{"paper_id":"aca5bc5a-e642-43db-a18b-2ba19fcedce1","body_text":"Endometriosis is an estrogen-dependent, benign, chronic inflammatory disease with\nectopic endometrial implants ( Macer & Taylor,\n2012 ), that affects at least 4% of women in reproductive age ( Ferrero  et al ., 2010 ).\nEndometrioma is a typical manifestation of the ovarian disease, and its prevalence\nranges from 17 to 44% of patients with endometriosis ( Busacca & Vignali, 2003 ).\nTo what extent the endometrioma and endometrioma surgery influence the ovarian\nreserve and spontaneous ovulation is controversial. It has been claimed that women\nwith endometriomas have lower levels of anti-Müllerian hormone (AMH) and\nantral follicle counts (AFC) compared to women without ovarian cysts, suggesting\nthat the presence of endometrioma is associated with a reduction in ovarian reserve\n( Uncu  et al ., 2013 ). On\nthe other hand, a prospective observational study showed that endometriomas,\nirrespective of their volume, do not influence the rate of spontaneous ovulation in\nthe affected ovary; furthermore, a good spontaneous pregnancy rate was demonstrated\nif the couple had no other risk factor for infertility ( Leone Roberti Maggiore  et al ., 2015 ).\nThe majority of publications show that surgery does not increase the success rate of\nin vitro fertilization (IVF) and that it may harm the assisted reproductive\ntechnology (ART) resulted by reducing the ovarian response to controlled ovarian\nstimulation (COH) ( Gupta  et al .,\n2006 ;  Hamdan  et al .,\n2015 ;  Kuroda  et al .,\n2012 ). Besides, several studies have reported a reduced AMH after\nendometrioma surgery ( Cranney  et\nal ., 2017 ;  Somigliana  et\nal ., 2012 ;  Streuli\n et al ., 2012 ), while antral follicle count seems to\nbe comparatively less affected ( Muzii  et\nal ., 2014 ). On the other hand, some studies showed recovery\nof the ovarian reserve after endometrioma surgery for up to one year ( Chang  et al ., 2010 ;  Iwase  et al ., 2016 ), so that\nspontaneous conception can be expected one year after surgery.\nSince the first description of the Endometriosis fertility index (EFI),\npredictability of the best fertility treatment for women with endometriomas received\nmore attention in recent decades ( Adamson &\nPasta, 2010 ). To further investigate this topic, we conducted a\nretrospective analysis examining the spontaneous conception rate after endometrioma\nsurgery. The aim of this study was to assess the impact of pre-operative and\noperative characteristics on future fertility likelihood in women who underwent\nendometrioma surgery.\n\nIn the present retrospective cohort study, we reviewed data from women with the\nhistological diagnosis of endometriosis who underwent surgery at a university-based\ninfertility clinic between January 2005 and June 2020. The study was approved by the\nClinical Research Ethical Committee of Ankara University School of Medicine\n(Approval no: 15-775-16). The patient data and the follow-up information (up to 12\nmonths) were extracted from the medical records. Inclusion criteria consisted of (1)\nhistologically diagnosed uni/bilateral endometrioma(s), (2) women ≤40 years,\n(3) women with regular unprotected intercourse. Exclusion criteria were as follows:\n(1) histologically diagnosed endometriosis without uni/bilateral endometrioma, (2)\npostmenopausal status at the time/after the operation, (3) women >40 years, (4)\nwomen without follow-up information, (5) women with contraception, (6) women with\nother uncorrected gynecological problems such as leiomyomas or uterine\nabnormalities. All infertile patients were assessed for tubal patency using\nhysterosalpingogram (HSG) before surgery and/or chromopertubation at surgery. In\naddition, patients who underwent surgery because of pain and had future fertility\nplans were also assessed for tubal patency using chromopertubation at the surgery.\nHence, the patients with documented bilateral tubal obstruction were excluded from\nthe study. Besides, semen analysis was also performed for all infertility patients\nand the patients with male factor infertility were excluded from the study.\nAll patients included in the study underwent either a laparotomy or a laparoscopic\nsurgery by the same experienced team under general anesthesia with a standard\ntechnique. Laparoscopy was performed in almost all patients, and a laparotomy only\nin clinically indicated cases. During laparoscopy, the cyst wall was detached from\nthe healthy surrounding ovarian tissue with two atraumatic grasping forceps by\ntraction and countertraction after identifying the cleavage plane. If necessary,\nhemostasis was achieved with bipolar forceps, which were used as little as possible\nto avoid damaging healthy tissue. In the laparotomy, the cyst wall was removed by\nhand using an atraumatic forceps, and hemostasis was performed with bipolar forceps.\nThe operation was indicated for uni/bilateral endometrioma(s) detected by ultrasound\nwith accompanying symptoms (either pain symptom or infertility). For the multiple\nendometriomas, the size of all endometriomas calculated together was determined as\nthe endometrioma size. The main outcome measure was spontaneous clinical pregnancy\nwithin twelve months following surgery, that was defined as the presence of a fetus\nwith a heartbeat at 6 weeks of gestation. In addition, demographics were compared\nbetween the women who got pregnant spontaneously and those who could not.\nData analyses were performed by using the SPSS Version 21.0 (IBM Corporation,\nArmonk, NYC, USA). The samples were tested using the Kolmogorov-Smirnov test to\ndetermine normality of distribution. According to the results, non-parametric\ntests were preferred. Continuous variables were compared using the Mann-Whitney\nU test and the categorical variables were compared using the Chi-square test or\nthe Fisher’s exact test, where appropriate. Multivariate logistic regression\nanalyses with a model building strategy were used to determine independent\npredictors of spontaneous conception following endometrioma surgery. Variables\nincluded in the model were age, unilateral salpingectomy, unilateral\noophorectomy, type of operation, and endometrioma recurrence. A\n p  value of <0.05 was considered statistically\nsignificant.\n\nOf a total of 1929 histologically diagnosed endometriosis cases, 1718 patients were\nexcluded since they didn’t meet the inclusion criteria of the study. A total of 211\nwomen with uni- or bilateral endometriomas were included in the final analyses.\n Figure 1  summarizes the flow diagram of the\nstudy population. Eighty-four women with spontaneous conception formed the case\ngroup and 127 women without successful spontaneous conception the control group. The\nmedian age of the case group was 27 years and the control group 32 years,\nrespectively ( p <0.001).  Tables\n1  and  2  show the demographic data\nof the study population as well as the comparison of various parameters between\nwomen that could and couldn’t conceive spontaneously.\nDemographics of the study population.\nComparison of the endometrioma related features in women with and without a\nsuccessful spontaneous conception.\nFigure 1 Flow diagram of the study population.\nFlow diagram of the study population.\nFifty patients (59.5%) in the case group and seventy-three patients (57.5%) in the\ncontrol group had a unilateral endometrioma. On the other hand, thirty-four (41.5%)\nin the case group and fifty-four patients (42.5%) in the control group had bilateral\nendometriomas ( p =0.768). Six patients in the case group (7.1%) and\nsix patients (4.7%) in the control group had multilocular endometriomas\n( p =0.458). Twenty-five (29.8%) patients in the case group and\nsixty-seven (52.8%) in the control group had recurrences (>1cm in diameter)\ndetected by ultrasound ( p =0.001). Due to endometrioma recurrence,\nfour patients (16%) in the case group and twenty-three patients (34.4%) in the\ncontrol group were operated for a second time ( p =0.122). One\npatient (1.2%) in the case and fifteen patients (11.8%) in the control group had a\nhistory of unilateral salpingectomy or had a salpingectomy during the operation\n( p =0.003). Both ovaries were present in all patients in the\ncase group and twelve patients (9.4%) in the control group had a history of\nunilateral oophorectomy or had an oophorectomy during the operation\n( p =0.002). The median (range) of previous pregnancies was 0\n(0-1) in both groups ( p =0.077). Thirteen patients (15.5%) in the\ncase group and twenty-seven patients (21.3%) in the control group had evidence of\ndeep endometrioses ( p =0.29), although a detailed classification was\nmissing in many surgical reports. Sixty-four (76.2%) of the patients in the case\ngroup and one hundred (78.7%) of the patients in the control group had chronic\ncyclic pain before surgery ( p =0.663). Most women in both groups\nunderwent laparoscopy, with the laparoscopy rate being significantly higher in the\ncase group (97.5%  vs . 84.3%;  p =0.002). Additional\noperations, such as myomectomy and other uterine or tubal operations have been also\nconsidered but didn’t show any difference in both groups ( Table 2 ).\nMost of the patients in both groups did not receive any hormonal add-back therapy\nafter the operation [case group n=53 (63.1%); control group n=74 (58.3%);\n p =0.24]. Postoperative use of combined oral contraceptives\n(COCs) for three months was ordered for 16 patients (19%) in the case group and for\n37 patients (29.1%) in the control group. A subcutaneous injection of GnRH-analogues\nwas given to 15 patients (17.9%) in the case group and to 15 patients (11.8%) in the\ncontrol group. Only in one patient in the control group, a levonorgestrel-releasing\nintrauterine system (LNG-IUS), Mirena ®  was inserted for three\nmonths. A multivariate regression analysis showed a significant independent effect\nof age, recurrence of endometrioma, and type of operation and did not suggest a\nsignificant effect of unilateral salpingectomy ( Table 3 ).\nLogistic regression for the chance of obtaining spontaneous conception among\nwomen, that tried to conceive.\n\nOur study showed a significant independent effect of age and endometrioma recurrence\non spontaneous conception after endometrioma surgery. The patients in our case group\nwere younger and the recurrence rate was less than that in the control group. There\nwas no significant difference between the two groups regarding the side, number and\nsize of the endometrioma cyst, smoking, BMI, preoperative pain symptom and\npreoperative pregnancy rate.\nSince the incidence of endometrioma increases with age, and family planning being\npostponed to older ages, the issue of endometrioma related to fertility has received\nmore attention in recent decades. Oocyte quality is known to have direct effects on\nART success ( de Ziegler  et al .,\n2019 ). The effect of endometriosis on oocyte quality, on the other hand,\nis controversial. Several studies claim that especially advanced stage endometriosis\nnegatively affects oocyte quality ( Brosens,\n2004 ;  Hauzman  et al .,\n2013 ), while several others show the opposite ( González-Comadran  et al ., 2017 ;  Juneau  et al ., 2017 ). A\ndiminished ovarian reserve (DOR) reflects a decrease in the number and quality of\noocytes, which currently is the second leading cause of infertility ( Buyuk  et al ., 2011 ). Although\nit can arise from a variety of factors, DOR is mainly caused by advanced maternal\nage. In the present study the maternal age was one of the main factors of successful\nconception. The women with endometriomas who could conceive spontaneously were\nsignificantly younger than those who could not conceive spontaneously (median 27\n vs . 32 years;  p <0.001). The median time\nbetween endometrioma surgery and spontaneous conception was less than one-year\n(median (Interquartile Range (IQR)): 6 (2-10) months). In this study, the women\nwithout success in spontaneous conception were not examined for the other causes of\ninfertility. If the other causes of infertility could be ruled out, the ratio of\nsuccessful spontaneous conception could increase. On the other hand, the higher rate\nof successful conception can be explained by the fact that some of the patients did\nnot have a history of infertility and our cohort consisted of relatively young\npatients.\nIn a prospective analysis of AMH levels in women undergoing surgery, there was no\ndifference between endometrioses patients at all stages and controls, but levels\nwere lower in women who had previously undergone endometrioma surgery ( Streuli  et al ., 2012 ). The\nrisk of reduced ovarian reserve after endometriosis surgery occurs especially in the\npresence of large (> 7 cm), bilateral endometriomas, as well as the surgical\nremoval of multiple endometrioma cysts ( Chen\n et al ., 2014 ;  Cranney\n et al ., 2017 ;  Hamdan\n et al ., 2015 ;  Streuli  et al ., 2012 ). Causes of ovarian damage during\nendometrioma surgery include mechanical damage associated with removal of healthy\novarian tissue along with the cyst wall, and heat damage produced by the energy\nmodalities used during hemostasis after cyst removal, especially if the operation is\nperformed by a surgeon with limited experience ( Muzii  et al ., 2011 ). In addition, it has been shown\nthat the age of menopause is significantly lower in women who have undergone\nprevious endometrioma surgery compared to the normal population ( Coccia  et al ., 2011 ). On the\nother hand, some studies showed recovery of the ovarian reserve after endometrioma\nsurgery up to one year in reproductive women ( Chang\n et al ., 2010 ;  Iwase\n et al ., 2016 ). Our results showed no differences in\nthe number, size, or side of the endometriomas in both groups. Contradictory\nfindings in the literature and the high pregnancy rate found in the current study\nafter an endometrioma surgery suggests that, despite the decrease in ovarian reserve\nafter endometrioma surgery, it could be restored thereafter up to one year\npostoperative. Therefore, favorable preoperative ovarian reserve and an operation\nperformed by a surgeon with high experience may implicate a postsurgical pregnancy\nafter endometrioma surgery.\nOur results indicate that, women without endometrioma recurrence are significantly\nmore likely to get spontaneously pregnant. Furthermore, a second surgery after\nrecurrence of endometrioma seemed to decrease the likelihood of spontaneous\nconception. European Society of Human Reproduction and Embryology (ESHRE) guidelines\nrecommend a cystectomy rather than CO2 laser vaporization in women with ovarian\nendometrioma, because of a lower recurrence rate of the endometrioma ( Dunselman  et al ., 2014 ). The\nreduced conception that we found in patients with recurrent endometriomas and the\nrecommendation of ESHRE indicating that, a cystectomy should be performed by an\nexperienced surgeon during the first operation.\nLaparoscopy is the gold standard for diagnosing endometriosis and also provides for\nan opportunity for treatment ( Nezhat  et\nal ., 2022 ). The majority of women in both groups underwent\nlaparoscopy, with the laparoscopic rate being significantly higher in women with\nsuccessful spontaneous conception. In addition, laparoscopic surgery rather than\nlaparotomy independently increased the likelihood of spontaneous conception after\nsurgery. This could be related to the higher stage of endometriosis and the\nassociated laparotomy indication and fertility risk. Cyst stripping and\nelectrocoagulation of the cyst wall was the only method used in all operations. A\nunilateral salpingectomy reduced the success of spontaneous conception (11.8%\n vs . 1.2%;  p =0.003), as well as a unilateral\noophorectomy (0  vs . 9.4%;  p =0.003), whereby no\nsignificant influence of adhesions and Douglas obliteration could be demonstrated. A\nlimiting factor for this evaluation was the inaccurate classification of the\nendometriosis in the operation reports, so that it is difficult to conclude\nregarding the endometriosis stage and adhesions.\nAlthough postoperative hormone therapy could have some effects on the success rate of\nspontaneous conception, we could not evaluate it in this study, since both groups\nwere relatively similar vis-a-vis the hormonal treatment.\nOur study may have some limitations. The retrospective design implies a lower level\nof evidence for the conclusions. The lack of a determination of ovarian reserve was\nalso a limitation of the present study. Since our patients were initially diagnosed\nwith endometrioma independent of their fertility status, there was not enough data\nto evaluate the ovarian reserve whether with AMH or with AFC. In ART, AMH can be\nused to predict the ovarian response to gonadotrophin stimulation. However, it has\nonly a minor influence on the likelihood of achieving natural conception ( Hamdine  et al ., 2015 ;  La Marca  et al ., 2010 ). In\naddition, pre-operative AMH concentration is increased in women with endometriomas,\nespecially with a cyst size of over 6 cm ( Marcellin\n et al ., 2019 ;  Roman\n et al ., 2021 ), so that AFC was recommended as a\nmarker for the ovarian reserve in contrast to AMH in women with endometriomas ( González-Foruria  et al .,\n2020 ). One of the major limitations of this study was lack of an accurate\nclassification of endometriosis in the operation reports, since information on\nendometriosis stage and adhesion is very important to relation to the subject of\nthis study. Another limitation of the study was that the male factor was only\nexamined in the infertility patients and not in the patients who underwent surgery\nbecause of pain. The lack of a control group of women without endometrioses was\nanother limitation. Nonetheless, the lack of a control group did not affect the\ndesign, as the comparisons between women with and without success of spontaneous\nconception were evaluated.\nAll in all, despite its its limitations, the current study suggests that the maternal\nage and endometrioma recurrence may have major influence on the success rate of\nspontaneous conception for endometrioma patients after endometrioma surgery. A\nfavorable preoperative ovarian reserve, better determined with AFC, and a cystectomy\nperformed by an experienced surgeon may lead to postoperative pregnancy after\nendometrioma surgery. Future prospective studies are required to assess the\nspontaneous pregnancy rate after endometrioma surgery.","source_license":"public-domain-us","license_restricted":false}