Significance of surgery for infertile patients with endometrioma

Background: The significance of cystectomy for infertile patients with endometrioma remains con- troversial.

Between 1997 and 2013, 852 female pa- tients visited Kindai University Hospital and were treated for infertility, and the significance of sur - gery for infertile patients with endometrioma was retrospectively analyzed in this study.

Among patients without endometrioma (N=740), patients with unilateral endometrioma (N=81), and patients with bilateral endometrioma (N=31), the proportion of patients with reduced ovarian reserve at the start of treatment was not different in patients <35 years old (5.0% vs 8.0% vs 10.5%, p=0.41) but was significantly different in patients 35 to 39 years old (15.6% vs 29.6% vs 45.5%, p=0.014). Among these three groups, the cumulative pregnancy rates in patients before sur - gery or in those who did not undergo surgery were significantly different in patients <35 years old (59.9% vs 27.3% vs 18.0%, p=0.008) and were not different in patients 35 to 39 years old (45.3% vs 38.0% vs 10.0%, p=0.93). Among the three groups, the cumulative pregnancy rates of patients who underwent surgery were not different in patients <35 years old (51.2% vs 45.2% vs 50.0%, p=0.71) but were significantly different in patients 35 to 39 years old (40.7% vs 31.3% vs 0%, p=0.025).

Surgery, including cystectomy, for infertile patients with endometrioma improves fertility in patients <35 years old by correcting the pelvic environment to the same extent as that in patients without endometrioma but may decrease fertility in 35- to 39-year-old patients by reducing ovarian reserve. Key words : endometrioma, infertility, ovarian reserve, surgery, ART

Endometriosis is defined as the presence of endometrium or endometrial-like tissue outside of the uterine cavity; this tissue grows and pro- liferates by estrogen and causes dysmenorrhea, chronic pelvic pain and infertility. Endometriosis affects 10% of women of reproductive age 1 and 20-50% of infertile patients. 2,3 Endometriosis can cause infertility by leading to abnormal pelvic anatomy, alterations in the pelvic environment, disorders in sperm function, a decline in oocyte quality, and impaired implantation. 4-6 Endometri- omas are ovarian endometriotic lesions observed in 17-44% of endometriosis patients. 7 Endometri- omas can cause ovulation disorders, reduce ovar - ian reserve, and decrease ovarian responsiveness to hyperstimulation. 4,8 Surgery has been the main treatment choice for infertile patients with endo- metriomas, especially cystectomy, which is con- sidered the standard surgery due to a higher post- operative pregnancy rate and lower recurrence rate of endometrioma compared with electrocoag- ulation and fenestration. 9-11 In patients who do not undergo surgery for an endometrioma, there are various risks, such as the infection of endometri- omas during oocyte retrieval in assisted reproduc- tive technology (ART) treatment, follicular fluid contamination with endometrioma content, ob- stetrical complications, including endometrioma Received July 10, 2019; Accepted November 20, 2019 I.Tsuji et al. 2 rupture, during the pregnancy period, and the ma- lignant transformation of endometriomas. 12 How- ever, whether cystectomy truly improves fertility is controversial. 13 In some studies, surgical endo- metrioma treatment, including cystectomy prior to ART, did not alter reproductive outcomes 14,15 , and cystectomy caused severe ovarian damage. 14,16,17 Previous reports relating endometrioma and infer - tility treatment outcomes are mainly retrospective studies, 18-36 and many of these reports have the problem of selection bias because of comparisons based on treatment content, such as surgery group vs nonsurgery group, and inconsistent data that were not examined according to age stratifica- tion. This study retrospectively examined whether analyses based on the state of endometrioma in the same treatment group exhibited a difference in pregnancy rates when stratified by age.

Patients and study design Between 1997 and 2013, 852 patients visited Kindai University Hospital with the desire to be- come pregnant and were subsequently followed for at least 6 months. The clinical diagnosis of endometriosis was made by the presence of sub- jective symptoms, such as dysmenorrhea, pain during internal examination, or endometrioma by MRI. Ovarian function was assessed by base- line concentrations of FSH and AMH. The base- line concentration of FSH was measured with an electrochemiluminescence immunoassay (Rosch Diagnostics KK). The concentration of AMH was measured with a chemiluminescent enzyme immunoassay (Beckman Coulter, Inc.). Baseline concentrations of FSH ≥10 mIU/ml 37 and AMH <2 ng/ml 38 were defined as a reduced ovarian reserve. Since AMH was adapted as an infertility test at our hospital in 2011, the evaluation of ovarian re- serve by AMH is limited to cases after 2011. Sur - gery was performed for patients who did not be- come pregnant following conservative infertility treatment, and ART was recommended for those who did not become spontaneously pregnant after surgery. Cystectomy was performed for endome- triomas. Other infertility factors were treated as follows: tubal occlusion was treated by fallopo- scopic tuboplasty; peritubal and/or perifimbrial adhesions were lysed; hydrosalpinx was treated by salpingostomy or salpingectomy; endometrio- sis was treated by bipolar coagulation; and ade- nomyosis was treated by extirpation. The current study was retrospective. All study protocols were approved by the Kindai University Faculty of Medicine Ethics Committee (Approval number: 31-025). Informed consent was obtained from all patients. Statistics Statistical analysis was performed using StatMateV (ATMS, Tokyo). The chi-square test, log rank test and Kruskal-Wallis test were applied to obtain multiple group comparisons. Statistically significant differences were defined as p < 0.05.

Patient background The mean age of the patients at the start of the infertility treatment was 32.5±4.5 years (19–46 years), and the mean duration of infertility was 3.8 ± 5.8 years (0.5–15 years). A total of 546 pa- tients (64.1%) had primary infertility, and 306 patients (35.9%) had secondary infertility. A total of 112 (13.1%) patients had endometrioma and were stratified according to the presence or ab- sence of surgery and ART (Fig 1). Twenty-sev- en patients underwent ART treatment, including 6 patients (22%) before surgery and 21 patients (78%) after surgery. The mean size of the endo- metriomas was 4.5±2.3 cm (1-11 cm). Eighty-one patients (72.3%) had unilateral endometriomas, and 31 patients (27.7%) had bilateral endometri- omas. There were no differences in the findings at surgery between unilateral and bilateral endo- metriomas. Regarding other infertility factors, 260 patients (30.5%) had an ovulatory factor, 209 patients (24.5%) had a tubal factor, 92 patients (10.8%) had a male factor, and 25 patients (2.9%) had adenomyosis. Patient characteristics other than ovarian function were examined for all age groups according to the presence or absence of endometrioma (Table 1). As a result, pregnancy history (p=0.003), tubal factor infertility (p=0.001), and adenomyosis (p=0.005) were significantly higher in the patient group with endometrioma (N=112) compared to the patient group without endometrioma (N=740). Differences in infertility treatment outcomes based on the clinical diagnosis of endometriosis Differences in infertility treatment outcomes when diagnosed with clinical endometriosis or endometrioma were examined. The patients were classified into three groups: patients without Surgery and endometrioma 3 suspected endometriosis (N=482), patients with suspected endometriosis and without endometri- oma (N=258), and patients with endometrioma (N=112). The cumulative pregnancy rates for pa- tients <35 years old and for those between 35 and 39 years old were significantly different among the three groups, and the rates in the group with endometrioma were lower (<35 years old; 65.4% vs 62.7% vs 51.1%, p=0.015, Fig 2a. 35-39 years old; 49.6% vs 52.3% vs 30.0%, p=0.034, Fig 2b). The cumulative pregnancy rates for patients ≥40 years old were not different among the three groups (23.1% vs 22.6% vs 20.0%, p= 0.65, Fig 2c). To evaluate the accuracy of the clinical diagno- sis of endometriosis, the pre- and postoperative diagnoses were compared among patients who un- derwent surgery. The proportion of patients diag- nosed with endometriosis after surgery was 32.9% (47/143 patients) in the patient group without sus- pected endometriosis and 53% (53/100 patients) Table 1. The analysis of factors other than ovarian function. Endometrioma (-) (n=740) Endometrioma (+) (n=112) p value Age (years) 32.4 ± 4.5 32.7 ± 4.3 0.51 Duration of infertility (years) 3.8 ± 5.8 3.7 ± 5.3 0.85 Pregnancy history 272 (36.8%) 25 (22.3%) 0.003 Associated infertile factors Tubal 167 (22.6%) 42 (37.5%) 0.001 Male 75 (10.1%) 17 (15.2%) 0.11 Adenomyosis 17 (2.3%) 8 (7.1%) 0.005 Size of endometrioma (cm) ― 4.5 ± 2.3 Pregnancy history (p=0.003), tubal factor infertility (p=0.001), and adenomyosis (p=0.005) were significantly higher in the patient group with endometrioma compared to the patient group without endometrioma. There were no differences between the two groups for the other factors. Fig.1 The classification of patients with endometrioma. Patients with endometrioma were divided into four groups according to the presence or absence of surgery and ART. I.Tsuji et al. 4 Fig.2 The differences in infertility treatment outcomes based on clinical diagnosis of endometriosis. The X-axis shows the observation period, the Y-axis shows the cumulative pregnancy rates, and the circle graph shows the ratios of the treatment methods used during pregnancy. a: <35 years old There were significant differences in the cumulative pregnancy rates among three groups (p=0.015). Many of the pregnancies following treatment among the three groups in each age stratification were conceived without ART. b: 35- 39 years old There were significant differences in the cumulative pregnancy rates among three groups (p=0.034). Many of the pregnancies following treatment among the three groups in each age stratification were conceived without ART. c: ≥40 years old There were no differences in the cumulative pregnancy rates among three groups (p=0.65). Surgery and endometrioma 5 in the patient group with suspected endometriosis and without endometrioma before surgery. One hundred percent of the patients (81/81) diagnosed with endometrioma after surgery had also been di- agnosed before surgery. Collectively, the diagnosis of clinical endome- triosis by symptoms and examination findings does not have an influence on infertility treatment outcomes in patients without endometrioma and is inaccurate since it often differs from the diagnosis after surgery. Therefore, the following analyses were performed based on the presence or absence of endometrioma. Furthermore, since the number of patients over 40 years old was small (N=51) and their infertility treatment outcomes were re- markably worse, the analysis was performed on patients ≤39 years old. The analysis of ovarian function at the start of infertility treatment Ovarian function was compared among three groups: patients without endometrioma (N=694), patients with unilateral endometrioma (N=77), and patients with bilateral endometrioma (N=30) (Table 2). In patients <35 years old, the mean baseline FSH concentrations in the three groups were 6.6 ± 6.9, 6.8 ± 2.3, and 7.6 ± 2.6 mIU/ ml (p=0.82), respectively, and the median AMH concentrations were 4.5 (0.25-28.8), 1.6 (1.3- 5.4), and 1.4 ng/ml (p=0.11), respectively. The proportion of patients diagnosed with reduced ovarian reserve according to baseline FSH ≥10 mIU/ml and AMH <2 ng/ml were 5.0%, 8.0% and 10.5%, respectively, (p=0.41) (Table 2a). In 35- to 39-year-old patients, the mean baseline FSH concentrations in the three groups were 7.6 ± 4.1, 7.7 ± 2.3, and 10.2 ± 6.8 mIU/ml (p=0.13), re- spectively, and the median AMH concentrations were 2.3 (0.4-8.0), 1.7 (0.1-13.1), and 1.3 (0.5- 2.3) ng/ml (p=0.45), respectively. The proportion b: 35-39 years old Endometrioma (-) (n=192) Unilateral endometrioma (n=27) Bilateral endometrioma (n=11) p value Ovarian reserve Baseline FSH (mIU/ml) 7.6 ± 4.1 7.7 ± 2.3 10.2 ± 6.8 0.13 AMH (ng/ml) 2.3 (0.4-8.0) n=20 1.7 (0.1-13.1) n=8 1.3 (0.5-2.3) n=3 0.45 The ratio of patients with diminished ovarian reserve FSH≧10mIU/ml or AMH<2ng/ml 30 (15.6%) 8 (29.6%) 5 (45.5%) 0.014 Mean baseline FSH concentrations and median AMH concentrations were not different among the three groups. There was a significant differ- ence in the proportion of patients diagnosed with reduced ovarian reserve according to baseline FSH ≥10 mIU/ml and AMH <2 ng/ml among the three groups (p=0.014). Table 2. The analysis of ovarian function at the start of infertility treatment. a: < 35 years old Endometrioma (-) (n=502) Unilateral endometrioma (n=50) Bilateral endometrioma (n=19) p value Ovarian reserve Baseline FSH (mIU/ml) 6.6 ± 6.9 6.8 ± 2.3 7.6 ± 2.6 0.82 AMH (ng/ml) 4.5 (0.25-28.8) n=15 1.6 (1.3-5.4) n=5 1.4 n=1 0.11 The ratio of patients with diminished ovarian reserve FSH≧10mIU/ml or AMH<2ng/ml 25 (5.0%) 4 (8.0%) 2 (10.5%) 0.41 Mean baseline FSH concentrations, median AMH concentrations, and the proportion of patients diagnosed with reduced ovarian reserve ac- cording to baseline FSH ≥10 mIU/ml and AMH <2 ng/ml were not different among the three groups. I.Tsuji et al. 6 of patients who had reduced ovarian reserve was 15.6%, 29.6%, and 45.5%, and these proportions increased significantly with the incidence of en- dometrioma (p=0.014) (Table 2b). Differences in infertility treatment outcomes based on the state of endometrioma 1) Infertility treatment outcomes of patients without surgery The cumulative pregnancy rates for patients who did not undergo surgery and for patients prior to surgery were analyzed and compared among three groups: patients without endo- metrioma (N=694), patients with unilateral endometrioma (N=77), and patients with bi- lateral endometrioma (N=30). The pregnancy rates were low in <35-year-old patients with endometrioma (59.9% vs 27.3% vs 18.0%, p=0.008) (Fig 3a) and were not different among the three groups in patients between 35 and 39 years old (45.3% vs 38.0% vs 10.0%, p=0.93) (Fig 3b). Many of the pregnancies Fig.3 Infertility treatment outcomes of patients prior to surgery and patients who did not undergo surgery. The X-axis shows the observation period, the Y-axis shows the cumulative pregnancy rates, and the circle graph shows the ratios of the treatment methods used during pregnancy. a: <35 years old There were significant differences in the cumulative pregnancy rates among three groups (p=0.008). Many of the pregnancies following treatment among the three groups in each age stratification were conceived without ART. b: 35- 39 years old There were no differences in the cumulative pregnancy rates among three groups (p=0.93). Many of the pregnancies following treatment among the three groups in each age stratification were conceived without ART. Surgery and endometrioma 7 following treatment among the three groups in each age stratification were spontaneously conceived (Fig 3a, b). 2) Infertility treatment outcomes after surgery In patients <35 years old, the cumulative pregnancy rates after surgery were not differ - ent among the three groups, suggesting that surgery improved infertility treatment out- comes (51.2% vs 45.2% vs 50.0%, p=0.71) (Fig 4a). In patients between 35 and 39 years old, the cumulative pregnancy rates after sur - gery were significantly different, especially among patients with bilateral endometrioma, none of whom became pregnant, suggesting that surgery reduced ovarian reserve (40.7% vs 31.3% vs 0%, p=0.025) (Fig 4b). The pro- portions of ART-mediated conceptions fol- lowing surgeries among the three groups were large (Fig 4a, b). Fig.4 Infertility treatment outcomes after surgery The X-axis shows the observation period, the Y-axis shows the cumulative pregnancy rates, and the circle graph shows the ratios of the treatment methods used during pregnancy. a: <35 years old There were no differences in the cumulative pregnancy rates among three groups (p=0.71). The proportions of ART-mediated conceptions following treatments resulting in pregnancy among the three groups were large compared with infertility treatment outcomes in patients who did not undergo surgery. b: 35- 39 years old There were significant differences in the cumulative pregnancy rates among three groups (p=0.025). The cumulative pregnancy rates in the patient group with bilateral endometrioma were very low. I.Tsuji et al. 8 The analysis of ART treatment outcomes in pa- tients who underwent ART ART treatment outcomes were compared among three groups: patients without endometrioma (N=694), patients with unilateral endometrioma (N=77), and patients with bilateral endometrioma (N=30). The mean number of retrieved oocytes per cycle among the three groups were 8.6±6.3, 4.1± 1.6, and 4.6± 2.4 (p=0.008), respectively, in pa- tients <35 years old and 5.4 ± 4.5, 5.3 ± 4.8, and 1.9 ± 0.6 (p=0.035), respectively, in patients between 35 and 39 years old; these results were significantly different. However, the pregnancy rates were not different among the three groups (Table 3).

Whether the presence of endometrioma reduc- es ovarian reserve is unclear. However, the fol- lowing mechanisms have been proposed. An en- dometrioma contains reactive oxygen species. Reactive oxygen species potentially permeating the surrounding ovarian tissues are likely to cause the substitution of normal ovarian cortical tis- sue with fibrous tissue and intraovarian vascular injury, followed by follicular loss. 39 In a recent meta-analysis, the baseline FSH was higher in pa- tients with endometrioma than in patients without endometrioma. 14 Some reports have shown that AMH in patients with endometrioma is lower than that in control groups without endometrioma, 40 while other studies have reported no difference. 41 In this study, the mean baseline FSH and median AMH were not different among three groups: pa- tients without endometrioma, patients with unilat- eral endometrioma, and patients with bilateral en- dometrioma. The number of patients with reduced ovarian reserve at the start of infertility treatment increased with the presence of endometrioma, es- pecially among patients 35 to 39 years old (Table 2). Reduced ovarian reserve due to the presence of endometrioma may be remarkable in patients with reduced ovarian reserve due to old age. Cystectomy has been performed in infertile pa- tients with endometrioma. 9-11 However, there is no consensus as to whether cystectomy should be performed since cystectomy reduces ovarian reserve. 14,16,17 To date, only one prospective ran- domized study on this subject has been reported. 42 Demirol et al. examined intracytoplasmic sperm injection (ICSI) treatment outcomes by compar - ing the surgery group (49 patients) to the non- surgery group (50 patients), and reported that the pregnancy rates did not differ between the two groups (surgery group: 34.4%, nonsurgery group: 38.2%). Because this study was conducted in a small group limited to patients who underwent ICSI, whether cystectomies should be performed for endometrioma or not in infertility patients re- mains inconclusive. To our knowledge, there are 10 retrospective studies that examined pregnancy rates by com- b: 35-39 years old Endometrioma (-) (n=192) Unilateral endometrioma (n=27) Bilateral endometrioma (n=11) p value The mean number of retrieved oocytes per cycle 5.4 ± 4.5 5.3 ± 4.8 1.9 ± 0.6 0.035 Clinical pregnancy rate per patient 20.0% (10/50) 20.0% (1/5) 0% (0/6) 0.48 There was a significant difference in the mean number of retrieved oocytes per cycle among the three groups (p=0.035). Clinical pregnancy rate per patient was not different among the three groups. Table 3. The analysis of ART treatment outcomes in patients who underwent ART. a: < 35 years old Endometrioma (-) (n=502) Unilateral endometrioma (n=50) Bilateral endometrioma (n=19) p value The mean number of retrieved oocytes per cycle 8.6 ± 6.3 4.1 ± 1.6 4.6 ± 2.4 0.008 Clinical pregnancy rate per patient 47.8% (33/69) 53.8% (7/13) 75.0% (3/4) 0.55 There was a significant difference in the mean number of retrieved oocytes per cycle among the three groups (p=0.008). Clinical pregnancy rate per patient was not different among the three groups. Surgery and endometrioma 9 paring patients who had cystectomies performed for endometrioma to those who did not have cys- tectomies. 18,20-22,29,31-34,36 Several studies have sug- gested that there is no difference in the pregnan- cy rates between surgery groups and nonsurgery groups, 18,20,21,29,32-34,36 while other reports suggest that the pregnancy rates in surgery groups were higher than those in nonsurgery groups. 22,31 Retro- spective studies seem to be affected by selection bias because the comparisons in these studies are based on differences in treatment method. That is, more aggressive treatments might be performed in patients with severe conditions, making it diffi- cult to evaluate treatment efficacy. There were three retrospective studies analyz- ing pregnancy rates based on the endometrioma status of the patient but not the difference in treat- ment method. Some studies have reported that the pregnancy rates did not differ between patients with unilateral versus bilateral endometrioma, 25 while other studies have reported that the preg- nancy rates among patients with bilateral endo- metrioma were lower. 28,30 These studies did not conduct analyses according to age stratification, which may be the reason for the inconsistent re- sults because ovarian reserve is remarkably re- duced as age increases. The current study compared pregnancy rates based on the endometrioma status according to age stratification. As a result, the cumulative pregnancy rates in endometrioma patients <35 years old who did not undergo surgery were lower than the pregnancy rates in patients without endo- metrioma (Fig 3a), and the pregnancy rates after surgery did not differ between the two groups (Fig 4a). Previous studies have suggested that surgery improves fertility by correcting the pelvic envi- ronment, such as endometrioma, tubal pathology and adenomyosis, 44,45 in patients <35 years old. Consistent with this idea, endometrioma patients had higher rates of tubal pathology and adenomy- osis (Table 1). The cumulative pregnancy rates in endometrioma patients 35 to 39 years old who did not undergo surgery did not significantly differ from the rates in patients without endometrioma (Fig 3b), and the rates after surgery were lower than those for patients without endometrioma (Fig 4b). In agreement with our results, it has been re- ported that reduced ovarian reserve by cystecto- my increases with age, 7,14,16,17 and ovarian reserve is remarkably reduced after surgery for bilateral endometrioma. 7,40,43 In this study, the number of retrieved oocytes, reflecting ovarian reserve, decreased among en- dometrioma patients (Table 3). This finding is consistent with the results of a previous me- ta-analysis. 14 The limitations of this study are that it was a retrospective study that was conducted at one in- stitution and included a relatively small sample size. However, we conducted careful analyses to avoid selection bias and obtained results that sup- port the recent hypothesis of the association of infertility with endometrioma. In the future, pro- spective, multicenter randomized trials are need- ed to establish a standard therapy for this disease, and the results of this study could be a resource for future protocol preparation. Pregnancy rates are lower in infertile patients with endometrioma than in those without endo- metrioma. In patients <35 years old, the pregnan- cy rates in patients who underwent surgery for endometrioma were the same as the pregnancy rates in patients without endometrioma. This re- sult may involve fertility improvements that occur by correcting the pelvic environment. For patients <35 years old, cystectomy should be recommend- ed but carries the risk of reduced ovarian reserve. However, in patients 35 to 39 years old, pregnan- cy rates were lower in patients who underwent surgery for endometrioma than in patients with- out endometrioma. The reduction in ovarian re- serve due to surgery may cause this result. In the future, prospective, multicenter randomized trials are needed to establish standard therapy. Conflict of interest The authors have no conflicts of interest.

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