{"paper_id":"393f922c-8dac-450f-900d-c12d154e0d4e","body_text":"1 \nCharacterization of patients that can continue 1 \nconservative treatment for adenomyosis 2 \n 3 \nChiho Miyagawa, M.D.1,2 4 \nKosuke Murakami, M.D.1* 5 \nTakako Tobiume, M.D., Ph.D.3 6 \nTakafumi Nonogaki, M.D., Ph.D.2 7 \nNoriomi Matsumura, M.D., Ph.D.1 8 \n1 Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, 9 \nOsaka-sayama, Osaka, Japan 10 \n2 Department of Obstetrics and Gynecology, Osaka Red Cross Hospital, Osaka, Japan 11 \n3 Department of Obstetrics and Gynecology, National Hospital Organization Osaka 12 \nNational Hospital, Osaka, Japan 13 \n 14 \nContinuation of conservative treatment for adenomyosis 15 \n 16 \n*Corresponding author: Kosuke Murakami 17 \nDepartment of Obstetrics and Gynecology, Kindai University Faculty of Medicine 18 \n377-2, Ohnohigashi, Osaka-sayama, Osaka, Japan, 589-8511 19 \nE-mail: kmurakami@med.kindai.ac.jp 20 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n 2 \nAbstract 21 \nIntroduction 22 \nHistorically, hysterectomy has been the radical treatment for adenomyosis. 23 \nHowever, some patients do not wish to hysterectomy. Nevertheless, patients often 24 \nrequired hysterectomy during the course of conservative treatment, but the factors 25 \ninvolved remain unknown. The purpose of this study was to determine which patients 26 \ncan continue conservative treatment for adenomyosis. 27 \nMaterials and Methods 28 \nWe selected women diagnosed with adenomyosis and provided with 29 \nconservative treatment at the Kindai University Hospital and Osaka Red Cross Hospital. 30 \nAge at diagnosis, parity, uterine size, subtype of adenomyosis, type of conservative 31 \ntreatment, and timing of hysterectomy for cases with difficulty continuing conservative 32 \ntreatment were examined retrospectively. 33 \nResults 34 \nA total of 885 patients were diagnosed with adenomyosis, and 124 started 35 \nconservative treatment. Conservative treatment was continued in 96 patients (77.4%) 36 \nand hysterectomy was required in 28 patients (22.6%). The cumulative hysterectomy 37 \nrate was 32.4%, and all women had hysterectomy within 63 months. In the decision tree 38 \nanalysis, 82% (23/28) of women aged 46 years or younger were able to continue 39 \nconservative treatment when parity was zero or one. If parity was two and over, 95% 40 \n(20/21) of those aged 39 years and older had hysterectomy. 41 \nConclusions 42 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 3 \nPatients that continue conservative treatment for approximately 5 years are 43 \nmore likely to have successful preservation of the uterus. Multipara and higher age of 44 \ndiagnosis are factors that contribute to hysterectomy after conservative treatment. Parity 45 \nand age at diagnosis may be stratifying factor in future clinical trials on hormone 46 \ntherapy. 47 \n  48 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 4 \n1. Introduction 49 \n Adenomyosis is a benign disorder in which the endometrium and endometrial 50 \nstromal cells proliferate in the muscle layer of the uterus.1 2 Associated symptoms of 51 \nanemia, abdominal pain, and chronic pelvic pain due to excessive menstruation and 52 \ndysmenorrhea are common in women of reproductive age and significantly impair 53 \nquality of life.3 Traditionally, adenomyosis was often first diagnosed by pathological 54 \nexamination after hysterectomy and was considered a disorder that affected the peri-55 \nmenopausal period.4 5 However, with the widespread use of ultrasonography and 56 \nmagnetic resonance imaging (MRI) in recent years, it has become possible to accurately 57 \ndiagnose adenomyosis by imaging, and it is now diagnosed in relatively young 58 \nwomen .6-9 59 \n Historically, the radical treatment for adenomyosis has been hysterectomy.7 60 \nHowever, conservative treatments of adenomyosis, such as hormone therapy and 61 \nadenomyomectomy, are preferred by patients who are young and wish to preserve 62 \nfertility, or do not want hysterectomy or may be at high risk for perioperative 63 \ncomplications.10 For women who do not wish to become pregnant immediately, 64 \nconservative treatment mainly involves hormone therapy, which is continued until 65 \nmenopause.11 However, even with hormone therapy for adenomyosis, patients often 66 \nexperience persistent symptoms, including pain and drug side effects, such as irregular 67 \nbleeding or osteoporosis, that result in the need for hysterectomy.10 12-14 To date, it has 68 \nbeen unclear which women can continue conservative treatment for adenomyosis. The 69 \nidentification of factors related to the success or failure of conservative treatment would 70 \ngreatly contribute to the choice of treatment strategy, and significantly benefit the 71 \nquality of life of women and the health care economy. 72 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 5 \nThe purpose of this study was to evaluate the treatment course of patients with 73 \nadenomyosis who have requested conservative treatment, and to determine which 74 \nwomen can continue conservative treatment. 75 \n 76 \n2. Materials and Methods 77 \n2.1. Cases 78 \nFrom January 2008 to December 2017, patients diagnosed with adenomyosis 79 \nand started conservative treatment at Kindai University Hospital and Osaka Red Cross 80 \nHospital were selected and studied retrospectively. Exclusion criteria was the absence 81 \nof symptoms due to adenomyosis (e.g., if the patient is being monitored for 82 \nendometriosis or other comorbidities) or pre-treatment imaging, request for 83 \nhysterectomy at the first visit, presence of submucosal myoma or 3 cm/three or more 84 \nintramuscular myomas that may cause hypermenorrhea. 85 \n 86 \n2.2. Diagnosis 87 \n The diagnosis of adenomyosis was made using patients’ symptoms, such as 88 \ndysmenorrhea and hypermenorrhea, and imaging techniques, such as MRI or 89 \ntransvaginal ultrasound. The criteria for diagnosis by MRI were the presence of an 90 \nenlarged myometrium with an indistinct limbus and a heterogeneous internal signal on 91 \nT2-weighted images or thickening of the junctional zone (>12 mm).15 16 The diagnostic 92 \ncriteria for transvaginal ultrasonography were asymmetrical enlargement of the 93 \nmyometrium and an asymmetrical decrease in echogenicity of the lesion.1 10 Most of the 94 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 6 \ncases were diagnosed by MRI, but only two cases were diagnosed by transvaginal 95 \nultrasonography without pre-treatment MRI. Age was defined as the time when 96 \nadenomyosis was diagnosed on imaging. 97 \n 98 \n2.3. Size Measurement 99 \n Measurements of the size of the uterus and the myometrium were performed 100 \nusing MRI (figure1). In sagittal sections of MRI T2-weighted images, the length from 101 \nthe cervix to the bottom of the uterus was defined as the long axis diameter of the uterus 102 \n(a), the maximum diameter perpendicular to long axis diameter was defined as the short 103 \naxis diameter of the uterus (b), and the thickness of the uterine muscle layer within the 104 \nshort axis diameter of the uterus was defined as the muscle layer thickness (c). The 105 \nmaximum transverse diameter of the uterus in the axial section of MRI T2-weighted 106 \nimages was defined as the transverse diameter of the uterus (d). In the two cases 107 \nmeasured by transvaginal ultrasonography, (a), (b), and (c) were measured at the 108 \nposition of maximum sagittal section. 109 \n 110 \n2.4. Type of Adenomyosis 111 \nAdenomyosis was classified into four subtypes based on MRI imaging 112 \nfeatures.17 Subtype I adenomyosis involved adenomyotic lesions that extended from the 113 \nendometrium and did not extend to the entire myometrium. Subtype II adenomyosis 114 \nwas defined as adenomyotic lesions that extended from the perimetrium and did not 115 \nextend into the junctional zone. Subtype III adenomyosis was an isolated adenomyotic 116 \nlesion in the myometrium that did not extend into the junctional zone and the 117 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 7 \nperimetrium. Subtype IV adenomyosis was defined as a lesion that could not be 118 \nclassified as types I–III, where the lesion involved the entire muscle layer. Two cases 119 \ndiagnosed by transvaginal ultrasonography were not evaluated. 120 \n 121 \n2.5. Type of conservative treatment 122 \nHormone therapy (gonadotropin releasing hormone agonist (GnRHa), progestins, 123 \nlevonorgestrel-releasing intrauterine system (LNG-IUS, Mirena intrauterine delivery 124 \nsystem®, Bayer Yakuhin, Ltd), oral contraceptives (OCs), and danazol (BONZOL 125 \ntablets®, Mitsubishi Tanabe Pharma Corporation) and adenomyomectomy were 126 \nprovided as conservative treatment for adenomyosis. Hysterectomy was performed after 127 \nconsultation with the patient when the symptoms worsened, or it became difficult to 128 \ncontinue hormone therapy. Treatment was started on the date of the first visit, and the 129 \nend of treatment was set at the date of the hysterectomy surgery or at the end of the 130 \nobservation period. 131 \n 132 \n2.6. Statistical analysis 133 \n Statistical analysis was performed using Graphpad Prism ver. 8.2.0 (GraphPad 134 \nSoftware, San Diego, CA, USA). The cumulative hysterectomy rate was determined by 135 \nthe Log-rank test, and comparison between the two groups used the Mann-Whitney U 136 \ntest and χ2 test, with P<0.05 as a significant difference. Decision tree analysis was 137 \nperformed using weka (https://doi.org/10.1016/j.knosys.2019.04.013). 138 \n 139 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 8 \n2.7. Ethics statement 140 \n This study was conducted with the approval of the ethics committees of Kindai 141 \nUniversity Hospital and Osaka Red Cross Hospital (The approval numbers are R02-090 142 \nfor Kindai University Hospital and J-0156 for Osaka Red Cross Hospital). 143 \n 144 \n2.8. Patients and public involvement  145 \n Patients and the public were not involved in this study, including data 146 \ncollection, analysis and interpretation.  147 \n 148 \n3. Results 149 \n A total of 885 patients were diagnosed with adenomyosis and started on 150 \ntreatment; 694 with no symptoms or no pre-treatment imaging, 51 who requested a 151 \nhysterectomy at the time of first visit, and 16 with submucosal myoma or 3 cm/three or 152 \nmore intramuscular myomas that may cause hypermenorrhea were excluded, and 124 153 \npatients were started on conservative treatment (figure 2). Baseline characteristics of the 154 \n124 patients are presented in table 1. The median treatment period was 28 months (1–155 \n132 months), median age was 41 years (24–53 years), median parity was 1 (0–3), 156 \nmedian long axis diameter of the uterus was 9.7 cm (6.3–17.7 cm), median short axis 157 \ndiameter was 6.7 cm (3.5–12.9 cm), median transverse diameter was 6.8 cm (2.8–14.2 158 \ncm) and the median muscle layer thickness was 3.9 cm (1.3–8.8 cm). Adenomyosis 159 \nsubtypes I, II, III and IV were identified in 33 (26.6%), 28 (22.6%), 3 (2.4%) and 60 160 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 9 \n(48.4%) of these patients, respectively. Conservative treatment with hormone therapy 161 \nalone was provided for 117 patients (94.4%), adenomyomectomy alone was performed 162 \nfor three patients (2.4%), and a mixture of these two procedures were provided for four 163 \npatients (3.2%). The breakdown of hormone therapy is presented in figure 3. 164 \n Ninety-six women (77.4%) were able to continue conservative treatment 165 \nthroughout the treatment period, and 28 patients (22.6%) required hysterectomy during 166 \nthe course of conservative treatment (figure 4). The cumulative total hysterectomy rate, 167 \ndetermined from the log-rank test of 124 patients who started conservative treatment, 168 \nwas 32.4% and the 28 that required hysterectomy (Group A) all had hysterectomy 169 \nwithin 63 months (figure 4). Of the 96 patients who were able to continue conservative 170 \ntreatment, 26 were able to continue conservative treatment for adenomyosis beyond 63 171 \nmonths (Group B), and all of them ultimately did not require hysterectomy (figure 4). 172 \n The characteristics of Group A and Group B are presented in Table 2. Group A 173 \nhad a significantly higher age (Group A: 43 years, Group B: 37 years, p<0.001), higher 174 \ngravidity (Group A: 2, Group B: 0, p<0.001) and parity (Group A: 2, Group B: 0, 175 \np<0.001), and a significantly higher proportion of multipara (Group A: 82.1%, Group 176 \nB: 42.3%, p<0.001) compared with Group B. The long axis diameter (Group A: 11.1 177 \ncm, Group B: 9.0 cm, p<0.001), short axis diameter (Group A: 9.0 cm, Group B: 7.7 178 \ncm, p=0.002), transverse diameter Group A: 8.0 cm, Group B: 6.6 cm, p=0.012), and 179 \nmuscle layer thickness (Group A: 4.6 cm, Group B: 3.6 cm, p=0.018) were significantly 180 \nlarger in Group A than those in Group B. The proportion of subtype IV adenomyosis 181 \nand other complications of endometriosis were not significantly different between the 182 \ntwo groups. 183 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 10 \nTo determine the critical factors involved in whether conservative treatment for 184 \nsymptomatic adenomyosis can be continued or not, we performed a decision tree 185 \nanalysis of Groups A (group of discontinued conservative treatment) and B (group of 186 \ncontinued conservative treatment) using all the factors presented in Table 2, as shown in 187 \nfigure 5. Interestingly, only parity and age, rather than factors related to adenomyotic 188 \nlesions, such as uterine size or adenomyosis subtype classification, had a decisive 189 \nimpact on the success rate of conservation treatment. The first and most important 190 \nfactor was parity, with 74% (23/31) of women with a parity of zero or one continuing 191 \nconservative treatment, compared to only 13% (3/23) with a parity of two or more 192 \ncontinuing conservative treatment. A total of 80% of patients were divided into two 193 \ngroups based on whether or not they could continue treatment with parity alone. For 194 \nexample, three cases of hysterectomy occurred in patients aged 47 years and older who 195 \nhad a parity of zero or one. When parity was two or more, only two patients younger 196 \nthan 38 years continued conservative treatment. 197 \n 198 \n4. Discussion 199 \n We retrospectively examined the course of attempted uterine preservation in 200 \npatients with symptomatic adenomyosis to determine in which patient conservative 201 \ntreatment could be continued and in which patient hysterectomy was necessary. This 202 \nstudy was unique in that (i) we extracted continued and discontinued conservative 203 \ntreatment cases from the curves of the cumulative hysterectomy rate increase in women 204 \nwho attempted uterine preservation, and (ii) we identified factors that distinguish 205 \nbetween uterine preservation and non-preservation were clarified by decision tree 206 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 11 \nanalysis. For the first time, this study showed that parity and age may be important 207 \nfactors for the consideration of conservative treatment for adenomyosis. Women in this 208 \nstudy were relatively young, with a median age of 41 years, making them younger than 209 \nthose in reports from the early 2000s, but more consistent with recent reports.18-21 The 210 \nmedian parity was also low (at one), which may reflect the recent increase in aging of 211 \nprimipara and the trend of low fertility (United nations: World Population Prospects 212 \n2019). In previous reports examining the benefit of hormone therapy in adenomyosis, 213 \nthe mean pre-treatment uterine volume was 86 cm3 22, 96.5 cm3 3, 113.8 cm3 23, 158.9 214 \nml 24, 278 cm3 25, and 311 cm3 26. The median uterine volume calculated from the long, 215 \nshort, and transverse uterine diameters in the present study was 217 (71–1400) cm3, so 216 \nthe size of the uterus was consistent with those previously reported. Adenomyosis was 217 \nclassified as subtype IV in half of the cases, which tended to be more severe than 218 \npreviously reported.17 This may be due to the fact that the two centers participating in 219 \nthe study were core hospitals in the region, and therefore accepting patients with 220 \nadvanced or difficult diagnosis. In conservative treatment for adenomyosis, 221 \nadenomyomectomy is indicated when hormone therapy is difficult to continue or when 222 \nthe patient is undergoing infertility treatment. Because the uterine myometrium must be 223 \nrepaired after removal of the adenomyotic lesion, it is limited to lesions that are 224 \nlocalized and capable of preserving the normal muscle layer 27. In the present study, 225 \nadenomyomectomy was chosen for a very small number of cases during infertility 226 \ntreatment or when there was a desire for surgery. Multiple methods of hormone therapy 227 \nwere used in most cases, including GnRHa, OCs, progestins, LNG-IUS and danazol.228 \n Multiple reports have shown that the smaller the size of the uterus at the start of 229 \nhormone therapy, the more successful hormone therapy has been in treating 230 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 12 \nadenomyosis 3 22-25 28 29. In this study, the size of the uterus at the start of treatment was 231 \nalso significantly smaller in Group B, which was able to continue with conservative 232 \ntreatment of adenomyosis (table 1). However, previous reports have had mixed follow-233 \nup periods and may have included women who ultimately needed hysterectomy. In the 234 \npresent study, of the 124 patients who started conservative treatment, the failure to 235 \ncontinue treatment and necessary hysterectomy were most frequent within the first year. 236 \nThis frequency then decreased, and treatment continued in all patients without much 237 \nchange until the fifth year. Women who were able to continue conservative treatment 238 \nbeyond 63 months did not require a hysterectomy. This novel analysis and the above 239 \nresults may provide guidance for planning the treatment of adenomyosis. Furthermore, 240 \nour study exploring factors involved in the acceptability of conservative treatment found 241 \nthat patients undergoing conservative treatment for at least 5 years should be compared 242 \nwith those who have had hysterectomy. 243 \n Decision tree analysis was able to extract the fewest factors needed to most 244 \nclearly separate the two patient groups (Group A and B) in terms of sensitivity and 245 \nspecificity. Surprisingly, our current study revealed that uterine size and adenomyosis 246 \nsubtype classification17 were not among the factors. The most important factor was 247 \nparity, and most patients with a parity of two or more were found to eventually require 248 \nhysterectomy. This may reflect the psychological factor of patients with two or more 249 \nchildren wanting to prioritize parenthood, rather than continuing conservative treatment, 250 \nwhich is also associated with symptoms such as irregular bleeding and pain. It has been 251 \nreported that patients who had undergone hysterectomy for any condition, not just 252 \nadenomyosis, were significantly more likely to have had a parity of two or more.4 In 253 \naddition, parity was reported to correlate with the incidence of adenomyosis11 30, which 254 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 13 \nmay have influenced this result. The second most important factor in the decision tree 255 \nanalysis was age. This may also be related to the intensity of the desire to preserve the 256 \nuterus and the frequency of adenomyosis. Parity and age of diagnosis may be stratifying 257 \nfactor in future clinical trials on hormone therapy. 258 \n One limitation of this study was the small number of cases. We screened 885 259 \ncases of adenomyosis, but only 124 patients matched the criteria for inclusion in the 260 \nanalysis. The number of cases was further reduced to 26, because we found that only 261 \npatients successfully treated for more than 63 months could be considered to have 262 \nsuccessful uterine preservation. Therefore, it is expected that about 5000 patients with 263 \nadenomyosis would be needed to perform a similar analysis with more than 100 cases 264 \nper group. Furthermore, this study was a retrospective study of routine practice over a 265 \n10-year period, and the diversity in treatments available over this period is also a 266 \nlimitation. In Japan, progestins and the levonorgestrel-releasing intrauterine system 267 \nwere approved within the last 5 years for the treatment of adenomyosis, the increased 268 \nfrequency of their use may have influenced the results. Additionally, criteria for the 269 \ndiagnosis of adenomyosis are not yet clear, so it is possible that the patient may not be 270 \ndiagnosed even if she has symptoms. It is hoped that further research will establish clear 271 \ncriteria for the diagnosis and treatment of adenomyosis. 272 \n5. Conclusions 273 \nUterine preservation in patients with adenomyosis is more likely to be 274 \nsuccessful if they can continue conservative treatment for approximately 5 years. In 275 \naddition, multipara and higher age at diagnosis are factors for hysterectomy during 276 \nconservative treatment of adenomyosis. The results of this study may be useful in 277 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 14 \ndecision-making and for informed consent when treating patients with adenomyosis. 278 \nParity and age at diagnosis may be stratifying factor in future clinical trials on hormone 279 \ntherapy. 280 \n 281 \n  282 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 15 \nReferences 283 \n1. Levy G, Dehaene A, Laurent N, et al. 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Comparison of dienogest versus triptorelin acetate in 349 \npremenopausal women with adenomyosis: a prospective clinical trial. Arch 350 \nGynecol Obstet. 2015;292(6):1267-1271. 351 \n26. Zhang P, Song K, Li L, Yukuwa K, Kong B. Efficacy of combined 352 \nlevonorgestrel-releasing intrauterine system with gonadotropin-releasing 353 \nhormone analog for the treatment of adenomyosis. Med Princ Pract. 354 \n2013;22(5):480-483. 355 \n27. Abbas S, Raybould JE, Sastry S, de la Cruz O. Respiratory viruses in transplant 356 \nrecipients: more than just a cold. Clinical syndromes and infection prevention 357 \nprinciples. Int J Infect Dis. 2017;62:86-93. 358 \n28. Shaaban OM, Ali MK, Sabra AM, Abd El Aal DE. Levonorgestrel-releasing 359 \nintrauterine system versus a low-dose combined oral contraceptive for treatment 360 \nof adenomyotic uteri: a randomized clinical trial. Contraception. 361 \n2015;92(4):301-307. 362 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n 19 \n29. Neriishi K, Hirata T, Fukuda S, et al. Long-term dienogest administration in 363 \npatients with symptomatic adenomyosis. J Obstet Gynaecol Res. 364 \n2018;44(8):1439-1444. 365 \n30. Vercellini P, Viganò P, Somigliana E, Daguati R, Abbiati A, Fedele L. 366 \nAdenomyosis: epidemiological factors. Best Pract Res Clin Obstet Gynaecol. 367 \n2006;20(4):465-477. 368 \n 369 \n 370 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\na b\nc\nA\nd\nB\nFigure.1 Measurement of uterine size.\nT2-Weighted Image (T2WI) of MRI. \nA: We used the sagittal T2WI of the uterus to measure (a); the uterine long axis diameter, \n(b); the uterine short axis diameter and (c); the muscle layer thickness.\nB: We used the axial T2WI of the uterus to measure (d); the uterine transverse diameter.\n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n761 cases were excluded;\n• 694 cases had no symptom without treatment or no uterine size before treatment\n• 51 cases wanted to receive hysterectomy at first visit\n• 16 cases had myoma (subendometrial or over 3cm or three pieces)\n124 cases were started conservative treatment\n885 cases were diagnosed adenomyosis\nFigure.2 Cases flow chart.\nOf the 885 patients diagnosed with uterine adenomyosis, conservative treatment \nwas initiated in 124 patients.\n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n53\n75\n18\n23\n1\nNumber  of cases\nGnRHaprogestinsLNG-IUS\nOCs DNZ\n0\n20\n40\n60\n80\nFigure.3 Number of cases treated with hormone therapy.\nGnRHa: gonadotropin releasing hormone agonist, LNG-IUS: levonorgestrel-\nreleasing intrauterine systems, OCs: Oral contraceptives, DNZ: danazol.\nY-axis shows the number of cases.\n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\n0 50 100 150\n0\n10\n20\n30\n40\n50\nTime (month)\nCumulative Hysterectomy Rate (%)\nCumulative Hysterectomy Rate\nTreatment period\nCumulative Hysterectomy Rate\n0\n10\n20\n30\n50\n40\n0 50 63 100 150 (months)\n(%)\n32.4\nTreatment period (month)  12 36 63    84 108 132\nContinuing Conservative treatment number  87 54  26     15 11 2\nTotal number of Hysterectomy 13 23 28     0 0 0\nFigure.4 Cumulative hysterectomy rate. \nKaplan-Meier analysis of the treatment period. The X-axis is the duration of treatment and \nY-axis is the cumulative hysterectomy rate.\nThe cumulative hysterectomy rate was 32.4% and reached a plateau after 63 months. The \nmedian treatment period was 28 months (1–132 months). \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\nAge\nGroup A : 5\nGroup B : 23\n47 or older46 or younger\nParity\n38 or younger\n0 or 1\nAge\n2 or more\nGroup A : 28 cases\nGroup B : 26 cases\nGroup A : 3\nGroup B : 0\nGroup A : 8\nGroup B : 23\nGroup A : 20\nGroup B : 3\nGroup A : 0\nGroup B : 2\nGroup A : 20\nGroup B : 1\n39 or older\nFigure.5 Decision tree analysis.\nGroup A; cases that required hysterectomy, Group B; cases that continued conservative \ntreatment of adenomyosis. Accuracy: 77.8%\n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\nTable 1 Clinical characteristics of the 124 patients undergoing conservative treatment for \nadenomyosis \n \n \nn=124 \nAge 41 (24-53) \nParity 1 (0-3) \nGravida 1 (0-6) \n  \nSize of Uterus  \nLong axis diameter (cm) 9.65 (63-177) \nShort axis diameter (cm) 6.65 (35-129) \nTransvers diameter (cm) 6.75 (28-142) \nMuscle layer thickness (cm) 3.9 (13-88) \n  \nType of Adenomyosis  \nType Ⅰ 33 (26.6%) \nType Ⅱ 28 (22.6%) \nType Ⅲ 3 (2.4%) \nType Ⅳ 60 (48.4%) \n  \nType of Treatment  \nHormonal Therapy 117 (94.4%) \nAdenomyomectomy 3 (2.4%) \nHormonal & Adenomyomectomy 4 (3.2%) \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint \n\nTable 2 Comparison of clinical characteristic of at baseline between cases failed \nconservative therapy (Group A) and continued uterine conservative therapy (Group B). \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n*the Mann-Whitney U test, †χ2 test \n \n \n \n \nGroup A \n (n=28) \nGroup B \n(n=26) \nP value \nAge† 43 (33-53) 37 (27-46) <0.001 \nGravida† 2 (0-6) 0 (0-3) <0.001 \nParity† 2 (0-3) 0 (0-2) <0.001 \nMultipara† 23 (82.1%) 11 (42.3%) <0.001 \n    \nLong axis diameter (cm)* 11.1 (76-177) 9.0 (64-130) <0.001 \nShort axis diameter (cm)* 7.7 (47-129) 6.0 (35-99) 0.002 \nTransvers diameter (cm)* 8.0 (41-142) 6.6 (37-92) 0.012 \nMuscle layer thickness (cm)* 4.6 (25-73) 3.5 (13-64) 0.018 \n    \nType Ⅳ adenomyosis* 18 (64.3%) 10 (38.5%) 0.059 \nAnother of endometriosis* 11 (39.3%) 13 (50.0%) 0.766 \n . CC-BY-NC-ND 4.0 International licenseIt is made available under a \n is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)\nThe copyright holder for this preprintthis version posted March 6, 2021. ; https://doi.org/10.1101/2021.03.03.21252870doi: medRxiv preprint","source_license":"CC0","license_restricted":false}