{"paper_id":"33ac3649-3803-44d0-91d1-086afeda4a93","body_text":"Citation: Yun BH, Choi YS, Lee BS. Management of Endometriosis-Associated Infertility. J Androl Gynaecol. 2014;2(2): 7.\nManagement of Endometriosis-\nAssociated Infertility\nKeywords: Endometriosis, Infertility, Pregnancy, Surgery, Assisted \nreproductive technology\nAbstract\nEndometriosis is a common, chronic disease. Patients typically \npresent with pelvic pain, infertility, and/or an adnexal mass. Results \nfrom the limited number of studies that have been published indicate \nthat the true prevalence of endometriosis, along with the associated \ninfertility, has been increasing. Debates about infertility management \narise from the contradiction between the contraceptive nature of \nmedical treatments for endometriosis and the unpredictable ovarian \nreserve after surgery. There is moderate quality evidence that surgery \nincreases clinical pregnancy rate and live birth in minimal to mild \nendometriosis. However, insufficient evidences which supports the \neffect of surgery in moderate to severe endometriosis in term of \nsubfertility. On this basis, artificial reproductive technologies have \nbeen become the most efficient way of overcoming endometriosis-\nassociated infertility, particularly in stage III/IV endometriosis. The \nobjective of this paper is to review recent trends in endometriosis, from \nthe pathophysiology of the disease to the management of infertility. \nendometriosis and infertility and to assess the current approaches and \nmanagement modalities used for infertile women with endometriosis. \nPathophysiology\nAs previously mentioned, how endometriosis contributes to \ninfertility remains controversial. However, there are a few hypotheses \nthat describe the pathophysiology of endometriosis-associated \ninfertility when the endometriotic lesion is located in the pelvic \ncavity, ovary, or uterus [8].\nDistorted Pelvic Anatomy \nPelvic adhesions that develop as a consequence of endometriosis \ncan interfere with ovulation, transport of the oocyte or ovum, and \npick-up by the fimbriae. The oviducts may be patent bilaterally, but \nexisting adhesions around the adnexa can interrupt the dynamic \nmovements of the fimbriae that are necessary for oocyte uptake [9].  \nAltered Peritoneal Milieu\nThe chronic inflammatory status of the pelvic cavity in \nendometriosis patients has been recognized for decades. This \ninflammation is accompanied by increased infiltration of \nmacrophages in the pelvic fluid. The pathophysiology has not \nbeen well-described, but increased recruitment of immune cells \nand dysregulated apoptosis of endometrial cells present in the \nlesion are thought to be contributing factors. Additional support \nfor this hypothesis arises from the observation that in addition to \nthe macrophages, inflammatory cytokines, and prostaglandins, \nchemokines stimulate and aggregate monocytes and granulocytes. \nRANTES [10], monocyte inflammatory protein-1[ 11,12], eotaxin \n[13], interleukin-8 [ 14], and ENA-78 [ 15] have been identified in \nperitoneal fluid of endometriosis patients. Increased numbers of \nmacrophages with phagocytic dysfunction, abnormal activation, and \naltered Th1/Th2 immunity, [16] have also been reported. Abnormal \nsurvivability of endometrial cells regurgitated into the peritoneal \nBo Hyon Yun1,3, Young Sik Choi1,3 and Byung Seok \nLee2,3*\n1Department of Obstetrics and Gynecology, Severance Hospital, \nYonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-\ngu, Seoul 120-752, Republic of Korea\n2Department of Obstetrics and Gynecology, Gangnam Severance \nHospital, Yonsei University College of Medicine,712 Eonju-ro, \nGangnam-gu, Seoul135-720, Republic of Korea \n3Institute of Women’s Life Medical Science, Yonsei University \nCollege of Medicine, 134 Shinchon-dong, Seodaemun-gu Seoul 120-\n752, Republic of Korea\n*Address for Correspondence\nDr. Byung Seok Lee, M.D., Department of Obstetrics and Gynecology, \nGangnam Severance Hospital, Yonsei University College of Medicine,712 \nEonju-ro, Gangnam-gu, Seoul135-720, Republic of Korea; Tel: 82-2-\n2019-3430; Fax: 82-2-3462-8209; E-mail: dr222@yuhs.ac\nSubmission: 07 July 2014\nAccepted: 18 August 2014\nPublished: 21 August 2014\nReview ArticleOpen Access\nIntroduction \nEndometriosis is a disease characterized by ectopic endometrial \nglands and stromal tissue external to the uterine cavity. The \nprevalence of the disease has been reported to be 5–10% in women \nof reproductive age, 20–30% in women diagnosed with infertility, \nand 40–60% in women with chronic pelvic pain [ 1]. Fecundity, the \nprobability of giving live birth in a menstrual cycle, has been shown \nto be 0.02–0.1 per month in women with endometriosis, but is \n0.15–0.2 per month in normal women [ 2]. The live birth rate is also \nsignificantly decreased in women with endometriosis [2]. \nThe pathophysiology of endometriosis has not been clarified. \nHowever, pain in endometriosis patients has been correlated with \ndisease severity, degree of endometrial tissue infiltration, and the \nlocation of the lesion [3-5]. Although endometriosis seems to be highly \nrelated to infertility, how endometriosis contributes to infertility \nremains controversial [6]. The generally accepted process includes \ninduction of local inflammation by estrogen-dependent ectopic \nendometriotic lesions that serially induce endometrial fragment \nadhesion, proliferation, and neovascularization, with subsequent \ndevelopment of fibrosis, adhesions, and distortion of the pelvic \nanatomy [3,6,7]. Infertility in women with endometriosis is thought \nto have multifactorial causes that can interfere with reproduction. \n The management of infertility in endometriosis patients should \nbe considered in the context of understanding the pathophysiology \nbetween endometriosis and fertility. Medical treatment of \nendometriosis includes the use of gonadotropin-releasing hormone \nagonists, oral contraceptives, and progestins, which mainly suppress \nthe secretion of estrogen from the ovary. These approaches cannot \nbe used for women who are planning to conceive. When surgery and \nmedical treatment fail or natural conception becomes impossible, \nassisted reproductive techniques (ARTs) are other options. The \nprimary objective of this review is to examine the pathophysiology of \nJournal of\nAndrology & \nGynaecology \nAvens Publishing Group\nInvi ting Innova tions\nAvens Publishing Group\nInvi ting Innova tions\nJ Androl Gynaecol \nAugust 2014 Vol.:2, Issue:2\n© All rights are reserved by Byung Seok Lee \n\nCitation: Yun BH, Choi YS, Lee BS. Management of Endometriosis-Associated Infertility. J Androl Gynaecol. 2014;2(2): 7.\nJ Androl Gynaecol 2(2): 7 (2014) Page - 02\nISSN: 2332-3442\ncavity is associated with overexpression of anti-apoptotic factors and \nsuppression of pro-apoptotic factors [ 17,18]. Because the peritoneal \nfluid surrounds the pelvic organs, and the ampulla is exposed to the \nfluid, change in the milieu can affect fertilization that occurs in the \nampulla. Ultimately, an altered peritoneal milieu might negatively \naffect oocyte, sperm, embryo, or tubal function. \nImpaired Implantation \nRecently, decreased expression of integrin-αvβ3 has been found in \nthe endometrium of endometriosis patients [ 19]. This abnormality \nmay cause implantation failure. Increased immunoglobulin A and \nG, and lymphocytes in the endometrium as a result of peritoneal \ninflammation have been suggested to affect implantation and \nendometrial receptivity [7]. \n Alteration of the endometrial milieu in women with endometriosis \nresults from changes that include abnormal production of estradiol by \nlocal inflammation. Progesterone resistance is also well known. It was \nalso suggested that cyclooxygenase-2 (COX-2) expression increased \nin the eutopic endometrium as well as ovarian endometriotic tissue \nin patients with endometriosis [20]. The alteration contains abnormal \nprostaglandin production in the eutopic endometrium, and abnormal \nactivation of the inflammation loop by cytokines. These processes can \nresult in local production of estradiol, which increases peristalsis of \nthe myometrium. There is little evidence that supports the hypothesis \nthat alteration of the endometrium induces implantation and \nultimately affects the pregnancy rate, but results indicate that there \nare obvious differences when compared with eutopic endometrium \nfrom normal women. \nEndocrine and Ovulatory Abnormalities \nIt is generally accepted that ovulatory problems associated with \nendometriosis are related to decrease of ovarian function caused by \nrepeated surgery from the endometrioma, or by the endometrioma \nitself which result in space-occupying effects, local reactions, and \nreduction of available functional ovarian tissue. \nOvulation of immature oocytes that induce an impaired luteal \nphase and abnormal folliculogenesis and abnormal follicular \nmaturation in endometriosis patients have been suggested to cause \nendocrinologic ovulatory disorders. In early studies, ovulatory \ndysfunction or alteration were suggested to be responsible for the \nlower implantation rate in women with endometriosis [ 21,22]. \nRecently, altered expression of estrogen and progesterone receptors \nin granulosa cells have been found in advanced stage endometriosis \n[23]. This altered expression might contribute to an explanation of the \ncause of ovarian dysfunction in endometriosis. The hypothesis that \nendometrioma affects oocyte quality has been controversial. Some \ninvestigators have reported that the fertilization rate is reduced in \nwomen with endometriosis. However, ART data that have indicated \nthat pregnancy rates are preserved suggest that the effect on oocyte \nquality may be minimal in women with endometriosis. \nManagement of Infertility \nAmong the management options for endometriosis, surgery is the \nonly option that can improve the chances that pregnancy will occur. \nHowever, surgery cannot be used for all patients. If possible, surgery \nshould be offered as early as the diagnostic work up stage, because \nsurgery increases the chances for successful natural conception. \nThe evidence from a randomized trial performed by Marcoux et \nal. provides support for this recommendation [ 24]. The odds ratio \n(OR) for spontaneous pregnancy was 1.66 [95% confidence interval \n(CI) 1.09–2.51] after surgical removal of superficial endometriosis. \nHowever, although cumulative pregnancy rate seems to increase \nafter conservative surgery in mild to moderate endometriosis [25], in \npatients who are planning to undergo the ART, whether the surgical \nmanagement shall be proceeded or not remains uncertain [ 26]. It \nhas been shown that surgery could reduce ovarian reserve or ovarian \nresponse to gonadotropin without improving pregnancy outcomes in \nwomen undergoing IVF. In recent review, the opinion suggested that \novarian surgery for removal of endometrioma seemed to lower ovarian \nreserve. Furthermore, they pointed that removing endometrioma \ndid not affect the quality of oocyte in IVF cycle as an evidence of \nno additional advantage of surgery in ART cycle [ 27]. On the other \nhand, some investigators did not support the same opinion [ 28-31]. \nIt is clear that considerable surgical expertise is requied to decrease \novarian damage and avoid incomplete surgery [ 32]. It was suggested \nthat the presence of ovarian endometrioma as per se is associated with \na reduced responsiveness to gonadotropins [ 33]. There is growing \nevidence that endometrioma per se decreases follicular density in the \novarian cortex [34]. It was suggested that laparoscopic management \nof endometriomas may be beneficial to protect the ovarian \nreserve in women with endometriomas. Considering the relevant \nrecommendations and evidences, at least 12 months is necessary to \nachieve a natural pregnancy after surgery. Patient characteristics that \nshould be considered when deciding whether to stress the advantages \nof surgery include patient age and ovarian reserve, and the capacity \nto conceive naturally. If the patient has decreased ovarian reserve, \nis >38 years of age, or has experienced a long duration of infertility, \nuse of direct ARTs might be more appropriate. If infertile couple \nhas been combined with male factor or tubal factor additionally \nto endometriosis, ART would be a better choice. If the patient has \nsimultaneously existing pelvic pain, hydrosalpinx, or one or more \nendometriomas >3-4cm diameter, surgery could be considered \nas the first option. The strategies briefly summarized above are in \naccordance with the guidelines of the European Society of Human \nReproduction and Embryology(ESHRE) [35] and American Society \nfor Reproductive Medicine(ASRM) [\n36]. A detailed discussion with \nsupporting evidence follows in this manuscript.\nI. Medical management \n Medical treatments for endometriosis (e.g., oral contraceptives, \nprogestin, gonadotropin releasing hormone analogs, and aromatase \ninhibitors) inhibit ovarian function by suppressing ovulation. Medical \ntreatments are effective for pain relief and to prevent postoperative \nrecurrence, but are ineffective for recovery of fecundity [37]. The \nresults of a Cochrane review indicated that patients with ovulation \nsuppression did not have an increased odds of successful pregnancy \n(OR0.74, 95% CI 0.48–1.15), compared with the placebo or untreated \ngroups [38]. Overall, the results of randomized studies of minimal \nto mild endometriosis have indicated that there is no improvement \nin pregnancy rate with any medical treatment or with expectant \nmanagement [39-41]. The results of a meta-analysis comparing \nmedical treatment to no treatment or placebo indicated that the OR \nfor pregnancy is 0.85 (95% CI 0.95–1.22) [42]. \n\nCitation: Yun BH, Choi YS, Lee BS. Management of Endometriosis-Associated Infertility. J Androl Gynaecol. 2014;2(2): 7.\nJ Androl Gynaecol 2(2): 7 (2014) Page - 03\nISSN: 2332-3442\nII. Surgical treatment \nLaparoscopy is the most effective modality for diagnosis and \nstaging of endometriosis. Surgery can help to recover the distorted \npelvic anatomy and increase the chances for natural conception. \nHowever, surgery cannot improve the biochemical environment \nassociated with endometriosis, such as the increased inflammatory \nfactors and the altered endometrial milieu. \nThe indications for laparoscopic surgery in endometriosis \npatients are diagnosis of infertility in women when the cause is \nunknown, severe dyspareunia, dysmenorrhea, or chronic pelvic \npain, suspicious deep infiltrating endometriosis, a tender nodule on \nuterosacral ligament revealed by a pelvic examination, and suspicion \nof, or diagnosis of ovarian endometrioma.\nSurgical Treatment for Minimal to Mild Endometriosis \n(Stage I/II) \nThe results of observational studies have suggested that \nlaparoscopic surgery does not affect postoperative conception \nin patients with minimal to mild endometriosis. However, a \nrandomized controlled trial (RCT)that evaluated the effectiveness \nof laparoscopic surgery for stage I/II endometriosis in infertile \npatients revealed that the use of laparoscopic surgery increases the \nlive birth rate[24]. Based on a systematic review and meta-analysis, \nthe ESHRE guideline has proposed that compared with diagnostic \nlaparoscopy, ablation of endometriotic lesions with adhesiolysis \nin minimal to mild endometriosis improves fertility[43].A more \nrecent meta-analysis revealed that the live birth rate increases (OR \n1.94, 95% CI 1.2–3.16), and the clinical pregnancy rate increases (OR \n1.89, 95% CI 1.25–2.86), in laparoscopic ablation or excision patients \ncomparedwith diagnostic laparoscopy patients in women with stage \nI/II endometriosis[25]. \nSurgical Treatment for Moderate to Severe \nEndometriosis (Stage III/IV) \nThere have been no results available from RCTs or meta-\nanalyses that indicate whether surgical management of stage III/IV \nendometriosis improves pregnancy rates. Laparoscopic cystectomy \nfor ovarian endometrioma >3-4cm results in improvements in \npregnancy rates compared with cyst drainage and coagulation [ 44]. \nAlthough in a review by Vercellini et al. demonstrated that the overall \nweighted mean of pregnancy rate after laparoscopic treatment of \novarian endometrioma in stage III/IV was about 50%, they also stated \nthat it is most likely to be overestimated due to multiple confounding \nfactors [37]. The evidences from observational studies suggest that \nwomen who have stage III/IV endometriosis without any other \nidentifiable infertility factors may benefit from surgical treatment \nto increase fertility [ 45,46]. However, the potential adverse effects \nshould be considered. For example, the loss of viable ovarian cortex \nmay lead to a decrease in ovarian function. \nSurgical Treatment for Other Conditions in \nEndometriosis: Rectovaginal Lesions, Recurrent \nendometriosis \nRectovaginal endometriosis usually results in severe pain that is a \nconsequence of deep, infiltrating endometriosis. The primary objective \nof surgical treatment of rectovaginal endometriosis is pain relief. The \nresection of the rectovaginal lesion has been reported to significantly \nrelieve the pain, but is ineffective for fertility enhancement. \nFew studies have been performed that examine options for \nsecond-line surgery for patients with recurrent endometriosis. \nRepeated surgery has only rarely increased fecundity [ 47,48], and \nASRM has recommended ART for patients who have a history of \nat least one surgical treatment [ 36]. The results of another meta-\nanalysis suggested that expectant management followed by ART may \nresult in a better prognosis for pregnancy compared with repeated \nsurgery in women with recurrent endometriosis [ 31]. However, if \nthe patients suffer from severe pain or from endometrioma >4cm, \nthe Royal College of Obstetricians and Gynecologists(RCOG) has \nrecommended that repeated surgery could be considered [49]. \nGuidelines \nESHRE [35], ASRM [36], and RCOG [49] commissions have \nsuggested guidelines for infertility management in women with \nendometriosis that have mostly coincided ( Table 1). Surgical \ntreatment has demonstrated benefit in stage I/II endometriosis \nin ESHRE and RCOG guidelines, but insufficient benefit to be \nrecommended solely to increase the likelihood of pregnancy in \nASRM guideline. Surgical treatment is a possible treatment modality \nfor stage III/IV endometriosis in all three guidelines. Postoperative \nadjuvant management is not currently recommended; because \nthere is little evidence that the postoperative ovarian suppression \neffects may improve future fertility. Although controversial, all three \ncommittees recommended that surgical treatment can be performed \nbefore ART for patients with endometrioma >3-4cm especially to \nimprove endometriosis-associated pain or accessibility of follicles \nor to detect occult malignancy. The ASRM committee opinion was \nthat ART rather than repeated surgical procedures should be used for \nwomen with recurrent endometriosis.\nIII. Role of postoperative hormonal treatment \nThe results of a meta-analysis of six case-control studies \nindicated that there is a significant improvement in pain after 3 to 6 \nmonths of postoperative GnRH agonist, danazol, or combined oral \ncontraceptives use, compared with untreated and placebo groups. \nHowever, a systematic review that compared comparative studies \nrevealed that there were no significant differences in pregnancy rate \namong groups (i.e., surgery, surgery with a postoperative placebo, \nand surgery with postoperative hormonal treatment) [50].\nIv. Assisted Reproductive Technology in Women with \nEndometriosis \nIntrauterine insemination\nIntrauterine insemination (IUI) has been used in a number of cases \nof subfertile couples, and the pregnancy rate has increased somewhat. \nSome studies have reported a modest benefit of IUI in women with \nminimal and mild endometriosis [51-55] (Table 2). In particular, IUI \nwith controlled ovarian stimulation (COS) resulted in increases in \npregnancy rate compared with expectant management in a few large \nRCTs and in a large population study [ 56-58]. The results of an RCT \nperformed by Tummon et al. indicated that IUI with stimulated cycles \nsignificantly increases pregnancy rate (OR 5.6, 95% CI 1.8–17.4) \n[56]. The results of a systematic review of six RCTs indicated that \nthe pregnancy rate was higher per IUI cycle with clomiphene citrate, \n\nCitation: Yun BH, Choi YS, Lee BS. Management of Endometriosis-Associated Infertility. J Androl Gynaecol. 2014;2(2): 7.\nJ Androl Gynaecol 2(2): 7 (2014) Page - 04\nISSN: 2332-3442\nClinical condition ESHRE 2014 ASRM 2012 RCOG 2006\nMinimal-mild  \n(stage I-II)\nDemonstrated benefit :  \nsurgery recommended\nSmall benefit: \ninsufficient to recommend surgery solely to \nincrease the likelihood of pregnancy\nDemonstrated benefit: surgery \nrecommended\nModerate-severe  \n(stage III-IV)\nPossible benefit: \nsurgery can be considered\nPossible benefit: \nsurgery may be beneficial\nPossible benefit:  \nrecommendation uncertain\nPostoperative adjuvant treatment No benefit :  \nnot recommended\nNo benefit:  \nnot recommended\nNo benefit:  \nnot recommended\nSurgery before IVF\nUncertain benefit in stage I –II: may be \nconsidered \nNo benefit \nif endometrioma>3cm: \nonly consideredto improve pain or the \naccessibility of follicles \nInsufficient benefit: \nno recommendation \nsurgery should be considered  \nif endometrioma> 4cm\nRecommended  \nif endometrioma \n> 4cm\nRecurrent endometriosis Surgery should be considered carefully if the \nwomen has had previous ovarian surgery\nSecond-line surgery not recommended; IVF-\nET is an effective alternative No recommendation\nTable 1: International guidelines for surgical treatment of endometriosis-associated infertility in asymptomatic women.\nIVF, in vitro fertilization; ET, embryo transfer\nGroup Unexplained Endometriosis-associated infertility\nTreatment Guzick  \net al. (1999)\nDeaton at al. \n(1990)\nChaffkin et al. \n(1991)\nFedele et al. \n(1991)\nKemmann et al. \n(1993)\nNo treatment or intracervical insemination 0.02 0.033 - 0.045 0.028\nIUI 0.05* - - - -\nClomiphene - - - - 0.066\nClomiphene/IUI - 0.095* - - -\nGonadotropins 0.04* - 0.066 - 0.073*\nGonadotropins/IUI 0.09* - 0.129* 0.15* -\nIVF - - - - 0.022*\nTable 2: Cycle fecundity in women with stage I/II endometriosis by treatment.\nIUI, intrauterine insemination; IVF, in vitro fertilization. * P<0.05 for treatment vs. no treatment.\ncompared with timed interc ourse during the natural cycle (OR 4.6, \n95% CI 1.9–11.3) [57]. Clinical pregnancy rate using IUI with COS \nafter surgical management for stage I/II endometriosisis comparable \nto the rate associated with unexplained infertility. The controlled \ncohort study revealed that clinical pregnancy rate per cycle is 21%, \n18.9%, and 20.5% for minimal endometriosis, mild endometriosis, \nand unexplained infertility, respectively. Moreover, cumulative live \nbirth rates in first four cycles of IUI are also comparable between \ngroups (70.2%, 68.2%, and 66.5%, respectively) [ 59]. Thus, IUI with \nCOS may be considered as an option for patients with minimal/mild \nendometriosis. However, endometriosis itself has a considerable \nadverse impact on success of IUI compared with other causes such \nas unexplained infertility. Nuojua-Huttunen et al. reported that \npregnancy rates per cycle were 15.3% for unexplained infertility \nversus 6.5% for patients with endometriosis [ 60]. We performed \nretrospective analysis to determine predictive factors for pregnancy \nin patients undergoing the first four IUI cycles. the pregnancyrate \nwas 4.2% (2/48) in cases of endometriosis-related infertility, which \nwas lower than in male factor infertility (13.3%, 4/30) as well as \nunexplained infertility (17.2%, 48/279) with borderline significance \n(P=0.064), and endometriosis-related infertility was an unfavorable \npredictive factor in logistic regression. Low pregnancy rate in patients \nwith endometriosis could be due to advanced stage with 18 cycles with \nmoderate endometriosis and 27 cycles with severe endometriosis [61]. \nIt is unclear whether IUI is a better option after surgical diagnosis \nof endometriosis compared with clinically diagnosed or untreated \nendometriosis. \nIn Vitro Fertilization and Embryo Transfer \nIVF may represent a viable option that overcomes the influence \nof distorted pelvic anatomy in infertile women with endometriosis. \nHowever, because few studies have been performed that evaluate \nwhether IVF is superior to expectant management for patients with \nendometriosis, it is not a treatment of choice for infertile women with \nendometriosis. Yet, similar to patients without endometriosis, IVF is \nused for infertile couples with male factor and tubal factor issues, or \nwho have repetitively failed to conceive. Although most of the results \nfrom recent studies have suggested that endometriosis does not affect \nthe IVF outcome after adjusting for age, some discrepancies have \nbeen reported. Some of the studies have reported lower fertilization \n[62] or implantation rates [22,63], altered oocyte quality [22,23\n], and \nlower pregnancy rates in endometriosis patients, compared with the \ncontrols.\nFindings of early retrospective studies indicated that delivery \nrate per embryo transfer was comparable for endometriosis patients \ncompared with patients with tubal factor issues [ 64,65]. A serial \nprospective study also obtained similar results, the presence and \nseverity of endometriosis seems not to alter the IVF outcome [66]. In \nthe early 2000s, a meta-analysis that included 27 trials compared the \noutcome of IVF for patients with endometriosis with that of women \n\nCitation: Yun BH, Choi YS, Lee BS. Management of Endometriosis-Associated Infertility. J Androl Gynaecol. 2014;2(2): 7.\nJ Androl Gynaecol 2(2): 7 (2014) Page - 05\nISSN: 2332-3442\nundergoing IVF for other indications [ 67]. The chance of achieving \npregnancy was significantly lower in endometriosis patients (OR 0.56, \n95% CI 0.44–0.70), compared with the tubal controls. Fertilization \nand implantation rates were also significantly lower. Fewer oocytes \nwere retrieved from the endometriosis patients after adjusting for age, \nstimulation protocol, and publication date. In a large, retrospective, \ncohort study performed in Norway, the investigators compared \ncouples with minimal/mild endometriosis, tubal factor issues, and \nunexplained infertility [ 68]. The live birth rate was similar between \nthe endometriosis and tubal factor groups (66.0% and 66.7%, \nrespectively). The birth rates for these groups were lower than the \nrate for the unexplained factor group, which was 78.8% (P < 0.05). \nThe implantation rate was comparable among the three study groups. \nThe discrepancies among studies comparing the effect of \nendometriosis on IVF outcome may be caused by variations in the \nseverity of the endometriosis among the participants. The results of \na retrospective study performed in Israel indicated that there were \nsignificantly lower fertilization, pregnancy, and birth rates per IVF \ncycle in advanced stage (stage III/IV) endometriosis compared with \ntubal controls [69]. However, one limitation of the study is that it did \nnot include minimal/mild endometriosis in the comparison. Some \nstudies have reported unaffected pregnancy outcomes according \nto the stage [ 64,65], and others have found significantly decreased \nfertilization rates in stage III/IV endometriosis [70]. Recently, results \nof an observational study indicated that implantation and pregnancy \nrates in women with stage III/IV endometriosis were significantly \nlower compared with milder stages of endometriosis or tubal factors, \nindependent of age. Also, deep infiltrating endometriosis has not \nbeen included in the American Fertility Society staging definition, \nbut it has been suggested to deleteriously affect pregnancy outcome, \ncompared with superficial lesions [71,72]. \nThe effect of existing endometrioma on ART outcome has been \ndebated. There have been no randomized studies comparing IVF/\nICSI outcomes between expectant management and surgical treated \ngroups. Moreover, the effect of endometriomaon IVF outcome is \ndifficult to evaluate because endometrioma rarely occurs without \nperitoneal lesions or adhesions. Surgical removal of endometrioma \ncan have possible benefits, particularly for larger endometriomas, and \ncan prevent incidental or iatrogenic rupture of the endometrioma \nduring oocyte retrieval, early detection of ovarian malignancy, and \neasier oocyte retrieval. The disadvantages of surgical removal include \npotential surgical complications, decreased ovarian reserve after \nsurgery, economic costs, and lack of definitive evidence for a positive \neffect on ART outcome. The results of a case control study indicated \nthat there is no effect on ART outcome when endometrioma is \nremoved laparoscopically before IVF [ 73]. The authors of a recent \nCochrane review concluded that neither aspiration nor cystectomy \nbefore ART further improves pregnancy rate [74]. \nThe systematic review that summarized three RCTs concluded \nthat administrating GnRH agonists for 3 to 6 months prior to ART in \nwomen with endometriosis increases the odds of clinical pregnancy \n(OR 4.28, 95% CI 2.00–9.15). Short-term use of oral contraceptives \nprior to ART can be as effective as the use of a GnRH agonist, but \nfurther study is necessary [75]. It has been shown that use of a GnRH \nagonist might improve ART outcome, but it is unclear whether \npretreatment is beneficial for every stage of the endometriosis, and \nhow the pathophysiology is affected. \nSummary and Recommendations \n1. There have been few published randomized trials of \nmanagement of infertility in endometriosis. \n2. Before planning fertility management in endometriosis \npatients, women’s age, duration of infertility, other combined \ncauses of infertility, ovarian reserve, severity of pain, and stage of \nendometriosis should be thoroughly evaluated. Sufficient information \nabout the patient’s condition and management options should be \nprovided. \n3. When laparoscopy is performed, the operator must ablate or \nexcise the endometriotic lesion and restore normal pelvic anatomy as \ncompletely, and as safely, as possible. Surgery might improve fertility. \nHowever, repeated ovarian surgery should be avoided. If natural \nconception does not occur within 1 year after surgery, the clinician \nmay consider ART. \n4. In infertile, younger, patients with stage I/II endometriosis, \nexpectant management or COS with IUI after surgical management \nshould be considered. But, if the patient is >35 years of age, COS with \nIUI or IVF may be the preferred option.\n5. 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Fertil \nSteril 72: 1107-1109.\n70. Pal L, Shifren JL, Isaacson KB, Chang Y, Leykin L, et al. (1998) Impact \nof varying stages of endometriosis on the outcome of in vitro fertilization-\nembryo transfer. J Assist Reprod Genet 15: 27-31.\n71. Ballester M, Oppenheimer A, d’Argent EM, Touboul C, Antoine JM, et al. \n(2012) Nomogram to predict pregnancy rate after ICSI-IVF cycle in patients \nwith endometriosis. Hum Reprod 27: 451-456.\n72. Ballester M, Oppenheimer A, Mathieu d’Argent E, Touboul C, Antoine \nJM, et al. (2012) Deep infiltrating endometriosis is a determinant factor of \ncumulative pregnancy rate after intracytoplasmic sperm injection/in vitro \nfertilization cycles in patients with endometriomas. Fertil Steril 97: 367-372.\n73. Garcia-Velasco JA, Mahutte NG, Corona J, Zuniga V, Giles J, et al. (2004) \nRemoval of endometriomas before in vitro fertilization does not improve \nfertility outcomes: a matched, case-control study. Fertil Steril 81: 1194-1197.\n74. Benschop L, Farquhar C, van der Poel N, Heineman MJ (2010) Interventions \nfor women with endometrioma prior to assisted reproductive technology. \nCochrane Database Syst Rev 10:CD008571.\n75. Tokushige N, Markham R, Russell P, Fraser IS (2009) Effect of progestogens \nand combined oral contraceptives on nerve fibers in peritoneal endometriosis. \nFertil Steril 92: 1234-1239.\nCopyright: © 2014 Yun BH, et al. This is an open access article \ndistributed under the Creative Commons Attribution License, which \npermits unrestricted use, distribution, and reproduction in any medium, \nprovided the original work is properly cited.","source_license":"CC0","license_restricted":false}