Risk factors for postoperative recurrence of ovarian endometriosis: long-term follow-up of 358 women

Objective: To explore the risk factors for the recurrence of endometrioma and the risk factors for the recurrence of endometriosis-related pain after long-term follow-up.

This study retrospectively analyzed 358 women with endometriomas who had a minimum of 5-years follow up after laparoscopic endometrioma excision, which was performed at Peking Union Medical College Hospital from January 2009 to April 2013. All women were divided into recurrence group and nonrecurrence group. Analysis was performed with regard to preoperative history, laboratory analysis, findings during surgery, and symptoms during follow-up, including improvement and recurrence.

The cumulative incidence rates of recurrence from 5 to 10 years after surgery were 15.4, 16.8, 19.3, 22.5, 22.5, and 22.5%, respectively. Significant differences were found between two groups in terms of age at surgery (RR: 0.764, 95% CI: 0.615 –0.949, p = 0.015), duration of dysmenorrhea (RR: 1.120, 95% CI: 1.054 –1.190, p < 0.001), presence of adenomyosis (RR: 1.629, 95% CI: 1.008 –2.630, p = 0.046), CA125 level (RR: 1.856, 95% CI: 1.072 –3.214, p = 0.021) and severity of dysmenorrhea. The severity of dysmenorrhea (RR: 1.711, 95% CI: 1.175 –2.493, p = 0.005) and postoperative pregnancy (RR: 0.649, 95% CI: 0.460 –0.914, p = 0.013) were significantly correlated with endometrioma recurrence in the multivariate analysis. No significant associations were found between the recurrence rate and gravida, parity, body mass index, infertility, leiomyoma presence, the size of ovarian endometrioma, the presence of deep infiltrating endome triosis, disease stage or postoperative medication.

The severity of dysmenorrhea and postoperative pr egnancy were independent risk factors for the recurrence of ovarian endometriomas after surgery during the long-time follow up.

Ovarian endometriomas, Recurrence, Risk factors

Endometriosis is a chronic benign estrogen-dependent disease. It is observed primarily in patients of reproductive age, and its prevalence in this population is estimated to be 5–10%. Endometriosis is defined as the presence of ac- tive endometrial tissue outside the uterine cavity, usually on the peritoneum of the minor pelvis, ovaries and fallo- pian tubes and sometimes in extraperitoneal regions. Based on the locations of the lesions, the disease is classified as peritoneal, ovarian or deep infiltrating endo- metriosis [1, 2]. Endometriosis causes impaired quality of life (QoL) for women of reproductive age, and has malig- nant clinical manifestation despite being a benign disease. Ovarian endometriosis is the most common type, ac- counting 17% and 44% of all endometriosis. Laparoscopic conservative surgery has been considered the gold stand- ard treatment for ovarian endometrioma [ 3, 4]. However, surgery may affect ovarian reserve function, and thus, surgery, especially repeat surgery, is not recommended for ovarian endometrioma recurrence [ 5–7]. The recurrence rate following surgical intervention remains high, even for © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. * Correspondence: [email protected] †Xiao-Yan Li and Xiao-Pei Chao contributed equally to this work. Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Peking Union Medical College & Chinese Academy of Medical Science, Shuaifuyuan No. 1, Dongcheng District, Beijing 100730, China Li et al. Journal of Ovarian Research (2019) 12:79 https://doi.org/10.1186/s13048-019-0552-y those who receive postoperative medical therapy. Therefore, endometrioma recurrence is one of the most important unresolved problems in the management of endometriosis. The recurrence rate of ovarian endome- trioma after conservative laparoscopic surgery has been reported to be 29 –56% at 2 years and 43% at 5 years. When postoperative medical treatment was introduced, the endometrioma recurrence rate substantially declined to 3–11% at 2 years and 6% at 5 years [ 8, 9]. A pooled ana- lysis of 23 studies estimated recurrence rates of 21.5% at 2 years and 40.0–50.0% at 5 years after primary surgery [ 10]. Unfortunately, few studies have analyzed the determinants of the long-term recurrence rate for endometrioma be- yond 5 years after surgery. Therefore, the aim of this study was to explore the risk factors for endometrioma recurrence and the risk factors for the recurrence of endometriosis-related pain after long-term follow up.

Ethical approval This study was approved by the Ethics Committee of Peking Union Medical College Hospital. Written in- formed consent was obtained from all participants. Patient population We collected 358 women with endometriomas who had a minimum of 5 years of postoperative follow-up after under- going a laparoscopic cystectomy at Peking Union Medical College Hospital from January 2009 to April 2013. The inclusion criteria were as follows: (1) the diagno- sis was confirmed by pathologists; (2) ultrasonography was conducted to determine endometrioma recurrence at least 6 months after surgery; and (3) patients were observed without postoperative medications or were treated with postoperative gonadotropin-releasing hor- mone agonist (GnRHa) injections for 3 –6 cycles, with or without a Mirena levonorgestrel-releasing intrauter- ine device (LNG-IUD). (4) The duration of follow-up was at least 5 years. The exclusion criteria were as fol- lows: (1) age 45 years; (2) having underwent bilateral oophorectomy or hysterectomy; and (3) intra- operative conversion to laparotomy.

Medical charts were reviewed to collect data on age at sur- gery; body mass index; presence of adenomyosis or leio- myoma; surgical history; symptoms of dysmenorrhea; parity; size of endometriom a; location of cysts; serum CA125 levels; operative time; intraoperative blood loss; American Society for Reproductive Medicine (ASRM) stage [11]; postoperative medications ; postoperative pregnancy; a n dr e c u r r e n c et i m e .T h es i z eo ft h eo v a r i a ne n d o m e t r i o m a was defined as the largest diameter of cysts. Obliteration of the pouch of Douglas was defined when there was any ad- hesion in the pouch. All surgeries were performed by one expert laparos- copist. In all cases, the aim of the surgical procedures was to remove all visible implants of endometriosis, complete the opening of the pouch in the operation and perform lysis of adhesion. Endometriosis was staged according to the classification of the ASRM. The presence, localization, and extent of typical powder- burn and subtle lesions, adhesions, and deep infiltrating implants were recorded. Both ovaries were then com- pletely mobilized. A sharp cortical incision was made into the cyst, and a cleavage plane was identified. A traumatic forceps and counter traction were used to strip the endometrioma from the ovarian parenchyma. Hemostasis was achieved by the selective application of bipolar coagulation. After the endometriomas were re- moved, all remaining visible endometriotic lesions were excised or fulgurated. Anatomical restoration was then achieved. Specimens underwent thorough histological analysis. When complicatio ns occurred, laparoscopy was converted into laparotomy. Laparotomic conver- sions were not included in the study. In our center, all women are followed up according to an internal protocol. A standard gynecological examin- ation and a transvaginal ultrasound are conducted before surgery; at 3, 6, and 12 months after surgery; and then yearly after surgery. Menstrual-reproductive factors and pain symptoms of pain are also evaluated. During the follow-up visits, patients were asked whether dysmenor- rhea, pelvic pain or dyspareunia occurred during the follow-up period. The time of their first appearance and the intensity of the pain symptoms after laparoscopy were also documented. Pain was rated on the basis of a 10-cm visual analog scale (VAS), and the intensity was divided into none (0), mild (1 –4), moderate (5 –7), or se- vere (8 –10). The presence of pain before surgery and pain recurrence/occurrence were defined as the recur- rence of pain after a period of at least 3 months of relief after surgery. Threshold points defining different sever- ities of pain were chosen based on a previous correlation analysis [ 12]. Endometrioma recurrence was determined using ultrasonography. Recurrent endometrioma was defined as the presence of a persistent ovarian cyst that had a thin wall (with a diameter of at least 2 cm), regular margins, a homogenous low echogenic fluid content with scattered internal echoes and did not resolve after several successive menstrual cycles. An improvement in pain was defined as a decrease in the VAS score for at least two points. Persistent pain was defined as no improvement or an increase in the VAS score of less than 2 points after surgery. Recurrence was identified when the same VAS score as that before surgery was noted at follow-up. Li et al. Journal of Ovarian Research (2019) 12:79 Page 2 of 10 Statistical analysis Statistical analysis was performed using the Statistics Pack- age for Social Sciences Version 22.0 (SPSS Inc., Chicago, IL, USA). Quantitative variables were compared using t-tests and ANOVA with Bonferroni’s correction for multiple test- ing. Fisher’s exact or chi-square tests were used to analyze qualitative variables. Potential risk factors ( p <0 . 2 ) w e r e identified using univariate analysis and Cox ’sm u l t i v a r i a t e proportional hazard analysis. The hazard ratio (HR) and 95% confidence interval (CI) were calculated as a measure of the risk of recurrence in each study. Significance was de- fined as p < 0.05.

For the total of 358 women, the mean age and BMI were 33.2 ± 5.4 years and 21.2 ± 2.6 kg/m2. The median gravida, parity, and duration of dysmenorrhea were 1(0–10), 0(0–2) and 24 months (0 –360 months). The median CA125 level was 54 U/ml (8.4 –754 U/ml). The mean operation time, bleeding volume and duration of follow-up were 66.4 ± 22.3 min, 5.4 ± 73.5 ml, and 84.2 ± 14.6 months. Before surgery, dysmenorrhea was absent in 23.7% (85/358) of cases, mild in 14% (50/358), moderate in 21.8% (78/358), and severe in 40.5% (145/358). The infertility rate before surgery was 18.4% (66/358). 17.9% (64/358) cases had concurrent leio- myoma, 53.1% (190/358) had concurrent deep infiltrating endometriosis, and 39.9% (143/358) had concurrent adenomyosis. Abdominal and vaginal ultrasound revealed the presence of bilateral ovarian endometriomas in 46.1% (165/358) of cases and unilateral ovarian endometriomas in 53.9% (193/358) of cases (31.0%,111 left, 22.9%, 82 right). At laparoscopy, ovarian endometrioma was confirmed with a mean size of 5.4 ± 2.1 cm on the left side and 5.3 ± 1.9 cm on the right. Leiomyomas were present in 18% (64/358) of cases, deep infiltrating endometriosis 53.1% (190/358), and aden omyosis 39.9% (143/358). One hundred two patients had partial and 162 patients had total cul-de-sac obliteration. According to the rASRM classification, 134 (37.4%) and 213 (59.5%) cases were stage III and stage IV. Postoperative therapy was chosen on the basis of individual characteristics and careful counseling with the patient: 12 (3.4%) women had no therapy; 12 (3.4%) oral contraceptives (drospirenone and ethinylestradiol tablets for at least 1 year); 14 (3.9%) Mirena for least 1 year, 242 (67.6%) re- ceived GnRHa for 3 –6 months, and 78 (21.8%) had G n R H af o l l o w e db yM i r e n a . After more than 5-years follow-up (median 83, 60 – 120), we observed 9.4% (34/358) had pain recurrence, 6.4% (23/358) cyst recurrence and 3% (11/358) for both. The cumulative rate of endometrioma and/or endometriosis-related pain recurrence over 5 years was 19.0%. Sixty-eight women were in the recurrence group and 290 cases in the nonrecurrence group. Dysmenorrhea recurred in 34 women (68%), endome- trioma recurred in 23 women (33.8%), and both recurred in 11 patients (16.2%). The clinical charac- teristics of the different groups of endometriomas are s h o w ni nT a b l e1. Univariate analysis and Cox ’s multivariate proportional hazard analyses were performed. Differences were found between two groups in terms of age at surgery (RR: 0.764, 95% CI: 0.615–0.949, p = 0.015), duration of dysmenorrhea (RR: 1.120, 95% CI 1.054–1.190, p < 0.001), presence of ade- nomyosis (RR: 1.629, 95% CI: 1.008 –2.630, p = 0.046), CA125 level (RR: 1.856, 95% CI: 1.072 –3.214, p =0 . 0 2 1 ) and extent of dysmenorrhea. The risk ratio of mild dysmen- orrhea was 4.506 (95% CI: 1.413–14.368, p = 0.011), moder- ate was 2.451 (95% CI: 1.433 –4.193, p = 0.001), and severe dysmenorrhea was 1.771 (95% CI: 1.254–2.502, p = 0.001). No significant association was found between endome- trioma and/or endometriosis-related pain recurrence rate and gravida, parity, BMI, infe rtility, leiomyoma presence, ovarian endometrioma size, deep infiltrating endometriosis presence, obliteration of thepouch of Douglas, disease stage and postoperative medication (Table 2). Only the extent of dysmenorrhea (RR: 1.711, 95% CI: 1.175 –2.493, p =0 . 0 0 5 ) and postoperative pregnancy (RR: 0.649, 95% CI: 0.460 – 0.914, p = 0.013) were significantly correlated with endome- trioma and/or endometriosis-related pain recurrence in the multivariate analysis (Table2).

There are a variety of factors, both clinically and surgically, that might be related to the risk of endome- trioma and/or endometriosis-related pain recurrence. Accumulating evidence suggests that immune cells, adhesion molecules, extracellular matrix metallopro- teinase and pro-inflammatory cytokines activate/alter peritoneal microenvironment, creating the conditions for differentiation, adhesion, proliferation and survival of ectopic endometrial cells [ 13–15]. In a study by Tobiume et al., the rAFS score was an independent factor associated with recurrence [ 16]. Chon et al. re- ported that dysmenorrhea and ovarian cyst separations significantly affected the postoperative recurrence rate [17]. Selcuk et al. reported that the depth of penetration of the endometrial tissue into the ovarian cyst wall was an independent risk factor for recurrence [ 18]. Guzel et al. reported that the CA125 level, ovarian cyst size, and history of pelvic surgery affected the recurrence rate [19]. However, it is difficult to compare the results of the above studies due to differences in the study popu- lation, the follow-up duration, and the definition of endometrioma and/or endometriosis-related pain re- currence. Notably, most of the above studies reported the endometrioma and/or endometriosis-related pain recurrence rate within 5 years after initial surgery. We Li et al. Journal of Ovarian Research (2019) 12:79 Page 3 of 10 Table 1 Baseline characteristics of the endometrioma and/or endometriosis-related pain recurrence and nonrecurrence groups Characteristics Recurrence group ( n = 68) Nonrecurrence group ( n = 290) χ2 p value Age, y 31.8 ± 5.0 32.9 ± 5.2 1.457 0.146 Gravida 0 (0 –4) 1 (0 –10) 1.207 0.228 Parity 0 (0 –1) 0 (0 –2) 2.385 0.018 BMI, kg/m2 20.9 ± 2.5 21.2 ± 2.6 0.814 0.416 rAFS stage 3.093 0.377 Stage I 0 (0%) 1 (0.3%) Stage II 3 (4.4%) 7 (2.4%) Stage III 20 (29.4%) 113 (39.2%) Stage IV 45 (66.2%) 167 (58.0%) Largest-diameter endometrioma, cm Left 5.6 ± 1.9 5.4 ± 2.2 −0.707 0.481 Right 5.7 ± 2.0 5.2 ± 1.8 −1.631 0.104 CA125, U/ml 99.23 ± 89.72 100.37 ± 228.61 0.038 0.970 Dysmenorrhea, VAS 7 (0 –10) 5 (0 –10) −3.018 0.003 Extent of dysmenorrhea 15.420 0.001 None 4 (5.9%) 81 (27.9%) Mild 10 (14.7%) 40 (13.8%) Moderate 20 (29.4%) 58 (20.0%) Severe 34 (50.0%) 111 (38.3%) Duration of dysmenorrhea, m 84 (0 –360) 24 (0 –348) −3.514 0.001 Endometrioma side 3.082 0.214 Left 16 (23.5%) 95 (32.8%) Right 20 (29.4%) 62 (21.4%) Bilateral 32 (47.1%) 133 (45.9%) Obliteration of cul-de-sac 3.307 0.191 Absent 13 (19.1%) 81 (27.9%) Partial 18 (26.5%) 84 (29.0%) Complete 37 (54.4%) 125 (43.1%) Leiomyoma 18 (26.5%) 46 (16.0%) 5.057 0.044 (0.044) Deep infiltrating endometriosis 41 (63%) 149 (51.4%) 1.758 0.224 Adenomyosis 34 (50.0%) 108 (37.4%) 4.059 0.044 (0.044) Postoperative dysmenorrhea relief 55 (87.3%) 8 (90.0%) 1.770 0.413 Infertility 2.408 0.300 Primary 11 (16.2%) 32 (11.0%) Secondary 6 (8.8%) 17 (5.9%) Operation 0.705 0.590 Cystectomy 65 (95.6%) 21 (72%). Salpingo-oophorectomy 3 (4.4%) 269 (92.8%) Postoperative pregnancy 24 (35.3%) 113 (39.0%) 0.611 0.894 Postoperative medication 11.066 0.026 None 0 (0%) 12 (4.1%) OCP 1 (1.5%) 11 (3.8%) Mirena 1 (1.5%) 13 (4.5%) GnRHa with LNG-IUD 9 (13.2%) 69 (23.8%) Li et al. Journal of Ovarian Research (2019) 12:79 Page 4 of 10 have little information about the recurrence rate be- yond 5 years after surgery. This study found that the extent of dysmenorrhea and postoperative pregnancy were risk factors accord- ing to the multivariate analysis. To avoid multiple collinearity, the presence of dysmenorrhea was not selected for the multivariate analysis. Several studies identified dysmenorrhea as a possible risk factor for endometrioma recurrence [ 16, 20]. Our study also showed an association between the presence of dys- menorrhea after surgery and endometrioma and/or endometriosis-related pain recurrence in a univariate analysis (Fig. 1). Mechanisms of dysmenorrhea have not been uniformly determined; however, direct and indirect effects of focal bleeding from endometriotic implants, actions of inflammatory cytokines in the peritoneal cavity, and irritation or direct infiltration of nerves in the pelvic floor are causes [ 21]. It is hy- pothesized that cyclic recurrent microbleeding within endometriotic lesions with consequent inflammation may be the cause of severe dysmenorrhea among women with endometriosis [ 22]. Therefore, the longer the disease duration is, the deeper the lesions will infiltrate. In our series, women who suffered dysmen- orrhea over 6 months had higher endometrioma and/ or endometriosis-related pain recurrence rate (Fig. 2). Over time, most patients with endometriomas had a higher rASRM score and were categorized as having advanced-stage endometriosis. In fact, most of patients (96.9%) in this study demonstrated stage III or IV endometriosis. Adhesions may also cause deep pelvic pain associated with recurrent endometriosis, and postoperative dysmenorrhea also suggests endometrioma recurrence [ 23]. Because of extensive adhesions and inflammation, incomplete resection can occur in advanced stages of endometriosis. Incomplete surgical removal of endometriomas located on an endometriotic lesion or adhesion only decreases the severity of symptoms because only the removal of vi- sualized cystic lesions or separation of adhesions is performed; Although peritoneal superficial lesions and ovarian endometriomas represent the majority of endometriotic implants within the pelvis, deep infil- trating endometriosis and extrapelvic endometriosis are the most challenging conditions to face off. Despite sometimes medical therapy is enough to reduce symptoms and, in a large number of patients a complete eradication, with nerve-sparing and vascu- lar sparing approach is needed to restore the normal pelvic anatomy and its functions [ 24, 25]. In our study, all remaining visible endometriotic lesions were excised or fulgurated after the endometriomas were removed. Anatomical restoration was then achieved. However, surgery does not address the underlying mechanisms that are active and driving disease in the pelvic cavity. This naturally leads to recurrence of endometriosis in various forms after a certain period of time. The presence of adenomyosis is another risk factor for endometrioma and/or endometriosis-related pain recur- rence. It is well known that there is an overlap in the pathogenesis of endometriosis and adenomyosis [ 22]. Dior et al. found that sonographic features of adenomyo- sis may be included as a component of the clinical as- sessment when attempting to predict the presence of severe endometriosis [ 26]. We observed a statistically significant correlation between pelvic pain and the pres- ence of adenomyosis (Fig. 3), in agreement with the pre- viously reported results [ 27, 28]. Dysmenorrhea is a risk factor in the deep adenomyotic process with a high density of endometrial glands in the myometrium [ 29]. Perello et al. observed a clear trend associating of the presence of dysmenorrhea with adenomyosis, without statistical significance. Among the patients reporting these symptoms, 95.5% described the intensity as severe [30]. Our study showed that the concurrence rate of adenomyosis was up to 50.0% in the recurrence group. Unresolved adenomyosis may consequently lead to pain recurrences after pelvic surgery. Therefore, correct iden- tification of coexisting pathological conditions for DIE and adenomyosis is necessary for the development of ef- fective surgical protocols [ 30]. It was reported that age at surgery is associated with the postsurgical endometrioma recurrence rate, and the reason is unclear. We postulate that endometriosis is a hormone dependent disease. Thus, the higher circulation estrogen levels in younger women may produce a more aggressive form of endometriosis; therefore, the younger, the more likely to recur [ 18]. Seo et al. [ 31] reported that, at an average follow-up time of 29 months with no postoperative medication, the cumulative endometrioma recurrence rates were 43.3% for patients aged 20 –29 Table 1 Baseline characteristics of the endometrioma and/or endometriosis-related pain recurrence and nonrecurrence groups (Continued) Characteristics Recurrence group ( n = 68) Nonrecurrence group ( n = 290) χ2 p value GnRHa without LNG-IUD 57 (83.8%) 185 (63.8%) Duration of follow-up 83 (60 –120) 85 (60 –116) −0.459 0.646 Abbreviations: BMI Body mass index, CA-125 Cancer antigen 125, cm centimeter, GnRHa Gonadotropin-releasing hormone agonist, LNG-IUD Levonorgestrel- releasing intrauterine device, m month, OCP Oral contraceptive pills, VAS Visual analogue score Li et al. Journal of Ovarian Research (2019) 12:79 Page 5 of 10 years, 22.5% for 30 –39 years, and 10.2% for 40 –45 years. In our study, the cumulative endometrioma and/or endometriosis-related pain recurrence rates were 24.2% for patients aged 20 –30 years, 17.7% for 31 –40 years, and 7.9% for 41 –45 years, which was consistent with the literature. Our study also found that 33.5 years is a cutoff value in the ROC age analysis (Fig. 4a). Patients who are younger than 33.5 years may have a higher risk for Table 2 Univariate and multivariate analysis of risk factors in the endometrioma and/or endometriosis-related pain recurrence and nonrecurrence groups Factor Univariate analysis Multivariate analysis Relative risk 95%CI P value Relative risk 95%CI P value Age at surgery (per 5 years) 0.764 0.615 –0.949 0.015 0.738 0.520 –1.048 0.090 Gravida 0 1.000 1 0.673 0.370 –1.224 0.194 2 (and above) 0.757 0.557 –1.029 0.075 Parity 0 1.000 1 0.478 0.261 –0.876 0.017 0.002 0.000 –1.222 0.974 2 0.216 0.011 –4.254 0.314 BMI 0.820 0.478 –1.407 0.470 Infertility 1.527 0.882 –2.644 0.131 Extent of dysmenorrhea 1.711 1.175 –2.493 0.005 None 1.000 Mild 4.506 1.413 –14.368 0.011 Moderate 2.451 1.433 –4.193 0.001 Severe 1.771 1.254 –2.502 0.001 Duration of dysmenorrhea (per year) 1.120 1.054 –1.190 < 0.001 1.026 0.944 –1.114 0.548 Extent of dysmenorrhea 2.534 1.408 –4.563 0.002 VAS (0-4) VAS (5-10) Dyspareunia 1.734 1.049 –2.866 0.032 1.081 0.511 –2.285 0.839 Chronic pelvic pain 0.959 0.503 –1.828 0.898 Dyschezia 0.735 0.268 –2.018 0.550 Presence of leiomyoma 1.661 0.969 –2.848 0.065 1.713 0.825 –3.555 0.149 Presence of adenomyosis 1.629 1.008 –2.630 0.046 1.446 0.719 –2.908 0.301 Presence of deep infiltrating endometriosis 1.380 0.849 –2.243 0.194 1.118 0.582 –2.149 0.737 CA125 level (45 U/ml) 1.856 1.072 –3.214 0.021 1.020 0.965 –1.078 0.491 rARSM stage 1.204 0.774 –1.873 0.409 Bilateral involvement 1.046 0.650 –1.684 0.853 Large dimeter (per 10 mm) 1.016 0.944 –1.093 0.674 Postoperative medication None 1.000 GnRHa 21.818 0.125 –3810.382 0.242 OCP 4.057 0.019 –856.392 0.610 Mirena 2.741 0.048 –155.496 0.624 GnRHa+Mirena 1.991 0.375 –9.730 0.436 Postoperative pregnancy 0.938 0.655 –1.344 0.728 0.649 0.460 –0.914 0.013 Abbreviations: BMI Body mass index, CA-125 Cancer antigen 125, GnRHa Gonadotropin-releasing hormone agonist, OCP Oral contraceptive pills, VAS Visual analogue score Li et al. Journal of Ovarian Research (2019) 12:79 Page 6 of 10 recurrence (Fig. 4b). Our previous study showed that laparoscopic cystectomy for endometrioma with an age greater than 35 years may decrease the remaining ovar- ian reserve [ 32]. Therefore, a decrease in the rate of endometrioma and/or endometriosis-related pain recur- rence also results in a reduction in ovarian reserve func- tion. 33 to 35 years of age is a “dilemma window ”, and we should pay more attention to patients in this age group when performing surgery. Preventive use of medications after operation is rec- ommended for patients with a high risk of recurrence [33–36]. Many studies have investigated factors deter- mining the recurrence of endometrioma and pain after surgery [ 16, 19, 20]. The mechanism of oral contraceptive pills (OCPs) r educing ovarian endome- trioma recurrence is unclear . OCP increases apoptosis and decreases cell proliferati on in eutopic endometria, which can decrease both recurrence from small Fig. 1 Kaplan-Meier curves presenting the cumulative rate of recurrence according to the severity of dysmenorrhea. There were significant differences between the four groups according to the log-rank test analysis ( χ2 = 11.487, p = 0.001) Fig. 2 a The ROC analysis of duration of dysmenorrhea in recurrent endometrioma patients. Area under curve: 0.689, Cut-off value: 5.5 months; b Kaplan-Meier curves presenting the cumulative rate of recurrence according to duration of dysmenorrhea (< 6 months or ≥ 6 months). There were significant differences between the two groups according to the log-rank test analysis ( χ2 = 22.352, p < 0.001) Li et al. Journal of Ovarian Research (2019) 12:79 Page 7 of 10 endometriotic foci not seen at surgery and de novo disease development [ 33]. Some reports suggest that ovarian endometrioma can de velop from ovarian folli- cles or the corpus luteum and that consequent inhib- ition of ovulation may decrease the risk of endometrioma development [ 36–38]. Regardless of the mechanism, the present and previous studies sug- gest that postoperative medical treatment is known to delay but not completely prevent recurrence. Vercel- lini et al. [ 39]r e p o r t e dt h a tp o s t o p e r a t i v eu s eo f GnRHa could only prolong the recurrence interval but could not improve the overall recurrence rate. There is no consensus regarding whether the LNG- IUD could reduce the endometrioma recurrence rate either [ 40]. Notably, Jee et al. [ 41]r e p o r t e dt h a ta l - though postoperative GnRH agonist treatment does Fig. 4 a The ROC analysis of age at surgery in recurrent endometrioma patients. Area under curve: 0.413, Cut-off value: 33.5 yrs.; b Kaplan-Meier curves presenting the cumulative rate of recurrence according to age at surgery (< 33 yrs. or ≥ 33 yrs). There were significant differences between the two groups according to the log-rank test analysis ( χ2 = 22.352, p < 0.001) Fig. 3 Kaplan-Meier curves presenting the cumulative rate of recurrence according to the presence of adenomyosis. There were significant differences between the two groups according to the log-rank test analysis ( χ2 = 4.113, p = 0.043) Li et al. Journal of Ovarian Research (2019) 12:79 Page 8 of 10 not reduce objective disease recurrence in stage III/IV dis- ease, GnRHa delays the time of recurrence, as indicated by Vercellini et al. [39]. In our study, we also failed to observe a benefit for postoperative medication in preventing endo- metrioma and/or endometriosis-related pain recurrence. Patients with advanced-stage endometriosis may prefer to take postoperative medication. This may partially explain why a statistically significant difference was not reached in terms of postoperative medication between patients with and without recurrence. We found that the estimated cu- mulative endometrioma and/or endometriosis-related pain recurrence rates at 1 to 10 years after surgery were 2.2, 5.3, 9.2, 12.0, 15.4, 16.8, 19.3, 22.5, 22.5, and 22.5%, respectively. These relatively low endometrioma and/or endometriosis- related pain recurrence rates may be due to most patients having postoperative medication applied in our study. The recurrent rate increased yearly until 8 years after surgery. Most ovarian endometriomas are composed of an extraovarian pseudocystic s tructure with no cystic wall but are surrounded by fibrosis with underlying ovarian cortical follicles [ 42]. Therefore, the inner surface of an endometrioma is lined by endometriosis with variable penetration into the surrounding fibrosis. The mean cyst wall thickness varied between 1.2 and 1.6 mm. Endometriosis tissue covers the inner aspect of the cyst for approximately 60% of its surface with a mean depth of penetration of 0.6 mm [ 43]. With the aging of the endometrioma, infiltration and invasion of the ovarian interstitial, resulting in the incomplete removal of endometriomas [ 42]. Concordantly, the univariate ana- lysis in our study shows that the duration of dysmenor- rhea is significantly associated with endometrioma and/ or endometriosis-related pain recurrence (Fig. 2). It is clear that the prevalence of recurrent endometrioma varies according to whether there is a successful pregnancy after surgical treatment of the endometrioma [44, 45]. Koga et al. demonstrated that patients with postoperative preg- nancies had much lower rates of recurrence, which indi- cates that a subsequent pregnancy may have a protective effect on endometrioma recurrence [ 46]. In our study, postoperative pregnancies also prevented endometrioma re- currence (OR: 0.649, 95%CI: 0.460–0.914, p = 0.013). The merits of our study were the long time follow-up of more than 5 years, all with detailed record clinical data, the same experienced surgeon, and the large sample size. However, there are some limitations. This was a retro- spective study, and it may contain biases with regard to patient characteristics; women with severe forms of endo- metriosis may prefer to receive preoperative or postopera- tive medical treatment, and this is a single center study. Recurrent endometrioma was defined by ultrasound as the presence of a persistent ovarian cyst and did not re- solve after several successive menstrual cycles. It depends mainly on the skill and experience of radiologists. These

may have resulted in an under or over estima- tion of the associations in our study. In conclusion, we conducted a long-term follow-up study for more than 5 years. The rate of endometrioma and/or endometriosis-related pain recurrence increased yearly in the first 8 years. Our research revealed that the extent of dysmenorrhea and postoperative pregnancy are independent risk factors for endometrioma and/or endometriosis-related pain recurrence. For patients who have serious dysmenorrhea, we should pay more attention to their risk for endometrioma and/or endometriosis- related pain recurrence and apply individual management to achieve better efficacy. Acknowledgments We appreciate the stuff at Peking Union Medical College Hospital for their diligent clinical work and precise data recording about the cases we reported in this article. Authors’contributions XY-L and JH-L developed the idea for the project. The study was designed by XY-L and XP-C, and JJ-Z, Y-D, JH-S, SZ-J, and WZ performed the data analysis and takes full responsibility for the integrity of the data. XX-X, YS-W, WZ and XP-C drafted the manuscript with inputs and critical discussion from JH-L and XY-L. The final version has been approved by all authors. Funding Our work was supported by the National Key R&D Program of China (No. 2017YFC1001200), National Natural Science Foundation of China (No. 81501237), and 2016 PUMCH Science Fund for Junior Faculty (No. PUMCH-2016-2.2). Availability of data and materials The dataset supporting the conclusions of this article is included within the article and its additional files. Ethics approval and consent to participate This study was approved by the Ethics Committee of Peking Union Medical College Hospital. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Received: 11 April 2019 Accepted: 13 August 2019

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