Dydrogesterone for preventing endometrial polyp recurrence after transcervical resection of polyps: protocol for a multicentre randomised controlled trial in China.

Endometrial polyps (EPs) are common benign gynaecological conditions characterised by localised overgrowth of the stroma and endometrial glands. 1 3 The prevalence of EPs in various populations ranges between 7.8% and 34.9%. 1 4 EP-associated symptoms include abnormal uterine bleeding (AUB), infertility, recurrent reproductive failure and postmenopausal vaginal bleeding. 1 5 6 Hysteroscopic polypectomy, known as transcervical resection of polyps (TCRP), is the first-line diagnostic and therapeutic approach for treating EPs. 1 5 6 However, EP recurrence after TCRP remains a concern, with recurrence rates ranging between 2.5% and 43.6%, depending on the follow-up duration. 7 The recurrence rate at 12 months post-TCRP has been reported to range between 5.6% and 31.4%, 8 whereas that at 2-year post-TCRP has been reported to be 19.23%. 2 EP recurrence may lead to recurrence of AUB or infertility. 7 Therefore, preventing EP recurrence after TCRP remains an important clinical concern. The exact cause of EPs remains unclear; however, it may be associated with local oestrogen stimulation of the endometrium, dysregulation of the oestrogen and progesterone receptors 2 3 5 9 or chronic endometritis (CE). 810 12 Progesterone can induce atrophy, dedifferentiation and vascular changes in the endometrial epithelium 2 and enhance the immune status of the endometrium, 13 thereby inhibiting the formation of EPs. Progesterone treatments, including oral dydrogesterone 14 and the levonorgestrel-releasing intrauterine system (LNG-IUS), 15 have been recommended for the conservative treatment of EPs. 5 We hypothesise that progesterone administration after TCRP may prevent EP recurrence. We previously demonstrated in a retrospective cohort study that LNG-IUS insertion significantly reduces the EP recurrence rate after TCRP. 2 A subsequent single-centre randomised controlled trial is currently underway to further verify the effectiveness of LNG-IUS in preventing EP recurrence. 2 Dydrogesterone is an oral progestin that effectively treats EPs and exerts therapeutic effects on CE. Chen et al reported that administering 10 mg of dydrogesterone daily for 10 consecutive days (from days 15 to 24 of the menstrual cycle) over three treatment cycles resulted in EP symptom and ultrasound improvement rates of 95.1% and 55%, respectively. 14 In another retrospective cohort study, among patients with EPs and CE, the group receiving dydrogesterone and antibiotics after TCRP had a significantly higher cure rate than that receiving antibiotics alone (85.2% vs 74.3%). 13 However, no prospective studies have confirmed the effectiveness of dydrogesterone in preventing EP recurrence after TCRP. We hypothesised that the administration of oral dydrogesterone for three menstrual cycles after TCRP may effectively reduce the EP recurrence rate and improve abnormal bleeding symptoms. To test this hypothesis, we designed a multicentre randomised controlled trial with the primary objective of assessing the effect of oral dydrogesterone on the recurrence rate of EPs after TCRP. The secondary objective was to evaluate the effects of oral dydrogesterone on AUB symptoms after TCRP. In addition, we established other exploratory goals, such as assessing the time to the first recurrence of EPs after TCRP and exploring the association of patient characteristics and polyp features with recurrence risk.

This is a randomised, parallel, open-label, blank-controlled, multicentre study that will be conducted across 12 medical centres in China, including 11 in Zhejiang Province and 1 in Jilin Province. The participating institutions consist of general hospitals, women’s or women and children’s specialty hospitals. The Women’s Hospital, School of Medicine, Zhejiang University, is the primary investigation site. The study has been approved by the Ethics Committee of the Women’s Hospital, School of Medicine, Zhejiang University (IRB-20240077-R) and registered on the Chinese Clinical Trial Registry website (ChiCTR2400083097). The study protocol adheres to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines. 16 The Women’s Hospital of Zhejiang University reviewed and approved the study protocol (V.1.2, 1 May 2024), along with the operations and procedures manual, case report form (CRF), information manual and informed consent form. This study will be conducted between 22 April 2024 and 31 December 2026, and the participants will undergo follow-up for 24 months after surgical treatment and prophylactic intervention. Participants will be enrolled until 31 December 2024. Any protocol modifications affecting the study implementation or participants’ safety, including changes to objectives, design, population, sample size, procedures or major administrative aspects, will be approved by the Ethics Committee of the Women’s Hospital, School of Medicine, Zhejiang University. This study will include female patients aged 18–46 years diagnosed with EPs using ultrasonography and scheduled for TCRP. Eligible participants who meet the inclusion criteria during the 60-day screening period will be randomly assigned to either an intervention or control group at a 1:1 ratio. All participants will undergo TCRP, with the time between randomisation and surgery not exceeding 14 days. The intervention group will receive dydrogesterone after surgery for three menstrual cycles, whereas the control group will not receive any hormonal treatment. All participants will be followed up at 1, 3, 6, 12, 18 and 24 months postsurgery. Follow-up assessments will include evaluation of postoperative AUB, menstrual conditions, ultrasound examinations and laboratory tests. Participants must meet the eligibility criteria within a 60-day screening period, which includes undergoing two transvaginal ultrasound examinations across different menstrual cycles to confirm the diagnosis of EPs, followed by TCRP. According to the 2022 Chinese guidelines Clinical Pathway for Diagnosis and Management of Endometrial Polyps (doi: 10.3760/cma.j.cn112141-20220422-00269), the surgical indications for TCRP include (1) symptomatic EPs; (2) EPs with a diameter greater than 1 cm and (3) EPs suspected of malignancy or associated with high-risk factors for malignancy. Accordingly, the inclusion criteria for this study were defined based on ultrasound findings, which included the presence of a hyperechoic mass in the uterine cavity with at least one of the three diameters measuring between 10 and 50 mm. 17 In addition, the double-layered endometrial thickness should be ≤18 mm. The double-layered endometrial thickness of >18 mm may be associated with pathological abnormalities, such as atypical hyperplasia, polyp hyperplasia or endometrial adenocarcinoma ( table 1 ). 6 Signed and dated informed consent. Female sex, age between 18 and 46 years and a history of childbirth (at least one child). Diagnosis of EPs based on two vaginal three-dimensional ultrasonography scans. Maximum diameter of any EP <50 mm. TCRP is proposed. Overall good health, aside from EP-related conditions. Normal or clinically insignificant cervical smear results. No pregnancy or plans for pregnancy for 2 years after TCRP. Pregnancy or lactation (<3 months between childbirth, miscarriage or lactation and the start of treatment). Long-term use of steroid hormone drugs or effective medications during the three menstrual cycles before surgery. Current use of tamoxifen. Recurrent EPs with moderate to severe anaemia. Presence of malignant genital tract tumours or breast cancer. Contraindications for dydrogesterone use. Diseases, conditions or medications that may impair system function, alter absorption, cause accumulation, hinder metabolism or interfere with excretion. Conditions affecting the conduct of the study or interpretation of the results. Abuse of alcohol, drugs or medications. Treatments that may interfere with the conduct of the study or interpretation of the results. Concurrent participation in another clinical drug study. Close relationship with the research centre or staff. Inability to comply with the study protocol for any reason. At personal request or that of a legal guardian, refusal to continue with the study is possible at any time without providing a reason. Special circumstances that require withdrawal (significant noncompliance and safety concerns). Pregnancy. Surgical pathology confirming a condition other than EPs (endometrial hyperplasia, uterine fibroids and adenomyosis). Pathology confirming atypical hyperplasia, EIN or malignancy. Repeat surgery for EPs during the follow-up period. Abnormal laboratory test results posing a risk to participants’ health. EIN, endometrial Intraepithelial neoplasia; EPs, endometrial polyps; TCRP, transcervical resection of polyps. A cervical smear may be omitted if normal results have been documented within the previous 6 months. For participants with atypical squamous cells of undetermined significance (ASCUS), a human papillomavirus (HPV) test should be performed. Participants with ASCUS who test negative for high-risk HPV strains are eligible for inclusion. Barrier contraception is not required if permanent contraception has been achieved using bilateral tubal ligation (including Essure) or partner vasectomy, beginning at the start of the study and continuing to the end of the study. Participants who meet all the inclusion criteria and none of the exclusion criteria during the screening period will be enrolled in this study ( table 1 and Boxes1 3 ). Renal impairment. Elevated liver enzymes, as defined by any of the following: 2.1 GOT/AST levels exceeding twice the ULN. 2.2 ALT levels exceeding twice the ULN. 2.3 Alkaline phosphatase levels exceeding twice the ULN. 2.4 TB levels exceeding 1.5 times the ULN. Chronic intestinal diseases, such as Crohn’s disease or ulcerative colitis. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GOT, glutamic oxaloacetic transaminase; TB, total bilirubin; ULN, upper limit of normal. Known severe clotting disorders. Anaemia from a known cause other than AUB. Known haemoglobinopathies. Ultrasound findings before screening revealing one or more ovarian cysts measuring >30 mm in diameter, with cystic structures persisting for more than two menstrual cycles. Unexplained ovarian tumours or pelvic masses requiring further diagnosis. Known or suspected uterine fibroids measuring >50 mm in diameter. AUB, abnormal uterine bleeding. Gonadotropin-releasing hormone agonists, unless discontinued at least 60 days prior to enrolment. Tranexamic acid for menorrhagia, traditional Chinese medicine or other drugs targeting AUB, if not discontinued before enrolment. Anticoagulants, unless discontinued prior to enrolment. AUB, abnormal uterine bleeding. Women who have received oestrogen or progesterone preparations, hormonal contraceptives or hormone-releasing contraceptive devices during the three menstrual cycles before surgery are ineligible for this study. Patients with contraindications for dydrogesterone, such as allergies to dydrogesterone or a history of severe liver disease with unresolved liver function abnormalities, liver tumours (present or past), Dubin-Johnson syndrome, rotor syndrome or jaundice, will also be excluded from this study. Participants may be withdrawn from the study if they no longer meet the inclusion criteria or if they meet any exclusion criteria after enrolment ( table 1 and Box 4 ). If the pathological examination results—returned within 3–5 working days after TCRP—indicate a nonpolyp lesion or a nonbenign pathology (withdrawal criteria 4 and 5), the participant will be withdrawn from the study. If necessary, the recruitment period will be extended to ensure that the final sample includes a sufficient number of participants with a confirmed pathological diagnosis of benign EPs, in accordance with the required sample size. GPT/ALT or GOT/AST levels exceeding eight times the ULN. GPT/ALT or GOT/AST levels exceeding five times the ULN for >2 weeks. GPT/ALT or GOT/AST levels exceeding three times the ULN, with the TB level exceeding twice the ULN or an international normalised ratio of >1.5. GPT/ALT or GOT/AST levels exceeding three times the ULN, accompanied by symptoms such as fatigue, nausea, vomiting, right upper abdominal pain or tenderness, fever, rash and/or eosinophilia. ALT, alanine aminotransferase; AST, aspartate aminotransferase; GOT, glutamic oxaloacetic transaminase; GPT, Glutamic pyruvic transaminase; TB, total bilirubin; ULN, upper limit of normal. If any laboratory abnormalities occur during follow-up or researchers perceive a risk to participants’ life or health, they will be withdrawn from the study ( Box 4 ). Participants who experience menopause (defined as ≥12 months of amenorrhea without other medical causes) during follow-up will also be withdrawn from the study. After formal enrolment, participants will provide informed consent and sign a consent form (see online supplemental material 1 ). All participants will be randomised into two groups and assigned a subject identification number (SID) through an online program ( http://77.223.214.107/login.php ) by researchers at the enrolling medical centres. Randomisation will be performed in a 1:1 ratio. With the use of blank control, this is an open-label trial with no anonymity. After completing the screening, the enrolled participants will be randomly assigned at a 1:1 ratio to either the dydrogesterone or control group. All participants will undergo TCRP within 14 days of randomisation. To maximise patient inclusion, surgical methods will include, but will not be limited to, hysteroscopic electrosurgical polypectomy, cold knife resection and hysteroscopic tissue removal systems (HTRS) morcellation. The types of hospitalisations will include inpatient surgery, day surgery and office hysteroscopy. Hysteroscopic surgery will adhere to the ‘see-and-treat’ principle, removing all visually detectable intrauterine lesions. The procedure requires the complete excision of polypoid lesions down to the endometrial layer. Before concluding the surgery, a ‘second look’ will be performed to ensure the thorough removal of all polypoid lesions. All procedures will be performed by senior physicians. Given that EPs are generally benign, but other endometrial abnormalities—such as endometrial hyperplasia, atypical hyperplasia and endometrial carcinoma—may coexist within the endometrium; diagnostic curettage or endometrial aspiration will be performed concurrently with TCRP. 18 All excised polypoid lesions and endometrial tissue samples will undergo pathological examination. Based on the pathology results, participants who do not meet the criteria for benign polyps or who present with endometrial abnormalities will be excluded. Dydrogesterone treatment group (I): After TCRP, the participants will receive oral dydrogesterone for three menstrual cycles. The regimen will be initiated on the first postoperative day, with dydrogesterone being administered orally at a dose of 10 mg twice daily for 10 consecutive days. After the first postoperative menstrual cycle, dydrogesterone will be administered on the 14th day of the menstrual cycle at a dose of 10 mg twice daily for 10 consecutive days. The same method of administration will be repeated after the second menstrual cycle. Control group (C): Participants will undergo TCRP; however, no hormonal treatment or preventive intervention will be provided postoperatively. Participants with other gynaecological conditions treated simultaneously using hysteroscopy, such as submucosal myomectomy or adhesiolysis, will be excluded from the study. In addition, participants who experience serious complications, such as uterine perforation, during hysteroscopic surgery will be excluded. If serious adverse events (AEs), such as abnormal liver function or severe anaemia, occur during dydrogesterone treatment and if the withdrawal criteria are met, the participant will be withdrawn from the study. All participating medical centres will screen participants through outpatient clinics. During the 60-day screening period, participants will undergo a comprehensive medical history assessment and an ultrasound examination to complete the initial evaluation of the inclusion and exclusion criteria. They will also undergo a second assessment within this period, including a physical examination, gynaecological examination, laboratory tests and follow-up ultrasound examination ( table 2 ). After meeting the eligibility criteria, the participants will provide informed consent, sign a consent form and be randomly assigned to either the intervention or control group. TCRP will be performed within 14 days of randomisation, followed by the administration of an assigned intervention based on group allocation. Participants will then undergo six follow-up visits over a 24-month period postoperatively ( figure 1 ). Days 7–15 of the first or second menstrual cycle after the initial screening. If transvaginal ultrasound results suggest the presence of EPs, a repeat ultrasound will be performed during the next menstrual cycle (on days 5–8 of menstruation) or 4 weeks later for participants with irregular cycles. AEs, adverse events; AUB, abnormal uterine bleeding; HCG, human chorionic gonadotropin; SID, subject identification number; STDs, sexually transmitted diseases; TCRP, transcervical resection of polyps. The first follow-up visit for all participants will be held 1-month postsurgery. If a participant is menstruating at the time of the visit, the visit may be postponed for approximately 1 week. The primary focus of the first follow-up is to assess any surgery-related complications, such as bleeding or infection, and any AEs or symptoms related to dydrogesterone treatment. The subsequent five follow-up visits will be scheduled at 3, 6, 12, 18 and 24 months postsurgery. Each visit will include a transvaginal ultrasound re-evaluation and review of patient records regarding AUB symptoms and menstrual status. If a participant is menstruating at the time of any follow-up visit, the visit may be delayed by approximately 1 week ( table 2 ). All assessments and follow-up visits will be conducted by researchers at the study centre or by appropriately qualified, trained and authorised personnel designated by the study centre. All visit outcomes will be recorded using a CRF. If any abnormal conditions, such as abdominal pain or bloating, are observed during follow-up visits at 3, 6, 12, 18 and 24 months postsurgery, additional gynaecological and laboratory examinations will be performed. Unscheduled visits may be arranged for individual participants based on the clinical judgement of the researcher or authorised personnel. Potential reasons for unscheduled visits include suspected infection, possible pregnancy or other safety concerns with all results documented in the CRF. During the follow-up, transvaginal ultrasound examinations will be performed on days 5–8 of the menstrual cycle. If the ultrasound reveals a new regular hyperechoic lesion within the uterine cavity, accompanied by a surrounding hyperechoic halo and abnormal endometrial echoes, recurrence of EPs will be considered. 17 A repeat ultrasound will be performed during the next menstrual cycle (days 5–8) or 4 weeks later in participants with irregular cycles. If two transvaginal ultrasound examinations performed during different menstrual cycles meet the diagnostic criteria for EPs, a recurrence will be recorded, and the participant will be withdrawn from the study. If no recurrence is detected by transvaginal ultrasonography during follow-up and the participant does not meet any withdrawal criteria, follow-up will continue until 24 months postoperatively. The study will end once the last enrolled participant across all study centres completes their final follow-up visit. For participants with ultrasound-indicated recurrence within 3 months after surgery, the possibility of incomplete resection during TCRP cannot be ruled out, despite adherence to a standardised surgical protocol—particularly when recurrence is observed at the same anatomical location. These cases will be further evaluated during data analysis to assess their potential impact on study outcomes. Based on this assessment, a decision will be made regarding whether to exclude these participants from the final analysis. AUB and menstrual status (including cycle length, duration and volume) will be monitored during postoperative follow-up visits and recorded in the CRF. If AUB causes severe anaemia requiring additional surgical intervention and the withdrawal criteria are met, the study will be terminated early for that participant. Participants who discontinue the study early will undergo a post-treatment visit, which includes routine follow-up assessments and gynaecological examinations. To streamline patient management across multiple centres while ensuring patient privacy, all participants will be assigned a unique SID number on enrolment. At each centre, two research assistants will independently enter all collected data into the online data management system using a double-entry method. Before conducting descriptive and statistical analyses, data checks, such as CRF reviews and double verification of raw data, will be performed to ensure accuracy. Access to the dataset will be restricted to the clinical trial management team and the Data Safety and Monitoring Committee (DSMC). Serious AEs will be reported to an independent DSMC, which will provide recommendations on whether to continue, modify or terminate the intervention. Throughout the study, the dataset will be identified, analysed and archived using SID numbers to safeguard individual privacy. To calculate the sample size for two independent samples, the following formula is typically employed: N = ((Zα/2+Zβ) 2 * (P1(1 − P1) + P2(1 − P2))/(P1 − P2) 2 ). N denotes the sample size required for each group. Zα/2 represents the Z value associated with the first type error rate (α). For α=0.05, Zα/2 is typically 1.96 (for a two-sided test). Zβ is the Z value associated with the power of the test (1 − β). For a test power of 0.8, Zβ is approximately 0.84. P1 represents the event rate in the intervention group. The efficacy of suppository dydrogesterone in preventing EP recurrence aligns with that of LNG-IUS, with EP recurrence rate in the dydrogesterone group set at 0.05. 2 P2 is the event rate in the control group, with the EP recurrence rate in the control group set at 0.2 based on similar reports in the literature. 2 Using these values, the calculated sample size is 73 cases per group, resulting in a total of 146 cases. Accounting for a 20% dropout rate, the required sample size increases to 184 cases, with 92 cases in each group. The primary outcome, which is the recurrence rate of intrauterine polyps, will be compared between the groups using an independent samples t-test or the Mann-Whitney U test, depending on the data distribution. Survival analysis will be performed for the experimental and control groups based on the time to polyp recurrence. Secondary outcomes, including AUB and menstrual irregularities, will be analysed using similar methods. Subgroup analyses will be performed to evaluate the effect of patient characteristics (age, number of polyps and preoperative endometrial thickness) on treatment effectiveness. Interaction tests will be used to examine the differences in treatment effects across the subgroups. Multivariate regression models will be used to assess and adjust for potential confounding factors. These models will include key baseline variables, such as patient age, body mass index (BMI), baseline endometrial thickness and use of energy instruments during TCRP. Multiple imputation methods will be used to address missing data and reduce potential bias. All statistical analyses will be two-tailed, with statistical significance set at p<0.05. Statistical analyses will be performed using the SPSS software V.20.0 (IBM, New York, USA). Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research. All research procedures adhere to the latest version of the Declaration of Helsinki ( https://www.wma.net/policies-post/wma-declaration-of-helsinki ). This study has been approved by the Ethics Committee of the Women’s Hospital, School of Medicine, Zhejiang University (IRB-20240077-R). During the screening process, the participants will be informed of the study’s aim, inclusion criteria, research protocol, potential risks and expected benefits. All eligible participants who agree to participate will provide informed consent prior to enrolment in this study. They will also be informed of the possibility of withdrawing from the study at any time without any repercussions. The findings of this study will be published in peer-reviewed scientific journals within 12 months of completion and presented at academic conferences and seminars.

This study is the first multicentre randomised controlled trial to evaluate the efficacy of oral dydrogesterone in preventing the recurrence of EPs and improving AUB symptoms following TCRP. EPs are benign growths in the uterine lining that can lead to AUB, infertility and diminished quality of life. Although TCRP is effective for the removal of polyps, recurrence remains a significant concern, highlighting the need for preventive strategies. The inclusion of 12 hospitals across China in this study strengthens the external validity and generalisability of our findings to a broader patient population, minimising biases linked to regional or institutional practices. The primary outcome of this study is EP recurrence after TCRP. Presently, key risk factors for EPs include perimenopausal or postmenopausal status, overweight, medications used to treat breast cancer (tamoxifen) and hormone therapy for menopausal symptoms. 1 4 6 However, risk factors for EP recurrence after TCRP remain unclear. Potential high-risk factors for EP recurrence include perimenopausal status, incomplete resection and long follow-up periods. 4 In a prospective study, multiple EPs, endometriosis and a history of TCRP were identified as significant risk factors for EP recurrence. 8 In contrast, in a previous retrospective study, we found no association between EP recurrence and variables such as age, polyp size, polyp number or history of polypectomy; instead, the identified risk factors for recurrence were similar to those for initial EP development. 2 A separate predictive model suggested that BMI, polyp diameter and the presence of polycystic ovary syndrome were significant risk factors for EP recurrence. 19 To minimise bias from these high-risk factors, we will exclude participants who have received steroid hormone therapy or tamoxifen within the past 3 months, those aged >46 years and those who became menopausal during the study. The lower limit for polyp size detected by ultrasound was set at 1 cm in the inclusion criteria, primarily based on the 2022 Chinese clinical guidelines, which identifies EPs ≥1 cm as an independent indication for surgical treatment. Patients with polyps of this size are more likely to undergo surgical management rather than receive medical therapy. Moreover, this threshold enhances the accuracy of ultrasound-based screening. At enrolment, we will record patients’ age and BMI, the presence of endometriosis and the polyp size and number. Then, we will assess whether statistically significant differences exist between the groups. In addition, we will perform multivariate analysis and subgroup stratification to explore potential high-risk factors for EP recurrence after TCRP. The secondary outcome of this study is AUB, which is a common symptom of EPs. 5 6 17 20 Although LNG-IUS insertion effectively prevents EP recurrence, the main AE is AUB. 2 Weight gain, ovarian cyst formation and AUB are the common AEs of LNG-IUS insertion. 21 Moreover, 36% of patients remove the LNG-IUS within 2 years because of these AEs, 22 thus limiting long-term benefits. 23 In contrast, we will use oral dydrogesterone in the present study to prevent EP recurrence post-TCRP, thereby avoiding adverse bleeding associated with the LNG-IUS. The duration of the oral dydrogesterone intervention in this study will be kept short intentionally to minimise the impact of long-term progestogen therapy on patients. As a secondary outcome, postoperative AUB symptoms in patients after TCRP will be recorded to assess whether oral dydrogesterone intervention effectively alleviates these symptoms. This study has some limitations. Owing to the nature of the intervention, the design cannot be blinded to either the participants or researchers involved in this study. EP recurrence will be assessed using two repeat transvaginal ultrasound examinations instead of office hysteroscopy, which is the gold standard for diagnosing EPs. 5 However, office hysteroscopy is invasive and unavailable at all centres. To maximise patient enrolment, transvaginal ultrasonography, despite its lower specificity, will be used as the standard diagnostic tool. To further reduce bias, a protocol will require two separate ultrasound examinations at different menstrual cycles, with positive results in both confirming EP recurrence. Furthermore, while superior imaging methods such as saline-infused sonohysterography and three-dimensional ultrasonography exist, variability in ultrasound equipment across centres necessitates the use of transvaginal ultrasound. 5 6 CE is associated with a higher EP recurrence rate, with a rate of 26.6% reported within 1 year for patients with CE compared with 9.5% for those without CE, resulting in an overall rate of 14.2%. 8 CE diagnosis relies primarily on microscopic findings confirmed using CD138 immunohistochemistry, 24 which detects endometrial stromal plasma cells. Given the variability in the diagnostic criteria across centres, 25 coexisting CE will not be assessed in this study, which may introduce bias. Similarly, some molecular biomarkers, such as the matrix metalloproteinase-9/tissue inhibitor of metalloproteinase-1, hypoxia-inducible factor-1α and platelet-derived growth factor may independently predict EP recurrence after TCRP. 26 However, since not all centres can detect these biomarkers, they were excluded from the analysis, which may also introduce bias. Additionally, while HTRS offers clinical and surgical advantages over traditional electroresection, its use is limited in low-income settings. 6 Notably, many guidelines recommend bipolar electroresection 6 ; however, monopolar electroresection appears to be associated with a lower recurrence rate. 7 To maximise case enrolment, surgical methods will not be restricted in this study. A subgroup analysis based on surgical techniques will be performed to minimise bias. In conclusion, this study offers valuable insights into the optimal management of EP recurrence through a multicentre randomised controlled trial, emphasising the potential benefits of dydrogesterone in clinical practice. These findings may inform future research and the development of standardised guidelines for managing EPs. This study is currently ongoing, with the first participant enrolled on 17 September 2024. The remaining participants are being actively recruited. The study protocol is based on V.1.2, 1 May 2024, with participant recruitment commencing on 22 April 2024. Enrolment is expected to be completed by 31 December 2024.