Your privacy, your choice

We use essential cookies to make sure the site can function. We also use optional cookies for advertising, personalisation of content, usage analysis, and social media.

By accepting optional cookies, you consent to the processing of your personal data - including transfers to third parties. Some third parties are outside of the European Economic Area, with varying standards of data protection.

See our privacy policy for more information on the use of your personal data.

for further information and to change your choices.

Skip to main content

Prognostic factors of progesterone resistance in symptomatic adenomyosis: impact of lesion localization on treatment outcome of levonorgestrel intrauterine system

Abstract

Adenomyosis often causes dysmenorrhea in women of reproductive age. Progestins such as levonorgestrel intrauterine system (LNG-IUS) are often used for treatment, but some patients experience progesterone resistance, showing poor treatment response. However, the clinical characteristics of progesterone-resistant and progesterone-sensitive patients with symptomatic adenomyosis remain unclear. We analyzed data of 69 patients with adenomyosis treated with LNG-IUS. Dysmenorrhea was quantified using linear visual analog scale (VAS) scoring, and progesterone resistance was interpreted as continued dysmenorrhea during LNG-IUS treatment. The rate of change in VAS scores of dysmenorrhea was calculated: patients with the bottom 25% improvement were defined as progesterone-resistant group, and those with the top 25% improvement as progesterone-sensitive group. The localization of adenomyosis lesions was evaluated by magnetic resonance imaging (MRI) and classified as advanced (localized in all layers of the myometrium), extrinsic (localized on the uterine serosa side), and intrinsic (localized on the endometrial side) subtypes. Progesterone-resistant group had a significantly lower incidence of intrinsic adenomyosis (7.7% vs. 69.2%, p = 0.004) and a tendency toward a higher incidence of advanced adenomyosis (61.5% vs. 23.1%, p = 0.111) compared with progesterone-sensitive group. Progesterone-sensitive group showed significant improvement of dysmenorrhea 1 month after starting LNG-IUS treatment (p < 0.001). These findings indicate that the responsiveness to LNG-IUS treatment can be determined 1 month after starting the treatment and that intrinsic adenomyosis is a favorable prognostic factor for progestin treatment with LNG-IUS, while advanced and extrinsic adenomyosis are predictors for progesterone resistance.

Peer Review reports

Introduction

Adenomyosis is a benign gynecological disease characterized by pathological displacement of the endometrium in the myometrium, thereby triggering hypertrophy of the surrounding myometrium and causing uterine enlargement and various symptoms, including dysmenorrhea and menorrhagia [1]. Adenomyosis is found in approximately 20% of reproductive-age women, and uterine-sparing treatment is often desired [2]. For patients who wish to preserve their uterus, hormonal treatments such as low-dose estrogen-progestin, progestins, and gonadotropin-releasing hormone analogues (GnRH-a) are administered, and progestins such as Levonorgestrel Intrauterine System (LNG-IUS) and dienogest (DNG) are considered good options in terms of long-term treatment with less adverse events [3,4,5]. However, some patients respond poorly to progestins, resulting in severe dysmenorrhea [4, 6]. This poor response is known as progesterone resistance, a condition of the endometrium that involves a disruption of the progesterone signaling pathway, resulting in unresponsiveness to progesterone [7,8,9]. Progesterone resistance is a significant clinical challenge in the management of adenomyosis; however, the clinical characteristics of patients with adenomyosis that result in progesterone resistance remain unclear. Therefore, in this study, we retrospectively assessed predictive factors associated with progesterone resistance in patients with adenomyosis who were treated with LNG-IUS.

Materials and methods

Data collection

This study was performed in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Biological Research Involving Human Subjects formulated by the Japanese government. This study was reviewed and approved by the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo (IRB number: 3128). The collection of informed written consent was substituted with the informed opt-out procedure because of the retrospective nature of the study. Information about this study was posted on the website of the University of Tokyo Hospital to give participants the opportunity to opt out; those who did not opt out were considered to have provided tacit consent for study participation. Anonymous clinical data were used for the analysis, and individuals cannot be identified based on the data presented. Waiving of written consent and the use of the informed opt-out procedure were approved by the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo.

This study retrospectively analyzed deidentified medical records of 69 patients diagnosed with symptomatic uterine adenomyosis detected with magnetic resonance imaging (MRI) and treated with LNG-IUS (Mirena [52 mg], Bayer Yakuhin) between 2015 and 2024 at the University of Tokyo Hospital. Patients who were lost to follow-up, those with submucosal fibroids, endometrial polyps, or endometrial cancer, those without dysmenorrhea, and those who experienced expulsion of LNG-IUS within 6 months were excluded. Patients who were followed for longer than 6 months without expulsion of LNG-IUS after the insertion were included in the analyses. The degree of dysmenorrhea was evaluated using linear visual analog scale (VAS) scoring, which ranged from 0 cm (no pain) to 10 cm (worst pain possible) [10]. Clinical data used included age, nulliparity, symptoms, types and localization of adenomyosis, uterine size, the diameter of adenomyotic lesion, complications of leiomyoma or endometriosis, treatment history, hemoglobin level before LNG-IUS treatment and at 6 months after starting LNG-IUS treatment, and the VAS scores of menstrual pain and chronic pelvic pain before LNG-IUS treatment, and at 1 month, 3 months, 6 months, and 1 year after starting LNG-IUS treatment. The subtypes of adenomyosis were classified based on lesion localization on MRI according to the method of Kishi et al. [11]. Since no patients who were enrolled in this study were found to have an intramural adenomyosis (namely subtype 3 of the Kishi’s classification), the patients were classified into one of the following three subtypes: advanced (localized in all layers of the myometrium), extrinsic (localized on the uterine serosa side), and intrinsic (localized on the endometrial side) subtypes [11]. The uterine size (cm3) was estimated with the ellipsoid formula:

$$\begin{array}{c}= \,anteroposterior\,diameter\, \times \,longitudinal\,diameter\,\\\times \,transverse\,diameter\, \times \,0.5236\end{array}$$
(1)

[12].

Definition of progesterone resistance

Progesterone resistance is considered when patients with adenomyosis respond poorly to progestins, resulting in severe gynecological symptoms such as dysmenorrhea. However, there are no standardized clinical criteria for progesterone resistance in adenomyosis, as is also the case in endometriosis [9]. In this study, progesterone resistance was interpreted as the state in which dysmenorrhea continued after starting LNG-IUS treatment. Based on previous reports assessing changes in pain [13,14,15], the rate of change in VAS scores for menstrual pain was calculated as follows and used as an indicator of progesterone resistance:

$$= \,\frac{{(VAS\,at\,6\:months\, after\, LNG-IUS\,treatment)\, - \,(VAS\, before\, LNG-IUS\,treatment)}}{{\left( {VAS\, before\, LNG-IUS\,treatment} \right)}}$$
(2)

Based on previous reports on the classification of scoring systems [16, 17], patients with the bottom 25% improvement were defined as progesterone-resistant group, while those with the top 25% improvement were defined as progesterone-sensitive group. Thirteen patients were classified in each group and the clinical characteristics obtained from the medical records were compared.

Statistical analysis

All statistical data were analyzed using R version 4.3.2. Two groups were compared using Fisher’s exact test and Mann–Whitney U test. Pre- and post-treatment comparisons were performed using Wilcoxon signed-rank sum test. Furthermore, a p-value < 0.05 was considered statistically significant.

Results

Patient characteristics

Data of 69 patients with symptomatic adenomyosis detected with MRI and treated with LNG-IUS were reviewed. As the flowchart of this study (Fig. 1) shows, of the 69 patients, four patients who were lost to follow-up, four without dysmenorrhea, and eight with expulsion of LNG-IUS within 6 months were excluded. The characteristics of the remaining 53 patients are shown in Table 1. The average VAS scores before LNG-IUS treatment of 53 patients were significantly reduced 6 months after starting LNG-IUS treatment, showing the general effectiveness of LNG-IUS for the treatment of symptomatic adenomyosis (7.9 [6.4–8.9] vs. 2.3 [0.4–5.8], p < 0.001). As Fig. 2 shows, progesterone-resistant group and progesterone-sensitive group were classified based on the rate of change in VAS scores.

Fig. 1
figure 1

The flowchart of this study

Table 1 Characteristics of 53 patients analyzed in this study. SD, standard deviation
Fig. 2
figure 2

Classification of progesterone resistance

The 53 dots signify the rates of the change in VAS scores of menstrual pain of the 53 patients. Patients with the bottom 25% improvement were defined as progesterone-resistant group, while those with the top 25% improvement were defined as progesterone-sensitive group. Thirteen patients were classified in each group.

Intrinsic adenomyosis is a good prognostic factor, while extrinsic and advanced adenomyosis are predictors for progesterone resistance.

As Table 2 shows, the comparison between progesterone-resistant group and progesterone-sensitive group showed no differences in age, parity, hemoglobin level, complications with leiomyoma and endometriosis, localization of adenomyosis, the diameter of adenomyotic lesion, and uterine size. On the other hand, the rate of intrinsic adenomyosis was significantly lower in progesterone-resistant group (7.7% vs. 69.2%, p = 0.004), while the rate of advanced adenomyosis tended higher in progesterone-resistant group (23.1% vs. 61.5%, p = 0.111), indicating that intrinsic adenomyosis is a good prognostic factor for progesterone response and advanced and extrinsic adenomyosis are predictive factors for progesterone resistance.

Table 2 Clinical characteristics of the progesterone resistance group. SD, standard deviation

Progesterone resistance can be determined 1 month after starting LNG-IUS treatment

Figure 3a shows the change over time in the VAS scores of menstrual pain in the two groups. The VAS scores before LNG-IUS treatment did not differ between progesterone-resistant group and progesterone-sensitive group (6.4 [2.8-8.0] vs. 8.2 [6.4–8.9], p = 0.158), but progesterone-sensitive group showed significantly higher improvement rates compared to progesterone-resistant group 1 month after starting LNG-IUS treatment (6.2 [5.4-7.0] vs. 1.3 [0.0-1.7], p = 0.003), and this trend continued at 3 months, 6 months, and 1 year after starting LNG-IUS treatment. The same trend was also observed in terms of chronic pelvic pain: the VAS scores 1 month after starting LNG-IUS treatment were significantly different between the two groups, and the difference continued until 1 year after starting LNG-IUS treatment (Fig. 3b).

Fig. 3
figure 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 VAS scores of chronic pelvic pain

Discussion

In this study, we analyzed patients treated with LNG-IUS, a progestin medication for dysmenorrhea due to adenomyosis, to investigate the factors contributing to progesterone resistance. We found that intrinsic adenomyosis is a favorable prognostic factor, while advanced and extrinsic adenomyosis are predictors for progesterone resistance. Analysis of the VAS scores also indicated that progesterone resistance can be estimated at about 1 month after starting LNG-IUS treatment.

This study has revealed that intrinsic adenomyosis is a good prognostic factor, and subtypes other than intrinsic adenomyosis including advanced adenomyosis are predictors for progesterone resistance in terms of pain. However, the size of the uterus or adenomyosis and the presence of uterine fibroids or ovarian endometriomas are not predictive factors. Intrinsic adenomyosis is characterized by the development of adenomyotic lesions from the endometrial side of the uterus, with lesions confined to the junctional zone and the inner myometrium from the endometrium [11]. This means that chronic adhesion of the lesions to the pelvic peritoneum is less likely to occur than in extrinsic and advanced subtypes, where lesions are found on the serosal side of the uterus and are often complicated with deep infiltrating endometriosis [18, 19]. Even though we have to take into account that the pain of patients with extrinsic and advanced adenomyosis may be influenced by endometriosis with central sensitization that has progressed gradually since early reproductive years [20, 21], these findings suggest that intrinsic adenomyosis may be more responsive to progestin by LNG-IUS because there are fewer areas where progestin-mediated inhibition via the progesterone pathway is not active. Additionally, since the patients were treated with LNG-IUS placed in the uterine lumen, it is possible that intrinsic adenomyosis is easier for the progestin to physically reach because the lesions are localized closer to the endometrium. It is important for gynecologists to recognize the possibility of inadequate response to LNG-IUS treatment in advanced adenomyosis and better response in intrinsic adenomyosis. These are important findings guiding the selection of LNG-IUS for patients whose main symptoms are dysmenorrhea and/or chronic pelvic pain. Moreover, since the risk of bleeding with DNG is considered high in intrinsic adenomyosis, LNG-IUS is the optimal progestin therapy for intrinsic adenomyosis [6].

Furthermore, the progesterone resistance or the good response to progestin can be determined 1 month after starting LNG-IUS treatment, and in the absence of progesterone resistance, the effect of LNG-IUS on adenomyosis can be sustained for at least 1 year. Although there have been reports showing the efficacy of LNG-IUS for uterine adenomyosis [4], this is the first report showing the efficacy of LNG-IUS at 1 month, making it possible to determine the efficacy of treatment at an earlier point after starting LNG-IUS treatment. Furthermore, since the rate of patients who eventually underwent hysterectomy was significantly higher in progesterone-resistant group in this study, it may be necessary for patients with progesterone-resistant adenomyosis who wish to preserve their uterus to select a different treatment option, such as the use of GnRH-a or adenomyomectomy, at an early stage [22,23,24,25].

However, even though gynecological surgeries aimed at improving women’s quality of life have been developed for a variety of conditions [26,27,28,29], there are cases in which performing adenomyomectomy presents significant challenges. Since progestin is the first option to treat adenomyosis, progesterone resistance is clinically important. Progesterone has been reported to suppress the progression of adenomyosis. There have been reports on the efficacy of progestin therapy for adenomyosis and a report on the shrinkage of adenomyosis during pregnancy, during which progesterone is abundant [3,4,5,6, 30]. There are also some reports about the molecular mechanisms of progesterone resistance in adenomyosis, such as the decreased expression of progesterone receptor induced by KRAS mutations in the adenomyotic lesions and the activation of IL-6/STAT-3 signaling pathway, but further research is necessary for the elucidation and the development of the better treatment for the progesterone-resistant adenomyosis [7, 8, 31, 32]. The strength of this study is the identification of clinical factors of progesterone resistance: intrinsic adenomyosis is a favorable prognostic factor, while subtypes other than intrinsic adenomyosis are predictive factors for progesterone resistance. To find effective treatment for progesterone-resistant adenomyosis, it will also be necessary to elucidate the pathophysiology of progesterone resistance, which is still not fully understood.

There are also some limitations in this study. First, this is a retrospective study with a small number of patients. A certain number of patients with adenomyosis suffer from poor responsiveness to treatment with progestins in clinical practice. However, to analyze this poor responsiveness objectively and quantitatively, it is necessary to evaluate scores such as VAS continuously and regularly, and thus, the number of analyzed cases was limited. Regular, continuous, and quantitative observation of pain was used to improve the quality of this study, and MRI, rather than ultrasonography alone, was used to more accurately assess the type of adenomyosis, uterine size, and location of lesions [33]. The results of this study must be interpreted with caution due to limitations such as the small number of patients and the retrospective nature of the study, including the lack of washout periods for prior hormonal treatments. Further accumulation of the cases and consideration of other treatment strategies for progesterone resistant-adenomyosis, such as earlier administration of GnRH-a, are desirable for the establishment of better evidence and treatment strategies. Second, the observation period was limited to 12 months. Since our hospital refers patients to a nearby clinic when their symptoms are well-controlled with treatment, there were not enough patients treated with progestins for longer than 1 year. It is also important to accumulate cases with long-term follow-up to examine the possibility of progesterone resistance emerging during long term treatments. Third, other quantitative scores, such as the menorrhagia multi-attribute scale (MMAS) as a quality-of-life indicator during menstruation and the SF-36 as a quality-of-life indicator in general, were lacking [34, 35]. A subset of patients in this study population was assessed using the MMAS, and a difference in the rate of change in MMAS scores was observed between the progesterone-resistant and progesterone-sensitive groups (before LNG-IUS treatment: 26.1 [8.3–52.0] vs. 28.2 [26.1–28.9]; after LNG-IUS treatment: 35.4 [21.7–72.5] vs. 92.6 [62.0–100.0]). However, data on MMAS were missing for half of the patients, making it difficult to statistically assess these findings due to the limited sample size. To objectively evaluate patients’ symptoms, this study assessed not only the VAS score for dysmenorrhea but also the VAS score for chronic pelvic pain, aiming to capture a wide range of symptoms associated with uterine adenomyosis. The VAS score has been reported to correlate with the SF-36 score in studies on endometriosis, suggesting that it can serve as a proxy for evaluating quality of life in patients with adenomyosis [36]. In the future, it may be possible to define a more effective measure of progesterone resistance by collecting and evaluating quality-of-life indices together with the VAS scores.

In conclusion, the subtype of adenomyosis is the only key prognostic factor of progesterone resistance: intrinsic adenomyosis is a favorable prognostic factor for progestin treatment with LNG-IUS, while advanced and extrinsic adenomyosis are predictive factors for progesterone resistance in terms of dysmenorrhea. The responsiveness to progestin can be determined 1 month after starting LNG-IUS treatment.

Data availability

The datasets supporting the conclusions of this article are included within the article.

Abbreviations

DNG:

Dienogest

GnRH-a:

Gonadotropin-releasing hormone analogues

LNG-IUS:

Levonorgestrel intrauterine system

MRI:

Magnetic resonance imaging

VAS:

Visual analog scale

References

  1. Benagiano G, Brosens I. History of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006;20:449–63.

    Article  PubMed  Google Scholar 

  2. Naftalin J, et al. How common is adenomyosis? A prospective study of prevalence using transvaginal ultrasound in a gynaecology clinic. Hum Reprod. 2012;27:3432–9.

    Article  CAS  PubMed  Google Scholar 

  3. Kitawaki J. Adenomyosis: the pathophysiology of an oestrogen-dependent disease. Pract Res Clin Obstet Gynaecol. 2006;20:493–502.

    Article  Google Scholar 

  4. Ishizawa C, et al. Levonorgestrel-Releasing intrauterine system improves Menorrhagia-Related quality of life in patients with symptomatic adenomyosis. Reprod Sci. 2023;30:966–73.

    Article  CAS  PubMed  Google Scholar 

  5. Osuga Y, Watanabe M, Hagino A. Long-term use of dienogest in the treatment of painful symptoms in adenomyosis. J Obstet Gynaecol Res. 2017;43:1441–8.

    Article  CAS  PubMed  Google Scholar 

  6. Matsubara S, et al. Subtype I (intrinsic) adenomyosis is an independent risk factor for dienogest-related serious unpredictable bleeding in patients with symptomatic adenomyosis. Sci Rep. 2019;9:17654.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Inoue S, et al. Uterine adenomyosis is an oligoclonal disorder associated with KRAS mutations. Nat Commun. 2019;10:5785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bulun SE, et al. Endometriosis and adenomyosis: shared pathophysiology. Fertil Steril. 2023;119:746–50.

    Article  CAS  PubMed  Google Scholar 

  9. Tang HC, Lin TC, Wu MH, Tsai SJ. Progesterone resistance in endometriosis: A pathophysiological perspective and potential treatment alternatives. Reprod Med Biol. 2024;23:e12588.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Langley GB, Sheppeard H. The visual analogue scale: its use in pain measurement. Rheumatol Int. 1985;5:145–8.

    Article  CAS  PubMed  Google Scholar 

  11. Kishi Y, et al. Four subtypes of adenomyosis assessed by magnetic resonance imaging and their specification. Am J Obstet Gynecol. 2012;207:e1141–7.

    Article  Google Scholar 

  12. Goldstein SR, Horii SC, Snyde JR, Raghavendra BN, Subramanyam B. Estimation of nongravid uterine volume based on a nomogram of gravid uterine volume: its value in gynecologic uterine abnormalities. Obstet Gynecol. 1988;72:86–90.

    CAS  PubMed  Google Scholar 

  13. Zhu S, et al. Comparative evaluation of low-level light therapy and Ethinyl estradiol and desogestrel combined oral contraceptive for clinical efficacy and regulation of serum biochemical parameters in primary dysmenorrhoea: a prospective randomised multicentre trial. Lasers Med Sci. 2022;37:2239–48.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Åström M, Thet Lwin ZM, Teni FS, Burström K, Berg J. Use of the visual analogue scale for health state valuation: a scoping review. Qual Life Res. 2023;32:2719–29.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Li WC, et al. Can transcranial direct current stimulation at the motor cortex provide effective relief for severe menstrual pain? A preliminary behavioral and functional connectivity study. PAIN Rep. 2025;10:e1240.

    Article  Google Scholar 

  16. Broekman MM, Brinkman N, Swanson D, Ring D, van den Bekerom M, Jawa A. Variations in 1-year trajectories of levels of pain and capability after shoulder arthroplasty are associated with baseline mental health. Clin Orthop Relat Res. 2024;482:514–22.

    Article  PubMed  Google Scholar 

  17. Lawson CA, et al. Changing health related quality of life and outcomes in heart failure by age, sex and subtype. EClinicalMedicine. 2023;64:102217.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Khan KN, et al. Biological differences between intrinsic and extrinsic adenomyosis with coexisting deep infiltrating endometriosis. Reprod Biomed Online. 2019;39:343–53.

    Article  PubMed  Google Scholar 

  19. Han X, Gao X, Wang F, Shang C, Liu Z, Guo H. Heterogeneity of clinical symptoms and therapeutic strategies for different subtypes of adenomyosis: an initial single-center study in China. Int J Gynaecol Obstet. 2023;161:775–83.

    Article  CAS  PubMed  Google Scholar 

  20. Zannoni L, et al. Adenomyosis and endometriosis in adolescents and young women with pelvic pain: prevalence and risk factors. Minerva Pediatr (Torino). 2024;76:57–63.

    PubMed  Google Scholar 

  21. Raimondo D, et al. Prevalence and risk factors of central sensitization in women with endometriosis. J Minim Invasive Gynecol. 2023;30:73–e801.

    Article  PubMed  Google Scholar 

  22. Zhang P, Song K, Li L, Yukuwa K, Kong B. Efficacy of combined levonorgestrel-releasing intrauterine system with gonadotropin-releasing hormone analog for the treatment of adenomyosis. Med Princ Pract. 2013;22:480–3.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Tamura H, et al. Clinical outcomes of infertility treatment for women with adenomyosis in Japan. Reprod Med Biol. 2017;16:276–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Harada T, et al. The Asian society of endometriosis and adenomyosis guidelines for managing adenomyosis. Reprod Med Biol. 2023;22:e12535.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Hiratsuka D, et al. Adenomyosis with uterine abscess formation treated by adenomyomectomy: A report of two cases. J Obstet Gynaecol Res. 2025;51:e16185.

    Article  PubMed  Google Scholar 

  26. Seracchioli R, et al. Laparoscopic Mesh-Less cervicosacropexy for uterovaginal prolapse. Female Pelvic Med Reconstr Surg. 2018;24:399–403.

    Article  PubMed  Google Scholar 

  27. Paolo C, Alessandro A, Salucci P, Diego R, Renato S. Laparoscopic cervicopexy for correction of apical genital prolapse in 10 steps: a pilot study. Int Urogynecol J. 2021;32:1313–6.

    Article  PubMed  Google Scholar 

  28. Hiratsuka D, Isono W, Tsuchiya A, Okamura A, Fujimoto A, Nishii O. The effect of temporary uterine artery ligation on laparoscopic myomectomy to reduce intraoperative blood loss: A retrospective case-control study. Eur J Obstet Gynecol Reprod Biol X. 2022;15:100162.

    PubMed  PubMed Central  Google Scholar 

  29. Hiratsuka D, Tsuchiya A, Fujimoto A, Nishii O. Anesthesia-free In-office hysteroscopic morcellation for endometrial polyps: A prospective study. Gynecol Minim Invasive Ther. 2024;13:174–9.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Hiratsuka D et al. Pregnancy is associated with reduced progression of symptomatic adenomyosis: a retrospective pilot study. BMC Pregnancy Childbirth 20233;23:634.

  31. Inoue S, et al. KRAS mutations in uterine endometrium are associated with gravidity and parity. Cell Death Dis. 2020;11:347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hiraoka T, et al. Constant activation of STAT3 contributes to the development of adenomyosis in females. Endocrinology. 2022;163:bqac044.

    Article  PubMed  Google Scholar 

  33. Bazot M, Daraï E. Role of transvaginal sonography and magnetic resonance imaging in the diagnosis of uterine adenomyosis. Fertil Steril. 2018;109:389–97.

    Article  PubMed  Google Scholar 

  34. Pattison H, Daniels JP, Kai J, Gupta JK. The measurement properties of the menorrhagia multi-attribute quality-of-life scale: a psychometric analysis. BJOG. 2011;118:1528–31.

    Article  CAS  PubMed  Google Scholar 

  35. Habiba M, et al. Limited role of multi-attribute utility scale and SF-36 in predicting management outcome of heavy menstrual bleeding. Eur J Obstet Gynecol Reprod Biol. 2010;148:81–5.

    Article  PubMed  Google Scholar 

  36. Stull DE, et al. Validation of the SF-36 in patients with endometriosis. Qual Life Res. 2014;23:103–17.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This research was supported by AMED (Grant Numbers JP25gn0110085, JP24gn0110069, JP25gk0210039, JP24lk0310083, JP25gn0110097, JP25gk0210042 and JP25gk0210045), Children and Families Agency (Grant Number JPMH23DB0101) and JSPS KAKENHI (Grant Numbers JP25H01065, JP24K21911, JP25K02779, JP24K22157).

Author information

Authors and Affiliations

Authors

Contributions

DH, MM, CI, YF, TH, and YH collected data. DH, SA, GI, MH, OWH and YO discussed and interpreted the results. DH drafted the manuscript, edited by YH. MM and YH supervised the study.

Corresponding author

Correspondence to Yasushi Hirota.

Ethics declarations

Ethics approval and consent to participate

This study was reviewed and approved by the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo (IRB number: 3128). The collection of informed written consent was substituted with the informed opt-out procedure because of the retrospective nature of the study. Waiving of written consent and the use of the informed opt-out procedure were approved by the Research Ethics Committee of the Faculty of Medicine of the University of Tokyo.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hiratsuka, D., Matsuo, M., Ishizawa, C. et al. Prognostic factors of progesterone resistance in symptomatic adenomyosis: impact of lesion localization on treatment outcome of levonorgestrel intrauterine system. BMC Women's Health 25, 286 (2025). https://doi.org/10.1186/s12905-025-03817-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12905-025-03817-w

Keywords