A Novel Intrauterine Estrogen-Releasing System for Preventing the Postoperative Recurrence of Intrauterine Adhesion: A Multicenter Randomized Controlled Study

A Novel Intrauterine Estrogen-Releasing System for Preventing the Postoperative Recurrence of Intrauterine Adhesion: A Multicenter Randomized Controlled Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Novel Intrauterine Estrogen-Releasing System for Preventing the Postoperative Recurrence of Intrauterine Adhesion: A Multicenter Randomized Controlled Study Limin Feng, Yun Sun, Songying Zhang, Yonghong Qian, Suping Fang, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4016027/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Sep, 2024 Read the published version in BMC Medicine → Version 1 posted 12 You are reading this latest preprint version Abstract Background Transcervical resection of adhesions (TCRA) is the standard treatment for intrauterine adhesion (IUA). Previous studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can slowly release estrogen within the uterine cavity. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUAs. Methods This was a prospective randomized controlled multicenter 2-arm parallel trial that included patients who were diagnosed with moderate to severe IUA and who received TCRA. A total of 250 patients were randomly assigned, at a 1:1 ratio, to receive the intrauterine estrogen-releasing system or a Foley catheter balloon combined with oral estrogen therapy after surgery. The primary outcome was the rate of adhesion remission in the two groups. The secondary outcomes included endometrial thickness at the period of ovulation, menstrual improvement rates, serum estradiol levels, pregnancy rates, and other reported adverse events during follow-up. t test, chi-squared, Fisher’s exact probability tests and Cochran-Mantel-Haenszel test were used to assess the data in this research. Results At 60 days postoperatively, the rate of adhesion reduction was significantly greater in the experimental group than in the control group (93.33% vs. 58.56%, P<0.001). The endometrium of the experimental group was thicker than that of the control group (p<0.001). Consistently, the rate of improvement in menstruation was greater in the experimental group than in the control group (p=0.010). No grade 3-4 adverse events were found in the two groupsduring the one-year follow-up. Conclusion In the cohort of patients with moderate to severe IUA, the intrauterine estrogen-releasing system was more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system provides a new option for the management of IUA after surgery. Trial registration Registration number is NCT04972032. Date of registration: August 15, 2021. intrauterine adhesion estrogen releasing system recurrence transcervical resection of adhesions Background Intrauterine adhesion (IUA) is caused by irreversible damage to the endometrial basal layer such as infections or trauma. It is defined by the partial or total adhesion of the uterine walls, leading to partial or complete occlusion of the uterine cavity which may lead to amenorrhea, oligomenorrhea, dysmenorrhea, infertility, and miscarriage 1 . Currently, hysteroscopy followed by transcervical resection of adhesions (TCRA) under hysteroscopy is the standard diagnosis and treatment for IUA. However, postoperative re-adhesion is common, and preventing the recurrence of IUA remains a great challenge. The American Association of Gynecologic Laparoscopists (AAGL) and European Society of Gynecological Endoscopy (ESGE) guidelines recommend using cyclic estrogen-progestin therapy after TCRA to promote endometrial growth and repair 2 . Other strategies have also been used for preventing adhesion reformation after TCRA, including the placement of intrauterine devices (IUDs, e.g., Foley catheters, and heart-shaped Cook balloons), the use of biological gel materials or amniotic membranes, and stem cell therapy. However, there are some limitations of the current strategies, which do not yield satisfactory outcomes. For example, long-term high doses of oral estrogen increase the risk of breast cancer, endometrial cancer, venous thrombosis, etc. Intrauterine interventions also have imitations. The physical barrier area of the intrauterine contraceptive ring is limited, and the anterior and posterior walls of the uterus cannot be completely separated. Moreover, intrauterine contraceptive rings can lead to excessive inflammatory responses 1 , causing abnormal bleeding, uterine infections, entrapment, and uterine perforation. Other commonly used intrauterine devices such as balloons can compress the endometrium, causing ischemic damage. Furthermore, prolonged placement of extension tubes in the vagina may increase the risk of bacterial infections in the uterine cavity and cause discomfort during movement, reducing quality of life. Thus, balloons are not suitable for long-term use 3 . Biological gel materials, such as sodium hyaluronate gel, are also used as antiadhesion materials after hysteroscopic surgery. The results of a meta-analysis investigated the effects of sodium hyaluronate gel on IUA prevention. They found that sodium hyaluronate gel can effectively prevent the reoccurrence of mild IUA, but cannot effectively prevent adhesion recurrence in patients with severe IUA 4 . Moreover, sodium hyaluronate gel has a relatively rapid degradation rate, limiting its effectiveness for preventing adhesions to only 48–72 hours 5 . Consequently, sodium hyaluronate gel is only appropriate for early postoperative use. Amniotic membrane 6 and stem cells 7 are emerging strategies but are still in the early stages of research, and further testing is required to determine their effectiveness. Due to the high recurrence rate of IUA, oral estrogen treatment and intrauterine treatment are often used together in clinical practice to promote the proliferation of the endometrium when the surgical sites within the uterine cavity are physically isolated. Whether there is a device that combines the advantages of hormone treatment and an intrauterine physical barrier but does not cause adverse events during systemic treatment, such as the Mirena IUD, is unknown. Our team designed an intrauterine silicone rubber stent that can physically block the anterior and posterior walls of the uterus and prevent postoperative recurrence of adhesions. At the same time, a drug and delivery system are included in the silicone rubber, which continuously releases estradiol at a low dosage. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUAs. Methods Study design and participants This was a prospective randomized controlled multicenter 2-arm parallel trial. Between September 2020 and January 2022, patients were recruited from four academic tertiary care centers: Beijing Tiantan Hospital, Capital Medical University (Beijing City, China); Renji Hospital, Shanghai Jiaotong University School of Medicine (Shanghai City, China); Suzhou Municipal Hospital (Suzhou City, Jiangsu Province, China); and Sir Run Run Shaw Hospital (SRRSH), which is affiliated with the Zhejiang University School of Medicine (Hangzhou City, Zhejiang Province, China). The study was conducted according to the principles of the Declaration of Helsinki and approved by the ethics committees of all participating centers. Women were eligible if they were aged 18–40 years, diagnosed with moderate-to-severe IUA (American Fertility Society (AFS) score greater than or equal to 5 points) under hysteroscopy, and selected to receive the intrauterine estrogen-releasing system (experiment arm) or a Foley catheter balloon combined with oral estrogen therapy (control arm) after TCRA. Women were excluded if they were contraindicated for TCRA, used high-dose estrogen drugs within one month before surgery, or simultaneously suffered from genital tuberculosis, acute genital inflammatory disease, abnormal uterine bleeding, malignant tumors, or other systemic disease, such as chronic cardiocerebrovascular, liver, kidney, hematopoietic system, or psychiatric disorders. All enrolled participants provided written informed consent and agreed to the entire study protocol before the intervention. Randomization and blinding Eligible women were identified by the principal investigators in the participating centers and consented women were allocated in a 1:1 ratio to one of the two treatment arms. Enrollment at each center was performed with the use of blocks, and the participants were randomized for sample balance. SAS 9.4 software was used to generate a random assignment table. Because of the nature of the intervention, it was not possible to blind the participants or their treating doctors to the allocated treatment. Interventions TCRAs were performed by the same surgical team at each respective site (n = 4 teams total). After TCRA, the experimental group received a silicone rubber intrauterine stent system to prevent adhesion reformation, while the control group received a Foley catheter balloon combined with self-crosslinked sodium hyaluronate gel and cyclic estrogen-progestin therapy. In the experimental group, the silicone rubber intrauterine stent system was removed 60 days after TCRA, followed by a consecutive 5-day course of dydrogesterone at 20 mg/d. Sequential estrogen-progestin therapy was administered to the control group for two cycles following the TCRA, which consisted of continuous use of estradiol valerate tablets (6 mg/d) for the first cycle, followed by the addition of dydrogesterone tablets (20 mg/d) for the second half, or continuous use of estradiol valerate tablets for 60 days (6 mg/d), followed by dydrogesterone tablets (10 mg/d) for the last ten days (as dictated by surgical team preference). Outcome variables The primary outcome of this study was the rate of adhesion reduction at 60 days postoperatively. Adhesion reduction was defined as a decrease of ≥ 4 points based on AFS under hysteroscopy 8 . The severity of IUA is also evaluated by the criteria of the European Society of Gynecological Endoscopy (ESGE) classifications under hysteroscopy. The secondary outcomes were other efficacy and safety indicators, which included endometrial thickness at the period of ovulation, menstrual improvement rates, serum estradiol levels, daily estradiol release, pregnancy rates, and other reported adverse events during follow-up. Endometrial thickness (during the ovulation period) was evaluated through three-dimensional transvaginal ultrasound before and 60 days after surgery. Postoperative improvements in menstruation were assessed using the Pictorial Bleeding Assessment Chart (PBAC) score. Serum estradiol levels were evaluated at 24 h, 72 h, 14 days, 30 days, and 60 days postoperatively. The remaining drug content in the intrauterine stent was evaluated 60 days after surgery. The daily release amount was calculated as the total release amount divided by the number of days of implantation. Pregnancy rates were assessed 1-year post-surgery. Other adverse events including uterine perforation, postoperative bleeding, pain, genital tract infection, liver or kidney injuries, and coagulation abnormalities, were evaluated with CACTE 5.0 until 60 days postoperatively. Statistical analysis Statistical analysis was performed using SAS 9.4 statistical analysis software. All the statistical tests were two-tailed (unless otherwise specified), and a P value less than 0.05 was considered to indicate statistical significance. Mean differences were compared using paired t tests (when tests of normality and homogeneity of variance were satisfied), and categorical data were analyzed using chi-squared or Fisher’s exact probability tests (when a chi-squared test was inappropriate). Ranked data were analyzed using the Cochran-Mantel-Haenszel (CMH) test. Results Study population and baseline information A total of 250 patients (125 experimental patients and 125 control patients) were enrolled from the four participating sites. The baseline demographic and clinical characteristics of the two groups are shown in Table 1 . There were no statistically significant between-group differences in age, height, weight, preoperative AFS score, preoperative estradiol levels, or menstrual model (evaluated by the PBAC score). Additionally, there were no differences in preoperative endometrial thickness on the day of ovulation (4.32 ± 1.73 mm vs. 4.07 ± 1.46 mm in the experimental vs. control groups). Table 1 Baseline demographic and clinical characteristics Experimental group Control group P value Age (years) 33.45 ± 4.20 33.53 ± 3.47 0.858 Height (cm) 160.08 ± 5.40 160.02 ± 4.93 0.986 Weight (kg) 56.64 ± 8.11 57.56 ± 9.27 0.511 AFS score 8.30 ± 1.71 8.23 ± 1.74 0.851 Endometrial thickness (mm) 4.32 ± 1.73 4.07 ± 1.46 0.191 Serum estradiol (pg/mL) 94.57 ± 84.99 92.60 ± 84.29 0.489 After TCRA, the normalization rate of the uterine cavity was 100% in both groups, and all patients exhibited increased uterine volume. Both groups' AFS scores improved postoperatively, as assessed by hysteroscopy (Table 1 ). During the surgery, 3 patients (1 in the experimental group and 2 in the control group) who were not suitable for intrauterine device placement were evaluated. After surgery, 2 patients (1 in the experimental group and 1 in the control group) experienced the loss of the intrauterine device. Efficacy of the intrauterine estrogen-releasing system At 60 days post-surgery, 94.3% of the patients (231 of 245) completed the follow-up hysteroscopic evaluation, 120 of whom were in the experimental group and 111 of whom were in the control group. Fourteen patients (2 in the experimental group and 12 in the control group) did not undergo 60 days of hysteroscopy for the COVID-19 pandemic. The reduction in the number of adhesions was significantly greater in the experimental group (93.33%, 112/120) than in the control group (58.56%, 65/111) (P < 0.001). The degree of improvement was greater in the experimental group (-6.06 ± 2.01) than in the control group (-4.00 ± 2.45) (P < 0.001). The classification based on the ESGE grading system also validated the results: 44.17% of patients in the experimental group exhibited no adhesions (53/120), while 19.82% of patients in the control group exhibited no adhesions (22/111) (P < 0.001) (Table 2 ). Table 2 Efficacy outcomes Experimental group Control group P value AFS score (60 days post-surgery) 2.24 ± 2.14 4.23 ± 2.86 < 0.001 Reduction in adhesions (60 days post-surgery) 112(93.33%) 65(58.56%) < 0.001 Number (percentage) no adhesion (60 days post-surgery) 53(44.17%) 22(19.82%) < 0.001 Number (percentage) ESGE Grade I (60 days post-surgery) 27(22.50%) 26(23.42%) Number (percentage) ESGE Grade II (60 days post-surgery) 26(21.67%) 40(36.04%) Number (percentage) ESGE Grade III (60 days post-surgery) 9(7.50%) 12(10.81%) Number (percentage) ESGE Grade IV (60 days post-surgery) 2(1.67%) 6(5.41%) Number (percentage) ESGE Grade Va (60 days post-surgery) 2(1.67%) 4(3.60%) Number (percentage) ESGE Grade Vb (60 days post-surgery) 1(0.83%) 1(0.90%) Endometrial thickness (60 days post-surgery) (mm) 8.58 ± 7.43 4.87 ± 2.49 < 0.001 Number (percentage) menstrual improvement (60 days post-surgery) 68(56.67%) 44(39.64%) 0.010 Number (percentage) total pregnancy rate 38(31.67%) 28(25.23%) 0.279 Number (percentage) natural pregnancy rate 21(17.50%) 15(13.50%) 0.404 Number (percentage) assisted reproductive pregnancy rate 17(14.20%) 13(11.70%) 0.579 Number (percentage) repeat TCRA 10(10.42%) 12(12.63%) 0.632 Both groups underwent ultrasound evaluation of endometrial thickness during ovulation before and 60 days postoperatively. The experimental group had a significantly thicker endometrium (8.46 ± 7.37 mm) than did the control group (4.84 ± 2.48 mm) (P < 0.001). The rate of improvement in menstruation was also greater in the experimental group than in the control group (56.67% vs. 39.64%, p = 0.01). After 12 months of follow-up, 10 patients (10.42%) in the experimental group and 12 patients (12.63%) in the control group underwent repeat TCRA (P = 0.632). The pregnancy rate was 31.67% (38/120) in the experimental group and 25.23% (28/111) in the control group (P = 0.279). Safety of the intrauterine estrogen-releasing system None of the patients experienced severe postoperative complications during the one-year follow-up. The average daily drug release amount for all the tested stents was 0.21 mg/d. Serum estradiol levels were monitored at 24 hours, 72 hours, and 14 days postoperatively and the estradiol levels were significantly greater in the experimental group than in the control group (P > 0.05). No grade 3–4 adverse events were found in the two groups during the one-year follow-up on postoperative bleeding, pain, genital tract infections, device-related adverse events, or laboratory tests (Table 3 ). Table 3 Serum estradiol levels over time (pg/mL) Experimental group Control group P value baseline 94.57 ± 84.99 92.60 ± 84.29 0.489 24 hours post-surgery 806.70 ± 283.88 149.35 ± 118.18 < 0.001 72 hours post-surgery 697.50 ± 253.61 185.90 ± 111.26 < 0.001 14 days post-surgery 262.12 ± 240.12 214.08 ± 204.47 0.001 30 days post-surgery 143.54 ± 71.47 166.08 ± 149.99 0.948 60 days post-surgery 119.83 ± 101.28 113.13 ± 80.49 0.271 Discussion Studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can slowly release estrogen within the uterine cavity. In this study, we found that this estrogen-releasing intrauterine system is more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. To our knowledge, this is the first study on the use of intrauterine estrogen-releasing system for the management of IUA after surgery. IUA treatment usually involves surgery, preventing postoperative adhesions, promoting endometrial regeneration, and postoperative assessment of treatment efficacy, considering the etiology and risk factors associated with IUA. TCRA is the preferred surgical method for IUA. However, the high rate of adhesion reformation (up to 62.5%) after TCRA is concerning 9 . Various IUDs, including intrauterine contraceptive devices, Foley catheter balloons, and sodium hyaluronate gel, have been used to prevent postoperatively adhesion reformation. These devices serve as physical barriers and can act as carriers for certain agents that promote endometrial regeneration, such as estrogen and stem cells 10 . Estrogen can bind to estrogen receptors on the endometrium, effectively promoting regeneration of the damaged endometrium and the formation of new blood vessels 11 . Clinical and preclinical evidence suggests that the use of estrogen in patients with IUA reduces IUA recurrence and increases pregnancy rates. In current clinical practice, a common approach for preventing adhesion reformation is the combination of a Foley catheter balloon and oral estrogen therapy. However, this method has limitations, including low drug concentrations reaching the endometrium and poor patient compliance due to the need for prolonged oral estrogen therapy. In this randomized controlled trial (RCT), a single intrauterine slow-release device was investigated as an alternative treatment that has better compliance and is more effective than traditional methods in reducing adhesions after TCRA. Oral estrogen therapy, such as 17β-estradiol, is typically nonspecific and occurs at low concentrations in the target tissues. To address these limitations, many methods of local administration have been explored to improve the efficacy of estrogen therapy. Local administration, such as vaginal estrogen therapy, is often an ideal approach for treating atrophic vaginitis because of its lower dosage, longer treatment time, and fewer side effects than oral medications 12 . Vaginal estrogen therapy has been commonly used for preparing the endometrium for embryo transfer. Furthermore, intrauterine stents can deliver estrogen directly into the uterine cavity, thereby targeting the endometrium. Strategies such as poly (2-hydroxyethyl methacrylate) (pHEMA) hydrogel stents 13 have been developed to release estradiol to the uterine region. The intrauterine estrogen-releasing system in our study can deliver estrogen locally at a rate of 0.21 mg/day, providing a much lower dose than oral administration (6 mg/day). Endometrial thickness undergoes cyclic changes during the menstrual cycle and thus is an important indicator of endometrial receptivity 14 . We found that the intrauterine estrogen-releasing system could be more effective at promoting endometrial proliferation than oral estrogen, which results in a thicker endometrium. A greater percentage of patients in the experimental group than in one-year follow-up (31.67% vs. 25.23%). The relatively low pregnancy rate may be due to the short follow-up (one year after treatment). Long-term follow-up helps to investigate the effect of this intrauterine system on the pregnancy rates and fertility outcomes of patients. Compared to those after oral administration of the same dosage and preparation, average serum E2 levels were approximately 10 times greater, and average endometrial E2 concentrations were approximately 70 times graeter after vaginal administration 15 . A previous study suggested that estrogen receptors are highly expressed in patients with IUA 16 , potentially due to decreased estrogen concentrations. However, with prolonged administration, there were no significant differences in endometrial thickness between local and systemic administration. Amir et al. 17 reported that patients with serum E2 levels between 1001 and 1500 pg/mL, 1501 and 2000 pg/mL, and > 2000 pg/mL had significantly thicker endometrial linings than patients with serum E2 levels between 0 and 1000 pg/mL. Nevertheless, endometrial thickness did not significantly differ among these three groups. This study suggested that there is a threshold effect of serum estradiol on endometrial thickness. When the serum estradiol concentration exceeds a certain threshold, its dose-dependent effect on endometrial growth ceases. This may be due to the saturation of estrogen receptors on the endometrium when exposed to high-dose estrogen. The number of estrogen receptors in the endometrium may determine its growth potential. Under the influence of high-dose estrogen, its effect may no longer depend on serum estradiol levels. Increased microvessel density in the endometrium can promote vascular dilation and relaxation, facilitating endometrial regeneration and functional recovery 18 . However, after damage to the basal layer of the endometrium, small vessels that nourish the endometrium may also be impaired. In such cases, despite normal serum estrogen levels, estrogen cannot be effectively transported to the endometrium through damaged endometrial vessels. Previous research revealed no differences in treatment efficacy or pregnancy rates between high-dose and low-dose oral estrogen therapy 19 . High-dose estrogen can overload and damage the liver and can lead to adverse effects in target organs, including breast pain, breast cancer, cervical thrombosis, and even endometrial fibrosis 20 . The adverse effects mentioned above do not occur when serum estradiol levels are greater than 1000 pg/ml for 2 weeks 15 , 21 . Peak serum estradiol levels occurred on days 1–3 and were approximately 800 pg/ml after the use of the new estrogen sustained-release stent, which further supports its safety. Short-term high-dose estrogen therapy may promote endometrial proliferation. However, after postoperative day 14, the serum estrogen levels of the experimental group decreased and were similar to those of the control group. Compared to those in the control group, no intrauterine estrogen stent-related adverse events were found at the one-year follow-up in this study. In conclusion, our study reports an intrauterine estrogen-releasing system for the management of IUA after TCRA that combines the advantages of estrogen treatment and an intrauterine stent. The results showed that the intrauterine estrogen-releasing system is more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system is tolerable and provides a new option for the management of this population. Abbreviations TCRA Transcervical resection of adhesions IUA intrauterine adhesion AAGL The American Association of Gynecologic Laparoscopists ESGE European Society of Gynecological Endoscopy AFS American Fertility Society PBAC Pictorial Bleeding Assessment Chart CMH Cochran-Mantel-Haenszel RCT Randomized controlled trial Declarations Acknowledgments We would like to thank the Clinical Research Institute of Peking University for the statistical analysis. We would like to thank the anonymous reviewers for their constructive comments. Authors’ contributions Limin Feng, Yun Sun, Songying Zhang and Yonghong Qian conceived and designed the study. Limin Feng and Yun Sun supervised the study and data analysis. Limin Feng, Yun Sun, Songying Zhang and Yonghong Qian performed the operation as the lead surgeons. Suping Fang, Baojun Yang Lizhen Xu, Jinghua Li, Yichao Niu, Shengpeng Zhang, Luping Zhang and Jianmin Chen assisted in analyzing the data and the operation. Limin Feng and Yun Sun wrote the manuscript. All authors revised and approved the final manuscript. Funding The funding for the study was provided by YiPuRun(Shanghai)Biotechnology Co.,Ltd. No pharmaceutical manufacturers or other companies from the industry contributed to the planning, design, or conduct of the trial. Availability of data and materials The datasets generated during and/or analyzed during the current study are available from the corresponding authors upon request. Ethics approval and consent to participate This study was approved by the Ethics Committee of Beijing Tiantan Hospital affiliated to Capital Medical University on October 22, 2019. The ethics Committee approval number is QX2019-008-02. All participants enrolled in the present trial provided written informed consent. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. References Salazar CA, Isaacson K, Morris S. 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A cohort study comparing 4 mg and 10 mg daily doses of postoperative estradiol therapy to prevent adhesion reformation after hysteroscopic adhesiolysis. Hum Fertil Camb Engl. 2019;22(3):191–7. 10.1080/14647273.2018.1444798 . Ge J, Chen Y, Yang H, Zhao J, Ren D, Wu X. Expression and significance of estrogen receptor and progesterone receptor in endometrial tissue of patients with intrauterine adhesions. Gland Surg. 2021;10(4):1478–86. Fanchin R, Righini C, Schönauer LM, Olivennes F, Cunha Filho JS, Frydman R. Vaginal versus oral E(2) administration: effects on endometrial thickness, uterine perfusion, and contractility. Fertil Steril. 2001;76(5):994-8. 10.1016/s0015-0282(01)02841-2 . PMID: 11704123. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4016027","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276470358,"identity":"5756fcf2-3ac5-4244-a5dc-1abc85e41da4","order_by":0,"name":"Limin Feng","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYBAC+wNAogKI+ZmZDz8gSosBiDgDxJLtbGkGpGkxOM+jIEGcFonkZxIHKu7YbT7MA9RfYxNNUIu9RJqZxIEzz5K3HeY98IDhWFpuA2FbctikP7YdTjY7zJdgwNhwmDgtEgf/HU42buYxkCBBS8NhOwNmorXwPDO2OHDscILEYWAgJxDlF/bkhzcO1By25+8/fPjBhxobwlqAgAUUHYlglQlEKAcB5g9Awp5IxaNgFIyCUTASAQD4h0Bdu1ZD8gAAAABJRU5ErkJggg==","orcid":"","institution":"Beijing Tiantan Hospital Affiliated to Capital Medical University","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Limin","middleName":"","lastName":"Feng","suffix":""},{"id":276470359,"identity":"6c3aaca2-a05c-4ab3-9087-b17b5908f0b3","order_by":1,"name":"Yun Sun","email":"","orcid":"","institution":"Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yun","middleName":"","lastName":"Sun","suffix":""},{"id":276470360,"identity":"d2894cda-3464-41d2-814e-96e4ee1f0cc2","order_by":2,"name":"Songying Zhang","email":"","orcid":"","institution":"Shaw Hospital Affiliated to Zhejiang University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Songying","middleName":"","lastName":"Zhang","suffix":""},{"id":276470361,"identity":"6612c237-1420-4294-8227-c0f5b64d9354","order_by":3,"name":"Yonghong Qian","email":"","orcid":"","institution":"Suzhou Municipal Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yonghong","middleName":"","lastName":"Qian","suffix":""},{"id":276470362,"identity":"59414a46-7dae-41ac-9ae4-db0e31f796d9","order_by":4,"name":"Suping Fang","email":"","orcid":"","institution":"Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Suping","middleName":"","lastName":"Fang","suffix":""},{"id":276470363,"identity":"11f8554e-6fa5-4985-8e95-7aa4e32ea04f","order_by":5,"name":"Baojun Yang","email":"","orcid":"","institution":"Beijing Tiantan Hospital Affiliated to Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Baojun","middleName":"","lastName":"Yang","suffix":""},{"id":276470364,"identity":"6bb04b58-2332-41de-abb0-468bf018151b","order_by":6,"name":"Lizhen Xu","email":"","orcid":"","institution":"Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Lizhen","middleName":"","lastName":"Xu","suffix":""},{"id":276470365,"identity":"b29e8ae2-3eaa-4a8e-bcde-82c3635de823","order_by":7,"name":"Jinghua Li","email":"","orcid":"","institution":"Beijing Tiantan Hospital Affiliated to Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jinghua","middleName":"","lastName":"Li","suffix":""},{"id":276470366,"identity":"3e28db0d-0f71-4192-a352-6ff922b43bac","order_by":8,"name":"Yichao Niu","email":"","orcid":"","institution":"Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yichao","middleName":"","lastName":"Niu","suffix":""},{"id":276470367,"identity":"d8c7e3b9-46c3-4036-b6f7-adcd30f1ac2e","order_by":9,"name":"Shengpeng Zhang","email":"","orcid":"","institution":"Beijing Tiantan Hospital Affiliated to Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Shengpeng","middleName":"","lastName":"Zhang","suffix":""},{"id":276470368,"identity":"ab9c5789-8eaf-4740-8033-3d2c7a59a011","order_by":10,"name":"Luping Zhang","email":"","orcid":"","institution":"Beijing Tiantan Hospital Affiliated to Capital Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Luping","middleName":"","lastName":"Zhang","suffix":""},{"id":276470369,"identity":"666c25ca-0867-41f6-9a5b-8a76fd6a1eb5","order_by":11,"name":"Jianmin Chen","email":"","orcid":"","institution":"Shaw Hospital Affiliated to Zhejiang University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jianmin","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-03-05 08:44:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4016027/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4016027/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12916-024-03608-4","type":"published","date":"2024-09-16T15:58:07+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":65104138,"identity":"aabac327-36e5-4df3-87c1-d3a55d35d81b","added_by":"auto","created_at":"2024-09-23 16:12:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":505421,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4016027/v1/e1783661-9da6-4906-8d50-02c3455c7ee0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Novel Intrauterine Estrogen-Releasing System for Preventing the Postoperative Recurrence of Intrauterine Adhesion: A Multicenter Randomized Controlled Study","fulltext":[{"header":"Background","content":"\u003cp\u003eIntrauterine adhesion (IUA) is caused by irreversible damage to the endometrial basal layer such as infections or trauma. It is defined by the partial or total adhesion of the uterine walls, leading to partial or complete occlusion of the uterine cavity which may lead to amenorrhea, oligomenorrhea, dysmenorrhea, infertility, and miscarriage \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Currently, hysteroscopy followed by transcervical resection of adhesions (TCRA) under hysteroscopy is the standard diagnosis and treatment for IUA. However, postoperative re-adhesion is common, and preventing the recurrence of IUA remains a great challenge.\u003c/p\u003e \u003cp\u003eThe American Association of Gynecologic Laparoscopists (AAGL) and European Society of Gynecological Endoscopy (ESGE) guidelines recommend using cyclic estrogen-progestin therapy after TCRA to promote endometrial growth and repair \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Other strategies have also been used for preventing adhesion reformation after TCRA, including the placement of intrauterine devices (IUDs, e.g., Foley catheters, and heart-shaped Cook balloons), the use of biological gel materials or amniotic membranes, and stem cell therapy. However, there are some limitations of the current strategies, which do not yield satisfactory outcomes. For example, long-term high doses of oral estrogen increase the risk of breast cancer, endometrial cancer, venous thrombosis, etc. Intrauterine interventions also have imitations. The physical barrier area of the intrauterine contraceptive ring is limited, and the anterior and posterior walls of the uterus cannot be completely separated. Moreover, intrauterine contraceptive rings can lead to excessive inflammatory responses \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e, causing abnormal bleeding, uterine infections, entrapment, and uterine perforation. Other commonly used intrauterine devices such as balloons can compress the endometrium, causing ischemic damage. Furthermore, prolonged placement of extension tubes in the vagina may increase the risk of bacterial infections in the uterine cavity and cause discomfort during movement, reducing quality of life. Thus, balloons are not suitable for long-term use \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Biological gel materials, such as sodium hyaluronate gel, are also used as antiadhesion materials after hysteroscopic surgery. The results of a meta-analysis investigated the effects of sodium hyaluronate gel on IUA prevention. They found that sodium hyaluronate gel can effectively prevent the reoccurrence of mild IUA, but cannot effectively prevent adhesion recurrence in patients with severe IUA\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Moreover, sodium hyaluronate gel has a relatively rapid degradation rate, limiting its effectiveness for preventing adhesions to only 48\u0026ndash;72 hours\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Consequently, sodium hyaluronate gel is only appropriate for early postoperative use. Amniotic membrane \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e and stem cells \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e are emerging strategies but are still in the early stages of research, and further testing is required to determine their effectiveness.\u003c/p\u003e \u003cp\u003eDue to the high recurrence rate of IUA, oral estrogen treatment and intrauterine treatment are often used together in clinical practice to promote the proliferation of the endometrium when the surgical sites within the uterine cavity are physically isolated. Whether there is a device that combines the advantages of hormone treatment and an intrauterine physical barrier but does not cause adverse events during systemic treatment, such as the Mirena IUD, is unknown. Our team designed an intrauterine silicone rubber stent that can physically block the anterior and posterior walls of the uterus and prevent postoperative recurrence of adhesions. At the same time, a drug and delivery system are included in the silicone rubber, which continuously releases estradiol at a low dosage. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUAs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design and participants\u003c/h2\u003e \u003cp\u003eThis was a prospective randomized controlled multicenter 2-arm parallel trial. Between September 2020 and January 2022, patients were recruited from four academic tertiary care centers: Beijing Tiantan Hospital, Capital Medical University (Beijing City, China); Renji Hospital, Shanghai Jiaotong University School of Medicine (Shanghai City, China); Suzhou Municipal Hospital (Suzhou City, Jiangsu Province, China); and Sir Run Run Shaw Hospital (SRRSH), which is affiliated with the Zhejiang University School of Medicine (Hangzhou City, Zhejiang Province, China). The study was conducted according to the principles of the Declaration of Helsinki and approved by the ethics committees of all participating centers.\u003c/p\u003e \u003cp\u003eWomen were eligible if they were aged 18\u0026ndash;40 years, diagnosed with moderate-to-severe IUA (American Fertility Society (AFS) score greater than or equal to 5 points) under hysteroscopy, and selected to receive the intrauterine estrogen-releasing system (experiment arm) or a Foley catheter balloon combined with oral estrogen therapy (control arm) after TCRA. Women were excluded if they were contraindicated for TCRA, used high-dose estrogen drugs within one month before surgery, or simultaneously suffered from genital tuberculosis, acute genital inflammatory disease, abnormal uterine bleeding, malignant tumors, or other systemic disease, such as chronic cardiocerebrovascular, liver, kidney, hematopoietic system, or psychiatric disorders. All enrolled participants provided written informed consent and agreed to the entire study protocol before the intervention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eRandomization and blinding\u003c/h2\u003e \u003cp\u003eEligible women were identified by the principal investigators in the participating centers and consented women were allocated in a 1:1 ratio to one of the two treatment arms. Enrollment at each center was performed with the use of blocks, and the participants were randomized for sample balance. SAS 9.4 software was used to generate a random assignment table. Because of the nature of the intervention, it was not possible to blind the participants or their treating doctors to the allocated treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eInterventions\u003c/h2\u003e \u003cp\u003eTCRAs were performed by the same surgical team at each respective site (n\u0026thinsp;=\u0026thinsp;4 teams total). After TCRA, the experimental group received a silicone rubber intrauterine stent system to prevent adhesion reformation, while the control group received a Foley catheter balloon combined with self-crosslinked sodium hyaluronate gel and cyclic estrogen-progestin therapy. In the experimental group, the silicone rubber intrauterine stent system was removed 60 days after TCRA, followed by a consecutive 5-day course of dydrogesterone at 20 mg/d. Sequential estrogen-progestin therapy was administered to the control group for two cycles following the TCRA, which consisted of continuous use of estradiol valerate tablets (6 mg/d) for the first cycle, followed by the addition of dydrogesterone tablets (20 mg/d) for the second half, or continuous use of estradiol valerate tablets for 60 days (6 mg/d), followed by dydrogesterone tablets (10 mg/d) for the last ten days (as dictated by surgical team preference).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eOutcome variables\u003c/h2\u003e \u003cp\u003eThe primary outcome of this study was the rate of adhesion reduction at 60 days postoperatively. Adhesion reduction was defined as a decrease of \u0026ge;\u0026thinsp;4 points based on AFS under hysteroscopy \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. The severity of IUA is also evaluated by the criteria of the European Society of Gynecological Endoscopy (ESGE) classifications under hysteroscopy.\u003c/p\u003e \u003cp\u003eThe secondary outcomes were other efficacy and safety indicators, which included endometrial thickness at the period of ovulation, menstrual improvement rates, serum estradiol levels, daily estradiol release, pregnancy rates, and other reported adverse events during follow-up.\u003c/p\u003e \u003cp\u003eEndometrial thickness (during the ovulation period) was evaluated through three-dimensional transvaginal ultrasound before and 60 days after surgery. Postoperative improvements in menstruation were assessed using the Pictorial Bleeding Assessment Chart (PBAC) score.\u003c/p\u003e \u003cp\u003eSerum estradiol levels were evaluated at 24 h, 72 h, 14 days, 30 days, and 60 days postoperatively. The remaining drug content in the intrauterine stent was evaluated 60 days after surgery. The daily release amount was calculated as the total release amount divided by the number of days of implantation.\u003c/p\u003e \u003cp\u003ePregnancy rates were assessed 1-year post-surgery. Other adverse events including uterine perforation, postoperative bleeding, pain, genital tract infection, liver or kidney injuries, and coagulation abnormalities, were evaluated with CACTE 5.0 until 60 days postoperatively.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed using SAS 9.4 statistical analysis software. All the statistical tests were two-tailed (unless otherwise specified), and a P value less than 0.05 was considered to indicate statistical significance. Mean differences were compared using paired t tests (when tests of normality and homogeneity of variance were satisfied), and categorical data were analyzed using chi-squared or Fisher\u0026rsquo;s exact probability tests (when a chi-squared test was inappropriate). Ranked data were analyzed using the Cochran-Mantel-Haenszel (CMH) test.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStudy population and baseline information\u003c/h2\u003e \u003cp\u003eA total of 250 patients (125 experimental patients and 125 control patients) were enrolled from the four participating sites. The baseline demographic and clinical characteristics of the two groups are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. There were no statistically significant between-group differences in age, height, weight, preoperative AFS score, preoperative estradiol levels, or menstrual model (evaluated by the PBAC score). Additionally, there were no differences in preoperative endometrial thickness on the day of ovulation (4.32\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73 mm vs. 4.07\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46 mm in the experimental vs. control groups).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline demographic and clinical characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExperimental group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e33.45\u0026thinsp;\u0026plusmn;\u0026thinsp;4.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e33.53\u0026thinsp;\u0026plusmn;\u0026thinsp;3.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.858\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight (cm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e160.08\u0026thinsp;\u0026plusmn;\u0026thinsp;5.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e160.02\u0026thinsp;\u0026plusmn;\u0026thinsp;4.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.986\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e56.64\u0026thinsp;\u0026plusmn;\u0026thinsp;8.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e57.56\u0026thinsp;\u0026plusmn;\u0026thinsp;9.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.511\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFS score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e8.30\u0026thinsp;\u0026plusmn;\u0026thinsp;1.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e8.23\u0026thinsp;\u0026plusmn;\u0026thinsp;1.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.851\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e4.32\u0026thinsp;\u0026plusmn;\u0026thinsp;1.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e4.07\u0026thinsp;\u0026plusmn;\u0026thinsp;1.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.191\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum estradiol (pg/mL)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e94.57\u0026thinsp;\u0026plusmn;\u0026thinsp;84.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e92.60\u0026thinsp;\u0026plusmn;\u0026thinsp;84.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAfter TCRA, the normalization rate of the uterine cavity was 100% in both groups, and all patients exhibited increased uterine volume. Both groups' AFS scores improved postoperatively, as assessed by hysteroscopy (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). During the surgery, 3 patients (1 in the experimental group and 2 in the control group) who were not suitable for intrauterine device placement were evaluated. After surgery, 2 patients (1 in the experimental group and 1 in the control group) experienced the loss of the intrauterine device.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy of the intrauterine estrogen-releasing system\u003c/h2\u003e \u003cp\u003eAt 60 days post-surgery, 94.3% of the patients (231 of 245) completed the follow-up hysteroscopic evaluation, 120 of whom were in the experimental group and 111 of whom were in the control group. Fourteen patients (2 in the experimental group and 12 in the control group) did not undergo 60 days of hysteroscopy for the COVID-19 pandemic. The reduction in the number of adhesions was significantly greater in the experimental group (93.33%, 112/120) than in the control group (58.56%, 65/111) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The degree of improvement was greater in the experimental group (-6.06\u0026thinsp;\u0026plusmn;\u0026thinsp;2.01) than in the control group (-4.00\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The classification based on the ESGE grading system also validated the results: 44.17% of patients in the experimental group exhibited no adhesions (53/120), while 19.82% of patients in the control group exhibited no adhesions (22/111) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eEfficacy outcomes\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExperimental group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAFS score (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.24\u0026thinsp;\u0026plusmn;\u0026thinsp;2.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.23\u0026thinsp;\u0026plusmn;\u0026thinsp;2.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReduction in adhesions (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e112(93.33%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e65(58.56%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) no adhesion (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53(44.17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(19.82%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\" morerows=\"6\" rowspan=\"7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) ESGE Grade I (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27(22.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26(23.42%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) ESGE Grade II (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26(21.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40(36.04%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) ESGE Grade III (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(7.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(10.81%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) ESGE Grade IV (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(1.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(5.41%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) ESGE Grade Va (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2(1.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4(3.60%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) ESGE Grade Vb (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1(0.83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1(0.90%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEndometrial thickness (60 days post-surgery) (mm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8.58\u0026thinsp;\u0026plusmn;\u0026thinsp;7.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.87\u0026thinsp;\u0026plusmn;\u0026thinsp;2.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) menstrual improvement (60 days post-surgery)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68(56.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e44(39.64%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.010\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) total pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38(31.67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28(25.23%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.279\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) natural pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21(17.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15(13.50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.404\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) assisted reproductive pregnancy rate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17(14.20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13(11.70%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.579\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber (percentage) repeat TCRA\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10(10.42%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(12.63%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.632\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBoth groups underwent ultrasound evaluation of endometrial thickness during ovulation before and 60 days postoperatively. The experimental group had a significantly thicker endometrium (8.46\u0026thinsp;\u0026plusmn;\u0026thinsp;7.37 mm) than did the control group (4.84\u0026thinsp;\u0026plusmn;\u0026thinsp;2.48 mm) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The rate of improvement in menstruation was also greater in the experimental group than in the control group (56.67% vs. 39.64%, p\u0026thinsp;=\u0026thinsp;0.01).\u003c/p\u003e \u003cp\u003eAfter 12 months of follow-up, 10 patients (10.42%) in the experimental group and 12 patients (12.63%) in the control group underwent repeat TCRA (P\u0026thinsp;=\u0026thinsp;0.632). The pregnancy rate was 31.67% (38/120) in the experimental group and 25.23% (28/111) in the control group (P\u0026thinsp;=\u0026thinsp;0.279).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety of the intrauterine estrogen-releasing system\u003c/h2\u003e \u003cp\u003eNone of the patients experienced severe postoperative complications during the one-year follow-up. The average daily drug release amount for all the tested stents was 0.21 mg/d. Serum estradiol levels were monitored at 24 hours, 72 hours, and 14 days postoperatively and the estradiol levels were significantly greater in the experimental group than in the control group (P\u0026thinsp;\u0026gt;\u0026thinsp;0.05). No grade 3\u0026ndash;4 adverse events were found in the two groups during the one-year follow-up on postoperative bleeding, pain, genital tract infections, device-related adverse events, or laboratory tests (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSerum estradiol levels over time (pg/mL)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExperimental group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eControl group\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ebaseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e94.57\u0026thinsp;\u0026plusmn;\u0026thinsp;84.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e92.60\u0026thinsp;\u0026plusmn;\u0026thinsp;84.29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.489\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e24 hours post-surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e806.70\u0026thinsp;\u0026plusmn;\u0026thinsp;283.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e149.35\u0026thinsp;\u0026plusmn;\u0026thinsp;118.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e72 hours post-surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e697.50\u0026thinsp;\u0026plusmn;\u0026thinsp;253.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e185.90\u0026thinsp;\u0026plusmn;\u0026thinsp;111.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e14 days post-surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e262.12\u0026thinsp;\u0026plusmn;\u0026thinsp;240.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e214.08\u0026thinsp;\u0026plusmn;\u0026thinsp;204.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e30 days post-surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e143.54\u0026thinsp;\u0026plusmn;\u0026thinsp;71.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e166.08\u0026thinsp;\u0026plusmn;\u0026thinsp;149.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.948\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e60 days post-surgery\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e119.83\u0026thinsp;\u0026plusmn;\u0026thinsp;101.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e113.13\u0026thinsp;\u0026plusmn;\u0026thinsp;80.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.271\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eStudies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can slowly release estrogen within the uterine cavity. In this study, we found that this estrogen-releasing intrauterine system is more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. To our knowledge, this is the first study on the use of intrauterine estrogen-releasing system for the management of IUA after surgery.\u003c/p\u003e \u003cp\u003eIUA treatment usually involves surgery, preventing postoperative adhesions, promoting endometrial regeneration, and postoperative assessment of treatment efficacy, considering the etiology and risk factors associated with IUA. TCRA is the preferred surgical method for IUA. However, the high rate of adhesion reformation (up to 62.5%) after TCRA is concerning\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Various IUDs, including intrauterine contraceptive devices, Foley catheter balloons, and sodium hyaluronate gel, have been used to prevent postoperatively adhesion reformation. These devices serve as physical barriers and can act as carriers for certain agents that promote endometrial regeneration, such as estrogen and stem cells\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Estrogen can bind to estrogen receptors on the endometrium, effectively promoting regeneration of the damaged endometrium and the formation of new blood vessels \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Clinical and preclinical evidence suggests that the use of estrogen in patients with IUA reduces IUA recurrence and increases pregnancy rates. In current clinical practice, a common approach for preventing adhesion reformation is the combination of a Foley catheter balloon and oral estrogen therapy. However, this method has limitations, including low drug concentrations reaching the endometrium and poor patient compliance due to the need for prolonged oral estrogen therapy. In this randomized controlled trial (RCT), a single intrauterine slow-release device was investigated as an alternative treatment that has better compliance and is more effective than traditional methods in reducing adhesions after TCRA.\u003c/p\u003e \u003cp\u003eOral estrogen therapy, such as 17β-estradiol, is typically nonspecific and occurs at low concentrations in the target tissues. To address these limitations, many methods of local administration have been explored to improve the efficacy of estrogen therapy. Local administration, such as vaginal estrogen therapy, is often an ideal approach for treating atrophic vaginitis because of its lower dosage, longer treatment time, and fewer side effects than oral medications \u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Vaginal estrogen therapy has been commonly used for preparing the endometrium for embryo transfer. Furthermore, intrauterine stents can deliver estrogen directly into the uterine cavity, thereby targeting the endometrium. Strategies such as poly (2-hydroxyethyl methacrylate) (pHEMA) hydrogel stents \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e have been developed to release estradiol to the uterine region. The intrauterine estrogen-releasing system in our study can deliver estrogen locally at a rate of 0.21 mg/day, providing a much lower dose than oral administration (6 mg/day). Endometrial thickness undergoes cyclic changes during the menstrual cycle and thus is an important indicator of endometrial receptivity \u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. We found that the intrauterine estrogen-releasing system could be more effective at promoting endometrial proliferation than oral estrogen, which results in a thicker endometrium. A greater percentage of patients in the experimental group than in one-year follow-up (31.67% vs. 25.23%). The relatively low pregnancy rate may be due to the short follow-up (one year after treatment). Long-term follow-up helps to investigate the effect of this intrauterine system on the pregnancy rates and fertility outcomes of patients.\u003c/p\u003e \u003cp\u003eCompared to those after oral administration of the same dosage and preparation, average serum E2 levels were approximately 10 times greater, and average endometrial E2 concentrations were approximately 70 times graeter after vaginal administration \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. A previous study suggested that estrogen receptors are highly expressed in patients with IUA \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e, potentially due to decreased estrogen concentrations. However, with prolonged administration, there were no significant differences in endometrial thickness between local and systemic administration. Amir et al. \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e reported that patients with serum E2 levels between 1001 and 1500 pg/mL, 1501 and 2000 pg/mL, and \u0026gt;\u0026thinsp;2000 pg/mL had significantly thicker endometrial linings than patients with serum E2 levels between 0 and 1000 pg/mL. Nevertheless, endometrial thickness did not significantly differ among these three groups. This study suggested that there is a threshold effect of serum estradiol on endometrial thickness. When the serum estradiol concentration exceeds a certain threshold, its dose-dependent effect on endometrial growth ceases. This may be due to the saturation of estrogen receptors on the endometrium when exposed to high-dose estrogen. The number of estrogen receptors in the endometrium may determine its growth potential. Under the influence of high-dose estrogen, its effect may no longer depend on serum estradiol levels. Increased microvessel density in the endometrium can promote vascular dilation and relaxation, facilitating endometrial regeneration and functional recovery \u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. However, after damage to the basal layer of the endometrium, small vessels that nourish the endometrium may also be impaired. In such cases, despite normal serum estrogen levels, estrogen cannot be effectively transported to the endometrium through damaged endometrial vessels. Previous research revealed no differences in treatment efficacy or pregnancy rates between high-dose and low-dose oral estrogen therapy \u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. High-dose estrogen can overload and damage the liver and can lead to adverse effects in target organs, including breast pain, breast cancer, cervical thrombosis, and even endometrial fibrosis \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. The adverse effects mentioned above do not occur when serum estradiol levels are greater than 1000 pg/ml for 2 weeks \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Peak serum estradiol levels occurred on days 1\u0026ndash;3 and were approximately 800 pg/ml after the use of the new estrogen sustained-release stent, which further supports its safety. Short-term high-dose estrogen therapy may promote endometrial proliferation. However, after postoperative day 14, the serum estrogen levels of the experimental group decreased and were similar to those of the control group. Compared to those in the control group, no intrauterine estrogen stent-related adverse events were found at the one-year follow-up in this study.\u003c/p\u003e \u003cp\u003eIn conclusion, our study reports an intrauterine estrogen-releasing system for the management of IUA after TCRA that combines the advantages of estrogen treatment and an intrauterine stent. The results showed that the intrauterine estrogen-releasing system is more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system is tolerable and provides a new option for the management of this population.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTCRA \u0026nbsp; Transcervical resection of adhesions\u003c/p\u003e\n\u003cp\u003eIUA \u0026nbsp; \u0026nbsp; \u0026nbsp; intrauterine adhesion\u003c/p\u003e\n\u003cp\u003eAAGL \u0026nbsp; The American Association of Gynecologic Laparoscopists\u003c/p\u003e\n\u003cp\u003eESGE \u0026nbsp; \u0026nbsp;European Society of Gynecological Endoscopy\u003c/p\u003e\n\u003cp\u003eAFS \u0026nbsp; \u0026nbsp; \u0026nbsp; American Fertility Society\u003c/p\u003e\n\u003cp\u003ePBAC \u0026nbsp; \u0026nbsp;Pictorial Bleeding Assessment Chart\u003c/p\u003e\n\u003cp\u003eCMH \u0026nbsp; \u0026nbsp; Cochran-Mantel-Haenszel\u003c/p\u003e\n\u003cp\u003eRCT \u0026nbsp; \u0026nbsp; \u0026nbsp;Randomized controlled trial\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank the Clinical Research Institute of Peking University for the statistical analysis. We would like to thank the anonymous reviewers for their constructive comments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLimin Feng, Yun Sun, Songying Zhang and Yonghong Qian conceived and designed the study. Limin Feng and Yun Sun supervised the study and data analysis. Limin Feng, Yun Sun, Songying Zhang and Yonghong Qian performed the operation as the lead surgeons. Suping Fang, Baojun Yang Lizhen Xu, Jinghua Li, Yichao Niu, Shengpeng Zhang, Luping Zhang and Jianmin Chen \u0026nbsp;assisted in analyzing the data and the operation. Limin Feng and Yun Sun wrote the manuscript. All authors revised and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe funding for the study was provided by YiPuRun(Shanghai)Biotechnology Co.,Ltd. No pharmaceutical manufacturers or other companies from the industry contributed to the planning, design, or conduct of the trial.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analyzed during the current study are available from the corresponding authors upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Beijing Tiantan Hospital affiliated to Capital Medical University on October 22, 2019. The ethics Committee approval number is QX2019-008-02. All participants enrolled in the present trial provided written informed consent.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSalazar CA, Isaacson K, Morris S. A comprehensive review of Asherman\u0026rsquo;s syndrome: causes, symptoms and treatment options. Curr Opin Obstet Gynecol. 2017;29(4):249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAAGL practice report. : practice guidelines on intrauterine adhesions developed in collaboration with the European Society of Gynaecological Endoscopy (ESGE). 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PMID: 11704123.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"intrauterine adhesion, estrogen, releasing system, recurrence, transcervical resection of adhesions","lastPublishedDoi":"10.21203/rs.3.rs-4016027/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4016027/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eTranscervical resection of adhesions (TCRA) is the standard treatment for intrauterine adhesion (IUA). Previous studies have shown that postoperative oral estrogen or an intrauterine physical barrier could reduce the recurrence of IUA by promoting the proliferation of the endometrium or inhibiting the reformation of adhesions. Our team designed an intrauterine stent that can slowly release estrogen within the uterine cavity. In this study, we aimed to investigate the efficacy and safety of the estrogen-releasing intrauterine system in preventing the recurrence of moderate to severe IUAs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eThis was a prospective randomized controlled multicenter 2-arm parallel trial that included patients who were diagnosed with moderate to severe IUA and who received TCRA. A total of 250 patients were randomly assigned, at a 1:1 ratio, to receive the intrauterine estrogen-releasing system or a Foley catheter balloon combined with oral estrogen therapy after surgery. The primary outcome was the rate of adhesion remission in the two groups. The secondary outcomes included endometrial thickness at the period of ovulation, menstrual improvement rates, serum estradiol levels, pregnancy rates, and other reported adverse events during follow-up. t test, chi-squared, Fisher’s exact probability tests and Cochran-Mantel-Haenszel test were used to assess the data in this research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eAt 60 days postoperatively, the rate of adhesion reduction was significantly greater in the experimental group than in the control group (93.33% vs. 58.56%, P\u0026lt;0.001). The endometrium of the experimental group was thicker than that of the control group (p\u0026lt;0.001). Consistently, the rate of improvement in menstruation was greater in the experimental group than in the control group (p=0.010). No grade 3-4 adverse events were found in the two groupsduring the one-year follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e In the cohort of patients with moderate to severe IUA, the intrauterine estrogen-releasing system was more effective at reducing adhesion than traditional oral estrogen combined with an intrauterine Foley catheter after TCRA. This novel intrauterine system provides a new option for the management of IUA after surgery.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e Registration number is NCT04972032. 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