{"paper_id":"4bce9306-6f45-4cb3-a32f-1205b818b623","body_text":"1 Department of Gynecology, Hanchuan People's Hospital, 431600 Hanchuan, Hubei, China\n2 Department of Laboratory Medicine, Hanchuan People's Hospital, 431600 Hanchuan, Hubei, China\nAbstract\nBackground: Postoperative recurrence remains a problem for endometriosis. The\nstudy aimed to study whether baseline serum vascular endothelial growth factor\n(VEGF) levels can predict postoperative endometriosis recurrence. Methods: We\nincluded 147 patients with ovarian endometriosis who received laparoscopic\nendometrioma excision and postoperative gonadotropin-releasing hormone agonist\ntreatment with hormonal add-back therapy between 2017 and 2019 in a tertiary\nhospital. According to endometriosis recurrence within 2 years, the patients were\ndivided into two groups and baseline serum VEGF level measured before the surgery\nwere compared. Logistic regression was used to examine the association between\nbaseline serum VEGF level and endometriosis recurrence, and the area under the\nreceiver operating characteristic curve (AUC) was calculated to examine its\npredictive performance. Results: The mean age of the patients was 30.1\nKeywords\n- postoperative\n- endometriosis\n- recurrence\n- ovarian\n- gynaecology\nEndometriosis is a benign disease that endometrial glands and stroma occur outside the uterine cavity, with a prevalence of about 10% among women of reproductive age [1]. Although it is not malignant, the ectopic endometrial tissue and resultant inflammation cause symptoms (such as dysmenorrhea, dyspareunia, chronic pain, and infertility) and greatly impair quality of life [2]. Currently, treatments recommended by the guidelines include medical treatment (such as nonsteroidal analgesics, hormonal contraceptives, gonadotropin-releasing hormone (GnRH) analogs, and aromatase inhibitors), and surgical treatment which is indicated when medical treatment is ineffective [3]. However, endometriosis recurrence remains a problem [4]. Compared with definitive surgery (e.g., hysterectomy with or without oophorectomy), conservative surgery is generally considered as the first choice of surgical treatment, because it preserves fertility and hormone production. However, a higher recurrence rate was observed in conservative surgery than definitive surgery (about 20% vs. 1.5% within a 5-year follow-up [5]). To reduce the risk of endometriosis recurrence, especially for the reduction of endometriosis-related pain recurrence, postoperative medical suppressive therapy is recommended for most women treated surgically for endometriosis [6, 7, 8]. GnRH analog have been shown as effective as other medical therapies (such as danazol or levonorgestrel) for relieving pain [9] by down-regulating the pituitary-ovarian axis and inducing hypoestrogenism [10]. Combing with progestin or both estrogen and progestin (i.e., the hormonal add-back therapy [11]) lowers risk of the side effects caused by the hypoestrogenic state induced by GnRH analogs, making it better tolerated than other medical treatment. However, little is known about the risk of endometriosis recurrence in postoperative patients receiving this medical treatment. Vascular endothelial growth factor (VEGF), an angiogenic cytokine which plays essential roles in various physiological and pathological processes, including angiogenesis, development and organogenesis, wound healing, tumor growth and metastasis, and vascular permeability, has been shown as a potentially valuable biomarker and treatment target for endometriosis [12, 13, 14], but most results were from preclinical studies. It is also unknown whether baseline serum VEGF levels can predict postoperative endometriosis recurrence. Together, the study aimed to investigate the risk of postoperative endometriosis recurrence and the predictive value of baseline serum VEGF levels in patients with ovarian endometriosis who received laparoscopic endometrioma excision and postoperative GnRH analogs with hormonal add-back therapy.\nWe retrospectively checked the medical records of patients with ovarian\nendometriosis admitted to the Department of Gynecology of Hanchuan People’s\nHospital between 2017 and 2019, and included patients who met the\ninclusion/exclusion criteria below. Inclusion criteria were: (1) patients with\novarian endometriosis confirmed by histologic evaluation of a lesion biopsied\nduring surgery; (2) patients who received laparoscopic endometrioma excision and\npostoperative GnRH analogs with hormonal add-back therapy; (3) patients with\navailable serum VEGF levels measured before the surgery; (4) patients whose\nrecurrence status of ovarian endometriosis within 2 years after the surgical\ntreatment, determined by reports of ultrasonography (see below). Exclusion\ncriteria were: (1) patients who had received surgical treatment for endometriosis\nbefore; (2) patients with deeply infiltrating endometriosis or lesions of\nnonreproductive organs; (3) patients who received hysterectomy, with or without\noophorectomy; (4) patients who had cancer, other gynecological diseases, or any\nother severe chronic diseases, or who had received previous abdominal/pelvic\nsurgery for other reasons (except for caesarean section); (5) patients aged\nThe following baseline characteristics were collected from the medical records: age, gravida, parity, duration of dysmenorrhea, menstrual pain (estimated by the Visual Analog Scale (VAS)), revised American Fertility Society (rAFS) stage [15], endometrioma side, largest diameter of endometrioma, and family history of endometriosis. This information was regularly collected for all hospitalized patients with endometriosis in the Department of Gynecology of Hanchuan People’s Hospital during the study period. The examination of serum VEGF was performed by the Department of Laboratory Medicine of Hanchuan People’s Hospital with standard procedures.\nAll patients who received surgical treatment in the Department of Gynecology of Hanchuan People’s Hospital were generally followed for at least 1 year with scheduled gynecological and ultrasound examination. We included patients who had at least 1 outpatient clinic or hospital visit (regardless of departments) more than 2 years after the surgery, and determined the recurrence status of ovarian endometriosis by examining all available reports of ultrasonography. We defined endometriosis recurrence as the presence of a persistent ovarian cyst with a diameter of at least 2 cm according to the reports of ultrasonography.\nAccording to whether there was recurrence of endometriosis within 2 years after\nthe surgical treatment, the patients were split into two groups, and baseline\nserum VEGF levels and other baseline characteristics were compared between the\ntwo groups. Quantitative variables were compared using t-test or\nMann-Whitney U Test, and qualitative variables were compared using chi-square\ntests or Fisher’s exact. Logistic regression was used to evaluate the association\nbetween baseline serum VEGF levels and endometriosis recurrence without and with\nadjustment for other baseline characteristics. Receiver operating characteristic\n(ROC) curve was plotted to study the predictive value of baseline serum VEGF\nlevels for predicting endometriosis recurrence. A p value\n147 patients were included in the study (Fig. 1). Before surgery, the mean age\nof the patients was 30.1\nFlowchart of the study. Abbreviation: GnRH, gonadotropin-releasing hormone; VEGF, vascular endothelial growth factor.\n| All patients (n = 147) | Endometriosis recurrence | ||||\n| No (n = 139) | Yes (n = 8) | p value | |||\n| Age (years) | 30.1 |\n30.3 |\n25.9 |\n0.040 | |\n| Gravida | 1 (0–1) | 1 (0–1) | 0 (0–1) | 0.239 | |\n| Parity | 0 (0–1) | 0 (0–1) | 0 (0–0.75) | 0.664 | |\n| Duration of dysmenorrhea (months) | 60.3 |\n58.9 |\n83.5 |\n0.053 | |\n| Menstrual pain (estimated by VAS) | 5.5 |\n5.5 |\n5.3 |\n0.819 | |\n| rAFS stage | 0.253 | ||||\n| Stage I | 3 (2.0) | 3 (2.2) | 0 (0.0) | ||\n| Stage II | 14 (9.5) | 14 (10.1) | 0 (0.0) | ||\n| Stage III | 42 (28.6) | 37 (26.6) | 5 (62.5) | ||\n| Stage IV | 88 (59.9) | 85 (61.2) | 3 (37.5) | ||\n| Endometrioma side | 0.496 | ||||\n| Left | 42 (28.6) | 38 (27.3) | 4 (50.0) | ||\n| Right | 29 (19.7) | 28 (20.1) | 1 (12.5) | ||\n| Bilateral | 76 (51.7) | 73 (52.5) | 3 (37.5) | ||\n| Largest diameter of endometrioma (cm) | 4.7 |\n4.7 |\n4.6 |\n0.778 | |\n| Positive family history | 20 (13.6) | 18 (12.9) | 2 (25.0) | 0.298 | |\n| VEGF (pg/mL) | 555.58 |\n547.87 |\n689.67 |\n0.023 |\nAbbreviations: VAS, Visual Analog Scale; rAFS, revised American Fertility Society; VEGF, vascular endothelial growth factor.\n8 (5.44%) patients had endometriosis recurrence within 2 years. Compared with\npatients without recurrence, patients with recurrence were significantly younger\n(25.9\nAs showed in Fig. 2, the probability of postoperative endometriosis recurrence increased with the increase of baseline serum VEGF levels. According to results of multivariate logistic regression (Table 2), baseline serum VEGF levels were significantly associated with endometriosis recurrence (unadjusted odds ratio (OR) 1.006 per pg/mL increase, 95% confidence interval (CI) 1.000–1.011, p = 0.034; adjusted OR 1.008 per pg/mL increase, 95% CI 1.001–1.014, p = 0.023). The area under the ROC curve (Fig. 3) of baseline serum VEGF levels for predicting postoperative endometriosis recurrence was 0.741 (95% CI 0.594–0.887). When using a cut-off of 498.58 pg/mL, the sensitivity was 100% and the specificity was 59%.\nFitting curve of baseline serum vascular endothelial growth factor level with probability of postoperative endometriosis recurrence (by local polynomial regression). Abbreviation: VEGF, vascular endothelial growth factor.\n| Odds ratio | 95% confidence interval | p value | |||\n| Univariate analysis | |||||\n| VEGF (per pg/mL increase) | 1.006 | 1.000–1.011 | 0.034 | ||\n| Multivariate analysis* | |||||\n| VEGF (per pg/mL increase) | 1.008 | 1.001–1.014 | 0.023 | ||\n| Age (years) | 0.859 | 0.733–1.006 | 0.059 | ||\n| Gravida | 0.427 | 0.039–4.699 | 0.487 | ||\n| Parity | 3.113 | 0.166–58.464 | 0.448 | ||\n| Duration of dysmenorrhea (months) | 1.030 | 0.994–1.068 | 0.107 | ||\n| Menstrual pain (estimated by VAS) | 1.026 | 0.745–1.413 | 0.877 | ||\n| rAFS stage | 0.334 | 0.082–1.363 | 0.126 | ||\n| Endometrioma side | |||||\n| Left | Reference | ||||\n| Right | 0.447 | 0.030–6.574 | 0.557 | ||\n| Bilateral | 0.641 | 0.079–5.228 | 0.678 | ||\n| Largest diameter of endometrioma (cm) | 0.968 | 0.431–2.174 | 0.937 | ||\n| Positive family history | 1.582 | 0.152–16.458 | 0.701 |\n*Adjusted for age, gravida, parity, duration of dysmenorrhea, menstrual pain (estimated by VAS), rAFS stage, endometrioma side, largest diameter of endometrioma, and family history.\nAbbreviations: VEGF, vascular endothelial growth factor; VAS, Visual Analog Scale; rAFS, revised American Fertility Society.\nROC curve analysis of baseline serum vascular endothelial growth factor level for predicting postoperative endometriosis recurrence. Abbreviation: ROC, receiver operating characteristic.\nAccording to results of univariate logistic regression (Table 3), age was associated with postoperative endometriosis recurrence (OR 0.87, 95% CI: 0.76–1.00), although the p value is not significant (p = 0.051). For the other baseline characteristics, no significant association with postoperative endometriosis recurrence was found.\n| Odds ratio | 95% CI | p value | ||\n| Age (years) | 0.87 | 0.76–1.00 | 0.051 | |\n| Gravida | 0.46 | 0.13–1.66 | 0.236 | |\n| Parity | 0.67 | 0.17–2.68 | 0.570 | |\n| Duration of dysmenorrhea (months) | 1.02 | 1.00–1.05 | 0.066 | |\n| Menstrual pain (estimated by VAS) | 0.97 | 0.77–1.23 | 0.818 | |\n| rAFS stage | 0.86 | 0.35–2.09 | 0.734 | |\n| Endometrioma side | ||||\n| Left | Reference | |||\n| Right | 0.34 | 0.04–3.20 | 0.345 | |\n| Bilateral | 0.39 | 0.08–1.84 | 0.234 | |\n| Largest diameter of endometrioma (cm) | 0.92 | 0.53–1.61 | 0.776 | |\n| Positive family history | 2.24 | 0.42–11.97 | 0.345 |\nAbbreviations: CI, confidence interval; VAS, Visual Analog Scale; rAFS, revised American Fertility Society.\nWe investigated the risk of endometriosis recurrence in a cohort of patients with ovarian endometriosis who received laparoscopic endometrioma excision and postoperative GnRH analogs with hormonal add-back therapy. According to our results, the recurrence rate was about 5% within two years after laparoscopic endometrioma excision with postoperative medical treatment. This result is similar to other studies [16, 17], although in our study we only included patients who received GnRH analogs with hormonal add-back therapy as postoperative medical therapy. Studies that included patients who received conservative surgical treatment only found a higher risk of recurrence rate [18, 19], suggesting the importance of additional medical treatment after surgical treatment.\nWe also especially examined the predictive value of serum VEGF levels. Hypervascularization both within and surrounding the implant is considered as one of the features of endometriosis, and VEGF as an angiogenic cytokine has attracted the attention of research. Elevated levels of VEGF have been found in the peritoneal fluid of patients with endometriosis [20, 21], but some following studies reported no difference in serum VEGF levels in patients with endometriosis [22, 23], while more subsequent investigations observed that there was an increase in serum VEGF levels [24, 25, 26, 27]. Meanwhile, evidence from preclinical research supports VEGF plays a crucial role in the pathogenesis of endometriosis [14, 28, 29, 30, 31]. A recent trial suggests targeting VEGF may benefit patients with endometriosis [32]. We found that compared with patients without endometriosis recurrence, those who experienced recurrence had significantly higher serum VEGF levels before surgery, and the association was independent of other baseline characteristics. The main implication of our findings is that serum VEGF levels may be useful to predict postoperative recurrence in patients who received surgical treatment following medical therapy.\nAs far as we know, the prognostic predictive value (instead of diagnosis) of serum VEGF levels has not been well established before. Mohamed et al. [33] conducted a prospective randomized case-control study which included 30 patients referred for laparoscopy complaining of unexplained primary infertility with or without chronic pelvic pain, and found advanced endometriosis patients had higher serum VEGF levels, and examination of VEGF helps the diagnosis of advanced endometriosis. The lack of similar studies increases implication of our findings. According to the ROC curve, we found the area under the ROC curve was 0.741, which is a fair predictive ability. However, serum VEGF itself may not be good enough to predict postoperative recurrence individually, and combining other risk factors may help to improve the predictive performance. We found young age was a risk factor of endometriosis recurrence, and patients with endometriosis recurrence seemed to have fewer gravida/parity, longer duration of dysmenorrhea, higher rAFS stage, and higher positive family history, although the differences were not statistically significant. This may be related to the small sample size. Nevertheless, these findings are consistent with other studies of larger sample sizes [16, 34].\nOur study had some limitations. We collected the data retrospectively, and some information was unavailable, such as detailed medication use or pelvic pain during the postoperative period. We identified the study outcome endometriosis recurrence by examining reports of ultrasonography and the absence of such reports was assumed to be without recurrence. This is at risk of misclassification. We assumed a patient would visit the same hospital for endometriosis within two years after surgery and therefore the relevant reports of ultrasonography within the two years would be available if a patient had inpatient/outpatient visit record after two years. This assumption is clearly not always true and we thus underestimated the recurrence rate. In addition to a small sample size, we only included patients who received postoperative GnRH analogs with hormonal add-back therapy. This was because during the study period, this medical treatment was the most frequently used strategy for patients after surgical treatment, so it is unknown whether our findings hold in endometriosis patients who received other medical therapy. To address these limitations, well-designed prospective studies with better follow-up for endometriosis recurrence are necessary to validate our findings, and when possible, to conduct on broader patient populations and to include more clinical outcomes.\nIn conclusion, for patients with ovarian endometriosis who received laparoscopic endometrioma excision and postoperative gonadotropin-releasing hormone agonist treatment with hormonal add-back therapy, baseline serum VEGF level is an independent risk factor of postoperative endometriosis recurrence with fair discriminatory power, which might be useful for predicting endometriosis recurrence.\nThe dataset generated during the current study is available from the corresponding author on reasonable request.\nBoth authors participated in the design and interpretation of the results. YD designed the research study and revised the manuscript. YZ performed the research including data analysis and preparation of the draft of the manuscript. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.\nThe study was approved by the Ethics Committee of Hanchuan People’s Hospital (approval number: 20230405), and informed consent was waived because of the retrospective study design. The study was carried out in accordance with The Code of Ethics of the World Medical Association (Declaration of Helsinki).\nNot applicable.\nThis research received no external funding.\nThe authors declare no conflict of interest.\nReferences\nPublisher’s Note: IMR Press stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}