Analysis of Non-responders to LNG-IUS in Cases of Heavy Menstrual Bleeding

Introduction Heavy menstrual bleeding (HMB) or menorrhagia, a common complaint among women during their reproduc- tive years, significantly impacts women's quality of life, productivity, and healthcare costs. The treatment options range from conservative medical management to minimally invasive procedures and hysterectomy. While levonorgestrel-intrauterine system (LNG-IUS) is established as an effective treatment for HMB, there is a lack of significant research on factors deter- mining non-response in women with HMB. This study aims to analyse the factors behind non-response to LNG-IUS in women with HMB.

A retrospective observational study was conducted at BARC Hospital, Mumbai, from January 2017 to March 2020, including 88 patients with HMB who received LNG-IUS. Non-responders to LNG-IUS were analysed for reasons of failure, including endometrial thickness, hysteroscopy, and biopsy reports. Patients were contacted one year later to assess treatment outcomes, and alternative treatments or surgery was offered to non-responders, with final histopathologi- cal findings documented.

and Discussion In this study, 29.5% of patients were non-responders, with the majority aged 40–44 years, and most experiencing persistent heavy bleeding, dysmenorrhea, device expulsion, or misplacement. Half of the non-responders had an endometrial thickness of less than 10 mm and proliferative endometrium on biopsy. Nine patients underwent hysterectomy, with adenomyosis found in seven of them.

LNG-IUS is effective in treating HMB, but factors, such as age, endometrial thickness, and certain underlying structural and non-structural pathologies, may contribute to non-response.

Heavy menstrual bleeding (HMB) · Levonorgestrel-intrauterine system (LNG-IUS) · Non-responders

and Background Menstruation is a physiological process associated with sev- eral disorders in which heavy menstrual bleeding is common [1]. Heavy menstrual bleeding can be defined as menstrual blood loss that is greater than 80 ml per cycle [2]. HMB can be measured objectively as well as subjectively. The cur - rent and most common definition of heavy menstrual bleed- ing is menstrual blood loss so excessive it interferes with a woman's physical, social, and emotional health and quality of life (QoL) [3]. The structural causes of HMB include polyp, adenomyo- sis, leiomyoma, and malignancy which can be evaluated by imaging or histopathology, while other non-structural causes include coagulopathy, ovulatory dysfunction, endometrial dis- orders like hyperplasia, iatrogenic causes, and not-yet-clas- sified causes. The provider needs to choose the most likely Gayatri Savani is a Consultant; Saroj Kumari is a Consultant; Shruti Ravinarayan is an Senior Resident; and Nigamananda Mishra is an Head of the Department. * Gayatri Savani [email protected] Saroj Kumari [email protected] Shruti Ravinarayan [email protected] Nigamananda Mishra [email protected] 1 Department of Obstetrics and Gynaecology, Bhabha Atomic Research Centre Hospital, Mumbai, Maharashtra, India 2 Department of Obstetrics and Gynaecology at Pt, Madan Mohan Malviya Shatabdi Hospital, Govandi, Mumbai, Maharashtra, India G. Savani et al. etiology to effectively and appropriately manage these patients. The treatment varies from conservative medical management to minimally invasive procedures to hysterectomy. The conservative management includes hormonal treatment such as medroxyprogesterone acetate, norethisterone acetate, and levonorgestrel-releasing intrauterine system (LNG-IUS). A systematic review and meta-analysis by Jin Qui et al. [4] revealed that the LNG-IUS was more effective for the manage- ment of menorrhagia as compared with conventional medical treatment. A study by Nelson AL et al. revealed that several studies exist that have assessed LNG-IUS as a suitable alternative to hysterectomy in women with HMB. LNG-IUS has been approved in 120 countries worldwide for contraception and in 115 countries for the management of menorrhagia [ 5]. Another study by Georgy Joy Eralil showed that as compared to usual medical therapies for menorrhagia, LNG-IUS leads to greater improvement in heavy menstrual bleeding in women concerning their daily routine, as well as physical and mental well-being [6]. Though LNG-IUS devices resulted in a large reduction in menstrual blood loss, not all patients responded to this method of treatment. Lack of effectiveness (37%) and irregular or pro- longed bleeding (28%), were cited as common reasons for dis- continuation of the LNG-IUS, according to a study conducted by Middleton LJ and others [7]. While LNG-IUS has been established as a suitable modal- ity of treatment for heavy menstrual bleeding, there is limited research on the factors determining non-response to LNG-IUS in women with HMB. Ultrasound, hysteroscopy, and histo- pathological findings in women with HMB who received alternate oral medical management and who underwent hys- terectomy following non-response to LNG-IUS have not been previously studied. By conducting this study, we aim to ana- lyse the factors responsible for non-response to LNG-IUS.

This retrospective observational study was conducted at BARC Hospital, Mumbai, on 88 patients with HMB who received LNG-IUS from January 2017 to March 2020. Patients sus- pected of malignancy or with contraindications to progester- one therapy were excluded. Patients were followed up one year post-study to assess treatment outcomes. Non-respond- ers to LNG-IUS were analysed for reasons of treatment fail- ure through their symptoms, measurement of endometrial thickness on ultrasound pre-insertion, hysteroscopy findings, and histopathological reports. Non-responders were offered alternative medical treatments as well as surgical options. Those who opted for surgical management underwent hyster- ectomy, and the final histopathological findings were docu- mented. The findings from all the non-responders were sub- sequently analysed and evaluated. Statistical Methods Qualitative variables were presented with numbers and per- centages, while quantitative variables were presented with means and standard deviations. Data were analysed using the independent samples t test for quantitative variables and the χ2 test for qualitative variables. Statistical significance was set at p < 0.05.

and Discussion In our study, LNG-IUS was inserted in 88 patients with HMB, of which 26 (i.e. 29.5%) were non-responders. Among non-responders, 50% were aged 40–44 years, 30% were aged 45–49 years, 15.3% were aged 35–39 years, and 7.7% were aged 50–54 years. A majority (88.5%) of non- responders were multiparous. Most non-responders had multiple comorbidities (77%). In a similar study conducted by Gupta Taru et al. [8 ], LNG-IUS was inserted in 70 patients with HMB with 8 non- responders (11.4%) (Table  1). The primary reasons for LNG-IUS removal among non- responders included persistent HMB (50%), dysmenorrhea (19.23%), spontaneous expulsion (15.4%), and device mis- placement (7.7%). In a study by Pleun Beelen et al. [9 ], LNG-IUS was inserted in 201 patients, out of which 46% of women discon- tinued LNG-IUS. The most common reason is being persis- tent HMB (42%), f/b dysmenorrhea, and pelvic pain in 17%. Gupta Taru et al. [8 ] in their study showed 30% of non- responders to have irregular bleeding, followed by 20% who had dysmenorrhea, 4.2% who had spontaneous expulsion, and 6.1% who had vaginitis (Table  2). Ultrasound findings before insertion showed that 50% of non-responders had an endometrial thickness of less than 10 mm, while 42.3% had ET of 10–15 mm and 7.7% had ET of 20–25 mm. No literature was found that correlated Table 1 Reasons for removal among non-responders Reason for removal across non- responders Dysmenorrhea Misplaced LNG Persistent HMB Recurrent inflammation Spontaneous expulsion Spotting Total No. of patients 5 2 13 1 4 1 26 Analysis of Non-responders to LNG-IUS the success or failure of LNG-IUS with pre-insertion endo- metrial thickness (Table  3). Histopathological findings of endometrial biopsy revealed that the majority of patients with HMB had pro- liferative endometrium. Even among non-responders, 65.4% had proliferative endometrium, followed by 19.2% having disordered proliferative endometrium and 15.4% having secretory endometrium (Table  4). Another study conducted by Das Subrata et al. [10] also showed the majority of patients with HMB to have prolif- erative endometrium (41/150). Gupta Taru et al. [8 ] in their study showed the majority of patients with HMB to have proliferative endometrium followed by disordered proliferative and lastly by secretory endometrium (Table  5). In our study, 50% of non-responders showed evi- dence of moderate endometrium on hysteroscopy, while 34.6% had profuse endometrium and 15.4% had scanty endometrium. Out of the 26 non-responders in our study, 65.4% were managed with alternative medical management, most of which belonged to those with complaints of persistent HMB, while the remaining 34.6% were managed surgically (hysterectomy). Pleun Beelen et al. [9 ], in their study, found that 32% of the patients who discontinued LNG-IUS were given additional medical management, while 14% of the non- responders underwent hysterectomy (Table  6). Histopathological reports of those patients who went through surgical management showed 44.4% of patients to have adenomyosis, f/b 33.3% with adenomyosis and leio- myoma, and 11.1% each having endometrial polyp and leiomyoma, respectively. A study by Eshna Gupta et al. [11] concluded that LNG-IUS is an effective method in the management of adenomyosis. Another study by Shuyi Chen et al. [ 12] also showed that LNG-IUS is effective in the management of types 1 and 2 of adenomyosis. However, it is seen from our study that although LNG-IUS is an effective method for the management of adenomyosis, the majority of the non-responders who underwent hysterectomy were found to have adenomyosis.

The study demonstrates that while LNG-IUS is effective for the treatment of HMB, a significant proportion of patients do not respond to this treatment. Factors such as age, endometrial thickness, and certain underlying struc- tural and non-structural pathologies play a role in non- response. Further research with a prospective study on a larger scale is needed to better understand these factors and improve treatment strategies for non-responders. Table 2 Pre-LNG-endometrial thickness on USG (mm) ET (mm) Non-respond- ers Responders Total < 10 13 33 46 0.446 10–15 11 21 32 15–20 0 5 5 20–25 2 2 4 25–30 0 1 1 Table 3 Histopathological findings of endometrial biopsy Histopathological findings Non- respond- ers Responders Total Proliferative 17 42 59 0.844 Secretory 4 7 11 Other (disordered prolifera- tive) 5 13 18 Table 4 Hysteroscopy findings Appearance of endometrium Moderate Profuse Scanty Total Total 13 09 04 26 Table 5 Reasons for removal versus treatment offered Medical Surgical Total Dysmenorrhea 3 2 5 Misplaced LNG 2 0 2 Persistent HMB 9 4 13 Recurrent inflammation 1 1 Spontaneous expulsion 1 3 4 Spotting 1 1 Total 17 9 26 Table 6 Surgical finding after hysterectomy Post-op HPR Adeno- myosis Adenomy- osis with leiomyoma Endome- trial polyp Leiomy- oma Total No. of patients 4 3 1 1 9 G. Savani et al. Funding Open access funding provided by Department of Atomic Energy. Declarations Conflict of interest The authors declare no conflict of interest. Ethical committee clearance for the study was obtained from the hospital. Ethical Approval This article does not contain any studies with human participants performed by any of the authors. Human and Animal Rights The report is in accordance with the 1964 Helsinki Declaration. Open Access This article is licensed under a Creative Commons Attri- bution 4.0 International License, which permits use, sharing, adapta- tion, 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 changes were made. 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:// creat iveco mmons. org/ licen ses/ by/4. 0/.

1. Sriprasert I, Pakrashi T, Kimble T, et al. Heavy menstrual bleed- ing diagnosis and medical management. Contracept Reprod Med. 2017;2(1):20. https:// doi. org/ 10. 1186/ s40834- 017- 0047-4. 2. Sawke NG, Sawke GK, Jain H. Histopathology findings in patients presenting with menorrhagia: a study of 100 hysterectomy speci- mens. J Midlife Health. 2015;6(4):160–3. https:// doi. org/ 10. 4103/ 0976- 7800. 172299. 3. Heavy menstrual bleeding: assessment and management. Pub- lished online 2021:33. 4. Hua J. Levonorgestrel-releasing intrauterine system versus medi- cal therapy for menorrhagia: a systematic review and meta-anal- ysis. Med Sci Monit. 2014;20:1700–13. 5. Nelson AL. Levonorgestrel intrauterine system: a first-line medi- cal treatment for heavy menstrual bleeding. Womens Health (Lond Engl). 2010;6:347–56. 6. Eralil G. The effectiveness of levonorgestrel-releasing intrauterine system in the treatment of heavy menstrual bleeding. J Obstetr Gynecol India. 2016;66(S1):505–12. 7. Middleton LJ, Champaneria R, Daniels JP, et al. Hysterectomy, endometrial destruction, and levonorgestrel releasing intrauter - ine system (Mirena) for heavy menstrual bleeding: systematic review and meta-analysis of data from individual patients. BMJ. 2010;341: c3929. 8. Taru G, Nupur G, Sangeeta G, et al. Levonorgestrel intrauterine system (LNG IUS) in menorrahgia: a follow-up study. Open J Obstetr Gynecol. 2014;5:2014. 9. Beelen P, van den Brink MJ, Herman MC, et al. Predictive factors for failure of the levonorgestrel releasing intrauterine system in women with heavy menstrual bleeding. BMC Womens Health. 2021;21:1–7. 10. Das S, Mondal R. Comparison of hysteroscopy and histopathology in diagnosing abnormal uterine bleeding: an experience from a tertiary care center of eastern India. Histopathology. 2021;2:6. 11. Gupta E, Prateek S, Mani P, et al. Role of LNG-IUS in adeno- myosis in reproductive age group women: a prospective inter - ventional study. Int J Reprod Contracept Obstet Gynecol. 2019;8(4):1254–60. 12. Chen S, Wang J, Sun W, et al. Efficacy of the levonorgestrel- releasing intrauterine device is associated with different sub- types of adenomyosis: a retrospective study. Ann Translat Med. 2020;8(21):1356. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.