Exploring the role of Chinese herbal medicine in the long-term management of postoperative ovarian endometriotic cysts: a systematic review and meta-analysis

Background Ovarian endometriotic cysts (OEC) represent the primary manifestation of endometriosis, constituting a hormonally dependent inflammatory disorder in gynecology. It significantly affects the quality of life and reproductive health of women. It is worth noting that traditional Chinese medicine (TCM), especially Chinese herbal medicine (CHM), has been widely applied in mainland China due to its unique therapeutic system and commendable clinical efficacy, bringing new hope for preventing and managing OEC. Objective This study aims to evaluate the efficacy and safety of CHM in the management of postoperative OEC. Simultaneously, it seeks to explore the medication laws, therapeutic principles, and specific treatment mechanisms of CHM. Methods Eight electronic databases were searched from their inception to 01 November 2023. Randomized controlled trials (RCTs) assessing the therapeutic effects and safety of CHM for postoperative OEC were included. The risk of bias for each trial was assessed using the Cochrane Collaboration’s tool. The certainty of the evidence was evaluated using the GRADE profiler 3.2. Additionally, we extracted formulation from the included studies, conducting a thorough analysis. Results (ⅰ) Twenty-two RCTs involving 1938 patients were included. In terms of the primary efficacy outcome, the CHM group demonstrated a potentially lower recurrence rate compared to both control (odds ratio (OR) = 0.25; 95% confidence intervals (CI): 0.10–0.64) and conventional western medicine (CWM) (OR = 0.26; 95% CI: 0.11–0.65) groups. Furthermore, the joint application of CHM and CWM resulted in a significant reduction in the recurrence rate (OR = 0.26; 95% CI: 0.17–0.40). (ⅱ) Regarding secondary efficacy outcomes, (a) Total clinical efficacy rate: CHM showcased an augmentation in clinical effectiveness compared to both the control (OR = 4.23; 95% CI: 1.12–15.99) and CWM (OR = 2.94; 95% CI: 1.34–6.43) groups. The combined administration of CHM and CWM substantially enhanced overall clinical effectiveness (OR = 3.44; 95% CI: 2.37–5.00). (b) VAS Score: CHM exhibited the capacity to diminish the VAS score in comparison to surgery alone (Mean difference (MD) = −0.86; 95% CI: -1.01 to −0.71). Nevertheless, no substantial advantage was observed compared to CWM alone (MD = −0.16; 95% CI: -0.49 to 0.17). The integration of CHM with CWM effectively ameliorated pain symptoms (MD = −0.87; 95% CI: -1.10 to −0.65). (c) Serum Level of Cancer antigen 125 (CA125): the CHM group potentially exhibited lower CA125 levels in comparison to CWM alone (MD = −11.08; 95% CI: -21.75 to −0.42). The combined intervention of CHM and CWM significantly decreased CA125 levels (MD = −5.31; 95% CI: -7.27 to −3.36). (d) Pregnancy Rate: CHM exhibited superiority in enhancing the pregnancy rate compared to surgery (OR = 3.95; 95% CI: 1.60–9.74) or CWM alone (OR = 3.31; 95% CI: 1.40–7.83). The combined utilization of CHM and CWM demonstrated the potential to enhance pregnancy rates compared to CWM (OR = 2.99; 95% CI: 1.28–6.98). Concerning safety outcome indicators, CHM effectively decreased the overall incidence of adverse events and, to a certain extent, alleviated perimenopausal symptoms as well as liver function impairment. (ⅲ) Most of CHMs were originated from classical Chinese herbal formulas. Prunus persica (L.) Batsch (Taoren), Angelica sinensis (Oliv.) Diels (Danggui), Salvia miltiorrhiza Bunge (Danshen), Paeonia lactiflora Pall. (Chishao), and Corydalis yanhusuo W.T.Wang (Yanhusuo) were most frequently used CHM. Conclusion CHM may be a viable choice in the long-term management of postoperative OEC, with the potential to enhance clinical efficacy while decreasing recurrence and adverse effects.


Introduction
Ovarian endometriotic cysts (OEC) arise from the growth of ectopic endometrial tissue within the ovarian cortex (Bulun et al., 2019), constituting a major manifestation of endometriosis and contributing to 17%-44% of its incidence (Wang G. et al., 2022).Clinically, OEC is characterized by pelvic pain, infertility, abnormal menstruation, significantly impacting the quality of life and reproductive health of women of childbearing age (Bonavina and Taylor, 2022).Currently, conservative surgery is the principal treatment for reproductive-age patients with OEC (Falcone and Flyckt, 2018).Unfortunately, the recurrence rate within 5 years postsurgery can reach up to 50% (Ceccaroni et al., 2019), rendering OEC a chronic condition.Post-surgery, dienogest and gonadotropinreleasing hormone agonists (GnRH-α) are commonly prescribed to eradicate microscopic lesions and mitigate OEC recurrence.Yet, prolonged use may suppress ovarian function and delay pregnancy (Zhao, 2023).Furthermore, adverse effects including vasoconstriction symptoms, insomnia, irregular vaginal bleeding, and gastrointestinal discomfort, pose significant challenges in the long-term management post-OEC surgery (Sauerbrun-Cutler and Alvero, 2019;Della Corte et al., 2020;Konninckx et al., 2021).According to a report in The Lancet (Taylor et al., 2021), endometriosis has been considered a systemic disease that may affect liver and adipose tissue metabolism, trigger systemic inflammation, alter brain gene expression, and lead to pain sensitization and mood disorders (Taylor et al., 2021).Therefore, seeking more effective and tolerable postoperative treatments for OEC holds significant clinical relevance.
In recent years, Chinese herbal medicine (CHM) has emerged as a promising alternative therapy within the field of gynecology due to its unique treatment system.Contemporary research has further validated the crucial role of CHM in treating a variety of gynecological diseases, including OEC.For instance, studies have shown CHM's ability to induce apoptosis in ovarian cancer cells through multiple signaling pathways (Wang et al., 2024), ameliorate perimenopausal syndrome by regulating hormones secreted by the ovaries (Xue et al., 2022), and exhibit potential therapeutic effects on pregnancy-related diseases, such as recurrent spontaneous abortion, pre-eclampsia, and gestational diabetes (Fang et al., 2023).Furthermore, a meta-analysis demonstrated that CHM significantly alleviates pain associated with endometriosis with fewer side effects compared to conventional therapies (Lin et al., 2023).These findings affirm the applicability of CHM in treating gynecological diseases and provide a scientific basis for its integration into the modern medical system.Therefore, exploring the role of CHM in the long-term management of postoperative OEC is not only a venture into the modern application of traditional medicine but also critically important for the advancement and development of innovative treatment methods in gynecology.
In the postoperative treatment of OEC, CHM adopts a patientcentered approach, adhering to natural law principles and emphasizing holistic care.It aims to bolster healthy qi, dispel pathogen, and facilitate the body's recovery (Xu et al., 2020).The mechanisms through which CHM aids in the postoperative management of OEC primarily include: 1) regulating the immune system to promote immune balance and enhance immunity, thereby facilitating the elimination of ectopic endometrial tissue (Zhang et al., 2013;Shen et al., 2016;Song et al., 2021); 2) exerting anti-inflammatory effects to significantly reduce postoperative inflammation and alleviate pain (MERESMAN et al., 2021;Chen et al., 2024); 3) modulating the endocrine system to correct endocrine dysregulation, inhibit the proliferation of ectopic tissue, and restore ovarian function (Lai et al., 2021;Ma et al., 2021;Zhao, 2023); (4) promoting blood circulation to repair tissue damage and decrease the recurrence of OEC (Zhou et al., 2019;Zhao et al., 2020); (5) directly targeting ectopic endometrial tissue to inhibit its growth and invasion (Pang et al., 2021;Tan et al., 2021;Huang et al., 2022;Zhang et al., 2023).Collectively, CHM plays a comprehensive and multi-level therapeutic role in the long-term management of postoperative OEC.
A considerable volume of clinical research, encompassing case reports, case series, and randomized controlled trials (RCTs), has demonstrated that CHM could decrease recurrence rates, boost pregnancy rates, and improve the quality of life, bringing new hope for clinical management and the development of novel therapeutic approaches for postoperative OEC (Ma, 2011;Ding and Shi, 2012;Zhang, 2012;Zhou and Liu, 2013;Li, 2014;Chen, 2015;Chen et al., 2015;Dou, 2015;Du, 2015;Han, 2016;Xing, 2016;Zhou, 2016;Chen, 2018;Hu and Y, 2018;Lu et al., 2019;Qiu and Wan, 2019;Song et al., 2019;Wang and Bo, 2019;Liu, 2020;Zhao and Xiao, 2020;Wu and Deng, 2021;Tong et al., 2023).Despite this, debates regarding its efficacy and safety persist.Although 3 systematic reviews regarding CHM treatment for postoperative OEC have been published in advance respectively, some issues were also identified.Two reviews investigated the efficacy of Salvia miltiorrhiza-containing CHM (Gao Q. et al., 2022) and black cohosh extracts (Peng et al., 2020) in improving the low estrogen status induced by GnRH-α in postoperative endometriosis patients.However, the outcome measures and the scope of exploring CHM were relatively limited.Regarding the review by Dr. Fan et al., (Fan et al., 2022), more databases and RCTs should be updated to reduce potential bias.Therefore, this study has updated the relevant literature, conducted a comprehensive systematic review of RCTs to evaluate the current clinical evidence on CHM for postoperative OEC.Additionally, it provided a summarizing analysis of medication characteristics and treatment principles, aiming to offer assistance for clinical medication.

Methods
This study was conducted and reported according to the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 (Page et al., 2021) (Supplementary Appendix S1).

Types of studies
RCTs which have evaluated the efficacy of CHM for OEC were included in this study.

Types of participants
Patients received conservative surgical intervention (laparoscopic or laparotomy excision or ablation of lesions while preserving the uterus and ovaries) and had a pathological diagnosis of OEC.In order to ensure including all relevant studies, no restriction on age and nationality was specified.

Types of interventions
Patients in the treatment group should be treated by CHM or combination of CHM and CWM.Patients in the control group should be treated by CWM or CHM placebo or be a blank control.CWM in the treatment and control group must be identical in name, usage, dosage, etc.No restrictions on dosage forms, route of administration, quantity, or treatment course of CHM was specified.

Types of outcome measures
The primary efficacy outcome measure was defined as recurrence rates, while secondary outcomes consist of total clinical efficacy rate, VAS score, serum level of Cancer antigen 125 (CA125), and pregnancy rate.Safety outcome measures encompass the total incidence of adverse events as well as the specific rate of adverse reactions.

Exclusion criteria
RCTs will be excluded if the following conditions are met: (a) clinical experiences, theoretical discussion, reviews, commentaries, editorials, case reports, case series, and experimental studies; (b) Studies limited to surgical exploration, diagnosis, or staging without any intervention on the lesions in patients; (c) Control groups receiving CHM treatment, with either no established control group or inconsistency in baseline treatments between groups; (d) no detailed information regarding clinical efficacy could be extracted; and (e) duplicate publications.

Literature search
Relevant literature assessing the efficacy and safety of CHM for OEC was searched in 8 electronic databases including PubMed, Web of Science, Cochrane Library, EMBASE, Chinese National Knowledge Infrastructure (CNKI), VIP Information Database (VIP), Chinese Biomedical Literature Database (CBM), and Wanfang Database from inception up to 01 November 2023.The following grouped keywords and Mesh/Emtree thesauri were used as search terms and modified according to each database: "Ovarian endometriotic cyst" "ovarian chocolate cyst" "Postoperative Period" "Surgical Procedures, Operative" "Laparoscopes" "Chinese herbal medicine" "traditional Chinese medicine" "zhong yi yao" "zhong yao" "formula" "decoction" "pill" "capsule" "granules" "powder" "paste" "recipe" "clinical trial" "randomized controlled trial", etc.Two different authors (DN Ding and SX Liu) independently conducted the literature search and evaluated the results.The search strategies for all the electronic databases can be found in Supplementary Appendix S2.To minimize bias, we also retrieved the ongoing registered clinical trials and unpublished papers on CHM for OEC.No language and status restriction were set in this review.

Assessment of methodological quality
Methodological quality of the included trials was also assessed by 2 authors (SL Hao and Y Shen) independently.According to Cochrane Collaboration's tool (Sterne et al., 2019), 7 fields of risk of bias (ROB) were evaluated as below: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias.Each field was assessed to be "yes" (low ROB), "no" (high ROB), or "unclear" (unclear ROB).The inconsistencies were discussed with the third author (FJ Han).

Data analysis
Review Manager software (RevMan, Version 5.4, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2020) was utilized to conduct data analysis of dichotomous and continuous outcome measures, which were extracted from the original studies.Mean difference (MD) was utilized for data measurement of continuous outcomes, while odds ratio (OR) for dichotomous outcomes.All of them were expressed with a 95% confidence interval (CI).When no statistical heterogeneity was identified (heterogeneity test, p ≥ 0.10, or I 2 ≤ 50%), fixed-effects model was selected, otherwise random-effects model was applied.Subgroup analysis and/or sensitivity analysis was conducted to identify the sources of heterogeneity.Funnel plot was also used to evaluate the publication bias when over 10 trials were included in the analysis.A significant difference was considered when p < 0.05.
Furthermore, in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation criteria) (Guyatt et al., 2008a), the quality of evidence for each outcome was assessed using GRADE profiler 3.2.

Assessment of methodological quality
As shown in Figure 2, the methodological quality of the included studies was evaluated based on the criteria in the Cochrane handbook.Detailed information on the sequence generation of randomization was not reported in 7 trials (Ma, 2011;Ding and Shi, 2012;Zhou and Liu, 2013;Han, 2016;Zhou, 2016;Song et al., 2019;Tong et al., 2023).There were no statistically significant differences in baseline between the intervention and control groups across all enrolled studies.A specific method of allocation concealment was not described in this review.Detailed information regarding blinding of patients and investigators was unclear in all enrolled trials.Outcome data were obtained for nearly all randomized groups of subjects.All studies were free of bias from other sources.Although all studies were unclear on the blinding of outcome assessment, patients with OEC have objective evaluation indexes for recurrence, efficacy, pregnancy and serum CA-125 levels, and it was difficult to affect the outcome's evaluation.No information mentioned that the results were analyzed in accordance with a published pre-specified analysis plan.Consistent outcome measures and data analysis methods were used for all included studies.
The frequency of each Chinese herb in this review was also summarized manually.In total, 97 Chinese herbs were included, with a cumulative frequency of 236.Classified by CHM efficacies, they were divided into 15 categories.The top three categories were invigorate blood and dissolve stasis (81/236, 34.32%), supplement deficiency (61/236, 25.85%), and soothe the liver/rectify qi (32/236, 13.56%), refer to Table 2   3.5 Efficacy assessment

CHM alone vs blank control
In a comparative analysis of CHM versus a blank control, one study assessed the recurrence rates of OEC in groups of 63 patients each (Tong et al., 2023).Recurrence was identified by the reappearance of endometriotic lesions.The result demonstrated that CHM was superior to blank control in decreasing the recurrence rate (1 trial, n = 126; OR = 0.25; 95% CI: 0.10-0.64;p = 0.004; Figure 3A).

CHM alone vs blank control
A single study evaluated the impact of CHM alone compared to a blank control on the overall clinical efficacy rate (Tong et al., 2023).The result indicated that CHM outperformed the blank control in improving clinical efficacy (1 trial, n = 126; OR = 4.23; 95% CI: 1.12-15.99;p = 0.03; Figure 4A).

CHM alone vs CWM
The comparative efficacy of CHM alone and CWM on the overall clinical efficacy rate was assessed in three studies (Ding and SHI, 2012;Li, 2014;Dou, 2015).With no notable heterogeneity detected between the studies, a fixed-effects model was applied.Meta-analysis revealed that CHM achieved a higher clinical efficacy rate than CWM (3 trials, n = 186; OR = 2.94; 95% CI: 1.34-6.43;I 2 = 0%, p = 0.007; Figure 4B).

CHM + CWM vs CWM
A meta-analysis of twelve studies (Ma, 2011;Zhou and Liu, 2013;Chen et al., 2015;Du, 2015;Zhou, 2016;Chen, 2018;Hu and Y, 2018;Lu et al., 2019;Wang and Bo, 2019;Zhao and Xiao, 2020;Wu and Deng, 2021) evaluated the combined effect of CHM and CWM versus CWM alone on the total clinical efficacy rate.The analysis included 614 patients in each of the combination and CWM-only groups, with no significant heterogeneity detected across the studies.The findings demonstrated that the combination of CHM and CWM significantly enhanced the overall clinical efficacy rate compared to CWM alone (12 trials, n = 1,228; OR = 3.44; 95% CI: 2.37-5.00;I 2 = 0%, p < 0.00001; Figure 4C).

CHM alone vs CWM
The effect of CHM alone versus CWM on VAS score was evaluated in 1 trial involving 60 patients (Zhang, 2012).The result showed that there was no significant difference between CHM and CWM on VAS score (1 trial, n = 60; MD = −0.16;95% CI: -0.49 to 0.17; p = 0.34; Figure 5B).

CHM alone vs blank control
One study reported the effect of CHM alone compared to a blank control on pregnancy rate, involving 126 patients (Tong et al., 2023).The result showed that CHM could increase the pregnancy rate in postoperative patients with OEC (1 trial, n = 126; OR = 3.95; 95% CI: 1.60-9.74;p = 0.003; Figure 7A).

CHM + CWM vs CWM
Three studies evaluated the impact of combining CHM with CWM on the pregnancy rate (Qiu and Wan, 2019;Liu, 2020;Zhao and Xiao, 2020).The analysis included 122 patients in each of the combination and CWM-only groups, with no significant heterogeneity across the studies.The combined treatment of CHM and CWM was found to significantly enhance the pregnancy rate (3 trials, n = 244; OR = 2.99; 95% CI: 1.28-6.98;I 2 = 0%, p = 0.01; Figure 7C).
Besides, the meta-analysis of CA125 levels in the CHM alone versus CWM group exhibited significant heterogeneity (I 2 = 95%).However, due to the limited number of included articles (only 2), it was not possible to conduct subgroup analyses.Hence, based on sensitivity analysis, the original studies were examined.The results revealed that patients who received CHM treatment for a duration of 6 months exhibited significantly reduced serum CA125 levels compared to the control group (Dou, 2015) (MD = −16.09;95% CI: -19.17 to −13.01; p < 0.00001).Nonetheless, following a 3-month CHM intervention, there was no discernible variation in the serum CA125 levels of the two groups (Zhang, 2012) (MD = −5.17;95% CI: -12.07 to 1.73; p = 0.14).Differential treatment duration might be the primary source of heterogeneity.

Publication bias
Publication bias was detected through the funnel plot analysis of recurrence rate, total clinical efficacy rate and adverse event.The asymmetry suggested mild publication bias in the study (Figure 12).

GRADE evaluation of evidence quality
According to the GRADE standard (Guyatt et al., 2008b), GRADE profiler 3.2.2 was used to evaluate the quality of evidence for each outcome.Outcome indexes were classified into four grades of high quality, moderate quality, low quality and very low quality according to five aspects of research limitation, inconsistency, indirectness, imprecision, and publication bias.The evidence Profile with quality assessment and summary of findings were reported in Table 6.

Discussion
OEC, a prevalent disorder in women of reproductive age, is known for its persistent nature and propensity for recurrence (Ceccaroni et al., 2019).Recently, some academics have incorporated the notion and framework of chronic disease management into the therapy of OEC, aiming to provide patients with comprehensive, uninterrupted, and proactive techniques for managing their condition (Falcone and Flyckt, 2018).Traditional Chinese Medicine (TCM) boasts a history spanning thousands of years.Recent studies have confirmed that CHM exerts therapeutic effects on OEC through multitarget mechanisms, minimizing adverse effects (Flower et al., 2012;Meresma et al., 2021;Chen et al., 2023;Zhao, 2023).To our knowledge, this is the first comprehensive systematic review and meta-analysis that integrates discussions on the principles of TCM treatment and laws of formula composition to assess the efficacy and safety of CHM for postoperative OEC in the English language.

Efficacy
The primary results derived from the meta-analysis are as follows.
(i) Conservative surgery combined with CHM treatment may reduce the recurrence of endometriotic lesions, enhance the overall clinical efficacy and pregnancy rates, and alleviate postoperative pain.(ii) In comparison to CWM alone, CHM alone may offer higher clinical efficacy and pregnancy rates, reduce endometriotic lesion recurrence, and lower serum CA125 levels, without a significant improvement in pain symptoms.(iii) The combination of CHM and CWM, versus CWM alone, can significantly increase the overall clinical efficacy and pregnancy rates, while also reducing the recurrence of endometriotic lesions and clinical symptoms, lowering CA125 levels, and alleviating postoperative pain.Forest plot illustrating the effect on adverse events of different intervention modes of CHM: (A) CHM Alone vs CWM, (B) CHM + CWM vs CWM.
Frontiers in Pharmacology frontiersin.org19 Ding et al. 10.3389/fphar.2024.1376037 TABLE 5 The effect of CHM intervention on the incidence of specific adverse events.(iv) Concerning the primary outcome, recurrence rate, CHM intervention has demonstrated efficacy in reducing both endometriotic lesion and clinical symptom recurrence.This might be attributed to its regulatory effects on the body's internal environment, immune enhancement, inflammation suppression, and angiogenesis inhibition (Meresman et al., 2021;Wu et al., 2022).Subgroup analysis revealed that CHM, compared to CWM, Forest plot illustrating the effect of CHM intervention modes on the recurrence rate of OEC during different follow-up periods: (A) CHM Alone vs CWM, (B) CHM + CWM vs CWM.
Frontiers in Pharmacology frontiersin.org21 Ding et al. 10.3389/fphar.2024.1376037significantly lowered the 12-month postoperative recurrence rate in OEC patients.However, no significant difference was observed at the 6-month follow-up, suggesting the therapeutic effects of CHM may be more pronounced over a longer duration.This observation aligns with the holistic and gradual healing approach traditionally attributed to CHM, which may not only target the symptoms but also the underlying imbalances contributing to the disease's recurrence (Zhao, 2023).Moreover, our analysis demonstrated that combining CHM with CWM could consistently reduce the recurrence rate across all follow-up intervals (3-36 months) compared to using CWM alone.This synergy suggested that CHM might enhance the efficacy of CWM, thereby offering a more sustainable and tolerable long-term management strategy for OEC.(v) The effect of CHM on alleviating postoperative pain in patients with OEC was evaluated using the Visual Analogue Scale.Our research indicated that the use of CHM alone does not significantly outperform CWM in terms of pain improvement.However, it is important to note this conclusion is based on limited evidence, highlighting the need for further rigorous studies to fully explore the potential of CHM as an independent modality for postoperative pain relief.Conversely, our analysis suggested a potentially positive role for CHM as an adjunct to CWM in postoperative OEC management, particularly in offering more effective pain relief in long-term treatment.This not only reflects the comprehensive effects of CHM in regulating pelvic microcirculation and alleviating inflammatory infiltration (Gao Y. et al., 2022;Lin et al., 2022;Yue et al., 2022) but also underscores the significance of an integrated Chinese and Western medical treatment strategy in enhancing postoperative quality of life.
(vi) CA125 is recognized as a marker for ovarian epithelial cell tumors.Although it exhibits lower sensitivity and specificity, making it not the most reliable indicator for diagnosing endometriosis (Association, 2021), elevated levels of CA125 are associated with the staging and clinical types of endometriosis (Kovalak et al., 2023).It is commonly used in clinical settings as a monitoring indicator to assess the progression of OEC and the response to treatment (Foster, 2016;Hirsch et al., 2016;Liu, 2020;Zhao and Xiao, 2020).Therefore, in this study, we have included CA125 levels as a secondary outcome, supplementing it with clinical outcomes such as recurrence rate and VAS score, to facilitate a more comprehensive evaluation of the therapeutic effects of CHM in the long-term management of OEC.Our meta-analysis results indicated that CHM interventions could effectively reduce postoperative CA125 levels.Notably, in subgroup analyses, combinations of CHM with Goserelin, Triptorelin, Gestrinone, and Mifepristone treatments have shown significant effects in lowering CA125 levels.However, combining CHM with Leuprorelin did not exhibit a synergistic effect in reducing CA125 levels, necessitating further in-depth research to explore potential influencing factors on its efficacy.These results prompt further considerations for treatment choices, with detailed comparisons between different treatment groups aiding clinicians in formulating more precise treatment plans.Sensitivity analysis revealed that after 6 months of treatment, the CA125 levels in the CHM group were lower than those in CWM group, with no significant difference observed at 3 months of treatment.As OEC is a chronic condition characterized by a long course and a propensity for recurrence, it is advisable in clinical treatment to consider extending the medication duration appropriately based on the patient's condition, to enhance clinical efficacy.

FIGURE 10
Forest plot depicting the effect of different durations of postoperative CHM combined with CWM treatment on reducing the VAS score.

Safety and adverse events
Regarding safety, previous meta-analyses focused on the overall adverse effect incidence rates of CHM treatment in postoperative OEC patients (Fan et al., 2022).In contrast, specific adverse reaction indicators could more accurately highlight TCM's advantages in pattern differentiation and treatment.This study revealed that CHM, alone or combined with CWM, was superior in reducing the overall adverse event incidence and improving perimenopausal symptoms and liver function.CHM mimics sex hormone effects, activating the hypothalamic-pituitary-ovarian axis and enhancing local microcirculation to improve ovarian blood supply (Chen, 2018).Consequently, it improves ovarian function, addresses low estrogen levels, and alleviates symptoms like tidal fever, night sweats, sleep disturbances, and irregular vaginal bleeding in the perimenopausal period.Additionally, according to TCM theory, the liver, viewed as pivotal in women's prenatal basis, plays a crucial role in physiological functioning.If the liver fails to govern the free flow of qi, it could lead to the occurrence of gynecological diseases.Therefore, it is important to emphasize the regulation of viscera and bowels postoperatively.Orderly transformation and qi flow may contribute to alleviating liver function impairment (Zhang et al., 2022).

Therapeutic principles
This study conducted a summary and synthesis of the included literature, revealing that medical practitioners adhered to the guiding principles of TCM "treat disease before it arises" and "concept of holism" in the treatment of postoperative OEC.To achieve personalized therapy, they clinically based their approach on the patient's constitution, supporting right and dispelling evil, and utilizing pattern identification as the basis for determining treatment.In my opinion, achievement of clinical efficacy is closely related to traditional medical experience and extensive use of a large number of classical Chinese herbal formulas.Although not recorded in TCM, it does not affect the understanding of TCM pathogenesis and the clinical treatment of OEC.As symptoms and signs including tongue coating and pulse are the basis of diagnosis and treatment in TCM, TCM syndrome and formulae syndrome rather than disease were focused accordingly.The following text will describe and discuss specific treatment principles from two perspectives.
(i) prevent disease before it arises, and expel pathogens to prevent recurrence Forest plot illustrating the effect of different Western medications combined with CHM on the reduction of serum CA125 levels.
Frontiers in Pharmacology frontiersin.org According to TCM theory, OEC are classified as "zhēng jiă" (concretions and conglomerations), with blood stasis being pivotal in their development (Zhao, 2023).While surgical intervention can address the pathological product of "static blood", it does not eradicate the underlying factors leading to postoperative recurrence.Consequently, postoperative treatment in TCM prioritizes the removal of excess pathogens and emphasizes the enhancement of blood circulation and the resolution of stasis, as outlined in Table 2. Clinically, tailored to the individual's constitution, employs flexible application of CHMs known for their efficacy in breaking stasis and invigorating blood, including P. persica (L.) Batsch (Taoren), A. sinensis (Oliv.)Diels (Danggui), and S. miltiorrhiza Bunge (Danshen) to prevent the recurrence of OEC.
(ii) Based on individual conditions, support right and dispel evil, aiming to adjust the body's constitution to a natural balance.Following OEC surgery, patients may experience diminished immune function, and inadequate postoperative care might lead to a deficiency of healthy qi, disrupting the normal circulation of qi and blood.This disruption fosters the regeneration of static blood, perpetuating a cycle of OEC recurrence.Therefore, the postoperative care should comply with the human body's innate resistance to evil and the physiological characteristics of the internal organs.The treatment aimed to supplement deficiency and support right, and regulate the viscera and bowels (Table 2).Observing the natures, flavors, and channel entry by these herbs (Table 4), their combination demonstrated the following effects: a) harmonizing the warm and cold natures to balance yin and yang; b) acrid opening and bitter downbearing to regulate the movement of qi; c) the combination of acrid and sweet medicinals supports yang, nourishing qi and blood; d) incorporating the expulsion of pathogen within tonifying effects.As shown in Table 3, the tonifying CHMs primarily included Cuscuta chinensis Lam.(Tusizi), Glycyrrhiza glabra L. (Gancao), Dipsacus asper Wall.Ex DC. (Xuduan), P. lactiflora Pall.(Baishao), Astragalus mongholicus Bunge (Huangqi), focusing on blood supplementation and invigoration while boosting qi and warming yang, simultaneously nourishing the blood, and dispelling stasis.Additionally, postoperative medication primarily targeted the foot jueyin liver channel, followed by the hand shaoyin heart channel, the foot taiyin spleen channel, and the foot shaoyin kidney channel (Table 4).Furthermore, recognizing the emotional challenges faced by patients post-surgery, the treatment also aims to soothe the liver, nourish the heart, fortify the spleen, and reinforce the kidney.Achieving equilibrium in zang-fu functions ensures a harmonious flow of qi and blood, fostering a balanced constitution and natural elimination of blood stasis.

Description of high-frequency CHM
The most frequently used CHMs were also analyzed in this study.Among the top five, P. persica (L.) Batsch (Taoren) possesses a bitter flavor, a neutral nature.It targets the hand shaoyin heart, foot jueyin liver, and hand yangming large intestine channels, exhibiting functions of invigorating blood and dissolving stasis.Its active metabolite, Amygdalin (Figure 13A), exhibits antioxidative, anti-tumor, antiinflammatory properties, immune modulation, and analgesic effects (Barakat et al., 2022).Research has shown Amygdalin's potential in triggering apoptosis in tumor cells and causing cell cycle arrest (Saleem et al., 2018).
Angelica sinensis (Oliv.)Diels (Danggui) is recognized for its sweet, acrid taste and warm nature, interacting with the foot jueyin liver, hand shaoyin heart, and the foot taiyin spleen channels.It aids in blood supplement and invigoration, menstrual regulation, and pain alleviation.Ferulic acid (Figure 13B), the active metabolite of Danggui, offers vascular endothelial protection through the ERK1/2 and  *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparator group and the relative effect of the intervention (and its 95% CI).CI: Confidence interval; MD: Mean difference; OR: Odds ratio.Factors of downgrade: 1 Unclear risk of detection bias, selection bias and performance bias; 2 Sample size is less than the optimal information size; 3 Significant statistical heterogeneity.GRADE Working Group grades of evidence: High quality: Further research is very unlikely to change our confidence in the estimate of effect.Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.Very low quality: We are very uncertain about the estimate.
NO/ET-1 pathways and exhibits anti-fibrosis properties via the TGF-β/ Smad and MMPs/TIMPs systems (Li et al., 2021;Li et al., 2022).Salvia miltiorrhiza Bunge (Danshen) has a bitter flavor and a slightly cold nature, entering the hand shaoyin heart channel and the foot jueyin liver channel.Its functions involve invigorating blood, dissolving stasis, regulating menstruation, and calming the mind, making it a crucial botanical drug in gynecology.Its principal active metabolite, tanshinone IIA (Figure 13C), plays a pivotal role in mitigating adhesion, invasion, and angiogenesis, thereby improving the pathological morphology of ectopic endometrium and inhibiting the formation of endometriotic lesions (Chen and Gong, 2020;Zhang et al., 2023).
Corydalis yanhusuo W.T.Wang (Yanhusuo) is widely used to alleviate general body pain.It exhibits significant anti-inflammatory, analgesic, neuroprotective, and antitumor properties, attributed to tetrahydropalmatine as its active metabolite (Figure 13E).A combination of tetrahydropalmatine, ferulic acid, and ligustrazine has been shown to inhibit epithelial-mesenchymal transition through the Wnt/β-catenin pathway (Zhang et al., 2021), exerting an anti-proliferative effect on endometriosis via modulation of the Notch pathway (Dai et al., 2023).
It is noteworthy that, oxidative stress, a negative effect stemming from the imbalance of oxidation system in the body, plays a significant role in apoptosis, aging, and the onset of various diseases (Reuter et al., 2010;Poprac et al., 2017;Hajam et al., 2022).OEC is intricately linked to oxidative damage, both in terms of its initiation and development (Matsuzaki and Schubert, 2010;Hayasti et al., 2020;Koninckx et al., 2021).Plant polyphenols, including flavonoids, tannins, phenolic acids, etc., have the ability to scavenge free radicals within the body, combat lipid oxidation, delay organismal aging (Yahfoufi et al., 2018;Maleki et al., 2019;Nani et al., 2021), and exhibit anti-inflammatory, antitumor, and analgesic properties (Arablou and Kolahdouz-Mohammadi, 2018; Liu et al., 2022).Numerous CHMs and natural metabolites, including the five botanical drugs previously mentioned, possess certain antioxidant, anti-tumor, anti-inflammatory, and anti-aging effects.These attributes underline the potential of CHMs in the multifaceted and comprehensive treatment of OEC.

Limitations and future perspectives
This review acknowledges several limitations that warrant consideration.First, suboptimal methodological design is a common issue in most included trials, demanding a careful explanation of our results.Second, the absence of sample size estimation in many studies undermines the precision of results, particularly in smaller-scale research.Third, the omission of OEC staging information in some studies may influence the aggregated results regarding OEC recurrence.Finally, the GRADE evaluation for various outcomes was of moderate to low quality, indicating constraints in stability and reliability of conclusions.
To address these limitations and improve the quality of future research, the following strategies are recommended.First, significant drawbacks regarding the sequence generation of randomization, concealment of allocation, reporting on blinding, attrition, and pre-estimation of sample size should be considered to minimize potential biases.Second, adopting a multicenter, large-sample research design is advisable to ensure the reliability and generalizability of results.Third, a detailed analysis of variables such as surgical techniques, patient age, severity of condition, and OEC staging could yield deeper insights.Fourth, integrating various types of real-world studies could be considered to enhance the evaluation of the therapeutic effects of CHM.Finally, future studies could further identify the specific components or formulations of CHM responsible for clinical benefits and elucidate the mechanisms of their synergistic effects with CWM.This would lay the groundwork for more personalized and effective treatment paradigms, integrating the best of traditional and modern medicine.

Conclusion
In general, this systematic review and meta-analysis suggested that CHM may be beneficial for the treatment of postoperative OEC in reducing recurrence, improving clinical efficacy, and decreasing side effects.CHM could serve as a potential candidate or supplemental therapy for postoperative OEC in the battle for long-term management.However, considering the limitations of existing studies, further large-scale, high-quality, and rigorously designed trials are warranted to substantiate the conclusions.
Trials were selected according to the inclusion/exclusion criteria by reading the titles, abstracts and (or) full texts of the published articles.Two authors (SX Liu and FY Liu) independently selected the studies and extracted data using a pre-designed data extraction sheet, evaluated and crosschecked.Detailed information of enrolled study was listed as follows: (a) basic characteristics of included studies: title of study, authors' name, publication date, sample size, diagnostic criteria, methodological quality, therapeutic schedule in treatment and control groups, components and dosage of CHM, withdrawals, and course of treatment; (b) basic characteristics of included patients: age, gender, duration of disease, size and staging of OEC, previous medical history, and laboratory examination; (c) both primary and secondary outcome measures; and (d) adverse effects.If disagreements on data extraction were identified, a third party (FJ Han) was consulted.
classified efficacy into four categories: (a) cured: total lesion disappearance and symptom resolution; (b) significantly effective: symptom resolution and lesion size reduction; (c) effective: symptom alleviation without notable lesion size change; (d) ineffective: no improvement or symptom exacerbation, alongside

FIGURE 3
FIGURE 3 Forest plot illustrating the effect on recurrence rate of different intervention modes of CHM: (A) CHM Alone vs Blank Control, (B) CHM Alone vs CWM, (C) CHM + CWM vs CWM.

FIGURE 4
FIGURE 4Forest plot illustrating the effect on total clinical efficacy rate of different intervention modes of CHM: (A) CHM Alone vs Blank Control, (B) CHM Alone vs CWM, (C) CHM + CWM vs CWM.

FIGURE 5
FIGURE 5 Forest plot illustrating the effect on VAS score of different intervention modes of CHM: (A) CHM Alone vs Blank Control, (B) CHM Alone vs CWM, (C) CHM + CWM vs CWM.

FIGURE 6
FIGURE 6Forest plot illustrating the effect on serum level of CA125 of different intervention modes of CHM: (A) CHM Alone vs CWM, (B) CHM + CWM vs CWM.

FIGURE 7
FIGURE 7Forest plot illustrating the effect on pregnancy rate of different intervention modes of CHM: (A) CHM Alone vs Blank Control, (B) CHM Alone vs CWM, (C) CHM + CWM vs CWM.

FIGURE 12 Funnel
FIGURE 12Funnel plot of relevant outcomes: (A) Recurrence rate, (B) Total clinical efficacy rate, (C) Adverse event.

TABLE 1
Basic characteristics of included trials and subjects.

TABLE 1 (
Continued) Basic characteristics of included trials and subjects.

TABLE 2
Categorization of Chinese herbal medicine efficacies in the included studies.Risk of bias summary.

TABLE 3
Frequency of Chinese herbal medicine Utilization in the Included Studies.

TABLE 3 (
Continued) Frequency of Chinese herbal medicine Utilization in the Included Studies.

TABLE 3 (
Continued) Frequency of Chinese herbal medicine Utilization in the Included Studies.

TABLE 4
Analysis of Chinese herbal medicine natures, flavors, and channel entries in the included studies.

TABLE 6
GRADE rating of the quality of each outcome.

TABLE 6 (
Continued) GRADE rating of the quality of each outcome.