A retrospective study of treatment outcomes and safety in patients receiving long-term relugolix administration

A retrospective study of treatment outcomes and safety in patients receiving long-term relugolix administration | 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 Research Article A retrospective study of treatment outcomes and safety in patients receiving long-term relugolix administration Yu Horibe, Jun Kumakiri, Akira Nakabayashi, Tsutomu Tabata This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7229530/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Relugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, is effective for uterine fibroids, but its recommended use is limited to 180 days. Data on the long-term efficacy and safety of relugolix monotherapy are scarce. This study aimed to evaluate the treatment outcomes and safety of long-term relugolix administration in a real-world clinical setting. Methods We conducted a retrospective study of patients prescribed relugolix at a single institution between 2013 and 2024. Patients who received relugolix for more than 180 days were included in the analysis. Key outcomes included changes in uterine fibroid volume and diameter, symptom improvement, bone mineral density (BMD), and the rate of subsequent surgical intervention. Multivariate imputation was used for missing data, and multiple linear regression analysis was performed to identify factors correlated with treatment response. Results Eighty-three patients were analyzed, with a mean relugolix administration duration of 357.1 ± 158.4 days. The mean age was 41.7 ± 6.8 years. A reduction in uterine volume (-10.1% ± 209.4%) and maximum fibroid diameter (1.5% ± 40.1%) was observed. Multiple regression analysis revealed that a larger initial fibroid diameter (p = 0.01) and older age (p < 0.01) were significantly correlated with a greater percentage reduction in fibroid size. Symptomatic improvement was reported by 60.2% of patients, and 36.1% no longer desired surgery. No significant decrease in BMD was observed. Ultimately, 44.5% of patients underwent surgery, while 8.4% successfully transitioned into menopause on therapy. No serious adverse events were reported during long-term administration. Conclusion Long-term administration of relugolix monotherapy was well-tolerated and effective in reducing uterine fibroid volume and improving symptoms. It allowed a substantial number of patients to improve their quality of life and avoid or delay surgery, suggesting it is a viable option for the long-term management of symptomatic uterine fibroids. Figures Figure 1 INTRODUCTION Uterine fibroids are among the most prevalent gynecological disorders, affecting approximately 25% of women of reproductive age. Approximately 25% of these patients require hospitalization owing to the severity of their symptoms. The treatment options include surgical intervention, uterine artery embolization, and pharmacological therapy. However, given the variability in fertility preferences and social backgrounds of patients, a standardized treatment approach has not yet been established. Although the need for surgical intervention tends to increase with symptom severity, patients' subjective experiences of their symptoms and preferences regarding surgery do not always align, and often make treatment decisions challenging. In Japan, relugolix is approved for insurance coverage for the treatment of uterine fibroids and endometriosis. It is a once-daily oral gonadotropin-releasing hormone (GnRH) antagonist administered at a dose of 40 mg. Compared with GnRH agonists, relugolix offers several advantages, including the absence of an initial symptom flare-up and more rapid recovery of estradiol (E2) levels after treatment discontinuation. Despite these benefits, the current recommendations limit the treatment duration to no more than 180 days. Although combination therapy with relugolix, estradiol, and a progestin has been reported to improve the quality of life and symptom control in several countries, data on the long-term efficacy and safety of relugolix monotherapy remain scarce. This retrospective study aimed to evaluate the long-term use of relugolix monotherapy in clinical practice. METHODS We conducted a retrospective study of patients who were prescribed relugolix at our institution over a 10-year period from 2013 to 2024. From this cohort, patients who received relugolix for more than 180 days were identified for analysis. To address the missing data, we employed multivariate imputation using the chained equations (MICE) method. 1 To enhance the statistical precision, the imputation process was repeated five times, and multiple linear regression analyses were conducted for each imputed dataset. The results were then combined using a pooled analysis. All statistical analyses were performed using the R software ( https://www.r-project.org/ ). The items to be examined were the number of days of administration, age at initiation of administration, height, weight, body mass index (BMI), pregnancy history, childbirth history, history of sexual intercourse, history of surgery, surgical procedure if any, symptoms before administration (dysmenorrhea, abdominal distension, menorrhagia, bladder symptoms, rectal symptoms, desire to have children), complications, use of medications that may affect gynecological diseases, female hormone medications used before administration of relugolix, indications for use of relugolix (endometriosis, uterine fibroids, or both), number of submucosal fibroids, number of subserosal fibroids, and intramural fibroids, total number of uterine fibroids, maximum diameter of uterine fibroids at first visit, uterine diameter (length, width, height), maximum diameter of uterine fibroids after treatment, uterine diameter (length, width, height), maximum diameter of uterine fibroids during follow-up, uterine diameter (length, width, height), number of days from one MRI to another, bone mineral density before administration (spine, left and right femoral heads), bone mineral density after administration (spine, left and right femoral heads), estradiol level during drug holiday period, lowest hemoglobin level, highest CA125 level, history of blood transfusion, desire for surgery, patient outcome, and symptoms after treatment. The calculation formula for the predicted values ​​reported by Bray et al. was used to estimate the volume of the fibroids. 2 RESULTS A total of 894 patients were identified. Among these, 149 cases had been prescribed relugolix for 180 days or more. However, after individually excluding cases in which the attending physician misjudged the number of prescription days, 83 cases were deemed eligible for the analysis. The patient characteristics are presented in Table 1 . Table 1 Patient Characteristics Patient Characteristics Relugolix administration (days) 357.1 ± 158.4 Age 41.7 ± 6.8 Height (cm) 159.4 ± 6.0 Weight (kg) 58.9 ± 12.5 BMI 22.9 ± 6.1 Gravida 0.53 ± 1.10 Parity 0.35 ± 0.81 Virginity (%) 3.6 (3/83) Experience of abdominal surgery (%) 30.1 (25/83) Symptom (%) None 8.4 (7/83) Dysmenorrhea 26.5 (22/83) Abdominal distension 10.8 (9/83) Hypermenorrhea 53.0 (44/83) Bladder symptoms 8.4 (7/83) Defecation disorder 1.2 (1/83) Desire for childbearing 2.4 (2/83) Other reasons 3.6 (3/83) Complications (%) 31.3 (26/83) Presence of affecting medication (ex. DOAC) 15.7 (13/83) Presence of other hormonal drugs before relugolix 32.5 (27/83) Diagnosis Uterine myoma 39 Endometriosis 8 Both 32 The mean duration of relugolix administration was 367.1 ± 158.4 days. The mean age was 41.7 ± 6.8 years, indicating that the majority of patients were in the premenopausal stage. The mean height was 159.4 ± 6.0 cm, weight 58.9 ± 12.5 kg, and BMI 22.9 ± 6.1. The mean number of pregnancies (gravida) was 0.53 ± 1.10, and the mean number of deliveries (parity) was 0.35 ± 0.81, indicating that most patients had no history of pregnancy. A small proportion (3.6%) of participants reported virginity. The rate of previous abdominal surgery was 30.1%. With respect to symptoms, 91.6% (76 out of 83) of patients reported at least one symptom. The reported symptoms included dysmenorrhea (26.5%), abdominal distension (10.8%), hypermenorrhea (53.0%), bladder symptoms (8.4%), defecation disorders (1.2%), desire for childbearing (2.4%), and other reasons (3.6%). Notably, more than half of the patients experienced hypermenorrhea. Comorbid conditions potentially affecting gynecological outcomes were observed in 31.3% of patients, among which 15.7% were on medications with potential gynecological impact (e.g., direct oral anticoagulants [DOACs]). Additionally, 32.5% of the patients were treated with other hormonal therapies prior to relugolix administration. The treatment outcomes are described in Table 2 ( uterine fibroid response) and Table 3 ( parameters such as bone mineral density and hemoglobin levels). Table 2 uterine fibroid response Treatment outcomes (myoma) Iteration of relugolix 2.2 ± 1.1 Total number of uterine myomas 6.0 ± 5.4 Total number of intramural myomas 4.9 ± 5.0 Total number of subserosal myomas 0.74 ± 0.92 Total number of submucosal myomas 0.30 ± 0.54 Maximum uterine diameter of myoma (first visit) (mm) 81.0 ± 41.6 Maximum length diameter of myoma (first visit) (mm) 119.0 ± 39.2 Maximum width diameter of myoma (first visit) (mm) 110.0 ± 38.7 Maximum height diameter of myoma (first visit) (mm) 89.0 ± 21.4 Volume (first visit) (cm 3 ) 700.6 ± 552.1 After administration of relugolix Maximum uterine diameter of myoma (after administration) (mm) 76.7 ± 34.6 Maximum length diameter of myoma (after administration) (mm) 108.4 ± 34.5 Maximum width diameter of myoma (after administration) (mm) 104.2 ± 32.6 Maximum height diameter of myoma (after administration) (mm) 84.7 ± 18.2 Volume (after administration) (cm 3 ) 573.9 ± 414.0 intervals MRI to MRI 587.4 ± 518.2 Reduction in uterine volume (%) -10.1 ± 209.4 Reduction in maximum uterine diameter (%) 1.5 ± 40.1 Reduction in uterine volume per day (%) 0.058 ± 0.34 We describe the treatment outcomes for uterine myomas. The mean total number of uterine myomas was 6.0 ± 5.4, with intramural myomas accounting for the majority (4.9 ± 5.0). Subserosal and submucosal myomas were less common, with mean numbers of 0.74 ± 0.92 and 0.30 ± 0.54, respectively. The maximum uterine diameter of myomas at the first visit was 81.0 ± 41.6 mm, and the mean uterine volume was 700.6 ± 552.1 cm³. No significant differences were observed between the length, width, and height. Following relugolix administration, the mean reduction in uterine volume was − 10.1% ± 209.4%, a figure influenced by several cases that were non-responsive to relugolix and demonstrated increased volume. The mean reduction in maximum uterine diameter was 1.5% ± 40.1%, and the mean daily reduction in uterine volume was 0.058% ± 0.34%. Table 3 Treatment Outcome (Others) Bone mineral density of the spine (pre-treatment) (%) 94.8 ± 14.0 Bone mineral density of the right caput femoris (pre-treatment) (%) 96.7 ± 18.2 Bone mineral density of the left caput femoris (pre-treatment) (%) 97.6 ± 19.9 Bone mineral density of the spine (post-treatment) (%) 93.4 ± 16.9 Bone mineral density of the right caput femoris (post-treatment) (%) 91.7 ± 15.6 Bone mineral density of the left caput femoris (post-treatment) (%) 89.2 ± 17.0 Reduction in the bone mineral density of the spine (%) 1.5 ± 20.7 Reduction in the bone mineral density of the right caput femoris (%) 5.2 ± 14.3 Reduction in the bone mineral density of the left caput femoris (%) 8.6 ± 14.6 E2 (post-treatment) (pg/mL) 163.3 ± 155.0 lowest Hb (post-treatment) (mg/dL) 9.6 ± 2.3 highest CA125 (post-treatment) (mg/dL) 112.4 ± 157.0 Blood transfusion history (%) 7.2 (6/83) No desire for surgery (%) 36.1 (30/83) Improvement of symptoms (%) 60.2 (50/83) Surgery (%) 44.5 (37/83) Cases of menopause after relugolix (%) 8.4 (7/83) Correlation and statistical analyses were performed for each parameter. The strengths of these correlations are shown in Fig. 1. Among the evaluated variables, those demonstrating strong correlations and statistical significance in the Spearman’s rank correlation were selected for further analysis. A multiple linear regression analysis was then conducted, with the percentage reduction in the maximum uterine myoma diameter after treatment as the dependent variable and the initial maximum myoma diameter at the first visit, duration of relugolix administration, age, and hemoglobin level (Hb) as independent variables. The analysis revealed a significant positive correlation between the initial maximum myoma diameter (p = 0.01) and age (p < 0.01), and a significant negative correlation with the duration of relugolix administration (p < 0.01). No significant correlation was observed between Hb levels and the total number of uterine myomas. Regarding bone mineral density (BMD), the extent of missing data was too large to allow for a reliable analysis using multiple imputation methods. Individual case-based assessments were conducted. No BMD reduction was observed after relugolix administration. The mean post-treatment estradiol (E2) level was 163.3 ± 155.0 pg/mL. The lowest recorded post-treatment hemoglobin (Hb) level was 9.6 ± 2.3 mg/dL, and the highest post-treatment CA125 level was 112.4 ± 157.0 mg/dL. A history of blood transfusion was documented in 7.2% of the patients. Regarding patient outcomes, 36.1% expressed no desire for surgery, whereas 60.2% reported symptomatic improvement, indicating that more than half of the patients experienced symptom relief. Ultimately, 44.5% of the patients underwent surgery, whereas 8.4% were able to continue treatment until menopause. Notably, among patients who received long-term relugolix administration, surgical intervention was rarely required. DISCUSSION Uterine fibroids are among the most common gynecological disorders and approximately 25% of women of reproductive age experience symptoms related to this condition. Of these, approximately 25% required hospitalization owing to the severity of their symptoms. As many women remain asymptomatic or gradually develop symptoms, the true prevalence of uterine fibroids is likely to be underestimated. A considerable number of cases remain undiagnosed and have not been thoroughly evaluated. 3 Moreover, even among symptomatic patients, a proportional decline in surgical interventions often presents challenges for attending physicians in establishing an appropriate treatment strategy. As a result, there is growing interest in the long-term administration of relugolix as a non-surgical option. However, evidence on the long-term efficacy and safety of relugolix is limited in the current literature. Relugolix Regarding relugolix, a Phase III clinical trial conducted in Japanese women reported high efficacy in relieving pain and favorable tolerability for the treatment of uterine fibroids. 4 However, relugolix is currently recommended to be administered for no longer than 180 days, and its long-term efficacy and safety remain unclear. Ayman et al. reported the safety of long-term relugolix use for up to 52 weeks. However, their study evaluated a combination therapy consisting of relugolix 40 mg with estradiol 1 mg and norethindrone acetate 0.5 mg. Thus, there is a paucity of data regarding the use of relugolix monotherapy over extended periods. 5 In our study, we demonstrated that relugolix monotherapy improved the quality of life in more than half of the patients who did not wish to undergo surgery, and this was achieved without any observed reduction in bone mineral density. The longest duration of relugolix administration at our institution was 1,030 days, during which no major adverse events were observed. From a pharmacological perspective, GnRH receptors are expressed in uterine smooth muscle tumors (leiomyomas), and GnRH analogs have been shown to directly bind to these receptors, modulating transcription, and suppressing the production of extracellular matrix (ECM) components in fibroid cells. In vitro studies on cetrorelix, an injectable GnRH antagonist, have demonstrated not only binding to GnRH receptors but also a reduction in the synthesis of several ECM proteins. 6 Given these findings, it is desirable that future studies evaluate how long-term relugolix administration, particularly as a monotherapy, may influence molecular pathways such as receptor downregulation and ECM-related mechanisms, especially in the context of our current clinical observations. Treatment Considerations The pathogenesis of uterine fibroids involves not only estrogen exposure, but also a complex interplay of genetic and epigenetic factors, individual lifestyle choices, and environmental influences. Additionally, several studies have reported that conditions, such as vitamin D deficiency, hypertension, and metabolic syndrome, may contribute to the development of fibroids in certain patients. 7 Given these multifactorial etiologies, personalized prevention and treatment strategies should be emphasized in the management of uterine fibroids. In particular, the duration of relugolix therapy should be considered on a case-by-case basis, especially considering its potential effects on bone mineral density. Therefore, a tailored patient-specific approach is essential. Treatment selection for uterine fibroids is inherently complex and should be based on the patient’s clinical symptoms, reproductive desires, and social background. 8 Available options include surgical procedures, uterine artery embolization, and various medical therapies such as GnRH agonists or selective estrogen receptor modulators (SERMs). However, as observed in our cohort, a significant proportion of patients with severe symptoms opted for surgical intervention, highlighting the challenges gynecologists often face when establishing appropriate treatment plans. Estrogen levels decline with age. 9 In this study, we observed a negative correlation between age and the rate of fibroid size reduction and found that the degree of shrinkage was more strongly related to the maximum size of the fibroids than to their number. These findings suggest that if a scoring system can be developed based on patient age and initial fibroid size, it may be possible to predict successful symptom control until menopause with medical therapy alone, particularly in patients unwilling to undergo surgery. Donnez et al. reported that oral GnRH antagonists produce a rapid improvement in heavy menstrual bleeding in over 70% of women and, when used without add-back therapy, can lead to a significant reduction in fibroid volume, up to approximately 50% at 24 weeks from baseline. 10 Additionally, a recent meta-analysis of the efficacy of GnRH antagonists in the treatment of uterine fibroids concluded that these agents were associated with symptom improvement and an average volume reduction of approximately 27%. 11 In the present study, we also observed a sustained reduction in fibroid size in the long-term treatment cases. Importantly, no new-onset osteoporosis was noted during extended administration, suggesting that long-term relugolix therapy may allow a substantial number of patients to avoid surgery. In case-specific observations, several cases involved patients with severe comorbidities, including cardiovascular disease and recipients of organ transplants (e.g., renal transplantation), in whom anemia due to fibroids or endometriosis had a direct impact on prognosis. In such high-risk patients, the continuous administration of relugolix until menopause appears inevitable, underscoring the clinical necessity for safe and effective long-term therapeutic strategies. Association with infertility While further investigation is needed to fully evaluate the efficacy of relugolix in treating infertility associated with uterine fibroids, fibroids larger than 4 cm in diameter have been reported to negatively affect fertility, even in the absence of protrusion into the endometrial cavity. 12 Therefore, long-term administration of relugolix may be a beneficial option for patients who wish to avoid surgery, but still hope to preserve or improve future fertility. In comparison with other pharmacological agents, a Phase III trial conducted in Japan demonstrated that relugolix provided relief from endometriosis-associated pain equal to that provided byas GnRH agonists. Importantly, relugolix is associated with a more rapid recovery of serum estradiol (E2) levels and earlier resumption of menstruation following treatment cessation, which is particularly valuable for planning pregnancy. Moreover, relugolix has been associated with faster recovery from treatment-emergent adverse events after discontinuation. 13 GnRH agonists are also known to reduce endometrial thickness and the associated bleeding; thus, pretreatment with a GnRH agonist may reduce bleeding during subsequent dienogest (DNG) therapy. The surgical treatment of fibroids may increase the risk of uterine rupture during pregnancy. 14 Although the required postoperative contraception period varies among institutions, long-term relugolix therapy during egg retrieval and the pre-embryo transfer phase may contribute to fibroid shrinkage and potentially shorten the time to pregnancy by enabling earlier embryo transfer. Limitations This study had several limitations. First, this study was conducted at a single institution and used a retrospective design, resulting in a certain degree of missing data. Future studies using more robust methodologies and higher levels of evidence are warranted. Additionally, both intermittent and continuous relugolix administration were determined by the attending physicians based on clinical judgment, which may have affected the treatment outcomes. Patient preferences also change over time and in response to symptoms, making it difficult to isolate the effects of relugolix alone. Therefore, interpretation of treatment efficacy should be approached with caution. CONCLUSION Long-term administration of relugolix was well tolerated without any serious adverse events. It contributes to the reduction of the uterine fibroid volume and maximum fibroid diameter, with a substantial number of patients experiencing an improved quality of life and successfully avoiding surgery. Future research should focus on assessing the expression of estrogen receptors (ER) and progesterone receptors (PR) in patients with uterine fibroids and endometriosis, as this may enable a better prediction of the likelihood of surgical avoidance, treatment efficacy, and degree of pain relief. Furthermore, the accumulation of additional cases and extended long-term follow-up are warranted to further elucidate the benefits and safety of prolonged relugolix therapy. Declarations Informed consent was obtained from all patients for this observational study. The study was conducted in compliance in accordance with the Declaration of Helsinki. Tokyo Women’s Medical University, the Internal Review Board Approval Number is 5704 Funding Declaration No Funding Human Ethics and Consent to Participate declarations Not applicable’. Availability of data and materials statement The data described in this article can be freely and openly accessed at Supplementary material References Zhang Z. Multiple imputation with multivariate imputation by chained equation (MICE) package. Ann Transl Med. 2016;4:30. Bray MJ, et al. Evaluating Risk Factors for Differences in Fibroid Size and Number Using a Large Electronic Health Record Population. Maturitas. 2018;114:9–13. Ahmad A, et al. Diagnosis and management of uterine fibroids: current trends and future strategies. J Basic Clin Physiol Pharmacol. 2023;34:291–310. Osuga Y et al. Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women. Fertil Steril. 2019;112:922-9.e2. Al-Hendy A, et al. Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas. Obstet Gynecol. 2022;140:920–30. Schwartz A. Relugolix reduces leiomyoma extracellular matrix production via the transforming growth factor-beta pathway. F S Sci. 2025;6:213–20. El Sabeh M. The Future of Uterine Fibroid Management: A More Preventive and Personalized Paradigm. Reprod Sci. 2021;28:3285–8. Donnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update. 2016;22:665–86. Lephart ED. A review of the role of estrogen in dermal aging and facial attractiveness in women. J Cosmet Dermatol. 2018;17:282–8. Donnez J. Uterine fibroid–related infertility: mechanisms and management. Fertil Steril. 2024;122:31–9. Martín MJS, et al. Efficacy of GnRH antagonists in the treatment of uterine fibroids: a meta–analysis. Arch Gynecol Obstet. 2025;311:685–96. Heertum KV, Barmat L. Uterine fibroids associated with infertility. Womens Health (Lond). 2014;10:645–53. Harada T, et al. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study. Fertil Steril. 2022;117:583–92. Kim HS, et al. Uterine rupture in pregnancies following myomectomy: A multicenter case series. Obstet Gynecol Sci. 2016;59:454–62. Additional Declarations No competing interests reported. Supplementary Files RGLXCalc10.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board 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-7229530","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":516994360,"identity":"fde229b8-e386-4d2f-bb5b-5144811e2c76","order_by":0,"name":"Yu Horibe","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYDCCA3CCh4HhA5BiYydFC+MMkBZmUrQw84BoQlr4jvcYPuY5c0fO4HbvMWmbX9vk+ZgZGD98zMGtRfLMGWNjnhvPjA3unEuTzu27bdjGzMAsOXMbbi0GN3LMpHk+HE7cBmLk9txmBGphY+YlWotlz217IrXcgGph+HE7kaAWyTPHig3nnDlsbH/njLFlb8Pt5DZmxma8fuE73rzxwZtjh+UkZ/cY3vjx57bt/Pbmgx8+4tHCwMBhAKElGFgkGNtALMYGfOqBgP0BTAvzB4Y/BBSPglEwCkbBiAQAohBYPfZXwqgAAAAASUVORK5CYII=","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":true,"prefix":"","firstName":"Yu","middleName":"","lastName":"Horibe","suffix":""},{"id":516994361,"identity":"cbabf807-09ae-45c0-b930-6d554c4d06ab","order_by":1,"name":"Jun Kumakiri","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Kumakiri","suffix":""},{"id":516994362,"identity":"cd60b104-93e1-4382-9a0c-675dc71817f8","order_by":2,"name":"Akira Nakabayashi","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"prefix":"","firstName":"Akira","middleName":"","lastName":"Nakabayashi","suffix":""},{"id":516994363,"identity":"cc57f655-3594-4a22-958e-9c21bef750f4","order_by":3,"name":"Tsutomu Tabata","email":"","orcid":"","institution":"Tokyo Women’s Medical University","correspondingAuthor":false,"prefix":"","firstName":"Tsutomu","middleName":"","lastName":"Tabata","suffix":""}],"badges":[],"createdAt":"2025-07-28 04:08:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7229530/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7229530/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":91934563,"identity":"e364e67b-1c9b-4027-80d2-e4285a9f83b8","added_by":"auto","created_at":"2025-09-23 02:40:43","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":67250,"visible":true,"origin":"","legend":"","description":"","filename":"Figure.docx","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/321e9a2d12b38944a149b4e6.docx"},{"id":91934516,"identity":"98c8c5fa-ec8e-4684-855f-b6a9349d04a3","added_by":"auto","created_at":"2025-09-23 02:40:28","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":47049,"visible":true,"origin":"","legend":"","description":"","filename":"20250730RelugolixEng.docx","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/713cc74449257e795437b1b5.docx"},{"id":91934564,"identity":"1b5ef571-ce22-4cef-91e6-004bd5a1d01a","added_by":"auto","created_at":"2025-09-23 02:40:43","extension":"json","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":6362,"visible":true,"origin":"","legend":"","description":"","filename":"4b96ae1e5fc6440980ec32ae968adeae.json","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/ada3f4086d96e6ea427a9ba0.json"},{"id":91934557,"identity":"6e53d481-37bc-4c95-b681-338c632febff","added_by":"auto","created_at":"2025-09-23 02:40:40","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":20236,"visible":true,"origin":"","legend":"","description":"","filename":"RGLXCalc10.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/9ecfc3e662567b8595df5866.xlsx"},{"id":91934599,"identity":"23de0723-831f-4bfe-9845-d53faa479413","added_by":"auto","created_at":"2025-09-23 02:40:53","extension":"xml","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":59224,"visible":true,"origin":"","legend":"","description":"","filename":"4b96ae1e5fc6440980ec32ae968adeae1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/88ee4df86bb7572c4ef73ba0.xml"},{"id":91934604,"identity":"60fd28a3-113c-4149-823c-0106d4612af9","added_by":"auto","created_at":"2025-09-23 02:40:54","extension":"jpeg","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":739427,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/e85521801b2b54a0ea7c6d62.jpeg"},{"id":91934517,"identity":"6ce18ad3-d888-4619-83f3-f217bb7d1a62","added_by":"auto","created_at":"2025-09-23 02:40:30","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":141155,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/19dec2362dba4769b13a2e41.png"},{"id":91934619,"identity":"a342ee77-426c-44ea-95fc-7665d28d84e4","added_by":"auto","created_at":"2025-09-23 02:40:55","extension":"xml","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":56933,"visible":true,"origin":"","legend":"","description":"","filename":"4b96ae1e5fc6440980ec32ae968adeae1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/f695052a0d40d6586c4a2427.xml"},{"id":91934519,"identity":"b04c4059-733b-4290-a35b-75c2a41b595a","added_by":"auto","created_at":"2025-09-23 02:40:33","extension":"html","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":62507,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/5166cb5a9771c0aad5f39940.html"},{"id":91934562,"identity":"31d7a1fc-f763-4ebe-9719-e73b2493fb64","added_by":"auto","created_at":"2025-09-23 02:40:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":131416,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlations between the study items are illustrated in the figure. Blue indicates a positive correlation, and red indicates a negative correlation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviation: \u003c/strong\u003eTotal_Myo=total number of myoma, Int=intramural myoma, Sero=Subserosal myoma, Muco=Submucosal myoma, FST_L=length of myoma at first visit, FST_W=width of myoma at first visit, FST_H=height of myoma at first visit, FST_MaxD=max diameter of myoma at first visit, FST_volume=expected volume of myoma at first visit, cure_L=length of myoma after treatment, cure_W=width of myoma after treatment,, cure_H=height of myoma after treatment, cure_MaxD=max diameter of myoma after treatment, cure_volume=expected volume of myoma after treatment, MRItoMRI=Duration between the baseline MRI and the post-treatment MRI, Vlm_Rdc=percentage of volume reduction of myoma, MaxDRdc=percentage of maximum diameter reduction of myoma, Rdc_perD=percentage of maximum diameter reduction of myoma per day, E2=estradiol, Hb=hemoglobin, CA125= Cancer antigen 125\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/934f3a6cbaf08f618be4d402.png"},{"id":93464343,"identity":"16588e9b-b161-44b9-9f69-fcc3eb32b808","added_by":"auto","created_at":"2025-10-14 07:02:14","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":588991,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/dfeda3b0-7b5e-4e59-bc55-715f6f4465a1.pdf"},{"id":91934565,"identity":"2eb2d85c-57ae-4be2-a000-a3abb9a25992","added_by":"auto","created_at":"2025-09-23 02:40:43","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":20236,"visible":true,"origin":"","legend":"","description":"","filename":"RGLXCalc10.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7229530/v1/9f464a3d57dc52cfcee464f0.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"A retrospective study of treatment outcomes and safety in patients receiving long-term relugolix administration","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eUterine fibroids are among the most prevalent gynecological disorders, affecting approximately 25% of women of reproductive age. Approximately 25% of these patients require hospitalization owing to the severity of their symptoms. The treatment options include surgical intervention, uterine artery embolization, and pharmacological therapy. However, given the variability in fertility preferences and social backgrounds of patients, a standardized treatment approach has not yet been established. Although the need for surgical intervention tends to increase with symptom severity, patients' subjective experiences of their symptoms and preferences regarding surgery do not always align, and often make treatment decisions challenging.\u003c/p\u003e\u003cp\u003e In Japan, relugolix is approved for insurance coverage for the treatment of uterine fibroids and endometriosis. It is a once-daily oral gonadotropin-releasing hormone (GnRH) antagonist administered at a dose of 40 mg. Compared with GnRH agonists, relugolix offers several advantages, including the absence of an initial symptom flare-up and more rapid recovery of estradiol (E2) levels after treatment discontinuation. Despite these benefits, the current recommendations limit the treatment duration to no more than 180 days. Although combination therapy with relugolix, estradiol, and a progestin has been reported to improve the quality of life and symptom control in several countries, data on the long-term efficacy and safety of relugolix monotherapy remain scarce. This retrospective study aimed to evaluate the long-term use of relugolix monotherapy in clinical practice.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cp\u003eWe conducted a retrospective study of patients who were prescribed relugolix at our institution over a 10-year period from 2013 to 2024. From this cohort, patients who received relugolix for more than 180 days were identified for analysis. To address the missing data, we employed multivariate imputation using the chained equations (MICE) method.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e To enhance the statistical precision, the imputation process was repeated five times, and multiple linear regression analyses were conducted for each imputed dataset. The results were then combined using a pooled analysis. All statistical analyses were performed using the R software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003cspan address=\"https://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe items to be examined were the number of days of administration, age at initiation of administration, height, weight, body mass index (BMI), pregnancy history, childbirth history, history of sexual intercourse, history of surgery, surgical procedure if any, symptoms before administration (dysmenorrhea, abdominal distension, menorrhagia, bladder symptoms, rectal symptoms, desire to have children), complications, use of medications that may affect gynecological diseases, female hormone medications used before administration of relugolix, indications for use of relugolix (endometriosis, uterine fibroids, or both), number of submucosal fibroids, number of subserosal fibroids, and intramural fibroids, total number of uterine fibroids, maximum diameter of uterine fibroids at first visit, uterine diameter (length, width, height), maximum diameter of uterine fibroids after treatment, uterine diameter (length, width, height), maximum diameter of uterine fibroids during follow-up, uterine diameter (length, width, height), number of days from one MRI to another, bone mineral density before administration (spine, left and right femoral heads), bone mineral density after administration (spine, left and right femoral heads), estradiol level during drug holiday period, lowest hemoglobin level, highest CA125 level, history of blood transfusion, desire for surgery, patient outcome, and symptoms after treatment. The calculation formula for the predicted values ​​reported by Bray et al. was used to estimate the volume of the fibroids.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 894 patients were identified. Among these, 149 cases had been prescribed relugolix for 180 days or more. However, after individually excluding cases in which the attending physician misjudged the number of prescription days, 83 cases were deemed eligible for the analysis. The patient characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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\u003ePatient Characteristics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePatient Characteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRelugolix administration (days)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e357.1\u0026thinsp;\u0026plusmn;\u0026thinsp;158.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8\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=\"left\" colname=\"c2\"\u003e\u003cp\u003e159.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0\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=\"left\" colname=\"c2\"\u003e\u003cp\u003e58.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGravida\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVirginity (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.6 (3/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExperience of abdominal surgery (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30.1 (25/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSymptom (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNone\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.4 (7/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDysmenorrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26.5 (22/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal distension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10.8 (9/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypermenorrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.0 (44/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBladder symptoms\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.4 (7/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDefecation disorder\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.2 (1/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDesire for childbearing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2.4 (2/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther reasons\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.6 (3/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eComplications (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31.3 (26/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresence of affecting medication (ex. DOAC)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15.7 (13/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePresence of other hormonal drugs before relugolix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32.5 (27/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiagnosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUterine myoma\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndometriosis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBoth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32\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\u003eThe mean duration of relugolix administration was 367.1\u0026thinsp;\u0026plusmn;\u0026thinsp;158.4 days. The mean age was 41.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 years, indicating that the majority of patients were in the premenopausal stage. The mean height was 159.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.0 cm, weight 58.9\u0026thinsp;\u0026plusmn;\u0026thinsp;12.5 kg, and BMI 22.9\u0026thinsp;\u0026plusmn;\u0026thinsp;6.1. The mean number of pregnancies (gravida) was 0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;1.10, and the mean number of deliveries (parity) was 0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81, indicating that most patients had no history of pregnancy. A small proportion (3.6%) of participants reported virginity. The rate of previous abdominal surgery was 30.1%.\u003c/p\u003e\u003cp\u003eWith respect to symptoms, 91.6% (76 out of 83) of patients reported at least one symptom. The reported symptoms included dysmenorrhea (26.5%), abdominal distension (10.8%), hypermenorrhea (53.0%), bladder symptoms (8.4%), defecation disorders (1.2%), desire for childbearing (2.4%), and other reasons (3.6%). Notably, more than half of the patients experienced hypermenorrhea. Comorbid conditions potentially affecting gynecological outcomes were observed in 31.3% of patients, among which 15.7% were on medications with potential gynecological impact (e.g., direct oral anticoagulants [DOACs]). Additionally, 32.5% of the patients were treated with other hormonal therapies prior to relugolix administration.\u003c/p\u003e\u003cp\u003eThe treatment outcomes are described in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e ( uterine fibroid response) and Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e ( parameters such as bone mineral density and hemoglobin levels).\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\u003euterine fibroid response\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment outcomes (myoma)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIteration of relugolix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;1.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of uterine myomas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of intramural myomas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of subserosal myomas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal number of submucosal myomas\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum uterine diameter of myoma (first visit) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e81.0\u0026thinsp;\u0026plusmn;\u0026thinsp;41.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum length diameter of myoma (first visit) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e119.0\u0026thinsp;\u0026plusmn;\u0026thinsp;39.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum width diameter of myoma (first visit) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e110.0\u0026thinsp;\u0026plusmn;\u0026thinsp;38.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum height diameter of myoma (first visit) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e89.0\u0026thinsp;\u0026plusmn;\u0026thinsp;21.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVolume (first visit) (cm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e700.6\u0026thinsp;\u0026plusmn;\u0026thinsp;552.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAfter administration of relugolix\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum uterine diameter of myoma (after administration) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e76.7\u0026thinsp;\u0026plusmn;\u0026thinsp;34.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum length diameter of myoma (after administration) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e108.4\u0026thinsp;\u0026plusmn;\u0026thinsp;34.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum width diameter of myoma (after administration) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e104.2\u0026thinsp;\u0026plusmn;\u0026thinsp;32.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMaximum height diameter of myoma (after administration) (mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e84.7\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVolume (after administration) (cm\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e573.9\u0026thinsp;\u0026plusmn;\u0026thinsp;414.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintervals MRI to MRI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e587.4\u0026thinsp;\u0026plusmn;\u0026thinsp;518.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction in uterine volume (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e-10.1\u0026thinsp;\u0026plusmn;\u0026thinsp;209.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction in maximum uterine diameter (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;40.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction in uterine volume per day (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e0.058\u0026thinsp;\u0026plusmn;\u0026thinsp;0.34\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\u003eWe describe the treatment outcomes for uterine myomas. The mean total number of uterine myomas was 6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.4, with intramural myomas accounting for the majority (4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0). Subserosal and submucosal myomas were less common, with mean numbers of 0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92 and 0.30\u0026thinsp;\u0026plusmn;\u0026thinsp;0.54, respectively. The maximum uterine diameter of myomas at the first visit was 81.0\u0026thinsp;\u0026plusmn;\u0026thinsp;41.6 mm, and the mean uterine volume was 700.6\u0026thinsp;\u0026plusmn;\u0026thinsp;552.1 cm\u0026sup3;. No significant differences were observed between the length, width, and height. Following relugolix administration, the mean reduction in uterine volume was \u0026minus;\u0026thinsp;10.1% \u0026plusmn; 209.4%, a figure influenced by several cases that were non-responsive to relugolix and demonstrated increased volume. The mean reduction in maximum uterine diameter was 1.5% \u0026plusmn; 40.1%, and the mean daily reduction in uterine volume was 0.058% \u0026plusmn; 0.34%.\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\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment Outcome (Others)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone mineral density of the spine (pre-treatment) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e94.8\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone mineral density of the right caput femoris (pre-treatment) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.7\u0026thinsp;\u0026plusmn;\u0026thinsp;18.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone mineral density of the left caput femoris (pre-treatment) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e97.6\u0026thinsp;\u0026plusmn;\u0026thinsp;19.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone mineral density of the spine (post-treatment) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e93.4\u0026thinsp;\u0026plusmn;\u0026thinsp;16.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone mineral density of the right caput femoris (post-treatment) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e91.7\u0026thinsp;\u0026plusmn;\u0026thinsp;15.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBone mineral density of the left caput femoris (post-treatment) (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e89.2\u0026thinsp;\u0026plusmn;\u0026thinsp;17.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction in the bone mineral density of the spine (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.5\u0026thinsp;\u0026plusmn;\u0026thinsp;20.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction in the bone mineral density of the right caput femoris (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;14.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReduction in the bone mineral density of the left caput femoris (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eE2 (post-treatment) (pg/mL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e163.3\u0026thinsp;\u0026plusmn;\u0026thinsp;155.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003elowest Hb (post-treatment) (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9.6\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ehighest CA125 (post-treatment) (mg/dL)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e112.4\u0026thinsp;\u0026plusmn;\u0026thinsp;157.0\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood transfusion history (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.2 (6/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo desire for surgery (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e36.1 (30/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImprovement of symptoms (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e60.2 (50/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgery (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.5 (37/83)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCases of menopause after relugolix (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.4 (7/83)\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\u003eCorrelation and statistical analyses were performed for each parameter. The strengths of these correlations are shown in Fig.\u0026nbsp;1. Among the evaluated variables, those demonstrating strong correlations and statistical significance in the Spearman\u0026rsquo;s rank correlation were selected for further analysis. A multiple linear regression analysis was then conducted, with the percentage reduction in the maximum uterine myoma diameter after treatment as the dependent variable and the initial maximum myoma diameter at the first visit, duration of relugolix administration, age, and hemoglobin level (Hb) as independent variables. The analysis revealed a significant positive correlation between the initial maximum myoma diameter (p\u0026thinsp;=\u0026thinsp;0.01) and age (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), and a significant negative correlation with the duration of relugolix administration (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01). No significant correlation was observed between Hb levels and the total number of uterine myomas.\u003c/p\u003e\n\u003cp\u003eRegarding bone mineral density (BMD), the extent of missing data was too large to allow for a reliable analysis using multiple imputation methods. Individual case-based assessments were conducted. No BMD reduction was observed after relugolix administration. The mean post-treatment estradiol (E2) level was 163.3 \u0026plusmn; 155.0 pg/mL. The lowest recorded post-treatment hemoglobin (Hb) level was 9.6 \u0026plusmn; 2.3 mg/dL, and the highest post-treatment CA125 level was 112.4 \u0026plusmn; 157.0 mg/dL. A history of blood transfusion was documented in 7.2% of the patients. Regarding patient outcomes, 36.1% expressed no desire for surgery, whereas 60.2% reported symptomatic improvement, indicating that more than half of the patients experienced symptom relief. Ultimately, 44.5% of the patients underwent surgery, whereas 8.4% were able to continue treatment until menopause. Notably, among patients who received long-term relugolix administration, surgical intervention was rarely required.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eUterine fibroids are among the most common gynecological disorders and approximately 25% of women of reproductive age experience symptoms related to this condition. Of these, approximately 25% required hospitalization owing to the severity of their symptoms. As many women remain asymptomatic or gradually develop symptoms, the true prevalence of uterine fibroids is likely to be underestimated. A considerable number of cases remain undiagnosed and have not been thoroughly evaluated.\u003csup\u003e3\u003c/sup\u003e Moreover, even among symptomatic patients, a proportional decline in surgical interventions often presents challenges for attending physicians in establishing an appropriate treatment strategy. As a result, there is growing interest in the long-term administration of relugolix as a non-surgical option. However, evidence on the long-term efficacy and safety of relugolix is limited in the current literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRelugolix\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegarding relugolix, a Phase III clinical trial conducted in Japanese women reported high efficacy in relieving pain and favorable tolerability for the treatment of uterine fibroids.\u003csup\u003e4\u003c/sup\u003e However, relugolix is currently recommended to be administered for no longer than 180 days, and its long-term efficacy and safety remain unclear.\u003c/p\u003e\n\u003cp\u003eAyman et al. reported the safety of long-term relugolix use for up to 52 weeks. However, their study evaluated a combination therapy consisting of relugolix 40 mg with estradiol 1 mg and norethindrone acetate 0.5 mg. Thus, there is a paucity of data regarding the use of relugolix monotherapy over extended periods.\u003csup\u003e5\u003c/sup\u003e In our study, we demonstrated that relugolix monotherapy improved the quality of life in more than half of the patients who did not wish to undergo surgery, and this was achieved without any observed reduction in bone mineral density. The longest duration of relugolix administration at our institution was 1,030 days, during which no major adverse events were observed.\u003c/p\u003e\n\u003cp\u003eFrom a pharmacological perspective, GnRH receptors are expressed in uterine smooth muscle tumors (leiomyomas), and GnRH analogs have been shown to directly bind to these receptors, modulating transcription, and suppressing the production of extracellular matrix (ECM) components in fibroid cells. In vitro studies on cetrorelix, an injectable GnRH antagonist, have demonstrated not only binding to GnRH receptors but also a reduction in the synthesis of several ECM proteins.\u003csup\u003e6\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eGiven these findings, it is desirable that future studies evaluate how long-term relugolix administration, particularly as a monotherapy, may influence molecular pathways such as receptor downregulation and ECM-related mechanisms, especially in the context of our current clinical observations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Considerations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pathogenesis of uterine fibroids involves not only estrogen exposure, but also a complex interplay of genetic and epigenetic factors, individual lifestyle choices, and environmental influences. Additionally, several studies have reported that conditions, such as vitamin D deficiency, hypertension, and metabolic syndrome, may contribute to the development of fibroids in certain patients.\u003csup\u003e7\u003c/sup\u003e Given these multifactorial etiologies, personalized prevention and treatment strategies should be emphasized in the management of uterine fibroids. In particular, the duration of relugolix therapy should be considered on a case-by-case basis, especially considering its potential effects on bone mineral density. Therefore, a tailored patient-specific approach is essential.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTreatment selection for uterine fibroids is inherently complex and should be based on the patient\u0026rsquo;s clinical symptoms, reproductive desires, and social background.\u003csup\u003e8\u003c/sup\u003e Available options include surgical procedures, uterine artery embolization, and various medical therapies such as GnRH agonists or selective estrogen receptor modulators (SERMs). However, as observed in our cohort, a significant proportion of patients with severe symptoms opted for surgical intervention, highlighting the challenges gynecologists often face when establishing appropriate treatment plans.\u003c/p\u003e\n\u003cp\u003eEstrogen levels decline with age.\u003csup\u003e9\u003c/sup\u003e In this study, we observed a negative correlation between age and the rate of fibroid size reduction and found that the degree of shrinkage was more strongly related to the maximum size of the fibroids than to their number. These findings suggest that if a scoring system can be developed based on patient age and initial fibroid size, it may be possible to predict successful symptom control until menopause with medical therapy alone, particularly in patients unwilling to undergo surgery.\u003c/p\u003e\n\u003cp\u003eDonnez et al. reported that oral GnRH antagonists produce a rapid improvement in heavy menstrual bleeding in over 70% of women and, when used without add-back therapy, can lead to a significant reduction in fibroid volume, up to approximately 50% at 24 weeks from baseline.\u003csup\u003e10\u003c/sup\u003e Additionally, a recent meta-analysis of the efficacy of GnRH antagonists in the treatment of uterine fibroids concluded that these agents were associated with symptom improvement and an average volume reduction of approximately 27%.\u003csup\u003e11\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eIn the present study, we also observed a sustained reduction in fibroid size in the long-term treatment cases. Importantly, no new-onset osteoporosis was noted during extended administration, suggesting that long-term relugolix therapy may allow a substantial number of patients to avoid surgery. In case-specific observations, several cases involved patients with severe comorbidities, including cardiovascular disease and recipients of organ transplants (e.g., renal transplantation), in whom anemia due to fibroids or endometriosis had a direct impact on prognosis. In such high-risk patients, the continuous administration of relugolix until menopause appears inevitable, underscoring the clinical necessity for safe and effective long-term therapeutic strategies.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAssociation with infertility\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWhile further investigation is needed to fully evaluate the efficacy of relugolix in treating infertility associated with uterine fibroids, fibroids larger than 4 cm in diameter have been reported to negatively affect fertility, even in the absence of protrusion into the endometrial cavity.\u003csup\u003e12\u003c/sup\u003e Therefore, long-term administration of relugolix may be a beneficial option for patients who wish to avoid surgery, but still hope to preserve or improve future fertility. In comparison with other pharmacological agents, a Phase III trial conducted in Japan demonstrated that relugolix provided relief from endometriosis-associated pain equal to that provided byas GnRH agonists. Importantly, relugolix is associated with a more rapid recovery of serum estradiol (E2) levels and earlier resumption of menstruation following treatment cessation, which is particularly valuable for planning pregnancy. Moreover, relugolix has been associated with faster recovery from treatment-emergent adverse events after discontinuation.\u003csup\u003e13\u003c/sup\u003e GnRH agonists are also known to reduce endometrial thickness and the associated bleeding; thus, pretreatment with a GnRH agonist may reduce bleeding during subsequent dienogest (DNG) therapy. The surgical treatment of fibroids may increase the risk of uterine rupture during pregnancy.\u003csup\u003e14\u003c/sup\u003e Although the required postoperative contraception period varies among institutions, long-term relugolix therapy during egg retrieval and the pre-embryo transfer phase may contribute to fibroid shrinkage and potentially shorten the time to pregnancy by enabling earlier embryo transfer.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLimitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study had several limitations. First, this study was conducted at a single institution and used a retrospective design, resulting in a certain degree of missing data. Future studies using more robust methodologies and higher levels of evidence are warranted. Additionally, both intermittent and continuous relugolix administration were determined by the attending physicians based on clinical judgment, which may have affected the treatment outcomes. Patient preferences also change over time and in response to symptoms, making it difficult to isolate the effects of relugolix alone. Therefore, interpretation of treatment efficacy should be approached with caution.\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eLong-term administration of relugolix was well tolerated without any serious adverse events. It contributes to the reduction of the uterine fibroid volume and maximum fibroid diameter, with a substantial number of patients experiencing an improved quality of life and successfully avoiding surgery. Future research should focus on assessing the expression of estrogen receptors (ER) and progesterone receptors (PR) in patients with uterine fibroids and endometriosis, as this may enable a better prediction of the likelihood of surgical avoidance, treatment efficacy, and degree of pain relief. Furthermore, the accumulation of additional cases and extended long-term follow-up are warranted to further elucidate the benefits and safety of prolonged relugolix therapy.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eInformed consent was obtained from all patients for this observational study.\u003c/p\u003e\n\u003cp\u003eThe study was conducted in compliance in accordance with the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003eTokyo Women\u0026rsquo;s Medical University, the Internal Review Board\u003c/p\u003e\n\u003cp\u003eApproval Number is 5704\u003c/p\u003e\n\u003cp\u003eFunding Declaration\u003c/p\u003e\n\u003cp\u003eNo Funding\u003c/p\u003e\n\u003cp\u003eHuman Ethics and Consent to Participate declarations\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data described in this article can be freely and openly accessed at Supplementary material\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZhang Z. Multiple imputation with multivariate imputation by chained equation (MICE) package. Ann Transl Med. 2016;4:30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBray MJ, et al. Evaluating Risk Factors for Differences in Fibroid Size and Number Using a Large Electronic Health Record Population. Maturitas. 2018;114:9\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAhmad A, et al. Diagnosis and management of uterine fibroids: current trends and future strategies. J Basic Clin Physiol Pharmacol. 2023;34:291\u0026ndash;310.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOsuga Y et al. Relugolix, a novel oral gonadotropin-releasing hormone antagonist, in the treatment of pain symptoms associated with uterine fibroids: a randomized, placebo-controlled, phase 3 study in Japanese women. Fertil Steril. 2019;112:922-9.e2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAl-Hendy A, et al. Long-term Relugolix Combination Therapy for Symptomatic Uterine Leiomyomas. Obstet Gynecol. 2022;140:920\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSchwartz A. Relugolix reduces leiomyoma extracellular matrix production via the transforming growth factor-beta pathway. F S Sci. 2025;6:213\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEl Sabeh M. The Future of Uterine Fibroid Management: A More Preventive and Personalized Paradigm. Reprod Sci. 2021;28:3285\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDonnez J, Dolmans MM. Uterine fibroid management: from the present to the future. Hum Reprod Update. 2016;22:665\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLephart ED. A review of the role of estrogen in dermal aging and facial attractiveness in women. J Cosmet Dermatol. 2018;17:282\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDonnez J. Uterine fibroid\u0026ndash;related infertility: mechanisms and management. Fertil Steril. 2024;122:31\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMart\u0026iacute;n MJS, et al. Efficacy of GnRH antagonists in the treatment of uterine fibroids: a meta\u0026ndash;analysis. Arch Gynecol Obstet. 2025;311:685\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHeertum KV, Barmat L. Uterine fibroids associated with infertility. Womens Health (Lond). 2014;10:645\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHarada T, et al. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, reduces endometriosis-associated pain compared with leuprorelin in Japanese women: a phase 3, randomized, double-blind, noninferiority study. Fertil Steril. 2022;117:583\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKim HS, et al. Uterine rupture in pregnancies following myomectomy: A multicenter case series. Obstet Gynecol Sci. 2016;59:454\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7229530/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7229530/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eRelugolix, an oral gonadotropin-releasing hormone (GnRH) antagonist, is effective for uterine fibroids, but its recommended use is limited to 180 days. Data on the long-term efficacy and safety of relugolix monotherapy are scarce. This study aimed to evaluate the treatment outcomes and safety of long-term relugolix administration in a real-world clinical setting.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a retrospective study of patients prescribed relugolix at a single institution between 2013 and 2024. Patients who received relugolix for more than 180 days were included in the analysis. Key outcomes included changes in uterine fibroid volume and diameter, symptom improvement, bone mineral density (BMD), and the rate of subsequent surgical intervention. Multivariate imputation was used for missing data, and multiple linear regression analysis was performed to identify factors correlated with treatment response.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eEighty-three patients were analyzed, with a mean relugolix administration duration of 357.1\u0026thinsp;\u0026plusmn;\u0026thinsp;158.4 days. The mean age was 41.7\u0026thinsp;\u0026plusmn;\u0026thinsp;6.8 years. A reduction in uterine volume (-10.1% \u0026plusmn; 209.4%) and maximum fibroid diameter (1.5% \u0026plusmn; 40.1%) was observed. Multiple regression analysis revealed that a larger initial fibroid diameter (p\u0026thinsp;=\u0026thinsp;0.01) and older age (p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) were significantly correlated with a greater percentage reduction in fibroid size. Symptomatic improvement was reported by 60.2% of patients, and 36.1% no longer desired surgery. No significant decrease in BMD was observed. Ultimately, 44.5% of patients underwent surgery, while 8.4% successfully transitioned into menopause on therapy. No serious adverse events were reported during long-term administration.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eLong-term administration of relugolix monotherapy was well-tolerated and effective in reducing uterine fibroid volume and improving symptoms. It allowed a substantial number of patients to improve their quality of life and avoid or delay surgery, suggesting it is a viable option for the long-term management of symptomatic uterine fibroids.\u003c/p\u003e","manuscriptTitle":"A retrospective study of treatment outcomes and safety in patients receiving long-term relugolix administration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:40:14","doi":"10.21203/rs.3.rs-7229530/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a262d669-87dd-4c40-827b-0b034e54ce60","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-14T06:54:04+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-23 02:40:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7229530","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7229530","identity":"rs-7229530","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}