establishment and persistence of endometriosis. Haptoglobin is synthesized in large amounts by endometriotic lesions and can act on peritoneal macrophages ...
FERTILITY AND STERILITY威 VOL. 81, NO. 5, MAY 2004 Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Understanding endometriosis is the key to successful therapeutic management Kathy L. Sharpe-Timms, Ph.D., and Steven L. Young, M.D., Ph.D. Department of Obstetrics and Gynecology, School of Medicine, University of Missouri-Columbia, Columbia, Missouri
Understanding endometriosis on a molecular, biochemical, and genetic level will lead to better methods for the diagnosis and therapeutic management of this enigmatic disease. (Fertil Steril威 2004;81:1201⫺3. ©2004 by American Society for Reproductive Medicine.)
Received September 30, 2003; revised and accepted September 30, 2003. Reprint requests: Kathy L. Sharpe-Timms, Ph.D., Department of Obstetrics and Gynecology, University of Missouri-Columbia, 1 Hospital Drive, N 625 Health Sciences Center, Columbia, Missouri 65212 (FAX: 573-882-9010; Email: timmsk@health. missouri.edu). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2003. 09.072
The presence of ectopic, nonneoplastic, hormonally responsive endometrium was described as early as 1860 by Von Rokitansky, and over the next century, various theories evolved to explain the origin of endometriosis (1, 2). Yet, our understanding of endometriosis remains incomplete, and controversy continues regarding endometriosis-associated disorders, including infertility. Women with infertility clearly demonstrate an increased incidence of endometriosis (2), but the mechanisms by which endometriosis is associated with infertility remain controversial and are likely complex. Clinical research has produced conflicting evidence regarding a causal relationship between endometriosis and infertility. Mechanistic studies have suggested adverse effects on oocyte and embryo development, ovum pickup, and implantation rates, bolstering the argument for a causal relationship between endometriosis and infertility (3). Thus, most clinicians and scientists believe that endometriosis can cause infertility.
DOES SURGERY FOR ENDOMETRIOSIS INCREASE FERTILITY? If endometriosis causes infertility, does removal of endometriosis increase fertility? Again, the literature contains conflicting data. Perhaps the highest-quality evidence, a recent systematic review combining two prospective, randomized trials of ablative surgery, supports the notion that laparoscopic surgery increases fertility for stage I and II disease (4 – 6). If we
accept the conclusions of the systematic review, a large number of relevant clinical questions follow. Do results differ in patients with stage III or IV endometriosis? Does treatment outcome depend on other biological variables? Do assisted reproductive technology (ART) techniques increase fertility in endometriosis? Which ART technique is optimal? Which is better, surgery or ART? Does surgery before ART improve outcome? Definitive answers to these questions remain unavailable, and clinical practice is based primarily on observational data and the advice of experienced and learned clinicians (3). Garcia-Velasco et al. (7), in this issue of Fertility and Sterility, address one of these many questions by studying the effects of endometrioma surgery on IVF success.
IS SURGERY BEFORE ART BENEFICIAL? A recent meta-analysis suggests a decreased IVF success rate for patients with endometriosis, demonstrating a worse outcome for patients with stages III to IV endometriosis vs. stages I to II (8). The meta-analysis is, however, based solely on observational data. Garcia-Velasco et al. (7) have contributed an additional observational study, which focused only on patients with moderate-to-large ovarian endometriomas (by definition American Society for Reproductive Medicine [ASRM] stage III to IV). Specifically, Garcia-Velasco et al. report a retrospective, case– control study comparing ART outcomes from women treated by laparoscopic cystectomy for an endometrioma ⬎3 cm (n ⫽ 1201
133) with those of women with an ovarian endometrioma ⬎3 cm, diagnosed by ultrasound, who had not undergone cystectomy (n ⫽ 56). In contrast to the findings of the prospective, randomized trials on patients with stage I to II disease and the collected observational data on stage III to IV disease, Garcia-Velasco et al. report no difference in IVF outcome between patients with endometriomas who had cystectomy before IVF and those who did not.
anism that is not modified by cystectomy. A unified theory of the effects of surgery on endometriosis-related infertility must also be reconciled with demonstrated benefit of surgery in stage I to II disease (4).
Because the retrospective data of Garcia-Velasco et al. (7) conflict somewhat with prior prospective data, it is useful to examine the current study more carefully. Although the Garcia-Velasco study is exemplary in design and execution, retrospective studies can always be criticized for possible bias resulting from the treatment and control groups being drawn from different populations. A salient difference between the two groups in the Garcia-Velasco study is that the clinical decision was made to operate on one set of patients and to not operate on the other. Could patients more likely to have surgery have more active, painful disease, which might result in baseline fertility differences from patients who did not have surgery? A further difference between the two groups is that presence of peritoneal disease cannot be ascertained in the nonsurgical group. Finally, because the surgery occurred as much as 12 months before the ART treatment cycle and without adjuvant medical therapy, significant numbers of the surgical patients likely had recurrent peritoneal or other lesions. The question of bias will only be eliminated by a prospective, randomized, controlled trial, which the authors report is in progress. An additional statistical issue that must be raised in any study that fails to find a difference between groups is statistical power. Although power calculations are not reported in the article, the sample size is not small, and the means are very similar, which suggests that lack of statistical power is not the most likely explanation of the findings.
It is clear that significant controversy pervades the clinical endometriosis literature. Systematic reviews and meta-analyses are helpful in that they allow rigorous review of data quality and combine data from multiple trials. However, without sufficient underlying basic knowledge, we cannot hope to design trials to test key questions, devise new treatment strategies, or evaluate the generalizability of clinical research to each unique patient. Because surgical stage does not correlate well with pain or infertility (14), perhaps an improved classification system would allow grouping of patients, who would have similar symptoms and respond to therapies in a similar fashion. Basic science research on endometriosis is emerging that might allow better grouping of patients, enable better interpretation of existing clinical data, and inform the design of future studies.
An interesting outcome of this study, not commented on by the authors, is that the clinical pregnancy rates per transfer (25.4% and 22.7%) in both groups are lower than might be expected. For comparison, year 2000 Society of Assisted Reproductive Technology data demonstrated that the average pregnancy rate per transfer for patients using fresh, non-donor oocytes is 38.2%. Furthermore the IVF cycles in the study were conducted at two highly successful, highvolume, state-of-the-art clinics. Thus, the article does not seem to contradict previous findings that stage III to IV endometriosis likely causes infertility and lowers success at IVF (8 –13). If we accept that endometriomas are associated with worse IVF outcomes, why did cystectomy not improve IVF success in the current study, even as surgery for stage III to IV endometriosis improved IVF outcome in prior studies (8)? Assuming that the aforementioned issues of power, bias, or recurrence are not the primary explanation, one could hypothesize that endometriosis causes infertility by a mech1202 Sharpe-Timms and Young
Understanding endometriosis
CAN THE CONFLICTING DATA BE RECONCILED?
Basic science data suggest that explanations of the clinical data might lie in biological differences between peritoneal and ovarian endometriosis and in recent findings that endometriosis is associated with abnormalities of eutopic endometrium and systemic immunity. Because ovarian endometriomas are not directly bathed in peritoneal fluid, twoway paracrine interactions between the endometriotic lesion and the pelvic tissues might be greatly attenuated. Thus, peritoneal lesions, stimulated by proinflammatory cytokines and capable of releasing factors that can directly diffuse throughout the pelvis, might have more profound effects on fertility. Along these lines, Nisolle and Donnez (15) have proposed that ovarian endometriosis, peritoneal endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. If this is the case, then a universal “one treatment fits all” approach might be woefully inadequate and might go some way to explain the different impact of surgery on ovarian and peritoneal endometriosis. Of particular interest regarding the data of GarciaVelasco et al. (7) are the findings that alterations in eutopic endometrium, as well as peritoneal and systemic immunity, exist in women with endometriosis (12, 16 –20). Abnormalities in eutopic endometrium from patients with endometriosis have been described for endometrial structure, proliferation and apoptosis, immune-cell function, cell adhesion molecules, proteases and inhibitors, steroid production and action, growth factor and cytokine production and action, and alterations in the expression of a host of genes. Thus, eutopic endometrium and/or immune function in women with endometriosis might be inherently aberrant. If this is true, surgical intervention, which treats only the endometriVol. 81, No. 5, May 2004
otic lesions, might play only a limited role in effective management of endometriosis-related infertility. Our research has focused on the role of haptoglobin in the establishment and persistence of endometriosis. Haptoglobin is synthesized in large amounts by endometriotic lesions and can act on peritoneal macrophages to block their phagocytic function and simultaneously upregulate production of inflammatory cytokines, including interleukin-6 (IL-6) (16, 21, 22). In turn, IL-6 dramatically upregulates haptoglobin production by endometriotic lesions (23). This feed-forward loop between endometriotic lesion production of haptoglobin and peritoneal macrophage production of IL-6 should favor the establishment and survival of endometriotic lesions, and thus, this loop is a potential target for future pharmacologic therapy. Interestingly, eutopic endometrium from patients with endometriosis displays markedly increased haptoglobin production. Haptoglobin might also be involved in endometriosisassociated infertility. Studies on rabbit implantation point to a potential role of haptoglobin in embryo implantation (24). Furthermore, an association between higher fertility and homozygosity for a specific haptoglobin allele (Hp*1) in humans has recently been reported (25), which suggests a potential link between altered haptoglobin structure and fertility. People with a Hp*1/Hp*1 genotype produce more as well as a smaller polymer, which might diffuse more readily at the site of implantation (26); this points to a possible explanation for the greater fertility of women with the Hp*1/*1 genotype compared with women with an Hp*2 allele. Although work connecting haptoglobin to endometriosis pathogenesis and pathophysiology has the potential to explain many aspects of the disease, further work is needed to establish the relationship of haptoglobin, fertility, and endometriosis in humans. The pattern of endometrial haptoglobin in the rabbit differs significantly from that of the human. Unlike in the rabbit, only minimal haptoglobin has been detected in normal eutopic endometrium from women without endometriosis. Conversely, haptoglobin is produced by the eutopic endometrium of women with endometriosis during the window of implantation; however, it is synthesized and secreted by the functionalis layer of the stroma, as opposed to the endometrial epithelium in the rabbit (16). D’Hooghe et al. (27) have insightfully proposed that future research in endometriosis should include integrated clinical and research teams that combine expert medical, surgical, and holistic care with state-of-the-art research expertise in immunology, endocrinology, and genetics to discover new diagnostic and treatment methods for endometriosis. Clearly, a better understanding of factors involved in the establishment, persistence, and pathophysiology of endometriosis will allow better interpretation of existing data, better grouping of patients into functional categories, and inform the design of future studies. Until such rigorous FERTILITY & STERILITY威
studies can be completed, the role of each therapy in optimal management will remain controversial. References 1. Ridley J. The histogenesis of endometriosis: a review of facts and fancies. Obstet Gynecol Surv 1938;23:1 :1. 2. Witz CA, Burns WN. Endometriosis and infertility: is there a cause and effect relationship? Gynecol Obstet Invest 2002;53(Suppl 1):2–11. 3. Barbieri R. Endometriosis and infertility. Wellesley, Massachusetts: UpToDate, 2003. 4. Jacobson T, Barlow D, Koninckx P, Olive D, Farquhar C. Laparoscopic surgery for subfertility associated with endometriosis. Cochrane Database Syst Rev 2001;(4):CD001300. 5. Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. Canadian Collaborative Group on Endometriosis. N Engl J Med 1997;337:217–22. 6. Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women: a randomized trial. Gruppo Italiano per lo Studio dell’Endometriosi. Hum Reprod 1999;14:1332–4. 7. Garcia-Velasco JA, Mahutte NG, Corona J, Zu´ n˜ iga V, Gile´ s J, Arici A, et al. Removal of endometriomas before in vitro fertilization does not improve fertility outcomes: a matched, case-control study. Fertil Steril 2004;81:1194 –7. 8. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril 2002;77:1148 –55. 9. Azem F, Lessing JB, Geva E, Shahar A, Lerner-Geva L, Yovel I, et al. Patients with stages III and IV endometriosis have a poorer outcome of in vitro fertilization-embryo transfer than patients with tubal infertility. Fertil Steril 1999;72:1107–9. 10. Cahill DJ, Hull MG. Pituitary-ovarian dysfunction and endometriosis. Hum Reprod Update 2000;6:56 –66. 11. Garrido N, Navarro J, Garcia-Velasco J, Remoh J, Pellicer A, Simon C. The endometrium versus embryonic quality in endometriosis-related infertility. Hum Reprod Update 2002;8:95–103. 12. Lessey BA. Implantation defects in infertile women with endometriosis. Ann N Y Acad Sci 2002;955:265–80; discussion 293–5, 396 – 406. 13. Isaacs JD Jr, Hines RS, Sopelak VM, Cowan BD. Ovarian endometriomas do not adversely affect pregnancy success following treatment with in vitro fertilization. J Assist Reprod Genet 1997;14:551–3. 14. Roberts CP, Rock JA. The current staging system for endometriosis: does it help? Obstet Gynecol Clin North Am 2003;30:115–32. 15. Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997;68:585–96. 16. Sharpe-Timms KL, Zimmer RL, Ricke EA, Piva M, Horowitz GM. Endometriotic haptoglobin binds to peritoneal macrophages and alters their function in women with endometriosis. Fertil Steril 2002;78: 810 –9. 17. Selam B, Arici A. Implantation defect in endometriosis: endometrium or peritoneal fluid. J Reprod Fertil Suppl 2000;55:121–8. 18. Kao LC, Germeyer A, Tulac S, Lobo S, Yang JP, Taylor RN, et al. Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. Endocrinology 2003;144:2870 –81. 19. Rana N, Braun DP, House R, Gebel H, Rotman C, Dmowski WP. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil Steril 1996;65:925–30. 20. Gagne D, Rivard M, Page M, Shazand K, Hugo P, Gosselin D. Blood leukocyte subsets are modulated in patients with endometriosis. Fertil Steril 2003;80:43–53. 21. Sharpe KL, Zimmer RL, Griffin WT, Penney LL. Polypeptides synthesized and released by human endometriosis tissue differ from those of the uterine endometrium in culture. Fertil Steril 1993;60:839 –51. 22. Piva M, Sharpe-Timms KL. Peritoneal endometriotic lesions differentially express a haptoglobin-like gene. Mol Hum Reprod 1999;5:71–8. 23. Piva M, Horowitz GM, Sharpe-Timms KL. Interleukin-6 differentially stimulates haptoglobin production by peritoneal and endometriotic cells in vitro: a model for endometrial-peritoneal interaction in endometriosis. J Clin Endocrinol Metab 2001;86:2553–61. 24. Olson GE, Winfrey VP, Matrisian PE, Melner MH, Hoffman LH. Specific expression of haptoglobin mRNA in implantation-stage rabbit uterine epithelium. J Endocrinol 1997;152:69 –80. 25. Bottini N, Gimelfarb A, Gloria-Bottini F, La Torre M, Lucarelli P, Lucarini N. Haptoglobin genotype and natural fertility in humans. Fertil Steril 1999;72:293–6. 26. Javid J. The effect of haptoglobin-polymer size on hemoglobin binding capacity. Vox Sang 1965;10:320 –5. 27. D’Hooghe TM, Debrock S, Hill JA, Meuleman C. Endometriosis and subfertility: is the relationship resolved? Semin Reprod Med 2003;21: 243–54.
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