptomatic endometriosis. I. Efficacy results. Am J Obstet Gynecol 1992; 167(5): 1367-71. [33] Henderson AF, Studd JWW. The role of definitive surgery and hormone replacement therapy in the treatment of endometriosis. In: Thomas EJ, Rock J, editors. Modern approaches to endometriosis. Dordrecht: Kluwer, 1991:275-97. [34] Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD. Laparoscopic endometriosis treatment: is it better. Fertil Steril 1993;59(l): 35-44. [35] Chong AP, Luciano A, O’ShaughnessyAM. Laser laparoscopy versuslaparotomy in the treatment of infertility patients with severeendometriosis. J Gynecol Surg 1990; 6: 179-83. [36] Kurtz BR, Daniel1JF. The role of lasersin the laparoscopit treatment of infertility and endometriosis. Reprod Med Rev 1993;2: 85-94. [37] Sutton C. Lasers in infertility. Hum Reprod 1993; 8: 133-46. 1381 Brosens IA, Verlayen A, Comillie F. The morphologic effect of short-term medical therapy of endometriosis. Am J Obstet Gynecol 1987; 157: 1215-21. [39] The Nafarelin European Endometriosis Trial Group. Nafarelin for endometriosis: a large scale, danazol controlled trial for efficacy and safety, with I year follow-up. Fertil Steril 1992; 57: 514-22.
Review article
Endometriosis, 1995- confusion or sense? E. J. Thomas ’ University of Southampton, Southampton University Hospital Trust, Southampton, UK
Received 12 September 1994;revision received 20 October 1994;accepted 26 October 1994
Abstract Objective: To review current understanding of endometriosis. Method: A review of etiology, pathogenesis,relationship with infertility, medical and surgical treatment. Results: It is likely that endometriosis occurs in most women at some stage in their reproductive years. Exposure to menstruation and estrogen are important etiologically. Current evidence suggeststhat implantation of menstrual endometrium is the commonest mechanismof pathogenesis.Clinical symptoms and signs are important in the diagnosis while laparoscopy remains the prime diagnostic technique. Treatment is not indicated for infertility but is for symptoms. Danazol and progestogensrepresent the best first-line therapy although gonadotropin-releasing hormone agonists are appropriate if economically justifiable. Both open and laparoscopic surgery are important especially in reconstructive work. The value of laser ablation in the treatment of infertility is unknown but it is effective in pain. The diseaseshould be regarded as a recurrent problem and treatment strategies designed appropriately. Conclusion: Endometriosis still represents an intellectual and therapeutic challenge but successful treatment is possible especially if it is individualized for each patient. Keywordr: Endometriosis; Pathogenesis; Infertility; Medical treatment; Surgery
1. Introduction Endometriosis was easier to understand 25 years ago when the diagnosis would only have been made by chance or because a laparotomy needed to be performed for a pelvic mass or severe symptoms. However the increasing use of laparoscopy has meant that access to the pelvis is much easier ’ Princess Anne Hospital, Coxford Road, Southampton SO16 SYA, UK, Tel.: +44 703 796044; Fax: +44 703 786933.
and is commoner in women with pelvic pain or who are asymptomatic, say in the investigation of infertility. It is becoming clear that endometriosis is a much more frequent and diverse phenomenon than was previously thought and may be physiological in menstruating women. Such information has created confusion about what constitutes endometriosis and when it requires treatment. This confusion has led to a division of opinion and there are now proponents of treating all endometriosis when it is diagnosed visually and others
0020-7292/95/$09.50 0 1995International Federation of Gynecology and Obstetrics SSDI 0020-7292(94)02277-6
150
E.J. Thomas/International Journal of Gynecology & Obstetrics 48 (1995) 149-155
who argue for a more selective approach. For the non-specialized gynecologist there are difficulties in deciding who to treat, when to treat and with what. This review highlights the main areas for discussion and the differing opinions that have been proposed. A simple framework for managing the disease, which should be relevant whatever level of health care is available, is described. 2. Deftition A literature review in 1985 [l] reported that endometriosis was diagnosed visually in 2.5% of laparoscopic sterilizations and between40 and 60% of laparoscopiesfor infertility. By 1992the incidence of the visual diagnosis of the diseasehad increased to 18% of laparoscopic sterilizations and in up to 80% of laparoscopies for infertility [2]. This does not represent a real increasein the incidence of the disease but rather an increase in the operator’s sensitivity to the diagnosis. It has also become clear that the manifestations of the disease are much more protean than the ‘powder burn’ spots or cysts that had been classically described. Jansen and Russel [3] reported that the diseasecould be found histologically in over 50% of clear vesicles, petechial and hemorrhagic areas,fibrous scarsand peritoneal defects. Furthermore there are reports that microscopic endometriosis could be found in up to 15% of normal peritoneal biopsies. In conclusion, it has become clear that the phenomenon is much more protean and ubiquitous than has ever been considered. Against this background it is difficult to be clear what constitutes endometriosis. A European consensusdocument [4] addressedthis and concluded that endometriosis per se is not a disease unless accompanied by signs of activity as defined by symptoms or local destruction. It is perhaps easier to think of two entities. The first is ectopic endometrium which can be defined as the presenceof tissue histologically similar to endometrium outside the uterine cavity and myometrium. This phenomenon is probably physiological and may be present in all menstruating women at somestagein their reproductive careers. The second is the disease, endometriosis, which is the presence of ectopic endometrium associated with symptoms or
local destruction or both. Whilst there is nothing formal about these definitions they do highlight the essential differences between the two phenomena. 3. Etiology Many factors have been postulated to be of etiological importance in endometriosis. Social class and personality have not been shown to be relevant except that women in higher social classes may delay childbearing longer and this may expose them to risk. Although differing incidences in racial groups have been reported there are so many confounding variables such as ease of accessto laparoscopy and timing of the investigation in differing countries, that no strong conclusions can be drawn. Three studies have reported a familial tendency to endometriosis. However care must be taken in interpreting this. It is likely that the diagnosis of endometriosis in one member of the family raises knowledge of the diseasewithin the family leading to an earlier recourse to medical help. The main etiological factors appear to be exposure to menstruation and estrogen. Goldman and Cramer [5] reported that endometriosis is more common in women with short menstrual cycles and longer menstruation. Vessey et al. [6], in a large longitudinal study, reported that the incidenceof endometriosis increasedwith age and that the oral contraceptive and pregnancy protected against the disease. This can be interpreted as aging leading to increasing exposure to menstruation and that the oral contraceptive and pregnancy would both decreasethat exposure. Goldman and Cramer [5] also reported that endometriosis was less common in smokers and in those with a low body mass index both of which would lead to a lower endogenous estrogen stimulation. The importance of these observations is that they emphasize how menstruation and estrogen are the two important etiological factors. It is not rational to recommend that women smoke cigarettes and becomeanorexic in order to avoid endometriosis. However, judicious use of the oral contraceptive and advice about early pregnancy may be valuable to women with a diagnosis made at a young age.
E.J. Thomas/International
Journal of Gynecology & Obstetrics 48 (1995) 149-155
4. Patbogenesis Endometriosis has been described as the disease of theories. There is compelling evidence that endometrium can be found in the veins and lymphatics draining the uterus suggesting that this may be one mechanism of dissemination especially to distant sites. Endometriosis can also occur through transplantation of endometrium at operation. However for most pelvic endometriosis the two main postulated mechanismsare through implantation of desquamated menstrual endometrium or mesothelial metaplasia either spontaneous or induced. Each mechanism has its proponents and it is possible to find endometriosis in males and in women without endometrium, so metaplasia is likely to occur. However there is evidence that endometriosis is very similar to endometrium in expression of growth factors [7], growth factor and steroid receptors [8-lo] and integrins [l l] in vivo. There is also considerable morphological similarity in endometriotic and endometrial stroma1and gland cultures in vitro and in the expression of epithelial antigens and intermediate filament proteins [ 12,131.Finally there are functional similarities in vitro between endometrium and endometriosis [ 13,141. Such similarities strongly suggestthat endometrium is the tissue of origin and thus that implantation is the main mechanism of pathogenesis. This is further supported by observations that peritoneal mesothelium does not express estrogen, progesterone or epidermal growth factor receptors [8,9], which would be vital for it to respond to an estrogenic signal. At the moment it appears that the etiological and experimental evidence supports the paradigm that most endometriosis results from the implantation of refluxed menstrual endometrium. The role of the immune system in allowing or aiding implantation is unclear. There are definite immune abnormalities reported in endometriosis [ 15,161. These include increases in endometrial autoantibodies, altered cell-mediated immunity, increasein important cytokines, and activation of lymphocytes and macrophages in the peritoneal fluid. However, there is considerable discussion
151
whether these are epiphenomenal or the result of the diseaserather than having a causal role and this still remains unresolved. 5. Natural history Three studies have reported the course of endometriosis if left either untreated or in a placebo arm [ 17-191. Overall they show that approximately 50% of endometriosis will either improve or remain the same over 6 months whilst there will be somedeterioration in the remainder. This deterioration is defined by an increase in the r-AFS [20] score but not necessarily by the appearance of symptoms.There is evidencethat the lesions in endometriosis have an evolution from active lesions which are vesicular and hemorrhagic to burnt out lesions represented by the ‘powder bum’ spots
WI. 6. Relationship with infertility Whilst there can be no doubt that endometriosis which damagesthe tubes and ovaries causesinfertility, there is no evidence that the successfultreatment of the diseasealone improves fertility [22]. As all medical treatments are contraceptive there is no indication for their use in infertility. There are still no properly designed studies of the surgical ablation of asymptomatic endometriosis in infertile women to determine whether this improves fertility. 7. Diagnosis The clinical presentation is still vital to the diagnosis of endometriosis. This is particularly important if it is acceptedthat some endometriosis may be found in many women, in which case it will occur coincidentally in some casesof pelvic pain. Attribution of causality will lead to inappropriate treatment in these women. The classic symptoms of endometriosis are cyclical pain and deep dyspareunia. The important signs are pelvic tenderness,nodules on the uterosacral ligaments, which are virtually diagnostic, and pelvic masses. The main diagnostic technique remains laparoscopy. Other techniques such as serum CA 125,im-
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munoscintigraphy with labelled ‘250C, magnetic resonanceimaging and ultrasound have not proved adequately sensitive or specific. Laparoscopy should be performed carefully with a good manipulator by an operator who is skilled in diagnosing the disease.Although there may be considerable clinical suspicion of endometriosis, the diagnosis should always be verified by laparoscopy before treatment is started, as the treatments are not without side effects and there can be considerable problems with women being labelled as having endometriosis when this may not be the case. 8. Indications for treatment As described before, infertility is not an indication to treat endometriosis. Symptomatic diseaseis the main indication. If the lesion is releasing inflammatory mediators that cause symptoms it should also be tender to touch in the same way that any acute inflammatory lesion is. Clinicians should be careful over attributing causality to a small amount of endometriosis where the symptom complex is not typical and the vaginal examination is normal. The role of perioperative medical treatment is unclear. Wheeler and Malinak [23] reported that some benefit accrued with postoperative medication but admitted the methodological flaws in their study. Otherwise there are no good methodological studies addressing the role of perioperative medication in open surgery. The recent developments in laparoscopic surgery have created new possibilities and recently Donnez et al. [24] showed that the combination of a GnRH agonist with laparoscopic cystectomy was beneficial. In conclusion, symptomatic endometriosis remains the main indication for treatment. 9. Medical treatment There are a number of potential medical treatments for endometriosis. The simplest are nonsteroidal antiinflammatory drugs (NSAIDs) taken during menstruation for dysmenorrhea. Good efticacy has been reported and these drugs have the benefit of few side effects in the short term and
they are not contraceptive. Progestogens have been popular in some countries for over 40 years. They decidualize the endometriosis leading to stromal edema,leukocyte infiltration and necrosis. There are a significant number of compounds available and they would all seemto have equivalent efficacy [25]. Their main side effects are edema, breast tenderness and poor bleeding control. Only a limited number of trials have beenperformed recently and in some countries their popularity has waned. Danazol (Danol; Sanoli, Guildford, UK) and gestrinone (Dimetriose; Roussel Laboratories, Uxbridge, UK) are complex drugs which are androgenic, progestogenic, antiestrogenic and antiprogestogenic. Although they are different compounds, it is logical to consider them together as they have similar mechanisms, the same efficacy and similar side effects [26,27]. Danazol has been the first-line medication in many countries. It is very effective but causes androgenic side effects. Gestrinone has equivalent efficacy (281 and tolerability and therefore the choice to use it instead of danazol should be based on economics although it is possible that the fact that it needsto be taken only every 3 days may be more acceptable to some women. The most recent additions to medical therapy are the GnRH agonists. These are analogs of native GnRH with a substitution at position 6 and often at 10 as well. Becausethey are metabolized more slowly than native GnRH and are much more potent, they act as a continual stimulation to the gonadotrophs in the anterior pituitary. This continual stimulation has the paradoxical effect of suppressing LH and FSH secretion so that the reproductive cycle is stopped. The subsequent hypoestrogenism leads to atrophy of the disease and healing. Their side effects are predictably hypoestrogenic with hot flushes, vaginal dryness and headaches [29]. Large randomized, comparative studies have shown them to be as effective as danazol and to have better tolerability [30-321. They would probably be the first-line treatment for endometriosis except that there is a substantial price differential betweenthem and danazol except for the nasal spray, nafarelin.
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10. Surgery The role of surgery in the treatment of endometriosis is well established. The timing of its use is a reflection of the personal preferenceof the practitioner, accessto modern laparoscopic techniques, the economics of the health care in that country, and the type of diseaseand presentation. Open laparotomy has been used for a long time both for conservative surgery and for hysterectomy with or without bilateral salpingo-oophorectomy. There are little new data published about open techniques except to address the role of oophorectomy at hysterectomy. Henderson and Studd [33] reported that the incidence of reoperation for continuing symptoms after hysterectomy was much less if the ovaries had been removed rather than conserved even if hormone replacement therapy was used. Clearly there is no defence for the wholesale removal of ovaries but the clinician needsto discussthis in detail with the woman and come to an agreed decision. Laparoscopic surgery for endometriosis has developed greatly in the last few years especially the use of the intraabdominal laser. Standard reconstructive laparoscopic surgery may lead to higher pregnancy rates than laparotomy [34]. Also the use of laser at laparotomy is equally effective as at laparoscopy [35] in subsequent pregnancy rates. The laser allows effective adhesiolysis without damaging adjacent tissue [36] and Sutton [37] has reported that adhesions are less likely to recur after laparoscopic surgery compared with laparotomy. In conclusion, laparoscopic surgery, in the right hands, with or without laser appears to be as effective as open surgery and probably better. The role of ablative laparoscopic surgery for pain is more controversial due to the lack of controlled studies. There are many uncontrolled studies claiming efficacy of this technique. One controlled study comparing laparoscopic laser ablation with sham operation has been performed and this shows no clear benefit at 3 months but a definite improvement in the laser group after 6 months (Sutton C, personal communication). The formal publication of these results is awaited with interest but if they are consistent then the amount
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of difference between the two groups at 6 months will determine whether it is economically justified to invest in an intraabdominal laser. Il. Treatment plans The next section provides a framework for the treatment of endometriosis for non-specialist clinicians. 11.1. Medical treatment
The first-line treatment for dysmenorrhea should be NSAIDs becausethey are cheap and can be used intermittently. If they are unsuccessful or if the problem is continuous pain or dyspareunia, then either progestogens or danazol should be used. There is clear evidence of intracellular degeneration in endometriosis after 2 months’ therapy [38] which is of such a degreethat it must lead to a change in cellular function and thus, symptoms. Therefore, if there is no change in symptoms after 3 months’ therapy both the diagnosis and treatment should be reviewed. If the clinician considers that the endometriosis was causal and not coincidental, then the medication should be changed to one which uses a different mechanism. The best of these would be the GnRH agonists which can also be used as a second-line therapy in patients who cannot tolerate other medications. The standard length of treatment is 6 months although that is not based on any well-conducted research. 11.2. Surgery
Laparoscopic ablation can be performed at diagnosis and is likely to be effective in women with symptomatic disease.However, as there is no evidencethat ablation improves fertility, there can be no justification for performing it in asymptomatic patients being investigated for infertility. Reconstructive surgery is clearly indicated in patients with pelvic damage wishing future fertility. Definitive surgery probably offers the best chance of cure of the problem although clearly this should only be undertaken after other avenueshave been explored and failed, and after considerable discussion with the patient about her future ambitions. The role of oophorectomy has already beendiscus-
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sed.One surgical strategy that could be considered in young women with resistant severediseaseis bilateral oophorectomy and the useof donor oocytes for future pregnancy. Such patients are rare and this management should only be considered at a tertiary referral center. 11.3. Recurrent disease
There is good evidence that medical therapy only suppressesthe diseaseand there is a clear recurrence rate of approximately 11% per annum [39]. In fact, if menstruation is a major causeof the diseasethen once this returns after either medical or surgical therapy there is a potential for recurrence. It is probably better to approach endometriosis as a chronic recurrent disease which can be managed with medication or conservative surgery but not cured. This is fairer to the patient and gives her realistic expectations. The problem with recurrence is knowing whether the treatment has failed or the diseasehas just inevitably returned. The return of symptoms within 6 months signals treatment failure and requires that a different strategy should be employed. The return of symptoms after 6 months signals that the disease has spontaneously recurred in spite of effective treatment and that the original treatment should be repeated. Further failure would require a change of treatment. In the end, the only treatment for severe, recurrent and resistant diseasemay well be a pelvic clearance. 12. Medical or surgical treatment Whether medical or surgical treatment is used is subject to many variables. Both are valid approaches for the initial treatment. Surgery will be more appropriate when there is tubal and ovarian damage,endometriotic cysts, diseaseat the end of the reproductive era, if there is other intercurrent gynecological disease or if medical therapy has failed. Medical treatment will be more appropriate in recurrent diseaseas repeated major surgical interventions are not easily justifiable. It may also be better in patients with normal pelvic anatomy as, unlessconsiderable skill is used, tubal and ovarian damage can occur as a result of the surgery thus creating more problems than it solves.
13. The patient The treatment should be individualized to each patient. Whether medical treatment or surgery is recommended will depend upon the absence or presenceof symptoms, the degree of the disease, the ageof the patient, her future fertility ambitions and her own feelings towards the disease and its implications. She therefore has a clear right to be involved in the decision-making as does her partner. Endometriosis is a complex diseasefor both doctor and patient and only by spending time and educating patients will a satisfactory service be provided. 14.
Conclusion
There has never been more knowledge about endometriosis currently, yet the causesof the disease and its rational treatment remain elusive. It still representsa major scientific and clinical challenge to clinicians, scientists and sufferers alike. References 111Thomas El. Investigations into the impact of gestrinone
upon the natural history of mild endometriosis and the relationship of that diseasewith infertility. University of Newcastle upon Tyne, 1987. PI Thomas EJ, Prentice A. The aetiology and pathogenesis of endometriosis. Reprod Med Rev 1992; 1: 21-36. [31 Jansen RP, Russel P. Nonpigmented endometriosis: clinical, laparoscopic and pathologic definition. Am J Obstet Gynecol 1986; 155: 1154-g. [41 Audebert A, Backstrom T, Barlow DH, et al. Endometriosis 1991:a discussion document. Hum Reprod 1992;7: 432-5. [51 Goldman MB, Cramer DW. The epidemiology of endometriosis. In: Chadha DR, Buttram VC, editors. Current concepts in endometriosis. New York: Liss, 1990: 15-31. 161Vessey MP, Villard-Mackintosh L, Painter R. Epidemiology of endometriosis in women attending family planning clinics. Br Med J 1993;306: 182-4. 171 Ferriani RA, Charnock-Jones DS, Prentice A, Thomas EJ, Smith SK. Immunohistochemical localization of fibroblast growth factors in normal human endometrium and endometriosis and the detection of their mRNA by polymerase chain reaction. Hum Reprod 1993; 8(l): 11-6. PI Prentice A, Randall B, Weddell A, et al. Epidermal growth factor receptor expression in normal endomet-
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