Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis: study protocol for a multicenter, prospective, randomized controlled trial

Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis: study protocol for a multicenter, prospective, randomized controlled trial | 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 Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis: study protocol for a multicenter, prospective, randomized controlled trial Wenwen Wang, Xiangyi Ma, Wei Zhang, Zhiying Li, Yan Wang, Zhiying Yu, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.2.12204/v4 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 28 Apr, 2020 Read the published version in Trials → Version 4 posted 3 You are reading this latest preprint version Show more versions Abstract Background: To preserve fertility or integrity of organs was on the rise for the most women with adenomyosis. Adenomyomectomy is now a widely applied conservative surgery, however relapse is a serious problem after operation. Postoperative treatment, such as gonadotropin-releasing hormone agonist (GnRHa) has been suggested to result in reducing the recurrence rate in patients. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy of GnRHa for decreasing the postoperative recurrence rate. Method/Design：Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis is a multicenter, prospective, randomized controlled trial. The primary outcome is relapse accessed with Visual Analogue Scale (VRS) and Numeric Rating Scale (NRS), Pictorial blood loss assessment chart (PBAC) score and the size of uterus and lesion are measured by two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI). The secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, and adverse events, assessing by Short Form (36) Health Survey and Female Sexual Function index, serum follicle-stimulating hormone, estradiol levels and anti-muellerian hormone and so on. All these indexes are measured at 3, 6, 12, 18, 24, 30, 36 months after conservative surgery. Discussion：The result of this large multicenter randomized trial will provide evidence for one of the strategies of long-term management in focal adenomyosis after conservative operation. Internal Medicine Integrative & Complementary Medicine Translational Medicine focal adenomyosis adenomyomectomy relapse triptorelin acetate Figures Figure 1 Background Adenomyosis is a common gynecologic benign disorder characterized by aberrant presence of endometrial glands and stromal within the myometrium[1-3]. The main symptoms are dysmenorrhea, chronic pelvic pain, dyspareunia, abnormal uterine bleeding (especial for heavy menstrual bleeding) and infertility, which seriously affect quality of life and work productivity in reproductive women[4, 5]. Hysterectomy considered to be a radical therapy for patients, who were refractory or will not desire to preserve fertility[6, 7]. However, many patients in reproductive age are very sensitive to preserve their fertility and organs[8]. Medical treatments or conservative surgery were options. The former contains non-steroidal anti-inflammatory drugs or hormone regulating drugs, which can keep a hypoestrogenic state, like gonadotropin releasing hormone agonist (GnRHa), danazol, progestogens or oral contraceptive pills[9, 10]. Gonadotropin releasing hormone agonist was the best acceptable treatment for patients in the past 20 years[11]. Unfortunately, these medicines could just provisionally improve symptoms and often lead to serious side effects[12]. Therefore, conservative surgeries come to be another choice, according to the extent of the focus, surgical options were classified into adenomyomectomy (for localized adenomyosis) and partial adenomyomectomy (for diffuse adenomyosis)[4, 13]. The rate of pain relief was higher in focal adenomyosis patients than diffuse adenomyosis women after conservative operation[14]. However, different ratio of systematic relapse was the main issue for this treatment, due to the no clear cut line between focus and normal myometrial tissue[14]. How to control recurrence after surgery has become the current Priority. Recently, some researchers confirmed that surgical-medical treatment provides a more effective treatment option for the symptomatic relief in focal adenomyosis than surgical treatment alone in some prospective or retrospective studies[7, 15, 16]. However, there is still a lack of evidence from randomized controlled study as to confirm whether GnRH agonists could decline the recurrence rate after conservative surgery in women with focal adenomyosis. This study is a multicenter randomized parallel controlled trial comparing efficacy of triptorelin acetate in protecting for relapse of post-operative treatment in focal adenomyosis patients. Method/design 308 postoperative participants after complete excision of focal adenomyosis are randomly assigned 1:1 to treatment group (triptorelin acetate) and control group. Patients will be recruited at 10 hospitals across Midwest China. All research units have been approved by the ethics committees. Every patient will sign an informed consent prior to this study. This report follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline (Additional file 1). Inclusion criteria The inclusion criteria are as follows: Women aged ≥18 and ≤45 years; Women with pathological diagnosis focal adenomyosis; Women who accept complete excision of adenomyosis, did not take any steroid hormone therapy three months before surgery; Women who are health before and not pregnant; Women who can comply with the study procedures and give written informed consent. Exclusion criteria Women who are also participating in other clinical trials at the same time; Women who are concomitant with have been diagnosed with ovarian endometrioma, deep infiltrating endometriosis, multiple leiomyomas; Women with congenital uterine abnormalities such as uterine malformation (unicornis uterus, septate uterus, or duplex uterus) or acute genital inflammation or malignant tumor; Women who are pregnant; Women who were taken steroid hormone therapy three months before surgery; Women with hereditary disease, blood disease, liver and kidney dysfunction or malnutrition diseases that cause anemia; Women who cannot suffer from surgery or are allergic to triptorelin acetate; Women who are unable to comply with the study procedures and give written informed consent. Screening and enrolment Previous medical history and current medication status are reviewed with the standardized case report forms. A physical examination and imaging such as two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI) are performed. Laboratory measurements as serum follicle-stimulating hormone (FSH), Estradiol (E2), anti-muellerian hormone (AMH), cancer antigen 125 (CA125)，safety assays include blood routine, urine routine, liver function, renal function, hepatitis virus, HIV, syphilis, coagulation, electrocardiogram (ECG), x-rays are measured in the local department of study sites. Either laparoscopy or transabdominal surgery is performed to completely remove all clinically recognizable lesions in patients who are suspected as focal adenomyosis. Written informed consent will be obtained from the patients after operation. Quality of life, degree of pain and menstrual volume will be recorded using the Short Form (36) Health Survey (SF-36), Female Sexual Function Index (FSFI), pictorial blood loss assessment chart (PBAC) score, Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS) after confirming by histology. A schedule of enrollment, interventions, and assessment is provided as in the table below (Table 1). Adenomyomectomy Laparotomy, hysteroscopy or laparoscopy were all contained in this study. During the laparoscopy, patients are taken the lithotomy position under general anesthesia with endotracheal intubation. After sterilization, pneumoperitoneum was created with carbon dioxide gas at 13 mm Hg (Karl Storz GmbH & Co. KG, Tuttlingen, Germany). Surgery was performed with 4 trocars for surgical instruments. Supine position and median incision are suitable for laparotomy. Hysteroscopic surgery is conducted for type 0 or type 1 adenomyoma (Karl Storz GmbH & Co. KG, Tuttlingen, Germany). Surgical approach is adenomyomectomy. The principle of these surgical options included completely removal of clinical visible lesions, maintained the integrity of uterine wall and keep the integrity of the uterine cavity as much as possible. The length of the surgery, size of the focus, blood loss and the integrity of the uterine cavity should be kept in record. Interventions Simple randomization is used to assign qualified participants to surgery only group (Group A) and surgery plus GnRH agonist group (Group B) with a 1:1 ratio. GnRH agonist was used for intervention group, using 3.75mg intramuscular injection (Diphereline, Ipsen, France) at the first day of the menstruation after surgery, then once every four weeks for six courses. The sign and symptoms of hypoestrogenism, including hot flushes, night sweat, sleep disorder, abnormal emotion and osteoporosis, could be caused by GnRH agonist, which should be carefully evaluated and could be treated with Tibolone 1.25 mg per day as add-back therapy to maintain estradiol at 30-50 pg/ml[17]. When intolerable adverse reaction is occurred on Group B patients, intervention will be discontinued or modified. Color doppler ultrasonography and steroid hormone test on the third and 6th month after conservative operation can help to monitor adherence. During the trial, other medication, such as use of steroid hormone or herbal medicine, or intervention, such as levonorgestrel-relesing intrauterine syste (LNG-IUS) will be prohibited. Randomization Eligible participants were assigned subjects to two groups with a 1:1 ratio simple randomization. The sequence of randomization has been set up by biostatisticians in data coordinator center with Microsoft Excel, using function of RAND (). The original sequence is safely kept by the staff in the data coordinator center, and it has been input into the online central randomization system by these staff members, who are not involved in enrolling subjects. The sequence is not accessible to any investigators or study coordinators. If a subject fulfills the enrollment criteria, the authorized study coordinator will get the assignment for her. After randomization, both subjects and investigators are informed about the assignments. Outcome and outcome assessments The primary outcome is relapse, which defines as recurrence of dysmenorrhea or pelvic pain or menorrhagia or 2D/3D-CDUS / MRI confirmed local recurrence compared to the first follow up time after surgery. Regarding imaging relapse, maximal diameter of suspicious recrudescent focus increase > 1cm during the follow-up period, measuring by 2D/3D-CDUS or MRI. During the follow up, if a positive finding is found by the same imaging examination should be conducted as a further evidence. In addition, the VRS and NRS are applied for evaluation of dysmenorrhea or pelvic pain and the recurrence was defined as any rating (VRS and NRS) upgraded and participants asking for other medical treatments for symptom release at the same time during follow-up. PBAC score is used to predict coagulation disorders in women with menorrhagia and recurrence was defined as score > 100. The proportion of the recurrence at 3, 6, 9,12, 18, 24, 30, 36 months will be followed-up. The secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, and adverse events. The quality of life is assessed by SF-36 and FSFI, regarding as a measure of health status and sexual functioning in women. Ovarian reserve is evaluated by FSH, E 2 and AMH, the first two are measured before surgery and during the follow-up period at the beginning of the menstrual cycle unless during the treatment of triptorelin acetate. AMH can be measured at any time before and after operation at the time of follow-up. Difference in score for eight dimensions (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) of SF-36 and FSFI and mean value of FSH, E 2 and AMH for participants in each group at 3, 6, 9,12, 18, 24, 30, 36 months will be assessed for quality of life and ovarian reserve. The pregnancy intention, pregnancy rate and outcome are recorded in a standard case report form, including abortion, premature delivery, full-term production, to evaluate difference of pregnancy outcome in each treatment arm at 36 months. The follow-up procedure is acquired from the outpatient department records. Follow-up visits occur at 3, 6, 12, 18, 24, 30, 36 months after conservative surgery. Treatment-related adverse effects are monitored at each visit. Adverse events are any unfavorable medical occurrences associated with the subject’s participation in the research, whether considered related to the study intervention. Serious adverse events are events that are temporally associated with the subject’s participation in research that meet any of the following criteria: death, life-threatening, severely or permanently disabling, requiring in-patient hospitalization or prolongation of existing hospitalization, or any events deemed as serious by the local principal investigator. Difference in the proportion of patients for adverse events in each group would be assessed at 36 months. Data analysis Sample size calculation Based on a prospective study revealed a relapse rate for only surgery group was about 49%, and for surgery and GnRH agonist treatment group was 28.1%[7]. A two-tailed test with alpha set at 0.05 and 85% power is used to detect a minimum clinical meaningful difference between control and intervention groups. The minimal sample size is calculated as 139 for each group. In consideration of a dropout rate of 10%, we will totally recruit 308 subjects. Data collection Data are collected with a standard case report form. Data are de-identified before being input into the database. Regular study site monitor and database checking are performed to ensure the accuracy of data collected. The data management, monitoring and reporting of this study will comply with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines. Data analysis plan Data analysis and reporting will be conducted in accordance to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement, which were recorded in our flow chart (Fig. 1), including the number of eligible participants and lost to follow-up for various reasons. Data analysts will be blinded after assignment to interventions. Unblinding of a participant’s allocated intervention during the trial is permissible after blind verification and a submission of data locking proof by statistical analyst. Intention to treat, which is based on the initial treatment intent, will be used as a foundation in our analysis. Participants begin the treatment is part of the trial, whether they finish it or not. The characteristics at baseline will be described between control and intervention groups. Continuous data will be summarized by means and standard deviation with Wilcoxon rank sum test to identify differences of baseline characteristic between two groups. Categorical data will be described by number and percentages, using Pearson chi-square test to compare discrepancy between groups. The primary outcome measure is the recurrence rate between Group A and Group B after three years’ follow-up, which will be analyzed by Pearson chi-square test. For efficacy parameters, such as score of pelvic pain and dysmenorrhea, menstruation blood loss, size of uterus and lesion will be analyzed using generalized estimating equations (GEE) or mixed effects model repeated measures (MMRM) to account for correlations among these observations in different follow up points. The parameters from secondary outcomes contains SF-36, FSFI, pregnancy rate and pregnancy outcome are calculated during 36 months’ follow-up are using generalized estimating equations (GEE) or mixed effects model repeated measures (MMRM) analysis to compare differences between Group A and Group B at different time points. The number of participants with adverse events (AE) or serious adverse events (SAE) will be presented for each arm. We will not take any formal statistical testing. Dissemination The results of the study will be publicated in a peer-reviewed medical journal without use of professional writer. After agreement of the Steering Committee, source data will be shared available through national or international anonymised datasets. Discussion To preserve fertility or integrity of organs was on the rise for the number of women with adenomyosis. Compare with relapse after withdrawal of the medical treatment, adenomyomectomy was widely applied. The remission rate of dysmenorrhea or dyspareunia was 50%-94.7% after complete excision and improvement of menorrhagia was 25%-80%[18]. Nevertheless, a symptomatic or local recurrence of the condition remained exist. About 2.8%-13.95% patients were relapsed at the end of first year. 14.28%-49% participants would recurrent in 24 months[18]. Therefore, the long-term management after surgery was the main issue. Recently，AI Jama retrospectively analyzed 18 patients, accepting adenomyomectomy and GnRHa for 24 weeks, 15 of which had systematic improvement after one year’s follow-up [16]. Liu carried out an uncontrolled descriptive study of 186 women with pathologically proven adenomyoma, who underwent ultramini-laparoscopic adenomyomectomy and a 6-month course of goserelin acetate treatment. After 3 years’ follow-up, the rate of systematic recurrence was 9% [19]. Wang et al.’ prospective non-randomized study found a significant decline of relapse rate in surgical-medical treatment group at the end of 2-year follow-up [7]. However, our retrospective result showed no difference between control and intervention group at the end of first or second year. It is noteworthy that there was a significant difference between control and GnRH agonist group with symptomatic or imaging relapse at the end of 36 months’ follow-up. In other words, postoperative treatment might be applied to reduce long-term recurrence rate. If we should use the postoperative method to prevent from relapse in adenomyosis patients is still unknown. This is the first multicenter, prospective, randomized controlled trial, comparing the efficacy of GnRH agonist in reducing recurrence for focal adenomyosis patients who have had been suffered from adenomyomectomy. We cannot use blinding to trial participants and care providers due to the drug-induced amenorrhea and/ or series of side effect after GnRHa therapy, which will be easy for patients and doctors to speculate the treatments. The lack of blinding might cause substantial bias, especially for the subjective judgment of patients, like pain scoring in primary outcome. To solve this problem, we set up two types of pain scoring system to reduce the chance of subjective error judgment for patients. In addition, recurrence of dysmenorrhea is defined according to the patient's pain score and treatment change needs, which can better evaluate the progress after conservative treatment. We plan to enroll 308 subjects from 10 teaching hospitals in China. The enrollment began in March 2018. At the time of manuscript preparation, more than 90 subjects have been enrolled. The result of this large multicenter randomized trial will provide level I evidence for the strategy of long-term management for focal adenomyosis after conservative operation. Trial status The Protocol Version is Version 1.0; March 8, 2018. Recruitment began on March 8, 2018. The expected date for recruitment completion is November–October 2019. Abbreviations GnRH: Gonadotropin-releasing hormone; VRS: Visual Analogue Scale; NRS: Numeric Rating Scale; PBAC: Pictorial blood loss assessment chart; 2D/3D-CDUS: two/three-dimensional color doppler ultrasonography; MRI: magnetic resonance imaging; SF-36: Short Form (36) Health Survey; FSFI: Female Sexual Function index; FSH: follicle-stimulating hormone; E2: estradiol levels; AMH: anti-muellerian hormone; GEE: generalized e5stimating equations; MMRM: mixed effects model repeated measures Declarations Acknowledgements We thank all subjects and physicians for volunteering their time to this study. Funding This is an investigator-initiated study without any grant from commercial funding agencies. Availability of data and materials No additional data available Authors’ contributions WW, XM contributed to the study design and manuscript drafting and revising; SW designed the study, is on the Steering Committee and revised the manuscript; WZ, ZL, YW, ZY, CZ, LH, RL, HX, WW, QY, JW, MZ were involved in the study concept and design and revision of the manuscript. All authors read and approved the final manuscript. Competing interests The authors declare that they have no competing interests. Ethics approval and consent to participate Central ethical approval has been confirmed from the Tongji Hospital of Tongji Medical College of Huazhong University Medical Ethics Committee (ref approval no. TJ-IRB20180310) and we will not begin recruiting at other centres in the trial until local ethical approval has been obtained”. Written informed consent is obtained from the patients after screening. Consent for publication Not applicable Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Author details 1 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 2 Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China. 3 Department of Obstetrics and Gynecology, Affiliated Renhe Hospital, China Three Gorges University, Yichang, Hubei, China. 4 Maternal and Child Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. 5 Department of Obstetrics and Gynecology, Shenzhen Second People's Hospital, Shenzhen, China. 6 Department of Obstetrics and Gynecology, Taihe Hospital, Shiyan, Hubei, China. 7 Department of Obstetrics and Gynecology, Wuhan University Renmin Hospital, Wuhan, Hubei, China. 8 Department of Obstetrics and Gynecology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, Hubei, China. 9 Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. 10 Department of Obstetrics and Gynecology, Affiliated Luoyang Central Hospital, Zhengzhou University, Luoyang, Henan, China. 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Fertility and sterility. 2009;92(3):876-85. doi:10.1016/j.fertnstert.2008.07.1744. Streuli I, Dubuisson J, Santulli P, de Ziegler D, Batteux F, Chapron C. An update on the pharmacological management of adenomyosis. Expert Opin Pharmacother. 2014;15(16):2347-60. doi:10.1517/14656566.2014.953055. Hirata JD, Moghissi KS, Ginsburg KA. Pregnancy after medical therapy of adenomyosis with a gonadotropin-releasing hormone agonist. Fertility and sterility. 1993;59(2):444-5. Cheng MH, Wang PH. Uterine myoma: a condition amenable to medical therapy? Expert Opin Emerg Drugs. 2008;13(1):119-33. doi:10.1517/14728214.13.1.119. Tsui KH, Lee FK, Seow KM, Chang WC, Wang JW, Chen SU et al. Conservative surgical treatment of adenomyosis to improve fertility: Controversial values, indications, complications, and pregnancy outcomes. Taiwan J Obstet Gynecol. 2015;54(6):635-40. doi:10.1016/j.tjog.2015.05.003. Guo SW, Groothuis PG. Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Human reproduction update. 2018;24(5):577-98. doi:10.1093/humupd/dmy020. Osada H, Silber S, Kakinuma T, Nagaishi M, Kato K, Kato O. Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis. Reproductive biomedicine online. 2011;22(1):94-9. doi:10.1016/j.rbmo.2010.09.014. Grimbizis GF, Mikos T, Tarlatzis B. Uterus-sparing operative treatment for adenomyosis. Fertility and sterility. 2014;101(2):472-87. doi:10.1016/j.fertnstert.2013.10.025. Huang BS, Seow KM, Tsui KH, Huang CY, Lu YF, Wang PH. Fertility outcome of infertile women with adenomyosis treated with the combination of a conservative microsurgical technique and GnRH agonist: long-term follow-up in a series of nine patients. Taiwan J Obstet Gynecol. 2012;51(2):212-6. doi:10.1016/j.tjog.2012.04.008. Al Jama FE. Management of adenomyosis in subfertile women and pregnancy outcome. Oman Med J. 2011;26(3):178-81. doi:10.5001/omj.2011.43. Zupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C et al. Add-back therapy in the treatment of endometriosis-associated pain. Fertility and sterility. 2004;82(5):1303-8. doi:10.1016/j.fertnstert.2004.03.062. Younes G, Tulandi T. Conservative Surgery for Adenomyosis and Results: A Systematic Review. Journal of minimally invasive gynecology. 2017;25(2):265-76. doi:10.1016/j.jmig.2017.07.014. Liu WM, Chen CH, Chiu LH, Tzeng CR. Long-term follow-up of severely symptomatic women with adenomyoma treated with combination therapy. Taiwan J Obstet Gynecol. 2013;52(1):85-9. doi:10.1016/j.tjog.2012.12.002. Table 1 Table 1. schedule of screening, enrollment and assessment. Evaluation Screening Enrolment Time of follow-up after surgery (month) 3 6 12 18 24 30 36 Written consent √ Inclusion/exclusion criteria √ Medical history √ Physical exam √ Safety test (preoperative examination) √ 2D/3D-CDUS /MRI √ √ √ √ √ √ √ √ FSH, E2, AMH, CA125 √ √ √ √ √ √ √ √ Side effects √ √ √ √ √ √ √ VAS and NRS √ √ √ √ √ √ √ √ SF-36 and FSFI √ √ √ √ √ √ √ √ PBAC score √ √ √ √ √ √ √ √ Supplementary Files SPIRITChecklistforrandomisedstudies.doc newCONSORT2010checklist.pdf Cite Share Download PDF Status: Published Journal Publication published 28 Apr, 2020 Read the published version in Trials → Version 4 posted Editorial decision: Accept 28 Mar, 2020 Editor assigned by journal 24 Feb, 2020 Submission checks completed at journal 23 Feb, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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12:25:58","currentVersionCode":4,"declarations":"","doi":"10.21203/rs.2.12204/v4","doiUrl":"https://doi.org/10.21203/rs.2.12204/v4","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13063-020-04294-2","type":"published","date":"2020-04-28T20:41:33+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":536715,"identity":"8359f1fc-b85b-4fb2-a0c2-da80acb1ce06","added_by":"auto","created_at":"2020-02-24 17:46:13","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":48388,"visible":true,"origin":"","legend":"Flowchart of this study.","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/4a5c4273-90bd-4f8c-97c7-052e69404bea/v4/Fig 1.jpg"},{"id":13490224,"identity":"e45e19b2-b632-4bb4-be67-a0aed49f6c94","added_by":"auto","created_at":"2021-09-16 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17:46:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":120103,"visible":true,"origin":"","legend":"","description":"","filename":"newCONSORT2010checklist.pdf","url":"https://assets-eu.researchsquare.com/files/4a5c4273-90bd-4f8c-97c7-052e69404bea/v4/new CONSORT 2010 checklist.pdf"}],"financialInterests":"","formattedTitle":"Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis: study protocol for a multicenter, prospective, randomized controlled trial","fulltext":[{"header":"Background","content":"\u003cp\u003eAdenomyosis\u0026nbsp;is a common gynecologic benign disorder characterized by aberrant presence of\u0026nbsp;endometrial glands and stromal\u0026nbsp;within the\u0026nbsp;myometrium[1-3]. The main symptoms are dysmenorrhea, chronic pelvic pain, dyspareunia, abnormal uterine bleeding (especial for heavy menstrual bleeding) and infertility, which seriously affect quality of life and work productivity in reproductive women[4, 5].\u003c/p\u003e\n\u003cp\u003eHysterectomy considered to be a radical therapy for patients, who were refractory or will not desire to preserve fertility[6, 7]. However, many patients in reproductive age are very sensitive to preserve their fertility and organs[8]. Medical treatments or conservative surgery were options. The former contains non-steroidal anti-inflammatory drugs or hormone regulating drugs, which can keep a hypoestrogenic state, like gonadotropin releasing hormone agonist (GnRHa), danazol, progestogens or oral contraceptive pills[9, 10]. Gonadotropin releasing hormone agonist was the best acceptable treatment for patients in the past 20 years[11]. Unfortunately, these medicines could just provisionally improve symptoms and often lead to serious side effects[12]. Therefore, conservative surgeries come to be another choice, according to the extent of the focus, surgical options were classified into adenomyomectomy (for localized adenomyosis) and partial adenomyomectomy (for diffuse adenomyosis)[4, 13]. The rate of pain relief was higher in focal adenomyosis patients than diffuse adenomyosis women after conservative operation[14]. However, different ratio of systematic relapse was the main issue for this treatment, due to the no clear cut line between focus and normal myometrial tissue[14]. How to control recurrence after surgery has become the current Priority.\u003c/p\u003e\n\u003cp\u003eRecently, some researchers confirmed that surgical-medical treatment provides a more effective treatment option for the symptomatic relief in focal adenomyosis than surgical treatment alone in some prospective or retrospective studies[7, 15, 16]. However, there is still a lack of evidence from randomized controlled study as to confirm whether GnRH agonists could decline the recurrence rate after conservative surgery in women with focal adenomyosis. This study is a multicenter randomized parallel controlled trial comparing efficacy of triptorelin acetate in protecting for relapse of post-operative treatment in focal adenomyosis patients.\u003c/p\u003e"},{"header":"Method/design","content":"\u003cp\u003e308 postoperative participants after complete excision of focal adenomyosis are randomly assigned 1:1 to treatment group (triptorelin acetate) and control group. Patients will be recruited at 10 hospitals across Midwest China. All research units have been approved by the ethics committees. Every patient will sign an informed consent prior to this study. This report follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guideline (Additional file 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria are as follows:\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eWomen aged \u0026ge;18 and \u0026le;45 years;\u003c/li\u003e\n\u003cli\u003eWomen with pathological diagnosis focal adenomyosis;\u003c/li\u003e\n\u003cli\u003eWomen who accept complete excision of adenomyosis, did not take any steroid hormone therapy three months before surgery;\u003c/li\u003e\n\u003cli\u003eWomen who are health before and not pregnant;\u003c/li\u003e\n\u003cli\u003eWomen who can comply with the study procedures and give written informed consent.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eExclusion criteria\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003eWomen who are also participating in other clinical trials at the same time;\u003c/li\u003e\n\u003cli\u003eWomen who are concomitant with have been diagnosed with ovarian endometrioma, deep infiltrating endometriosis, multiple leiomyomas;\u003c/li\u003e\n\u003cli\u003eWomen with congenital uterine abnormalities such as uterine malformation (unicornis uterus, septate uterus, or duplex uterus) or acute genital inflammation or malignant tumor;\u003c/li\u003e\n\u003cli\u003eWomen who are pregnant;\u003c/li\u003e\n\u003cli\u003eWomen who were taken steroid hormone therapy three months before surgery;\u003c/li\u003e\n\u003cli\u003eWomen with hereditary disease, blood disease, liver and kidney dysfunction or malnutrition diseases that cause anemia;\u003c/li\u003e\n\u003cli\u003eWomen who cannot suffer from surgery or are allergic to triptorelin acetate;\u003c/li\u003e\n\u003cli\u003eWomen who are unable to comply with the study procedures and give written informed consent.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eScreening and enrolment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePrevious medical history and current medication status are reviewed with the standardized case report forms. A physical examination and imaging such as two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI) are performed. Laboratory measurements as serum follicle-stimulating hormone (FSH), Estradiol (E2), anti-muellerian hormone (AMH), cancer\u0026nbsp;antigen 125 (CA125)，safety assays include blood routine, urine routine, liver function, renal function, hepatitis virus, HIV, syphilis, coagulation, electrocardiogram (ECG), x-rays are measured in the local department of study sites. Either laparoscopy or transabdominal surgery is performed to completely remove all clinically recognizable lesions in patients who are suspected as focal adenomyosis.\u003c/p\u003e\n\u003cp\u003eWritten informed consent will be obtained from the patients after operation. Quality of life, degree of pain and menstrual volume will be recorded using the Short Form (36) Health Survey (SF-36), Female Sexual Function Index (FSFI), pictorial blood loss assessment chart (PBAC) score, Visual Analogue Scale (VAS) and Numeric Rating Scale (NRS) after confirming by histology. A schedule of enrollment, interventions, and assessment is provided as in the table below (Table 1).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdenomyomectomy\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLaparotomy, hysteroscopy or laparoscopy were all contained in this study. During the laparoscopy, patients are taken the lithotomy position under general anesthesia with endotracheal intubation. After sterilization, pneumoperitoneum was created with carbon dioxide gas at 13 mm Hg (Karl Storz GmbH \u0026amp; Co. KG, Tuttlingen, Germany). Surgery was performed with 4 trocars for surgical instruments. Supine position and median incision are suitable for laparotomy. Hysteroscopic surgery is conducted for type 0 or type 1 adenomyoma (Karl Storz GmbH \u0026amp; Co. KG, Tuttlingen, Germany). Surgical approach is adenomyomectomy. The principle of these surgical options included completely removal of clinical visible lesions, maintained the integrity of uterine wall and keep the integrity of the uterine cavity as much as possible. The length of the surgery, size of the focus, blood loss and the integrity of the uterine cavity should be kept in record.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInterventions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSimple randomization is used to assign qualified participants to surgery only group (Group A) and surgery plus GnRH agonist group (Group B) with a 1:1 ratio. GnRH agonist was used for intervention group, using 3.75mg intramuscular injection (Diphereline, Ipsen, France) at the first day of the menstruation after surgery, then once every four weeks for six courses. The sign and symptoms of hypoestrogenism, including hot flushes, night sweat, sleep disorder, abnormal emotion and osteoporosis, could be caused by GnRH agonist, which should be carefully evaluated and could be treated with Tibolone 1.25 mg per day as add-back therapy to maintain estradiol at 30-50 pg/ml[17].\u003c/p\u003e\n\u003cp\u003eWhen intolerable adverse reaction is occurred on Group B patients, intervention will be discontinued or modified. Color doppler ultrasonography and steroid hormone test on the third and 6th month after conservative operation can help to monitor adherence. During the trial, other medication, such as use of steroid hormone or herbal medicine, or intervention, such as levonorgestrel-relesing intrauterine syste (LNG-IUS) will be prohibited.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRandomization\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible participants were assigned subjects to two groups with a 1:1 ratio simple randomization. The sequence of randomization has been set up by biostatisticians in data coordinator center with Microsoft Excel, using function of RAND (). The original sequence is safely kept by the staff in the data coordinator center, and it has been input into the online central randomization system by these staff members, who are not involved in enrolling subjects. The sequence is not accessible to any investigators or study coordinators. If a subject fulfills the enrollment criteria, the authorized study coordinator will get the assignment for her. After randomization, both subjects and investigators are informed about the assignments.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome and outcome assessments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome is relapse, which defines as recurrence of dysmenorrhea or pelvic pain or menorrhagia or 2D/3D-CDUS / MRI confirmed local recurrence compared to the first follow up time after surgery. Regarding imaging relapse, maximal diameter of suspicious recrudescent focus increase \u0026gt; 1cm during the follow-up period, measuring by 2D/3D-CDUS or MRI. During the follow up, if a positive finding is found by the same imaging examination should be conducted as a further evidence. In addition, the VRS and NRS are applied for evaluation of dysmenorrhea or pelvic pain and the recurrence was defined as any rating (VRS and NRS) upgraded and participants asking for other medical treatments for symptom release at the same time during follow-up. PBAC score is used to predict coagulation disorders in women with menorrhagia and recurrence was defined as score \u0026gt; 100. The proportion of the recurrence at 3, 6, 9,12, 18, 24, 30, 36 months will be followed-up.\u003c/p\u003e\n\u003cp\u003eThe secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, and adverse events. The quality of life is assessed by SF-36 and FSFI, regarding as a measure of health status and sexual functioning in women. Ovarian reserve is evaluated by FSH, E\u003csub\u003e2\u003c/sub\u003e and AMH, the first two are measured before surgery and during the follow-up period at the beginning of the menstrual cycle unless during the treatment of triptorelin\u0026nbsp;acetate. AMH can be measured at any time before and after operation at the time of follow-up. Difference in score for eight dimensions (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional and mental health) of SF-36 and FSFI and mean value of FSH, E\u003csub\u003e2\u003c/sub\u003e and AMH for participants in each group at 3, 6, 9,12, 18, 24, 30, 36 months will be assessed for quality of life and ovarian reserve. The pregnancy intention, pregnancy rate and outcome are recorded in a standard case report form, including abortion, premature delivery, full-term production, to evaluate difference of pregnancy outcome in each treatment arm at 36 months.\u003c/p\u003e\n\u003cp\u003eThe follow-up procedure is acquired from the outpatient department records. Follow-up visits occur at 3, 6, 12, 18, 24, 30, 36 months after conservative surgery.\u003c/p\u003e\n\u003cp\u003eTreatment-related adverse effects are monitored at each visit. Adverse events are any unfavorable medical occurrences associated with the subject\u0026rsquo;s participation in the research, whether considered related to the study intervention. Serious adverse events are events that are temporally associated with the subject\u0026rsquo;s participation in research that meet any of the following criteria: death, life-threatening, severely or permanently disabling, requiring in-patient hospitalization or prolongation of existing\u0026nbsp;hospitalization, or any events deemed as serious by the local principal investigator. Difference in the proportion of patients for adverse events in each group would be assessed at 36 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSample size calculation\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBased on a prospective study revealed a relapse rate for only surgery group was about 49%, and for surgery and GnRH agonist treatment group was 28.1%[7]. A two-tailed test with alpha set at 0.05 and 85% power is used to detect a minimum clinical meaningful difference between control and intervention groups. The minimal sample size is calculated as 139 for each group. In consideration of a dropout rate of 10%, we will totally recruit 308 subjects.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData are collected with a standard case report form. Data are de-identified before being input into the database. Regular study site monitor and database checking are performed to ensure the accuracy of data collected. The data management, monitoring and reporting of this study will comply with the International Conference on Harmonisation Good Clinical Practice (ICH-GCP) guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData analysis plan\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData analysis and reporting will be conducted in accordance to the Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement, which were recorded in our flow chart (Fig. 1), including the number of eligible participants and lost to follow-up for various reasons. Data analysts will be blinded after assignment to interventions. Unblinding of a participant\u0026rsquo;s allocated intervention during the trial is permissible after blind verification and a submission of data locking proof by statistical analyst.\u003c/p\u003e\n\u003cp\u003eIntention to treat, which is based on the initial treatment intent, will be used as a foundation in our analysis. Participants begin the treatment is part of the trial, whether they finish it or not. The characteristics at baseline will be described between control and intervention groups. Continuous data will be summarized by means and standard deviation with Wilcoxon rank sum test to identify differences of baseline characteristic between two groups. Categorical data will be described by number and percentages, using Pearson chi-square test to compare discrepancy between groups.\u003c/p\u003e\n\u003cp\u003eThe primary outcome measure is the recurrence rate between Group A and Group B after three years\u0026rsquo; follow-up, which will be analyzed by Pearson chi-square test. For efficacy parameters, such as score of pelvic pain and dysmenorrhea, menstruation blood loss, size of uterus and lesion will be analyzed using generalized estimating equations (GEE) or mixed effects model repeated measures (MMRM) to account for correlations among these observations in different follow up points.\u003c/p\u003e\n\u003cp\u003eThe parameters from secondary outcomes contains SF-36, FSFI, pregnancy rate and pregnancy outcome are calculated during 36 months\u0026rsquo; follow-up are using generalized estimating equations (GEE) or mixed effects model repeated measures (MMRM) analysis to compare differences between Group A and Group B at different time points.\u003c/p\u003e\n\u003cp\u003eThe number of participants with adverse events (AE) or serious adverse events (SAE) will be presented for each arm. We will not take any formal statistical testing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDissemination\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of the study will be publicated in a peer-reviewed medical journal without use of professional writer. After agreement of the Steering Committee, source data will be shared available through national or international anonymised datasets.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo preserve fertility or integrity of organs was on the rise for the number of women with adenomyosis. Compare with relapse after withdrawal of the medical treatment, adenomyomectomy was widely applied. The remission rate of dysmenorrhea or dyspareunia was 50%-94.7% after complete excision and improvement of menorrhagia was 25%-80%[18]. Nevertheless, a symptomatic or local recurrence of the condition remained exist. About 2.8%-13.95% patients were relapsed at the end of first year. 14.28%-49% participants would recurrent in 24 months[18]. Therefore, the long-term management after surgery was the main issue.\u003c/p\u003e\n\u003cp\u003eRecently，AI Jama retrospectively analyzed 18 patients, accepting adenomyomectomy and GnRHa for 24 weeks, 15 of which had systematic improvement after one year\u0026rsquo;s follow-up [16]. Liu carried out an uncontrolled descriptive study of 186 women with pathologically proven adenomyoma, who underwent ultramini-laparoscopic adenomyomectomy and a 6-month course of goserelin acetate treatment. After 3 years\u0026rsquo; follow-up, the rate of systematic recurrence was 9% [19]. Wang et al.\u0026rsquo; prospective non-randomized study found a significant decline of relapse rate in surgical-medical treatment group at the end of 2-year follow-up [7]. However, our retrospective result showed no difference between control and intervention group at the end of first or second year. It is noteworthy that there was a significant difference between control and GnRH agonist group with symptomatic or imaging relapse at the end of 36 months\u0026rsquo; follow-up. In other words, postoperative treatment might be applied to reduce long-term recurrence rate. If we should use the postoperative method to prevent from relapse in adenomyosis patients is still unknown.\u003c/p\u003e\n\u003cp\u003eThis is the first multicenter, prospective, randomized controlled trial, comparing the efficacy of GnRH agonist in reducing recurrence for focal adenomyosis patients who have had been suffered from adenomyomectomy. We cannot use blinding to trial participants and care providers due to the drug-induced amenorrhea and/ or series of side effect after GnRHa therapy, which will be easy for patients and doctors to speculate the treatments. The lack of blinding might cause substantial bias, especially for the subjective judgment of patients, like pain scoring in primary outcome. To solve this problem, we set up two types of pain scoring system to reduce the chance of subjective error judgment for patients. In addition, recurrence of dysmenorrhea is defined according to the patient's pain score and treatment change needs, which can better evaluate the progress after conservative treatment. We plan to enroll 308 subjects from 10 teaching hospitals in China. The enrollment began in March 2018. At the time of manuscript preparation, more than 90 subjects have been enrolled. The result of this large multicenter randomized trial will provide level I evidence for the strategy of long-term management for focal adenomyosis after conservative operation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe Protocol Version is Version 1.0; March 8, 2018. Recruitment began on March 8, 2018. The expected date for recruitment completion is November\u0026ndash;October 2019.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eGnRH: Gonadotropin-releasing hormone; VRS: Visual Analogue Scale; NRS: Numeric Rating Scale; PBAC: Pictorial blood loss assessment chart; 2D/3D-CDUS: two/three-dimensional color doppler ultrasonography; MRI: magnetic resonance imaging; SF-36: Short Form (36) Health Survey; FSFI: Female Sexual Function index; FSH: follicle-stimulating hormone; E2: estradiol levels; AMH: anti-muellerian hormone; GEE: generalized e5stimating equations; MMRM: mixed effects model repeated measures\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank all subjects and physicians for volunteering their time to this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis is an investigator-initiated study without any grant from commercial funding agencies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo additional data available\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWW, XM contributed to the study design and manuscript drafting and revising; SW designed the study, is on the Steering Committee and revised the manuscript; WZ, ZL, YW, ZY, CZ, LH, RL, HX, WW, QY, JW, MZ were involved in the study concept and design and revision of the manuscript. All authors read and approved the final manuscript.\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\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCentral ethical approval has been confirmed from the Tongji Hospital of Tongji Medical College of Huazhong University Medical Ethics Committee (ref approval no. TJ-IRB20180310) and we will not begin recruiting at other centres in the trial until local ethical approval has been obtained\u0026rdquo;. Written informed consent is obtained from the patients after screening.\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\u003ePublisher\u0026rsquo;s Note\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e1 \u003c/sup\u003eDepartment of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. \u003csup\u003e2\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, Hubei, China. \u003csup\u003e3\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Affiliated Renhe Hospital, China Three Gorges University, Yichang, Hubei, China.\u003csup\u003e 4 \u003c/sup\u003eMaternal and Child Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. \u003csup\u003e5\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Shenzhen Second People's Hospital, Shenzhen, China. \u003csup\u003e6\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Taihe Hospital, Shiyan, Hubei, China. \u003csup\u003e7\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Wuhan University Renmin Hospital, Wuhan, Hubei, China. \u003csup\u003e8\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Xiangyang Central Hospital, Hubei University of Arts and Science, Xiangyang, Hubei, China. \u003csup\u003e9\u003c/sup\u003eDepartment of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, Henan, China. \u003csup\u003e10\u003c/sup\u003eDepartment of Obstetrics and Gynecology, Affiliated Luoyang Central Hospital,\u0026nbsp; Zhengzhou University, Luoyang, Henan, China.\u003c/p\u003e"},{"header":"Reference","content":"\u003col\u003e\n\u003cli\u003eBergeron C, Amant F, Ferenczy A. Pathology and physiopathology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20(4):511-21. doi:10.1016/j.bpobgyn.2006.01.016.\u003c/li\u003e\n\u003cli\u003eFerenczy A. Pathophysiology of adenomyosis. Human reproduction update. 1998;4(4):312-22. doi:10.1093/humupd/4.4.312.\u003c/li\u003e\n\u003cli\u003eLevgur M. Diagnosis of adenomyosis: a review. J Reprod Med. 2007;52(3):177-93.\u003c/li\u003e\n\u003cli\u003eWood C. Surgical and medical treatment of adenomyosis. Human reproduction update. 1998;4(4):323-36. doi:10.1093/humupd/4.4.323.\u003c/li\u003e\n\u003cli\u003eCheong Y, Cameron IT, Critchley HOD. Abnormal uterine bleeding. Br Med Bull. 2017;123(1):103-14. doi:10.1093/bmb/ldx027.\u003c/li\u003e\n\u003cli\u003eOsada H. Uterine adenomyosis and adenomyoma: the surgical approach. Fertility and sterility. 2018;109(3):406-17. doi:10.1016/j.fertnstert.2018.01.032.\u003c/li\u003e\n\u003cli\u003eWang PH, Liu WM, Fuh JL, Cheng MH, Chao HT. Comparison of surgery alone and combined surgical-medical treatment in the management of symptomatic uterine adenomyoma. Fertility and sterility. 2009;92(3):876-85. doi:10.1016/j.fertnstert.2008.07.1744.\u003c/li\u003e\n\u003cli\u003eStreuli I, Dubuisson J, Santulli P, de Ziegler D, Batteux F, Chapron C. An update on the pharmacological management of adenomyosis. Expert Opin Pharmacother. 2014;15(16):2347-60. doi:10.1517/14656566.2014.953055.\u003c/li\u003e\n\u003cli\u003eHirata JD, Moghissi KS, Ginsburg KA. Pregnancy after medical therapy of adenomyosis with a gonadotropin-releasing hormone agonist. Fertility and sterility. 1993;59(2):444-5.\u003c/li\u003e\n\u003cli\u003eCheng MH, Wang PH. Uterine myoma: a condition amenable to medical therapy? Expert Opin Emerg Drugs. 2008;13(1):119-33. doi:10.1517/14728214.13.1.119.\u003c/li\u003e\n\u003cli\u003eTsui KH, Lee FK, Seow KM, Chang WC, Wang JW, Chen SU et al. Conservative surgical treatment of adenomyosis to improve fertility: Controversial values, indications, complications, and pregnancy outcomes. Taiwan J Obstet Gynecol. 2015;54(6):635-40. doi:10.1016/j.tjog.2015.05.003.\u003c/li\u003e\n\u003cli\u003eGuo SW, Groothuis PG. Is it time for a paradigm shift in drug research and development in endometriosis/adenomyosis? Human reproduction update. 2018;24(5):577-98. doi:10.1093/humupd/dmy020.\u003c/li\u003e\n\u003cli\u003eOsada H, Silber S, Kakinuma T, Nagaishi M, Kato K, Kato O. Surgical procedure to conserve the uterus for future pregnancy in patients suffering from massive adenomyosis. Reproductive biomedicine online. 2011;22(1):94-9. doi:10.1016/j.rbmo.2010.09.014.\u003c/li\u003e\n\u003cli\u003eGrimbizis GF, Mikos T, Tarlatzis B. Uterus-sparing operative treatment for adenomyosis. Fertility and sterility. 2014;101(2):472-87. doi:10.1016/j.fertnstert.2013.10.025.\u003c/li\u003e\n\u003cli\u003eHuang BS, Seow KM, Tsui KH, Huang CY, Lu YF, Wang PH. Fertility outcome of infertile women with adenomyosis treated with the combination of a conservative microsurgical technique and GnRH agonist: long-term follow-up in a series of nine patients. Taiwan J Obstet Gynecol. 2012;51(2):212-6. doi:10.1016/j.tjog.2012.04.008.\u003c/li\u003e\n\u003cli\u003eAl Jama FE. Management of adenomyosis in subfertile women and pregnancy outcome. Oman Med J. 2011;26(3):178-81. doi:10.5001/omj.2011.43.\u003c/li\u003e\n\u003cli\u003eZupi E, Marconi D, Sbracia M, Zullo F, De Vivo B, Exacustos C et al. Add-back therapy in the treatment of endometriosis-associated pain. Fertility and sterility. 2004;82(5):1303-8. doi:10.1016/j.fertnstert.2004.03.062.\u003c/li\u003e\n\u003cli\u003eYounes G, Tulandi T. Conservative Surgery for Adenomyosis and Results: A Systematic Review. Journal of minimally invasive gynecology. 2017;25(2):265-76. doi:10.1016/j.jmig.2017.07.014.\u003c/li\u003e\n\u003cli\u003eLiu WM, Chen CH, Chiu LH, Tzeng CR. Long-term follow-up of severely symptomatic women with adenomyoma treated with combination therapy. Taiwan J Obstet Gynecol. 2013;52(1):85-9. doi:10.1016/j.tjog.2012.12.002.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cbody\u003e\u003cp\u003eTable 1. schedule of screening, enrollment and assessment.\u003c/p\u003e\n\u003ctable class=table\u003e\u003ctbody\u003e\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003e\u003ca name=\"_Hlk10386762\"/\u003eEvaluation\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003eScreening\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003eEnrolment\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003eTime of follow-up after surgery (month)\u003c/p\u003e\n\u003ctd\u003e\u003c/td\u003e\u003ctd\u003e\u003c/td\u003e\u003ctd\u003e\u003c/td\u003e\u003ctd\u003e\u003c/td\u003e\u003ctd\u003e\u003c/td\u003e\u003ctd\u003e\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e6\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e12\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e18\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e24\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e30\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e36\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eWritten consent\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eInclusion/exclusion criteria\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e\u003ca name=\"OLE_LINK11\"/\u003e\u003ca name=\"OLE_LINK12\"/\u003e\u003ca name=\"OLE_LINK56\"/\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eMedical history\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003ePhysical exam\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eSafety test (preoperative examination)\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003e2D/3D-CDUS /MRI\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eFSH, E2, AMH, CA125\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eSide effects\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eVAS and NRS \u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003eSF-36 and FSFI\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e\u003ca name=\"OLE_LINK58\"/\u003e\u003ca name=\"OLE_LINK57\"/\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003ctr\u003e\t\u003ctd\u003e\u003cp\u003ePBAC score\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp/\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\t\u003ctd\u003e\u003cp\u003e√\u003c/p\u003e\n\u003c/td\u003e\u003c/tr\u003e\n\u003c/tbody\u003e\u003c/table\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":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"focal adenomyosis, adenomyomectomy, relapse, triptorelin acetate","lastPublishedDoi":"10.21203/rs.2.12204/v4","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.2.12204/v4","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background: To preserve fertility or integrity of organs was on the rise for the most women with adenomyosis. Adenomyomectomy is now a widely applied conservative surgery, however relapse is a serious problem after operation. Postoperative treatment, such as gonadotropin-releasing hormone agonist (GnRHa) has been suggested to result in reducing the recurrence rate in patients. However, there is still a lack of evidence from randomized clinical trials comparing the efficacy of GnRHa for decreasing the postoperative recurrence rate. Method/Design：Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis is a multicenter, prospective, randomized controlled trial. The primary outcome is relapse accessed with Visual Analogue Scale (VRS) and Numeric Rating Scale (NRS), Pictorial blood loss assessment chart (PBAC) score and the size of uterus and lesion are measured by two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI). The secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, and adverse events, assessing by Short Form (36) Health Survey and Female Sexual Function index, serum follicle-stimulating hormone, estradiol levels and anti-muellerian hormone and so on. All these indexes are measured at 3, 6, 12, 18, 24, 30, 36 months after conservative surgery. Discussion：The result of this large multicenter randomized trial will provide evidence for one of the strategies of long-term management in focal adenomyosis after conservative operation.","manuscriptTitle":"Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis: study protocol for a multicenter, prospective, randomized controlled trial","msid":"","msnumber":"","nonDraftVersions":[{"code":4,"date":"2020-02-24 17:46:12","doi":"10.21203/rs.2.12204/v4","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accept","date":"2020-03-28T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-02-24T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-02-23T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":3,"date":"2019-12-23 16:56:05","doi":"10.21203/rs.2.12204/v3","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2020-02-07T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-01-06T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-12-19T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-12-18T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":2,"date":"2019-12-02 12:14:00","doi":"10.21203/rs.2.12204/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Minor revision","date":"2019-12-09T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2019-11-26T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-11-25T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2019-07-31 18:18:46","doi":"10.21203/rs.2.12204/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2019-11-07T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-10-27T12:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-10-27T12:00:00+00:00","index":2,"fulltext":"Recommendation: Minor Revision\nForm responses:\n---\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Acceptable**\n* Quality of figures: **Acceptable**\n* Statistical review: **Yes, and I have assessed the statistics in my report**\n* Declaration of competing interests: **No**\n\nComments to Author:\n---\nComments to TRLS-D-19-00549 entitled \"Relapse after conservative surgery combined with Triptorelin Acetate versus conservative surgery only in women with focal adenomyosis: study protocol for a multicenter, prospective, randomized controlled trial \"\n\nThe authors would like to enroll 278 women with a diagnosis of uterine focal adenomyosis (adenomyoma) to investigate the effect of adding postoperative adjuvant gonadotropin releasing hormone agonist on the outcome of the patients after conservative surgery. This topic is interesting and worthy of consideration. Some comments are shown below.\n\n1. Please clearly demonstrate how many patients should be included to reach the statistical significant difference between two groups.\n2. The expected time of primary end point should be estimated.\n"},{"type":"reviewersInvited","content":"","date":"2019-10-23T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2019-10-23T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2019-10-23T12:00:00+00:00","index":1,"fulltext":"Recommendation: Major Revision\nForm responses:\n---\n* Level of interest: **An article of importance in its field**\n* Quality of written English: **Needs some language corrections before being published**\n* Quality of figures: **Acceptable**\n* Statistical review: **No, the manuscript does not need to be seen by a statistician**\n* Declaration of competing interests: **I declare that I have no competing interests**\n\nComments to Author:\n---\nThank you for submitting this trial protocol evaluating the use of Triptorelin Acetate after surgery for adenomyosis, compared with surgery alone. I have comments to help clarify the methods:\n1) Interventions: Please state whether any concomitant interventions will be prohibited during the trial.\n\n2) Randomization: As recommended by the SPIRIT guidelines, please specify how the random sequence was generated.\n\n3) Blinding: This is a major study limitation. Please explain why placebo could not be used to ensure blinding of physicians and patients. Also in the Discussion, please discuss the potential for substantial bias due to lack of blinding, especially given that components of the primary outcome (pain) are subjective and patient-reported.\n\n4) Primary outcome: Please be more specific in defining the outcome of relapse. What exact criteria will be used -- How is dysmenorrhea defined? What is the minimum value of VAS and NRS? What are the imaging measurements that will be used to define relapse? Will imaging be performed on every patient at every follow-up visit? Please state is the time point of interest (3 years) here.\n\n5) Secondary outcomes: please define the metric, method of aggregation, and time points for each outcome (see https://www.spirit-statement.org/outcomes-2)\n\n6) Sample size calculation: Should the alpha be 0.05 instead of 0.5? Also, the minimal sample size is 139 per group = 278, but then the total sample size also 278 despite saying that there is 10% dropout.\n\n7) Data Analysis Plan, lines 37-42: Formal statistical comparison of baseline characteristics between trial groups should not be performed, since by definition any differences are due to chance.\n\n8) Data Analysis Plan: Please specify how missing data will be handled, and whether any subgroup analyses are planned.\n\n9) Data Analysis Plan: The term 'intention-to-treat' should be defined, as different studies use different definitions (see https://www.spirit-statement.org/analysis-population-and-missing-data/).\n"},{"type":"editorAssigned","content":"","date":"2019-09-06T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2019-07-25T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2019-06-12T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"trials","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"trls","sideBox":"Learn more about [Trials](http://trialsjournal.biomedcentral.com/)","snPcode":"13063","submissionUrl":"https://www.editorialmanager.com/trls","title":"Trials","twitterHandle":"MedicalEvidence","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9ff71b8f-e60e-4405-9446-e64319ddc9cd","owner":[],"postedDate":"February 24th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":44932,"name":"Internal Medicine"},{"id":44933,"name":"Integrative \u0026 Complementary Medicine"},{"id":44934,"name":"Translational Medicine"}],"tags":[],"updatedAt":"2021-08-05T14:03:35+00:00","versionOfRecord":{"articleIdentity":"rs-2983","link":"https://doi.org/10.1186/s13063-020-04294-2","journal":{"identity":"trials","isVorOnly":false,"title":"Trials"},"publishedOn":"2020-04-28 20:41:33","publishedOnDateReadable":"April 28th, 2020"},"versionCreatedAt":"2020-02-24 17:46:12","video":"","vorDoi":"10.1186/s13063-020-04294-2","vorDoiUrl":"https://doi.org/10.1186/s13063-020-04294-2","workflowStages":[]},"version":"v4","identity":"rs-2983","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"identity":"rs-2983","version":["v4"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}