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Endometriosis and the outcome of in vitro fertilization
FERTILITY AND STERILITY威 VOL. 81, NO. 5, MAY 2004
RESPONSES
Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Endometriosis and the outcome of in vitro fertilization Ivo Brosens, M.D. Leuven Institute for Fertility and Embryology, Leuven, Belgium
A generalized reproductive dysfunction rather than endometriotic implants is likely to have an impact on the outcome of IVF. (Fertil Steril威 2004;81:1198⫺200. ©2004 by American Society for Reproductive Medicine.)
The impact of endometriosis on IVF has been the subject of numerous publications, although a number of critical issues related to the management of affected patients remain unsolved. For instance, asymptomatic ovarian endometriomas are relatively often detected before IVF, raising the question of whether these cysts should be removed. The topic has been addressed by Garcia-Velasco et al. (1) in the current issue of Fertility and Sterility. The answer to such a question is not simple and extends beyond the immediate effect of an ovarian cystectomy on IVF outcome. Accurate assessment of the impact of endometriosis on IVF outcome requires an appraisal of the diagnostic limitations, the consequences of surgical and hormonal management of endometriosis, and the potential impact of both disease and IVF on feto-maternal well-being.
LIMITATIONS OF THE DIAGNOSIS OF ENDOMETRIOSIS
Received September 19, 2003; revised and accepted September 19, 2003. Reprint requests: Ivo Brosens, M.D., Leuven Institute for Fertility and Embryology, Tiensevest 68, Leuven B-3000, Belgium (FAX: 32-16-270197; Email: ivo.brosens@med. kuleuven.ac.be). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2003. 09.071
1198
It is generally accepted that the diagnosis of endometriosis requires laparoscopy, although the limitations of visual inspection of the pelvis have been well documented. The many appearances of endometriosis, the microscopic implants, the extent of retroperitoneal endometriosis, and the difficult assessment of small deep ovarian endometriomas increase the likelihood of observational errors (2). Transvaginal ultrasound is an increasingly accepted technique for the diagnosis of an ovarian endometrioma. In a recent review, Moore et al. (3) identified 38 articles related to
the diagnosis of endometriosis by ultrasound scan, but only seven studies were found to be sufficiently sound for further analysis. The authors concluded that transvaginal ultrasound is indeed a useful test to detect or to exclude the presence of an ovarian endometrioma. However, the size of the endometriomas included in these studies ranged from 20 mm to 200 mm, with a mean of 40 mm, which suggests that the resolution obtained with current ultrasound techniques is inadequate to detect smaller endometriomas. To what extent the size of an endometrioma, or even the presence of noncystic ovarian implants, is a determinant of IVF outcome has not yet been investigated. An additional diagnostic problem is that luteal cysts frequently occur in patients with ovarian endometriosis, particularly after previous ovarian surgery (4). Moreover, there are no specific sonographic features that distinguish an endometrioma from a persisting luteal cyst, and at laparoscopy the typical features of an endometrioma are frequently absent after previous surgery. Conversely, in the absence of a proven beneficial effect of surgery for the ultrasound-visible endometrioma on subsequent IVF treatment outcome, the only rationale for surgery before IVF lies in the exclusion of malignancy or the prevention of potential complications associated with IVF, such as infection and abscess formation or rupture. A major consequence of the intrinsic limitations of current diagnostic methods for endometriosis is that retrospective studies often suffer from either over- or underdiagnosis.
THE IMPACT OF ENDOMETRIOSIS SURGERY ON OVARIAN FUNCTION Most ovarian endometriomas are not intraovarian hemorrhagic cysts but pseudocysts that result from invagination of the ovarian cortex. They can have a complex pathology, which is frequently not appreciated by the ultrasound scan or by visual inspection during laparoscopy. The characteristics of the typical endometrial cyst of the ovary were described in great detail by Sampson (5), who used 23 hysterectomy and salpingo-oophorectomy specimens with in situ endometriomas. All cysts were adherent to the posterior side of the uterus, parametrium, or uterine ligaments, were characterized by a fibrotic wall with a typical defect at the site of adhesions, and had adenomyotic lesions in the adherent muscular or fibromuscular tissues in 78% of the cases. Ovarian cystectomy, a term that denotes the excision of an intraovarian cyst, represents in most cases resection of healthy ovarian cortex with follicles and might not be the most appropriate approach for function-preserving surgery. The main concern of ovarian surgery is the risk of destruction of healthy ovarian tissue, which can result in a poor ovarian response during IVF and, as shown by de Boer et al. (6), an increased risk of early menopause. In young women attending the infertility clinic, the pathology of the asymptomatic endometrioma is usually less advanced. Dense adhesions can be absent, the site of invagination is easily identifiable for access to the cyst, and the wall has often retained the appearance of cortex and is sparsely lined with a thin, highly vascularized or hemorrhagic endometrial-like surface epithelium, which can be ablated by superficial coagulation (4). Conservative surgery of an advanced adherent endometrioma, however, involves first full adhesiolysis and mobilization of the ovary, followed by rotation of the ovary to identify the site of inversion for opening the pseudocyst and avoiding an antimesenteric incision through the cortex, and finally, destruction of all visible endometriotic tissue. In case of red vascularized implants, destruction can be achieved by ablation, similarly as on the outside cortex. However, excision might be appropriate to remove a thickened, black, and fibrotic cortical wall, as well as adenomyotic nodules in the adherent pelvic structures. Therefore, evaluation of the extent of ovarian damage during endometriotic surgery requires an accurate description of the pathology and the surgical techniques used. The outcome of surgery on ovarian function will be further determined by the extent of deep coagulation used for hemostasis during excision and by the proximity of the lesion to the hilus of the ovary. It is not surprising that controversy arises when simplified terminology, such as “excision” or “ablation,” is used to describe a complex surgical procedure. It is not surprising that in the hands of an experienced surgeon, the impact on subsequent IVF outcome seems to be comparable, regardless of whether excision or ablation is FERTILITY & STERILITY威
used (7, 8). However, it is also likely that in the hands of an inexperienced surgeon, cystectomy results in more ovarian damage than an ablative technique.
THE IMPACT OF HORMONAL THERAPY FOR ENDOMETRIOSIS ON IVF OUTCOME Accumulating evidence strongly suggests that endometriosis is characterized by a generalized dysfunction of the reproductive system, in addition to the extrauterine lesions. This is further supported by surgical studies demonstrating that elimination of the visible implants does not restore normal reproductive function. Paradoxically, endometriosis surgery in patients with infertility is relatively more effective for severe than for minimal or mild endometriosis. In a prospective, randomized study, Marcoux et al. (9) found that surgical elimination of mild endometriosis only modestly improved subsequent fertility, and the authors concluded that factors other than the implants interfere with fertility. Biochemical disturbances in endometrium or ovary might contribute to infertility associated with endometriosis (10). Although the exact nature of these perturbations and their clinical significance remain to be determined, several studies have indicated that a period of amenorrhea before IVF treatment might have a beneficial effect on subsequent pregnancy rate. Edwards et al. (11) found that pregnancy rates were higher in women who were previously amenorrheic, irrespective of age and number of embryos transferred. A prospective, randomized, controlled trial recently reported an increased pregnancy rate after IVF in endometriosis patients in whom amenorrhea was induced for 3 months with GnRH agonists (12). However, these observations require further validation by a large, prospective, randomized trial before 3-month GnRH agonist therapy before IVF can be routinely advocated in patients with unexplained or endometriosisassociated infertility. New medical therapies, such as aromatase inhibitors, are potential candidate drugs for improving IVF outcome in affected patients.
ENDOMETRIOSIS AND ADVERSE FETAL OUTCOME AFTER IVF Recent epidemiologic studies have established that IVF is associated with an increased risk of small and very small for gestational age infants, even in singleton pregnancy. Therefore, the success of IVF should be measured not only by immediate results, such as fertilization, implantation, and clinical pregnancy rate, but also by feto-maternal outcome. It is debatable whether the adverse neonatal outcome associated with IVF is directly related to the treatment or to the underlying cause of infertility. A major contention in the very large epidemiologic study by Schieve et al. (13) is the definition of the “healthy” control group. The authors equated unexplained infertility with no underlying cause of infertility and found that the increased risk of poor feto1199
maternal outcome is still apparent in this subgroup. This led the authors to conclude that the treatment modality is likely causative for the increased incidence of fetal growth retardation. However, no increased risk was found in patients with male infertility treated by intracytoplasmic sperm injection and in the 180 gestational carriers and, arguably, undiagnosed reproductive disorders are less likely to be present in these two subgroups. Therefore, the observations by Schieve et al. (13) could be interpreted as showing an increased risk of adverse fetal outcome in unexplained or endometriosis-associated infertility.
extrauterine implants per se. Finally, it is important that success or failure of IVF treatment is measured not only by clinical pregnancy rates but also by feto-maternal outcome.
This notion is further supported by another large, epidemiologic study demonstrating that patients with unexplained infertility, including endometriosis-associated infertility, are at higher risk of pregnancy complications, such as spontaneous miscarriage, preterm delivery, and small for gestational age infants (14). Emerging data suggest that impaired uterine remodeling during the conception cycle might predispose to a defective deep placentation, thereby providing an explanation for the association between the type of infertility and impaired pregnancy outcome after IVF (15, 16).
References
CONCLUSIONS Retrospective clinical studies addressing the impact of endometriosis on IVF outcome often fail to take in account the many possible confounding factors, such as the choice of the control group, the intrinsic diagnostic limitations, and the potential impact of surgical and hormonal treatment before IVF. It is important to realize that the first attempt at surgical treatment for ovarian endometriosis in a young woman might determine her reproductive future. Therefore, the patient should be made aware of the limitations of surgery in improving or restoring fertility and the potential risks. The value of inducing a period of amenorrhea before IVF treatment in affected patients requires further validation in a large, prospective, and well-controlled clinical trial. Perhaps the most important obstacles in defining the impact of endometriosis on IVF treatment outcome are the intrinsic diagnostic limitations of laparoscopy or ultrasound. Substantial advances in the clinical management of endometriosis are likely to depend on the development of noninvasive diagnostic biochemical markers of the disease. It can be argued that any biochemical test should focus on predicting clinical correlates of endometriosis, such as infertility, pain, and fetal outcome, rather than on the presence or absence of
1200 Brosens
Endometriosis and in vitro fertilization
Acknowledgments: The author thanks Jan J. Brosens for valuable critical comments.
1. 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. 2. Roberts CP, Rock JA. The current staging system for endometriosis: does it help? Obstet Gynecol Clin North Am 2003;30:115–32. 3. Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet Gynecol 2002;20:630 –4. 4. Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril 1994; 61:1034 –8. 5. Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg 1921;3:245–323. 6. de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, van Leeuwen FE, OMEGA-project group. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003;18:1544 –52. 7. Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of ⬎3 cm in diameter. Hum Reprod 2001;16:2583–6. 8. Donnez J, Wyns C, Nisolle M. Does ovarian surgery for endometriomas impair the ovarian response to gonadotropin? Fertil Steril 2001;76: 662–5. 9. Marcoux S, Maheux R, Be´ rube´ S, the Canadian Collabarative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Eng J Med 1997;337:217–22. 10. 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. 11. Edwards RG, Morcos S, Macnamee M, Balmaceda JP, Walters DE, Asch R. High fecundity of amenorrhoeic women in embryo-transfer programmes. Lancet 1997;338:292–4. 12. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization— embryo transfer in patients with endometriosis. Fertil Steril 2002;78:699 –704. 13. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–7. 14. Pandian Z, Bhattacharya S, Templeton A. Review of unexplained infertility and obstetric outcome. Hum Reprod 2001;16:2593–7. 15. Brosens JJ, Pijnenborg R, Brosens I. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies. Am J Obstet Gynecol 2002;187:1416 –23. 16. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003;69:1–7.
Vol. 81, No. 5, May 2004
RESPONSES
Copyright ©2004 American Society for Reproductive Medicine Published by Elsevier Inc. Printed on acid-free paper in U.S.A.
Endometriosis and the outcome of in vitro fertilization Ivo Brosens, M.D. Leuven Institute for Fertility and Embryology, Leuven, Belgium
A generalized reproductive dysfunction rather than endometriotic implants is likely to have an impact on the outcome of IVF. (Fertil Steril威 2004;81:1198⫺200. ©2004 by American Society for Reproductive Medicine.)
The impact of endometriosis on IVF has been the subject of numerous publications, although a number of critical issues related to the management of affected patients remain unsolved. For instance, asymptomatic ovarian endometriomas are relatively often detected before IVF, raising the question of whether these cysts should be removed. The topic has been addressed by Garcia-Velasco et al. (1) in the current issue of Fertility and Sterility. The answer to such a question is not simple and extends beyond the immediate effect of an ovarian cystectomy on IVF outcome. Accurate assessment of the impact of endometriosis on IVF outcome requires an appraisal of the diagnostic limitations, the consequences of surgical and hormonal management of endometriosis, and the potential impact of both disease and IVF on feto-maternal well-being.
LIMITATIONS OF THE DIAGNOSIS OF ENDOMETRIOSIS
Received September 19, 2003; revised and accepted September 19, 2003. Reprint requests: Ivo Brosens, M.D., Leuven Institute for Fertility and Embryology, Tiensevest 68, Leuven B-3000, Belgium (FAX: 32-16-270197; Email: ivo.brosens@med. kuleuven.ac.be). 0015-0282/04/$30.00 doi:10.1016/j.fertnstert.2003. 09.071
1198
It is generally accepted that the diagnosis of endometriosis requires laparoscopy, although the limitations of visual inspection of the pelvis have been well documented. The many appearances of endometriosis, the microscopic implants, the extent of retroperitoneal endometriosis, and the difficult assessment of small deep ovarian endometriomas increase the likelihood of observational errors (2). Transvaginal ultrasound is an increasingly accepted technique for the diagnosis of an ovarian endometrioma. In a recent review, Moore et al. (3) identified 38 articles related to
the diagnosis of endometriosis by ultrasound scan, but only seven studies were found to be sufficiently sound for further analysis. The authors concluded that transvaginal ultrasound is indeed a useful test to detect or to exclude the presence of an ovarian endometrioma. However, the size of the endometriomas included in these studies ranged from 20 mm to 200 mm, with a mean of 40 mm, which suggests that the resolution obtained with current ultrasound techniques is inadequate to detect smaller endometriomas. To what extent the size of an endometrioma, or even the presence of noncystic ovarian implants, is a determinant of IVF outcome has not yet been investigated. An additional diagnostic problem is that luteal cysts frequently occur in patients with ovarian endometriosis, particularly after previous ovarian surgery (4). Moreover, there are no specific sonographic features that distinguish an endometrioma from a persisting luteal cyst, and at laparoscopy the typical features of an endometrioma are frequently absent after previous surgery. Conversely, in the absence of a proven beneficial effect of surgery for the ultrasound-visible endometrioma on subsequent IVF treatment outcome, the only rationale for surgery before IVF lies in the exclusion of malignancy or the prevention of potential complications associated with IVF, such as infection and abscess formation or rupture. A major consequence of the intrinsic limitations of current diagnostic methods for endometriosis is that retrospective studies often suffer from either over- or underdiagnosis.
THE IMPACT OF ENDOMETRIOSIS SURGERY ON OVARIAN FUNCTION Most ovarian endometriomas are not intraovarian hemorrhagic cysts but pseudocysts that result from invagination of the ovarian cortex. They can have a complex pathology, which is frequently not appreciated by the ultrasound scan or by visual inspection during laparoscopy. The characteristics of the typical endometrial cyst of the ovary were described in great detail by Sampson (5), who used 23 hysterectomy and salpingo-oophorectomy specimens with in situ endometriomas. All cysts were adherent to the posterior side of the uterus, parametrium, or uterine ligaments, were characterized by a fibrotic wall with a typical defect at the site of adhesions, and had adenomyotic lesions in the adherent muscular or fibromuscular tissues in 78% of the cases. Ovarian cystectomy, a term that denotes the excision of an intraovarian cyst, represents in most cases resection of healthy ovarian cortex with follicles and might not be the most appropriate approach for function-preserving surgery. The main concern of ovarian surgery is the risk of destruction of healthy ovarian tissue, which can result in a poor ovarian response during IVF and, as shown by de Boer et al. (6), an increased risk of early menopause. In young women attending the infertility clinic, the pathology of the asymptomatic endometrioma is usually less advanced. Dense adhesions can be absent, the site of invagination is easily identifiable for access to the cyst, and the wall has often retained the appearance of cortex and is sparsely lined with a thin, highly vascularized or hemorrhagic endometrial-like surface epithelium, which can be ablated by superficial coagulation (4). Conservative surgery of an advanced adherent endometrioma, however, involves first full adhesiolysis and mobilization of the ovary, followed by rotation of the ovary to identify the site of inversion for opening the pseudocyst and avoiding an antimesenteric incision through the cortex, and finally, destruction of all visible endometriotic tissue. In case of red vascularized implants, destruction can be achieved by ablation, similarly as on the outside cortex. However, excision might be appropriate to remove a thickened, black, and fibrotic cortical wall, as well as adenomyotic nodules in the adherent pelvic structures. Therefore, evaluation of the extent of ovarian damage during endometriotic surgery requires an accurate description of the pathology and the surgical techniques used. The outcome of surgery on ovarian function will be further determined by the extent of deep coagulation used for hemostasis during excision and by the proximity of the lesion to the hilus of the ovary. It is not surprising that controversy arises when simplified terminology, such as “excision” or “ablation,” is used to describe a complex surgical procedure. It is not surprising that in the hands of an experienced surgeon, the impact on subsequent IVF outcome seems to be comparable, regardless of whether excision or ablation is FERTILITY & STERILITY威
used (7, 8). However, it is also likely that in the hands of an inexperienced surgeon, cystectomy results in more ovarian damage than an ablative technique.
THE IMPACT OF HORMONAL THERAPY FOR ENDOMETRIOSIS ON IVF OUTCOME Accumulating evidence strongly suggests that endometriosis is characterized by a generalized dysfunction of the reproductive system, in addition to the extrauterine lesions. This is further supported by surgical studies demonstrating that elimination of the visible implants does not restore normal reproductive function. Paradoxically, endometriosis surgery in patients with infertility is relatively more effective for severe than for minimal or mild endometriosis. In a prospective, randomized study, Marcoux et al. (9) found that surgical elimination of mild endometriosis only modestly improved subsequent fertility, and the authors concluded that factors other than the implants interfere with fertility. Biochemical disturbances in endometrium or ovary might contribute to infertility associated with endometriosis (10). Although the exact nature of these perturbations and their clinical significance remain to be determined, several studies have indicated that a period of amenorrhea before IVF treatment might have a beneficial effect on subsequent pregnancy rate. Edwards et al. (11) found that pregnancy rates were higher in women who were previously amenorrheic, irrespective of age and number of embryos transferred. A prospective, randomized, controlled trial recently reported an increased pregnancy rate after IVF in endometriosis patients in whom amenorrhea was induced for 3 months with GnRH agonists (12). However, these observations require further validation by a large, prospective, randomized trial before 3-month GnRH agonist therapy before IVF can be routinely advocated in patients with unexplained or endometriosisassociated infertility. New medical therapies, such as aromatase inhibitors, are potential candidate drugs for improving IVF outcome in affected patients.
ENDOMETRIOSIS AND ADVERSE FETAL OUTCOME AFTER IVF Recent epidemiologic studies have established that IVF is associated with an increased risk of small and very small for gestational age infants, even in singleton pregnancy. Therefore, the success of IVF should be measured not only by immediate results, such as fertilization, implantation, and clinical pregnancy rate, but also by feto-maternal outcome. It is debatable whether the adverse neonatal outcome associated with IVF is directly related to the treatment or to the underlying cause of infertility. A major contention in the very large epidemiologic study by Schieve et al. (13) is the definition of the “healthy” control group. The authors equated unexplained infertility with no underlying cause of infertility and found that the increased risk of poor feto1199
maternal outcome is still apparent in this subgroup. This led the authors to conclude that the treatment modality is likely causative for the increased incidence of fetal growth retardation. However, no increased risk was found in patients with male infertility treated by intracytoplasmic sperm injection and in the 180 gestational carriers and, arguably, undiagnosed reproductive disorders are less likely to be present in these two subgroups. Therefore, the observations by Schieve et al. (13) could be interpreted as showing an increased risk of adverse fetal outcome in unexplained or endometriosis-associated infertility.
extrauterine implants per se. Finally, it is important that success or failure of IVF treatment is measured not only by clinical pregnancy rates but also by feto-maternal outcome.
This notion is further supported by another large, epidemiologic study demonstrating that patients with unexplained infertility, including endometriosis-associated infertility, are at higher risk of pregnancy complications, such as spontaneous miscarriage, preterm delivery, and small for gestational age infants (14). Emerging data suggest that impaired uterine remodeling during the conception cycle might predispose to a defective deep placentation, thereby providing an explanation for the association between the type of infertility and impaired pregnancy outcome after IVF (15, 16).
References
CONCLUSIONS Retrospective clinical studies addressing the impact of endometriosis on IVF outcome often fail to take in account the many possible confounding factors, such as the choice of the control group, the intrinsic diagnostic limitations, and the potential impact of surgical and hormonal treatment before IVF. It is important to realize that the first attempt at surgical treatment for ovarian endometriosis in a young woman might determine her reproductive future. Therefore, the patient should be made aware of the limitations of surgery in improving or restoring fertility and the potential risks. The value of inducing a period of amenorrhea before IVF treatment in affected patients requires further validation in a large, prospective, and well-controlled clinical trial. Perhaps the most important obstacles in defining the impact of endometriosis on IVF treatment outcome are the intrinsic diagnostic limitations of laparoscopy or ultrasound. Substantial advances in the clinical management of endometriosis are likely to depend on the development of noninvasive diagnostic biochemical markers of the disease. It can be argued that any biochemical test should focus on predicting clinical correlates of endometriosis, such as infertility, pain, and fetal outcome, rather than on the presence or absence of
1200 Brosens
Endometriosis and in vitro fertilization
Acknowledgments: The author thanks Jan J. Brosens for valuable critical comments.
1. 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. 2. Roberts CP, Rock JA. The current staging system for endometriosis: does it help? Obstet Gynecol Clin North Am 2003;30:115–32. 3. Moore J, Copley S, Morris J, Lindsell D, Golding S, Kennedy S. A systematic review of the accuracy of ultrasound in the diagnosis of endometriosis. Ultrasound Obstet Gynecol 2002;20:630 –4. 4. Brosens IA, Puttemans PJ, Deprest J. The endoscopic localization of endometrial implants in the ovarian chocolate cyst. Fertil Steril 1994; 61:1034 –8. 5. Sampson JA. Perforating hemorrhagic (chocolate) cysts of the ovary. Arch Surg 1921;3:245–323. 6. de Boer EJ, den Tonkelaar I, te Velde ER, Burger CW, van Leeuwen FE, OMEGA-project group. Increased risk of early menopausal transition and natural menopause after poor response at first IVF treatment. Hum Reprod 2003;18:1544 –52. 7. Canis M, Pouly JL, Tamburro S, Mage G, Wattiez A, Bruhat MA. Ovarian response during IVF-embryo transfer cycles after laparoscopic ovarian cystectomy for endometriotic cysts of ⬎3 cm in diameter. Hum Reprod 2001;16:2583–6. 8. Donnez J, Wyns C, Nisolle M. Does ovarian surgery for endometriomas impair the ovarian response to gonadotropin? Fertil Steril 2001;76: 662–5. 9. Marcoux S, Maheux R, Be´ rube´ S, the Canadian Collabarative Group on Endometriosis. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Eng J Med 1997;337:217–22. 10. 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. 11. Edwards RG, Morcos S, Macnamee M, Balmaceda JP, Walters DE, Asch R. High fecundity of amenorrhoeic women in embryo-transfer programmes. Lancet 1997;338:292–4. 12. Surrey ES, Silverberg KM, Surrey MW, Schoolcraft WB. Effect of prolonged gonadotropin-releasing hormone agonist therapy on the outcome of in vitro fertilization— embryo transfer in patients with endometriosis. Fertil Steril 2002;78:699 –704. 13. Schieve LA, Meikle SF, Ferre C, Peterson HB, Jeng G, Wilcox LS. Low and very low birth weight in infants conceived with use of assisted reproductive technology. N Engl J Med 2002;346:731–7. 14. Pandian Z, Bhattacharya S, Templeton A. Review of unexplained infertility and obstetric outcome. Hum Reprod 2001;16:2593–7. 15. Brosens JJ, Pijnenborg R, Brosens I. The myometrial junctional zone spiral arteries in normal and abnormal pregnancies. Am J Obstet Gynecol 2002;187:1416 –23. 16. Kaufmann P, Black S, Huppertz B. Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia. Biol Reprod 2003;69:1–7.
Vol. 81, No. 5, May 2004