Endometriosis 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.

We 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.

We 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.

As 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].

Our 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.

In 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.

The dataset generated during the current study is available from the corresponding author on reasonable request.

Both 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.

The 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).

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.