{"paper_id":"60adf217-c567-4fd3-b915-a43bf9dcd5f3","body_text":"RESEARCH Open Access\n© The Author(s) 2025. Open Access  This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 \nInternational License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you \ngive appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the \nlicensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or \nother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the \nmaterial. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or \nexceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit  h t t p :   /  / c r e a t i  \nv e c  o m m  o n  s  . o  r  g /  l i c  e n s   e s  /  b y  - n c  -  n d / 4 . 0 /.\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nhttps://doi.org/10.1186/s12905-025-03817-w\nBMC Women's Health\n*Correspondence:\nYasushi Hirota\nhirotay-gyn@h.u-tokyo.ac.jp\n1Department of Obstetrics and Gynecology, Graduate School of \nMedicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku,  \nTokyo 113-8655, Japan\nAbstract\nAdenomyosis often causes dysmenorrhea in women of reproductive age. Progestins such as levonorgestrel \nintrauterine system (LNG-IUS) are often used for treatment, but some patients experience progesterone resistance, \nshowing poor treatment response. However, the clinical characteristics of progesterone-resistant and progesterone-\nsensitive patients with symptomatic adenomyosis remain unclear. We analyzed data of 69 patients with \nadenomyosis treated with LNG-IUS. Dysmenorrhea was quantified using linear visual analog scale (VAS) scoring, \nand progesterone resistance was interpreted as continued dysmenorrhea during LNG-IUS treatment. The rate of \nchange in VAS scores of dysmenorrhea was calculated: patients with the bottom 25% improvement were defined \nas progesterone-resistant group, and those with the top 25% improvement as progesterone-sensitive group. The \nlocalization of adenomyosis lesions was evaluated by magnetic resonance imaging (MRI) and classified as advanced \n(localized in all layers of the myometrium), extrinsic (localized on the uterine serosa side), and intrinsic (localized \non the endometrial side) subtypes. Progesterone-resistant group had a significantly lower incidence of intrinsic \nadenomyosis (7.7% vs. 69.2%, p = 0.004) and a tendency toward a higher incidence of advanced adenomyosis \n(61.5% vs. 23.1%, p = 0.111) compared with progesterone-sensitive group. Progesterone-sensitive group showed \nsignificant improvement of dysmenorrhea 1 month after starting LNG-IUS treatment ( p < 0.001). These findings \nindicate that the responsiveness to LNG-IUS treatment can be determined 1 month after starting the treatment \nand that intrinsic adenomyosis is a favorable prognostic factor for progestin treatment with LNG-IUS, while \nadvanced and extrinsic adenomyosis are predictors for progesterone resistance.\nKeywords Adenomyosis, Dysmenorrhea, Levonorgestrel intrauterine system, Progesterone resistance, Progestin\nPrognostic factors of progesterone resistance \nin symptomatic adenomyosis: impact \nof lesion localization on treatment outcome \nof levonorgestrel intrauterine system\nDaiki Hiratsuka1 , Mitsunori Matsuo1, Chihiro Ishizawa1, Yamato Fukui1, Takehiro Hiraoka1, Shizu Aikawa1, \nGentaro Izumi1, Miyuki Harada1, Osamu Wada-Hiraike1, Yutaka Osuga1 and Yasushi Hirota1*\n\nPage 2 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nIntroduction\nAdenomyosis is a benign gynecological disease charac -\nterized by pathological displacement of the endometrium \nin the myometrium, thereby triggering hypertrophy \nof the surrounding myometrium and causing uterine \nenlargement and various symptoms, including dysmen -\norrhea and menorrhagia [ 1]. Adenomyosis is found in \napproximately 20% of reproductive-age women, and uter-\nine-sparing treatment is often desired [ 2]. For patients \nwho wish to preserve their uterus, hormonal treatments \nsuch as low-dose estrogen-progestin, progestins, and \ngonadotropin-releasing hormone analogues (GnRH-a) \nare administered, and progestins such as Levonorgestrel \nIntrauterine System (LNG-IUS) and dienogest (DNG) are \nconsidered good options in terms of long-term treatment \nwith less adverse events [ 3– 5]. However, some patients \nrespond poorly to progestins, resulting in severe dys -\nmenorrhea [4, 6]. This poor response is known as proges-\nterone resistance, a condition of the endometrium that \ninvolves a disruption of the progesterone signaling path -\nway, resulting in unresponsiveness to progesterone [7– 9]. \nProgesterone resistance is a significant clinical challenge \nin the management of adenomyosis; however, the clinical \ncharacteristics of patients with adenomyosis that result \nin progesterone resistance remain unclear. Therefore, in \nthis study, we retrospectively assessed predictive factors \nassociated with progesterone resistance in patients with \nadenomyosis who were treated with LNG-IUS.\nMaterials and methods\nData collection\nThis study was performed in accordance with the Dec -\nlaration of Helsinki and the Ethical Guidelines for Medi -\ncal and Biological Research Involving Human Subjects \nformulated by the Japanese government. This study was \nreviewed and approved by the Research Ethics Commit -\ntee of the Faculty of Medicine of the University of Tokyo \n(IRB number: 3128). The collection of informed written \nconsent was substituted with the informed opt-out pro -\ncedure because of the retrospective nature of the study. \nInformation about this study was posted on the website \nof the University of Tokyo Hospital to give participants \nthe opportunity to opt out; those who did not opt out \nwere considered to have provided tacit consent for study \nparticipation. Anonymous clinical data were used for the \nanalysis, and individuals cannot be identified based on \nthe data presented. Waiving of written consent and the \nuse of the informed opt-out procedure were approved by \nthe Research Ethics Committee of the Faculty of Medi -\ncine of the University of Tokyo.\nThis study retrospectively analyzed deidentified medi -\ncal records of 69 patients diagnosed with symptomatic \nuterine adenomyosis detected with magnetic resonance \nimaging (MRI) and treated with LNG-IUS (Mirena \n[52  mg], Bayer Yakuhin) between 2015 and 2024 at the \nUniversity of Tokyo Hospital. Patients who were lost to \nfollow-up, those with submucosal fibroids, endometrial \npolyps, or endometrial cancer, those without dysmenor -\nrhea, and those who experienced expulsion of LNG-IUS \nwithin 6 months were excluded. Patients who were fol -\nlowed for longer than 6 months without expulsion of \nLNG-IUS after the insertion were included in the analy -\nses. The degree of dysmenorrhea was evaluated using \nlinear visual analog scale (VAS) scoring, which ranged \nfrom 0 cm (no pain) to 10 cm (worst pain possible) [ 10]. \nClinical data used included age, nulliparity, symptoms, \ntypes and localization of adenomyosis, uterine size, the \ndiameter of adenomyotic lesion, complications of leio -\nmyoma or endometriosis, treatment history, hemoglo -\nbin level before LNG-IUS treatment and at 6 months \nafter starting LNG-IUS treatment, and the VAS scores of \nmenstrual pain and chronic pelvic pain before LNG-IUS \ntreatment, and at 1 month, 3 months, 6 months, and 1 \nyear after starting LNG-IUS treatment. The subtypes of \nadenomyosis were classified based on lesion localization \non MRI according to the method of Kishi et al. [11]. Since \nno patients who were enrolled in this study were found \nto have an intramural adenomyosis (namely subtype 3 of \nthe Kishi’s classification), the patients were classified into \none of the following three subtypes: advanced (localized \nin all layers of the myometrium), extrinsic (localized on \nthe uterine serosa side), and intrinsic (localized on the \nendometrial side) subtypes [ 11]. The uterine size (cm 3) \nwas estimated with the ellipsoid formula:\n \n= anteroposterior diameter × longitudinal diameter\n× transverse diameter × 0.5236  (1)\n [12].\nDefinition of progesterone resistance\nProgesterone resistance is considered when patients with \nadenomyosis respond poorly to progestins, resulting in \nsevere gynecological symptoms such as dysmenorrhea. \nHowever, there are no standardized clinical criteria for \nprogesterone resistance in adenomyosis, as is also the \ncase in endometriosis [ 9]. In this study, progesterone \nresistance was interpreted as the state in which dysmen -\norrhea continued after starting LNG-IUS treatment. \nBased on previous reports assessing changes in pain [ 13–\n15], the rate of change in VAS scores for menstrual pain \nwas calculated as follows and used as an indicator of pro -\ngesterone resistance:\n \n= (V AS at6 months af ter LN G− IU S treatment) − (V AS bef ore LN G− IU S treatment)\n(V AS bef ore LN G− IU S treatment)  (2)\nBased on previous reports on the classification of scor -\ning systems [ 16, 17], patients with the bottom 25% \n\nPage 3 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nimprovement were defined as progesterone-resistant \ngroup, while those with the top 25% improvement \nwere defined as progesterone-sensitive group. Thirteen \npatients were classified in each group and the clinical \ncharacteristics obtained from the medical records were \ncompared.\nStatistical analysis\nAll statistical data were analyzed using R version 4.3.2. \nTwo groups were compared using Fisher’s exact test and \nMann–Whitney U test. Pre- and post-treatment compar -\nisons were performed using Wilcoxon signed-rank sum \ntest. Furthermore, a p-value < 0.05 was considered statis -\ntically significant.\nResults\nPatient characteristics\nData of 69 patients with symptomatic adenomyosis \ndetected with MRI and treated with LNG-IUS were \nreviewed. As the flowchart of this study (Fig.  1) shows, \nof the 69 patients, four patients who were lost to follow-\nup, four without dysmenorrhea, and eight with expul -\nsion of LNG-IUS within 6 months were excluded. The \ncharacteristics of the remaining 53 patients are shown in \nTable 1. The average VAS scores before LNG-IUS treat -\nment of 53 patients were significantly reduced 6 months \nafter starting LNG-IUS treatment, showing the general \neffectiveness of LNG-IUS for the treatment of symp -\ntomatic adenomyosis (7.9 [6.4–8.9] vs. 2.3 [0.4–5.8], \np < 0.001). As Fig. 2 shows, progesterone-resistant group \nFig. 1 The flowchart of this study\n \n\nPage 4 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nand progesterone-sensitive group were classified based \non the rate of change in VAS scores.\nThe 53 dots signify the rates of the change in VAS \nscores of menstrual pain of the 53 patients. Patients \nwith the bottom 25% improvement were defined as pro -\ngesterone-resistant group, while those with the top 25% \nimprovement were defined as progesterone-sensitive \ngroup. Thirteen patients were classified in each group.\nIntrinsic adenomyosis is a good prognostic factor , \nwhile extrinsic and advanced adenomyosis are predic -\ntors for progesterone resistance .\nAs Table 2 shows, the comparison between progester -\none-resistant group and progesterone-sensitive group \nshowed no differences in age, parity, hemoglobin level, \ncomplications with leiomyoma and endometriosis, local -\nization of adenomyosis, the diameter of adenomyotic \nTable 1 Characteristics of 53 patients analyzed in this study. SD, standard deviation\nCharacteristics Median [IQR] (Minimum - Maximum) p-value\nAge 44.0 [41–45] (32–50)\nNulliparous 54.7% (n = 29/53)\nDysmenorrhea 100.0% (n = 53/53)\nHypermenorrhea 73.6% (n = 39/53)\nSubtypes of adenomyosis Intrinsic: 30.2% (n = 16/53)\nExtrinsic: 18.9% (n = 10/53)\nAdvanced: 50.9% (n = 27/53)\nLocation of adenomyosis Anterior wall: 62.3% (n = 33/53)\nPosterior wall: 37.8% (n = 20/53)\nFundus: 71.7% (n = 38/53)\nUterine size (cm3) 131.6 [87.6-230.6] (37.0-1273.3)\nthe diameter of adenomyotic lesion (cm) 3.6 [2.6-5.0] (1.3–13.0)\nLeiomyoma 37.7% (n = 20/53)\nOvarian endometrioma 35.8% (n = 19/53)\nTreatment history before LNG-IUS\n Low dose Estrogen Progestin 17.0% (n = 9/53)\n Dienogest 22.6% (n = 12/53)\n GnRH analog 20.8% (n = 11/53)\nHemoglobin level (g/dL)\n before LNG-IUS treatment 12.0 [10.8–13.3] (6.4–15.1) 0.002\n six months after starting LNG-IUS treatment 13.0 [12.0-13.8] (8.9–14.7)\nVAS scores of menstrual pain\n before LNG-IUS treatment 7.9 [6.4–8.9] (0.5–10.0) < 0.001\n six months after starting LNG-IUS treatment 2.3 [0.4–5.8] (0.0–10.0)\nVAS scores of chronic pelvic pain\n before LNG-IUS treatment 3.4 [1.9–6.3] (0.0–10.0) 0.005\n six months after starting LNG-IUS treatment 0.9 [0.0–5.0] (0.0-9.4)\nHysterectomy 22.6% (n = 12/53)\nFig. 2 Classification of progesterone resistance\n \n\nPage 5 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nlesion, and uterine size. On the other hand, the rate of \nintrinsic adenomyosis was significantly lower in proges -\nterone-resistant group (7.7% vs. 69.2%, p = 0.004), while \nthe rate of advanced adenomyosis tended higher in pro -\ngesterone-resistant group (23.1% vs. 61.5%, p = 0.111), \nindicating that intrinsic adenomyosis is a good prognos -\ntic factor for progesterone response and advanced and \nextrinsic adenomyosis are predictive factors for proges -\nterone resistance.\nProgesterone resistance can be determined 1 month after \nstarting LNG-IUS treatment\nFigure 3a shows the change over time in the VAS scores of \nmenstrual pain in the two groups. The VAS scores before \nLNG-IUS treatment did not differ between progesterone-\nresistant group and progesterone-sensitive group (6.4 \n[2.8-8.0] vs. 8.2 [6.4–8.9], p = 0.158), but progesterone-\nsensitive group showed significantly higher improve -\nment rates compared to progesterone-resistant group 1 \nmonth after starting LNG-IUS treatment (6.2 [5.4-7.0] \nvs. 1.3 [0.0-1.7], p = 0.003), and this trend continued at \n3 months, 6 months, and 1 year after starting LNG-IUS \ntreatment. The same trend was also observed in terms of \nchronic pelvic pain: the VAS scores 1 month after starting \nLNG-IUS treatment were significantly different between \nthe two groups, and the difference continued until 1 year \nafter starting LNG-IUS treatment (Fig. 3b).\nDiscussion\nIn this study, we analyzed patients treated with LNG-\nIUS, a progestin medication for dysmenorrhea due to \nadenomyosis, to investigate the factors contributing to \nprogesterone resistance. We found that intrinsic adeno -\nmyosis is a favorable prognostic factor, while advanced \nand extrinsic adenomyosis are predictors for progester -\none resistance. Analysis of the VAS scores also indicated \nthat progesterone resistance can be estimated at about 1 \nmonth after starting LNG-IUS treatment.\nThis study has revealed that intrinsic adenomyosis is a \ngood prognostic factor, and subtypes other than intrin -\nsic adenomyosis including advanced adenomyosis are \npredictors for progesterone resistance in terms of pain. \nTable 2 Clinical characteristics of the progesterone resistance group. SD, standard deviation\nCharacteristics Progesterone-resistant group (n = 13) Progesterone-sensitive group (n = 13) p-value\nMedian (IQR, Minimum - Maximum)\nAge 44.0 [37.0–46.0] (33–50) 44.0 [42.0–45.0] (37–49) 0.876\nNulliparous 38.5% (n = 5/13) 69.2% (n = 9/13) 0.238\nDysmenorrhea 100.0% (n = 13/13) 100.0% (n = 13/13) 1.000\nHypermenorrhea 92.3% (n = 12/13) 92.3% (n = 12/13) 1.000\nSubtypes of adenomyosis\nIntrinsic type 7.7% (n = 1/13) 69.2% (n = 9/13) 0.004\nExtrinsic type 30.8% (n = 4/13) 7.7% (n = 1/13) 0.322\nAdvanced type 61.5% (n = 8/13) 23.1% (n = 3/13) 0.111\nLocalization of adenomyosis\nAnterior wall 53.8% (n = 7/13) 76.9% (n = 10/13) 0.411\nPosterior wall 76.9% (n = 10/13) 53.8% (n = 7/13) 0.411\nFundus 38.5% (n = 5/13) 53.8% (n = 7/13) 0.695\nUterine size (cm3) 114.2 [83.3-212.3] (37.0-405.3) 155.7 [112.2–259.0] (61.3-0.346.1) 0.362\nthe diameter of adenomyotic lesion (cm) 3.8 [2.8–4.6] (1.5–8.2) 4.3 [1.5-5.0] (1.3–7.7) 0.877\nLeiomyoma 23.1% (n = 3/13) 30.8% (n = 4/13) 1.000\nOvarian endometrioma 23.1% (n = 3/13) 15.4% (n = 2/13) 1.000\nTreatment history before LNG-IUS\n Low dose Estrogen Progestin 30.8% (n = 4/13) 15.4% (n = 2/13) 0.645\n Dienogest 23.1% (n = 3/13) 23.1% (n = 3/13) 1.000\n GnRH analog 30.8% (n = 4/13) 7.7% (n = 1/13) 0.322\nHemoglobin level (g/dL)\n before LNG-IUS treatment 12.1 [10.8–13.4] (8.1–14.3) 11.0 [9.5–12.7] (6.4–15.1) 0.608\n six months after starting LNG-IUS treatment 13.5 [11.6–13.7] (8.9–14.7) 12.9 [12.2–13.8] (10.8–14.7) 0.857\nVAS scores of menstrual pain\n before LNG-IUS treatment 6.4 [2.8-8.0] (0.5–10.0) 8.2 [6.4–8.9] (2.2–9.5) 0.158\n six months after starting LNG-IUS treatment 7.4 [5.3-8.0] (2.2–10.0) 0.0 [0.0–0.0] (0.0-0.4) < 0.001\nVAS scores of chronic pelvic pain\n before LNG-IUS treatment 4.8 [0.0-7.3] (0.0-9.1) 2.3 [0.4–3.5] (0.0-7.4) 0.396\n six months after starting LNG-IUS treatment 5.1 [2.7–6.5] (0.0-9.4) 0.0 [0.0–0.0] (0.0-7.8) 0.012\nHysterectomy 53.8% (n = 7/13) 7.7% (n = 1/13) 0.030\n\nPage 6 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nHowever, the size of the uterus or adenomyosis and the \npresence of uterine fibroids or ovarian endometriomas \nare not predictive factors. Intrinsic adenomyosis is char -\nacterized by the development of adenomyotic lesions \nfrom the endometrial side of the uterus, with lesions \nconfined to the junctional zone and the inner myo -\nmetrium from the endometrium [ 11]. This means that \nchronic adhesion of the lesions to the pelvic peritoneum \nis less likely to occur than in extrinsic and advanced sub -\ntypes, where lesions are found on the serosal side of the \nFig. 3 ( a) The comparison of the time-dependent change in the VAS scores of menstrual pain, (b)The comparison of the time-dependent change in the \nVAS scores of chronic pelvic pain\n \n\nPage 7 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nuterus and are often complicated with deep infiltrat -\ning endometriosis [ 18, 19]. Even though we have to take \ninto account that the pain of patients with extrinsic and \nadvanced adenomyosis may be influenced by endome -\ntriosis with central sensitization that has progressed \ngradually since early reproductive years [ 20, 21], these \nfindings suggest that intrinsic adenomyosis may be more \nresponsive to progestin by LNG-IUS because there are \nfewer areas where progestin-mediated inhibition via the \nprogesterone pathway is not active. Additionally, since \nthe patients were treated with LNG-IUS placed in the \nuterine lumen, it is possible that intrinsic adenomyosis \nis easier for the progestin to physically reach because \nthe lesions are localized closer to the endometrium. It \nis important for gynecologists to recognize the possi -\nbility of inadequate response to LNG-IUS treatment in \nadvanced adenomyosis and better response in intrinsic \nadenomyosis. These are important findings guiding the \nselection of LNG-IUS for patients whose main symptoms \nare dysmenorrhea and/or chronic pelvic pain. Moreover, \nsince the risk of bleeding with DNG is considered high in \nintrinsic adenomyosis, LNG-IUS is the optimal progestin \ntherapy for intrinsic adenomyosis [6].\nFurthermore, the progesterone resistance or the good \nresponse to progestin can be determined 1 month after \nstarting LNG-IUS treatment, and in the absence of pro -\ngesterone resistance, the effect of LNG-IUS on adenomy-\nosis can be sustained for at least 1 year. Although there \nhave been reports showing the efficacy of LNG-IUS for \nuterine adenomyosis [ 4], this is the first report showing \nthe efficacy of LNG-IUS at 1 month, making it possible \nto determine the efficacy of treatment at an earlier point \nafter starting LNG-IUS treatment. Furthermore, since \nthe rate of patients who eventually underwent hysterec -\ntomy was significantly higher in progesterone-resistant \ngroup in this study, it may be necessary for patients with \nprogesterone-resistant adenomyosis who wish to pre -\nserve their uterus to select a different treatment option, \nsuch as the use of GnRH-a or adenomyomectomy, at an \nearly stage [22– 25].\nHowever, even though gynecological surgeries aimed \nat improving women’s quality of life have been devel -\noped for a variety of conditions [ 26– 29], there are cases \nin which performing adenomyomectomy presents sig -\nnificant challenges. Since progestin is the first option to \ntreat adenomyosis, progesterone resistance is clinically \nimportant. Progesterone has been reported to suppress \nthe progression of adenomyosis. There have been reports \non the efficacy of progestin therapy for adenomyosis and \na report on the shrinkage of adenomyosis during preg -\nnancy, during which progesterone is abundant [ 3– 6, \n30]. There are also some reports about the molecular \nmechanisms of progesterone resistance in adenomyo -\nsis, such as the decreased expression of progesterone \nreceptor induced by KRAS mutations in the adenomy -\notic lesions and the activation of IL-6/STAT-3 signaling \npathway, but further research is necessary for the eluci -\ndation and the development of the better treatment for \nthe progesterone-resistant adenomyosis [7, 8, 31, 32]. The \nstrength of this study is the identification of clinical fac -\ntors of progesterone resistance: intrinsic adenomyosis is \na favorable prognostic factor, while subtypes other than \nintrinsic adenomyosis are predictive factors for proges -\nterone resistance. To find effective treatment for proges -\nterone-resistant adenomyosis, it will also be necessary to \nelucidate the pathophysiology of progesterone resistance, \nwhich is still not fully understood.\nThere are also some limitations in this study. First, this \nis a retrospective study with a small number of patients. \nA certain number of patients with adenomyosis suffer \nfrom poor responsiveness to treatment with progestins \nin clinical practice. However, to analyze this poor respon-\nsiveness objectively and quantitatively, it is necessary to \nevaluate scores such as VAS continuously and regularly, \nand thus, the number of analyzed cases was limited. Reg -\nular, continuous, and quantitative observation of pain \nwas used to improve the quality of this study, and MRI, \nrather than ultrasonography alone, was used to more \naccurately assess the type of adenomyosis, uterine size, \nand location of lesions [33]. The results of this study must \nbe interpreted with caution due to limitations such as the \nsmall number of patients and the retrospective nature of \nthe study, including the lack of washout periods for prior \nhormonal treatments. Further accumulation of the cases \nand consideration of other treatment strategies for pro -\ngesterone resistant-adenomyosis, such as earlier admin -\nistration of GnRH-a, are desirable for the establishment \nof better evidence and treatment strategies. Second, the \nobservation period was limited to 12 months. Since our \nhospital refers patients to a nearby clinic when their \nsymptoms are well-controlled with treatment, there were \nnot enough patients treated with progestins for longer \nthan 1 year. It is also important to accumulate cases with \nlong-term follow-up to examine the possibility of proges-\nterone resistance emerging during long term treatments. \nThird, other quantitative scores, such as the menorrhagia \nmulti-attribute scale (MMAS) as a quality-of-life indica -\ntor during menstruation and the SF-36 as a quality-of-life \nindicator in general, were lacking [ 34, 35]. A subset of \npatients in this study population was assessed using the \nMMAS, and a difference in the rate of change in MMAS \nscores was observed between the progesterone-resistant \nand progesterone-sensitive groups (before LNG-IUS \ntreatment: 26.1 [8.3–52.0] vs. 28.2 [26.1–28.9]; after \nLNG-IUS treatment: 35.4 [21.7–72.5] vs. 92.6 [62.0–\n100.0]). However, data on MMAS were missing for half of \nthe patients, making it difficult to statistically assess these \nfindings due to the limited sample size. To objectively \n\nPage 8 of 9\nHiratsuka et al. BMC Women's Health          (2025) 25:286 \nevaluate patients’ symptoms, this study assessed not only \nthe VAS score for dysmenorrhea but also the VAS score \nfor chronic pelvic pain, aiming to capture a wide range \nof symptoms associated with uterine adenomyosis. The \nVAS score has been reported to correlate with the SF-36 \nscore in studies on endometriosis, suggesting that it can \nserve as a proxy for evaluating quality of life in patients \nwith adenomyosis [ 36]. In the future, it may be possible \nto define a more effective measure of progesterone resis -\ntance by collecting and evaluating quality-of-life indices \ntogether with the VAS scores.\nIn conclusion, the subtype of adenomyosis is the only \nkey prognostic factor of progesterone resistance: intrinsic \nadenomyosis is a favorable prognostic factor for proges -\ntin treatment with LNG-IUS, while advanced and extrin -\nsic adenomyosis are predictive factors for progesterone \nresistance in terms of dysmenorrhea. The responsiveness \nto progestin can be determined 1 month after starting \nLNG-IUS treatment.\nAbbreviations\nDNG  Dienogest\nGnRH-a  Gonadotropin-releasing hormone analogues\nLNG-IUS  Levonorgestrel intrauterine system\nMRI  Magnetic resonance imaging\nVAS  Visual analog scale\nAcknowledgements\nNot applicable.\nAuthor contributions\nDH, MM, CI, YF, TH, and YH collected data. DH, SA, GI, MH, OWH and YO \ndiscussed and interpreted the results. DH drafted the manuscript, edited by \nYH. MM and YH supervised the study.\nFunding\nThis research was supported by AMED (Grant Numbers JP25gn0110085, \nJP24gn0110069, JP25gk0210039, JP24lk0310083, JP25gn0110097, \nJP25gk0210042 and JP25gk0210045), Children and Families Agency (Grant \nNumber JPMH23DB0101) and JSPS KAKENHI (Grant Numbers JP25H01065, \nJP24K21911, JP25K02779, JP24K22157).\nData availability\nThe datasets supporting the conclusions of this article are included within the \narticle.\nDeclarations\nEthics approval and consent to participate\nThis study was reviewed and approved by the Research Ethics Committee \nof the Faculty of Medicine of the University of Tokyo (IRB number: 3128). The \ncollection of informed written consent was substituted with the informed \nopt-out procedure because of the retrospective nature of the study. Waiving \nof written consent and the use of the informed opt-out procedure were \napproved by the Research Ethics Committee of the Faculty of Medicine of the \nUniversity of Tokyo.\nConsent for publication\nNot applicable.\nCompeting interests\nThe authors declare no competing interests.\nReceived: 22 March 2025 / Accepted: 21 May 2025\nReferences\n1. Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Obstet \nGynaecol. 2006;20:449–63.\n2. Naftalin J, et al. How common is adenomyosis? A prospective study of preva-\nlence using transvaginal ultrasound in a gynaecology clinic. Hum Reprod. \n2012;27:3432–9.\n3. Kitawaki J. Adenomyosis: the pathophysiology of an oestrogen-dependent \ndisease. Pract Res Clin Obstet Gynaecol. 2006;20:493–502.\n4. Ishizawa C, et al. Levonorgestrel-Releasing intrauterine system improves \nMenorrhagia-Related quality of life in patients with symptomatic adenomyo-\nsis. Reprod Sci. 2023;30:966–73.\n5. Osuga Y, Watanabe M, Hagino A. 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Qual Life \nRes. 2014;23:103–17.\nPublisher’s note\nSpringer Nature remains neutral with regard to jurisdictional claims in \npublished maps and institutional affiliations.","source_license":"CC0","license_restricted":false}