{"paper_id":"b7df65ad-e9e7-46d9-9a6d-21116bbbf84f","body_text":"Vol.:(0123456789)\nThe Journal of Obstetrics and Gynecology of India \nhttps://doi.org/10.1007/s13224-025-02141-5\nORIGINAL ARTICLE\nAnalysis of Non‑responders to LNG‑IUS in Cases of Heavy Menstrual \nBleeding\nGayatri Savani1 · Saroj Kumari2 · Shruti Ravinarayan2 · Nigamananda Mishra1\nReceived: 18 June 2024 / Accepted: 5 May 2025 \n© The Author(s) 2025\nAbstract\nIntroduction Heavy menstrual bleeding (HMB) or menorrhagia, a common complaint among women during their reproduc-\ntive years, significantly impacts women's quality of life, productivity, and healthcare costs. The treatment options range from \nconservative medical management to minimally invasive procedures and hysterectomy. While levonorgestrel-intrauterine \nsystem (LNG-IUS) is established as an effective treatment for HMB, there is a lack of significant research on factors deter-\nmining non-response in women with HMB. This study aims to analyse the factors behind non-response to LNG-IUS in \nwomen with HMB.\nMaterial and Methods A retrospective observational study was conducted at BARC Hospital, Mumbai, from January 2017 \nto March 2020, including 88 patients with HMB who received LNG-IUS. Non-responders to LNG-IUS were analysed for \nreasons of failure, including endometrial thickness, hysteroscopy, and biopsy reports. Patients were contacted one year later \nto assess treatment outcomes, and alternative treatments or surgery was offered to non-responders, with final histopathologi-\ncal findings documented.\nResults and Discussion In this study, 29.5% of patients were non-responders, with the majority aged 40–44 years, and most \nexperiencing persistent heavy bleeding, dysmenorrhea, device expulsion, or misplacement. Half of the non-responders had an \nendometrial thickness of less than 10 mm and proliferative endometrium on biopsy. Nine patients underwent hysterectomy, \nwith adenomyosis found in seven of them.\nConclusion LNG-IUS is effective in treating HMB, but factors, such as age, endometrial thickness, and certain underlying \nstructural and non-structural pathologies, may contribute to non-response.\nKeywords Heavy menstrual bleeding (HMB) · Levonorgestrel-intrauterine system (LNG-IUS) · Non-responders\nIntroduction and Background\nMenstruation is a physiological process associated with sev-\neral disorders in which heavy menstrual bleeding is common \n[1]. Heavy menstrual bleeding can be defined as menstrual \nblood loss that is greater than 80 ml per cycle [2]. HMB can \nbe measured objectively as well as subjectively. The cur -\nrent and most common definition of heavy menstrual bleed-\ning is menstrual blood loss so excessive it interferes with a \nwoman's physical, social, and emotional health and quality \nof life (QoL) [3].\nThe structural causes of HMB include polyp, adenomyo-\nsis, leiomyoma, and malignancy which can be evaluated by \nimaging or histopathology, while other non-structural causes \ninclude coagulopathy, ovulatory dysfunction, endometrial dis-\norders like hyperplasia, iatrogenic causes, and not-yet-clas-\nsified causes. The provider needs to choose the most likely \nGayatri Savani is a Consultant; Saroj Kumari is a Consultant; Shruti \nRavinarayan is an Senior Resident; and Nigamananda Mishra is an \nHead of the Department.\n * Gayatri Savani \n drgayatrisavani@gmail.com\n Saroj Kumari \n drsarojdhaka.sikar@gmail.com\n Shruti Ravinarayan \n rshruti106@gmail.com\n Nigamananda Mishra \n drnmishra1@gmail.com\n1 Department of Obstetrics and Gynaecology, Bhabha Atomic \nResearch Centre Hospital, Mumbai, Maharashtra, India\n2 Department of Obstetrics and Gynaecology at Pt, Madan \nMohan Malviya Shatabdi Hospital, Govandi, Mumbai, \nMaharashtra, India\n\n G. Savani et al.\netiology to effectively and appropriately manage these patients. \nThe treatment varies from conservative medical management \nto minimally invasive procedures to hysterectomy.\nThe conservative management includes hormonal treatment \nsuch as medroxyprogesterone acetate, norethisterone acetate, \nand levonorgestrel-releasing intrauterine system (LNG-IUS). \nA systematic review and meta-analysis by Jin Qui et al. [4] \nrevealed that the LNG-IUS was more effective for the manage-\nment of menorrhagia as compared with conventional medical \ntreatment.\nA study by Nelson AL et al. revealed that several studies \nexist that have assessed LNG-IUS as a suitable alternative \nto hysterectomy in women with HMB. LNG-IUS has been \napproved in 120 countries worldwide for contraception and \nin 115 countries for the management of menorrhagia [ 5]. \nAnother study by Georgy Joy Eralil showed that as compared \nto usual medical therapies for menorrhagia, LNG-IUS leads to \ngreater improvement in heavy menstrual bleeding in women \nconcerning their daily routine, as well as physical and mental \nwell-being [6].\nThough LNG-IUS devices resulted in a large reduction in \nmenstrual blood loss, not all patients responded to this method \nof treatment. Lack of effectiveness (37%) and irregular or pro-\nlonged bleeding (28%), were cited as common reasons for dis-\ncontinuation of the LNG-IUS, according to a study conducted \nby Middleton LJ and others [7].\nWhile LNG-IUS has been established as a suitable modal-\nity of treatment for heavy menstrual bleeding, there is limited \nresearch on the factors determining non-response to LNG-IUS \nin women with HMB. Ultrasound, hysteroscopy, and histo-\npathological findings in women with HMB who received \nalternate oral medical management and who underwent hys-\nterectomy following non-response to LNG-IUS have not been \npreviously studied. By conducting this study, we aim to ana-\nlyse the factors responsible for non-response to LNG-IUS.\nMaterial and Methods\nThis retrospective observational study was conducted at BARC \nHospital, Mumbai, on 88 patients with HMB who received \nLNG-IUS from January 2017 to March 2020. Patients sus-\npected of malignancy or with contraindications to progester-\none therapy were excluded. Patients were followed up one \nyear post-study to assess treatment outcomes. Non-respond-\ners to LNG-IUS were analysed for reasons of treatment fail-\nure through their symptoms, measurement of endometrial \nthickness on ultrasound pre-insertion, hysteroscopy findings, \nand histopathological reports. Non-responders were offered \nalternative medical treatments as well as surgical options. \nThose who opted for surgical management underwent hyster-\nectomy, and the final histopathological findings were docu-\nmented. The findings from all the non-responders were sub-\nsequently analysed and evaluated.\nStatistical Methods\nQualitative variables were presented with numbers and per-\ncentages, while quantitative variables were presented with \nmeans and standard deviations. Data were analysed using \nthe independent samples t test for quantitative variables and \nthe χ2 test for qualitative variables. Statistical significance \nwas set at p < 0.05.\nResults and Discussion\nIn our study, LNG-IUS was inserted in 88 patients with \nHMB, of which 26 (i.e. 29.5%) were non-responders. \nAmong non-responders, 50% were aged 40–44 years, 30% \nwere aged 45–49 years, 15.3% were aged 35–39 years, and \n7.7% were aged 50–54 years. A majority (88.5%) of non-\nresponders were multiparous. Most non-responders had \nmultiple comorbidities (77%).\nIn a similar study conducted by Gupta Taru et al. [8 ], \nLNG-IUS was inserted in 70 patients with HMB with 8 non-\nresponders (11.4%) (Table  1).\nThe primary reasons for LNG-IUS removal among non-\nresponders included persistent HMB (50%), dysmenorrhea \n(19.23%), spontaneous expulsion (15.4%), and device mis-\nplacement (7.7%).\nIn a study by Pleun Beelen et al. [9 ], LNG-IUS was \ninserted in 201 patients, out of which 46% of women discon-\ntinued LNG-IUS. The most common reason is being persis-\ntent HMB (42%), f/b dysmenorrhea, and pelvic pain in 17%.\nGupta Taru et al. [8 ] in their study showed 30% of non-\nresponders to have irregular bleeding, followed by 20% who \nhad dysmenorrhea, 4.2% who had spontaneous expulsion, \nand 6.1% who had vaginitis (Table  2).\nUltrasound findings before insertion showed that 50% of \nnon-responders had an endometrial thickness of less than \n10 mm, while 42.3% had ET of 10–15 mm and 7.7% had \nET of 20–25 mm. No literature was found that correlated \nTable 1  Reasons for removal among non-responders\nReason for removal across non-\nresponders\nDysmenorrhea Misplaced LNG Persistent HMB Recurrent\ninflammation\nSpontaneous expulsion Spotting Total\nNo. of patients 5 2 13 1 4 1 26\n\nAnalysis of Non-responders to LNG-IUS\nthe success or failure of LNG-IUS with pre-insertion endo-\nmetrial thickness (Table  3).\nHistopathological findings of endometrial biopsy \nrevealed that the majority of patients with HMB had pro-\nliferative endometrium. Even among non-responders, \n65.4% had proliferative endometrium, followed by 19.2% \nhaving disordered proliferative endometrium and 15.4% \nhaving secretory endometrium (Table  4).\nAnother study conducted by Das Subrata et al. [10] also \nshowed the majority of patients with HMB to have prolif-\nerative endometrium (41/150).\nGupta Taru et al. [8 ] in their study showed the majority \nof patients with HMB to have proliferative endometrium \nfollowed by disordered proliferative and lastly by secretory \nendometrium (Table  5).\nIn our study, 50% of non-responders showed evi-\ndence of moderate endometrium on hysteroscopy, while \n34.6% had profuse endometrium and 15.4% had scanty \nendometrium.\nOut of the 26 non-responders in our study, 65.4% were \nmanaged with alternative medical management, most of \nwhich belonged to those with complaints of persistent \nHMB, while the remaining 34.6% were managed surgically \n(hysterectomy).\nPleun Beelen et al. [9 ], in their study, found that 32% \nof the patients who discontinued LNG-IUS were given \nadditional medical management, while 14% of the non-\nresponders underwent hysterectomy (Table  6).\nHistopathological reports of those patients who went \nthrough surgical management showed 44.4% of patients to \nhave adenomyosis, f/b 33.3% with adenomyosis and leio-\nmyoma, and 11.1% each having endometrial polyp and \nleiomyoma, respectively.\nA study by Eshna Gupta et al. [11] concluded that \nLNG-IUS is an effective method in the management of \nadenomyosis. Another study by Shuyi Chen et al. [ 12] also \nshowed that LNG-IUS is effective in the management of \ntypes 1 and 2 of adenomyosis. However, it is seen from \nour study that although LNG-IUS is an effective method \nfor the management of adenomyosis, the majority of the \nnon-responders who underwent hysterectomy were found \nto have adenomyosis.\nConclusion\nThe study demonstrates that while LNG-IUS is effective \nfor the treatment of HMB, a significant proportion of \npatients do not respond to this treatment. Factors such as \nage, endometrial thickness, and certain underlying struc-\ntural and non-structural pathologies play a role in non-\nresponse. Further research with a prospective study on a \nlarger scale is needed to better understand these factors \nand improve treatment strategies for non-responders.\nTable 2  Pre-LNG-endometrial thickness on USG (mm)\nET (mm) Non-respond-\ners\nResponders Total\n < 10 13 33 46 0.446\n10–15 11 21 32\n15–20 0 5 5\n20–25 2 2 4\n25–30 0 1 1\nTable 3  Histopathological findings of endometrial biopsy\nHistopathological findings Non-\nrespond-\ners\nResponders Total\nProliferative 17 42 59 0.844\nSecretory 4 7 11\nOther (disordered prolifera-\ntive)\n5 13 18\nTable 4  Hysteroscopy findings\nAppearance of endometrium Moderate Profuse Scanty Total\nTotal 13 09 04 26\nTable 5  Reasons for removal versus treatment offered\nMedical Surgical Total\nDysmenorrhea 3 2 5\nMisplaced LNG 2 0 2\nPersistent HMB 9 4 13\nRecurrent inflammation 1 1\nSpontaneous expulsion 1 3 4\nSpotting 1 1\nTotal 17 9 26\nTable 6  Surgical finding after hysterectomy\nPost-op \nHPR\nAdeno-\nmyosis\nAdenomy-\nosis with \nleiomyoma\nEndome-\ntrial polyp\nLeiomy-\noma\nTotal\nNo. of \npatients\n4 3 1 1 9\n\n G. Savani et al.\nFunding Open access funding provided by Department of Atomic \nEnergy.\nDeclarations \nConflict of interest The authors declare no conflict of interest. Ethical \ncommittee clearance for the study was obtained from the hospital.\nEthical Approval This article does not contain any studies with human \nparticipants performed by any of the authors.\nHuman and Animal Rights The report is in accordance with the 1964 \nHelsinki Declaration.\nOpen Access  This article is licensed under a Creative Commons Attri-\nbution 4.0 International License, which permits use, sharing, adapta-\ntion, distribution and reproduction in any medium or format, as long \nas you give appropriate credit to the original author(s) and the source, \nprovide a link to the Creative Commons licence, and indicate if changes \nwere made. The images or other third party material in this article are \nincluded in the article's Creative Commons licence, unless indicated \notherwise in a credit line to the material. If material is not included in \nthe article's Creative Commons licence and your intended use is not \npermitted by statutory regulation or exceeds the permitted use, you will \nneed to obtain permission directly from the copyright holder. To view a \ncopy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/.\nReferences\n 1. Sriprasert I, Pakrashi T, Kimble T, et al. Heavy menstrual bleed-\ning diagnosis and medical management. Contracept Reprod Med. \n2017;2(1):20. https:// doi. org/ 10. 1186/ s40834- 017- 0047-4.\n 2. Sawke NG, Sawke GK, Jain H. Histopathology findings in patients \npresenting with menorrhagia: a study of 100 hysterectomy speci-\nmens. J Midlife Health. 2015;6(4):160–3. https:// doi. org/ 10. 4103/ \n0976- 7800. 172299.\n 3. Heavy menstrual bleeding: assessment and management. Pub-\nlished online 2021:33.\n 4. Hua J. Levonorgestrel-releasing intrauterine system versus medi-\ncal therapy for menorrhagia: a systematic review and meta-anal-\nysis. Med Sci Monit. 2014;20:1700–13.\n 5. Nelson AL. Levonorgestrel intrauterine system: a first-line medi-\ncal treatment for heavy menstrual bleeding. Womens Health (Lond \nEngl). 2010;6:347–56.\n 6. Eralil G. The effectiveness of levonorgestrel-releasing intrauterine \nsystem in the treatment of heavy menstrual bleeding. J Obstetr \nGynecol India. 2016;66(S1):505–12.\n 7. Middleton LJ, Champaneria R, Daniels JP, et al. Hysterectomy, \nendometrial destruction, and levonorgestrel releasing intrauter -\nine system (Mirena) for heavy menstrual bleeding: systematic \nreview and meta-analysis of data from individual patients. BMJ. \n2010;341: c3929.\n 8. Taru G, Nupur G, Sangeeta G, et al. Levonorgestrel intrauterine \nsystem (LNG IUS) in menorrahgia: a follow-up study. Open J \nObstetr Gynecol. 2014;5:2014.\n 9. Beelen P, van den Brink MJ, Herman MC, et al. Predictive factors \nfor failure of the levonorgestrel releasing intrauterine system in \nwomen with heavy menstrual bleeding. BMC Womens Health. \n2021;21:1–7.\n 10. Das S, Mondal R. Comparison of hysteroscopy and histopathology \nin diagnosing abnormal uterine bleeding: an experience from a \ntertiary care center of eastern India. Histopathology. 2021;2:6.\n 11. Gupta E, Prateek S, Mani P, et al. Role of LNG-IUS in adeno-\nmyosis in reproductive age group women: a prospective inter -\nventional study. Int J Reprod Contracept Obstet Gynecol. \n2019;8(4):1254–60.\n 12. Chen S, Wang J, Sun W, et al. Efficacy of the levonorgestrel-\nreleasing intrauterine device is associated with different sub-\ntypes of adenomyosis: a retrospective study. Ann Translat Med. \n2020;8(21):1356.\nPublisher's Note Springer Nature remains neutral with regard to \njurisdictional claims in published maps and institutional affiliations.","source_license":"CC0","license_restricted":false}