Clinical evaluation of the effect of the levonorgestrel intrauterine system on the treatment of abnormal uterine bleeding

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RESEARCH ARTICLE

Hippokratia 2025, 29(1): 1-5

Fang QJ, Sang L, Du SH, Wang RQ, Wu HH, Yang L, Yu J
Department of Obstetrics and Gynecology, The Second People’s Hospital of Hefei, Hefei Hospital affiliated to Anhui Medical University, Hefei, Anhui, China

Abstract

Background: This study aims to explore the clinical effect of the levonorgestrel intrauterine system (LNG-IUS) on the treatment of abnormal uterine bleeding in women of childbearing age.

Material and methods: We retrospectively collected clinical data of women who underwent elective hysteroscopy and concurrent curettage to treat abnormal uterine bleeding at Hefei Hospital, affiliated with Anhui Medical University, from January 2019 to January 2023. We assigned to the LNG-IUS group (n =117) those who received post-surgery LNG-IUS therapy and to the control group (n =161) patients administered dydrogesterone tablets orally instead of LNG-IUS. We recorded detailed data regarding patients’ symptoms, pre-hysteroscopy hemoglobin and hematocrit levels, and transvaginal ultrasound evaluations of endometrial thickness and uterine volume. All enrolled patients had scheduled follow-up visits three and six months post-operation at the hospital’s outpatient department to assess treatment efficacy and subsequently compare the two groups’ efficacy.

Results: In the LNG-IUS group, abnormal uterine bleeding significantly improved with a marked response rates at three and six months (83.76 and 94.87 %, respectively), compared to the control group (54.66 and 64.60 %, respectively) (p =0.031 and p =0.007, respectively). The endometrial thickness was significantly reduced post-treatment in the LNG-IUS group after three months of treatment (p =0.022). Both groups significantly improved hemoglobin levels after three months of treatment compared to pre-treatment levels (p =0.031 and p=0.025, respectively). Only the LNG-IUS group showed a statistically significant decrease in uterine volume at six compared to three months post-treatment (p =0.009).

Conclusions: In women of childbearing age, LNG-IUS shows significant clinical efficacy in treating abnormal uterine bleeding and can be considered an appropriate therapy for women not wishing to have children. HIPPOKRATIA 2025, 29 (1):1-5.

Keywords: Levonorgestrel intrauterine system, abnormal uterine bleeding, dydrogesterone, hypermenorrhea

Corresponding author: Qian-Jin Fang, MM, Department of Obstetrics and Gynecology, The Second People’s Hospital of Hefei, Hefei Hospital affiliated to Anhui Medical University, 246 Heping rd, Yaohai District,Hefei, Anhui 230011,China, tel: +8618019942562, e-mail: fangqianjinfqja@126.com

Introduction

Any alteration in menstrual volume or pattern represents abnormal uterine bleeding (AUB). It manifests in various conditions among women of childbearing age, including severe or irregular menstrual bleeding and non-menstrual vaginal bleeding1,2. Severe hemorrhage constitutes the primary reason those women seek medical attention and can lead to complications such as anemia and excessive bleeding, thereby significantly impairing their quality of life. Even though many treatment modalities exist for AUB, endometrial ablation, and hysterectomy remain the most common. Hysterectomy is a major surgical intervention associated with inherent risks and substantial costs. Therefore, endometrial ablation has gained popularity as an alternative, aiming to resect or destroy the endometrial tissue. However, it does not eliminate the surgical risks3-5.

The levonorgestrel intrauterine system (LNG-IUS), initially developed as a contraceptive device, demonstrates a potent contraceptive effect and efficacy in treating AUB. It releases continuously and quantitatively into the uterine cavity levonorgestrel at a rate of 20 μg/24h. LNG-IUS can remarkably reduce menstrual volume6-8. It has also been proposed as a treatment for endometrial cancer and as a non-surgical alternative for menorrhagia9,10.

This study aimed to evaluate the clinical efficacy of LNG-IUS (20 μg/24h) in treating AUB in childbearing-age women. 

Method and Materials

Clinical data

We retrospectively collected and analyzed clinical data of women who underwent elective hysteroscopy and concurrent curettage to treat AUB at Hefei Hospital, affiliated with Anhui Medical University, from January 2019 to January 2023. In the study, we included 117 women who received post-surgery LNG-IUS therapy and 161 controls who were administered post-surgery dydrogesterone tablets orally. The study was conducted in accordance with the Helsinki Declaration and was approved by the Ethics Committee of the Second People’s Hospital of Hefei, Hefei Hospital affiliated with Anhui Medical University (decision No 112/2023), and informed consent was obtained from all enrolled patients. The criteria for inclusion in the study were i) women with AUB according to diagnostic criteria outlined in the guidelines11, ii) no systemic disease-related abnormal coagulation, and iii) no recent history of related medication. We excluded from the study women with i) severe systemic diseases, ii) mental disorder, iii) endometrial biopsy indicating malignant or precancerous lesions, iv) AUB caused by organic lesions in the female reproductive system, v) AUB related to a reproductive system infection, vi) pregnancy-related bleeding or those who were lactating, and vii) those not able to tolerate LNG-IUS due to pain or other reason. We recorded detailed data regarding patients’ symptoms, pre-hysteroscopy hemoglobin and hematocrit levels, and transvaginal ultrasound (TVS) evaluations of endometrial thickness and uterine volume. We obtained details of the main complaints and related findings after LNG-IUS placement from outpatient follow-up records. 

Treatment

All patients were admitted for elective hysteroscopy and concurrent curettage to treat AUB, with postoperative pathology showing non-precancerous lesions. Post-surgery treatment regimens depended on patient preference. Some women immediately received LNG-IUS (52 mg to deliver up to 20 μg/24h; Mirena, Bayer AG, Leverkusen, Germany), while others were administered oral dydrogesterone tablets (10 mg; Abbott Biologicals B.V., Netherlands) every 8 hours for 20 consecutive days, starting from the fifth day of their menstrual cycle and continuing for a total of three cycles. The latter group of patients constituted the control group. All enrolled patients were instructed to visit the hospital’s outpatient department for follow-up at three and six months post-operation. Follow-up assessments included detailed recording of symptoms and signs, menstrual cycle, routine blood results, and uterine size using TVS.

Observation indicators

We defined as observation indicators i) AUB symptom improvement, ii) overall response rate to treatment, calculated as: symptom improvement cases/total cases ×100 %, iii) routine blood results (hemoglobin), iv) assessment tool for AUB symptoms: Pictorial Blood Assessment Chart (PBAC), an image-based method where patients estimate bleeding amount by selecting images that match their menstrual blood loss, and iv) endometrial condition and uterine volume, measured through TVS using the ellipsoidal volume formula12:

V =0.5233 x long diameter x anteroposterior diameter x transverse diameter

Statistical methods

We performed sample size estimation using PASS 15.0.13 software (NCSS). Based on previous studies13, we hypothesized that the effectiveness of the LNG-IUS (three months post-surgery) would increase from 77.5 to 95 % with an α-error and power set at 0.05 (two-sided) and 80 %, respectively. We calculated the minimum sample size required for this study at 114 patients and enrolled a total of 278 patients in the study.

We conducted statistical analyses using the IBM SPSS Statistics for Windows, Version 22.0 (IBM Corp., Armonk, NY, USA). Quantitative data are expressed as mean ± standard deviation. Intergroup comparisons are performed using t-tests or repeated-measures ANOVA, and intragroup comparisons were conducted using paired t-tests. Enumeration data are tested using the χ² test. A p-value less than 0.05 indicated statistical significance. 

Results

General information on hospitalization

The average age of patients in the LNG-IUS group was 35.83 ± 4.21 years, compared to 36.09 ± 3.84 years in the control group. The endometrial thickness in the LNG-IUS group was 9.86 ± 3.12 mm, while in the control group, it was 10.34 ± 2.93 mm. The uterine volume was 22.43 ± 1.52 cm3 in the LNG-IUS group and 24.05 ± 1.78 cm3 in the control group. The hemoglobin level was 8.82 ± 0.67 g/dL in the LNG-IUS group and 9.33 ± 0.79 g/dL in the control group. There were no significant differences in these baseline clinical data between the two groups (Table 1 and Table 2).

Clinical data from follow-up after treatment

Hemoglobin levels in both the LNG-IUS and control groups significantly improved after three months of treatment compared to pre-treatment levels (p =0.031 and p =0.025, respectively). No significant difference in hemoglobin levels was observed between the two groups after three months (p =0.078). The endometrial thickness in the LNG-IUS group was significantly reduced after three months of treatment (p =0.022), while no significant change was observed in the control group (p =0.084). Uterine volumes in both groups did not show significant differences after three months compared to pre-treatment volumes (p =0.074 and p =0.06, respectively), and no significant difference was observed between the two groups (p =0.062). At six months, the endometrial thickness in the LNG-IUS group was significantly thinner than at three months (p =0.009) and was also significantly different from that in the control group (p =0.031). The uterine volume in the LNG-IUS group significantly decreased compared to pre-treatment levels (p =0.044) and was significantly lower than that in the control group (p =0.018) (Table 2).

Comparison of menstrual improvement after treatment

The diagnosis of AUB is based on clinical symptoms. AUB was defined as a menstrual period of less than three days or more than seven days, a menstrual cycle of less than 21 days or more than 35 days, and a menstrual flow of less than 5 mL or more than 80 mL. In the LNG-IUS group, AUB significantly improved after three months, with a marked response rate (defined as more than 50 % reduction in bleeding or patient-reported bleeding less than normal menstrual flow) of 83.76 %, which was significantly better than that in the control group (54.66 %; p =0.031). After six months, the marked response rate in the LNG-IUS group reached 94.87 %, which was significantly higher than that in the control group (p =0.007). In contrast, the response rate in the control group after six months was similar to that at three months, reaching only 64.6 % (Table 3).

Discussion

The LNG-IUS continuously and slowly releases levonorgestrel into the uterine cavity, leading to various morphological changes in the endometrium, such as endometrial atrophy, gland inactivation, decreased gland secretion, and extensive decidual stroma. Endometrial receptors for sex hormones are downregulated, including estrogen, progesterone, and androgen receptors. Levonorgestrel has been widely used for contraception and for perimenopausal and postmenopausal women receiving estrogen replacement therapy to provide endometrial protection14,15. As a progesterone derivative, dydrogesterone can rapidly bring the endometrium into a secretory state, inhibiting endometrial carcinomatosis and excessive proliferation risks, thereby reducing bleeding. Levonorgestrel possesses the biological activities of progesterone, androgen, antiestrogen, and gonadotropin16. However, clinicians are increasingly recognizing levonorgestrel as a treatment for AUB. This study primarily compared the clinical effects of dydrogesterone and LNG-IUS in treating AUB in women of childbearing age. It evaluated the endometrial and volume changes after LNG-IUS implantation, aiming to provide more clinical evidence for promoting LNG-IUS in treating AUB.

AUB is common among non-pregnant women of childbearing age. AUB caused by organic lesions of the reproductive system, such as uterine fibroids, adenomyosis, and endometrial polyps, is mainly treated through surgery, with satisfactory results often obtained with the assistance of corresponding medication, depending on the post-surgical condition17-19. In contrast, some patients with AUB exhibit no evidence of organic disease and present to the hospital with anemia caused by long-term, repeated massive hemorrhage, leading to a decline in their quality of life. Although some patients’ symptoms and quality of life improve during hormone therapy, the side effects caused by long-term medication and even missed medication cannot be ignored20. Eventually, most patients choose to undergo hysterectomy. However, surgery is not the most appropriate treatment for women of childbearing age due to related risks and the irreversibility of surgical intervention. After medical intervention, the bleeding of AUB patients is quickly reduced, and anemia symptoms often improve rapidly, with hemoglobin levels returning to normal over a short period. In the present study, patients treated with dydrogesterone experienced a rapid progression of the endometrium into the complete secretory phase, which suppressed endometrial hyperproliferation and alleviated AUB symptoms. However, as the endometrium did not enter a shrinking state, some patients still experienced symptoms such as excessive menstrual volume21. LNG-IUS can antagonize estrogen and progesterone receptors, quickly repair the endometrium in a hyperplastic state, inhibit endometrial hyperplasia, and rapidly shrink the endometrial glands. This results in endometrial atrophy and thinning, achieving the expected clinical therapeutic effect consistent with the results of this study. LNG-IUS plays a key role in regulating the menstrual cycle22, leading to a sharp decrease in blood volume and even amenorrhea, significantly improving the patient’s quality of life 23.

Based on the obtained results, after ultrasound, hysteroscopic evaluations, and endometrial biopsy, LNG-IUS is recommended for women who cannot tolerate systemic endometrial treatment or who do not respond to such treatment. Specifically, it is applicable to women of childbearing age affected by AUB who may need reversible contraception, as the therapeutic effect is reversible, including for endometrial atrophy. LNG-IUS is an effective and reversible treatment option for AUB. Most women’s quality of life is affected before they seek medical care, indicating a need for an effective treatment method. Moreover, during this period, some women try conservative medical methods, including hormone therapy. Although this offers short-term relief, their quality of life does not improve, and it often causes greater harm due to missed medication or unauthorized drug withdrawal. Previous studies have revealed that most women who use LNG-IUS experience spot bleeding over a short period, but this symptom often disappears suddenly, resulting in amenorrhea24,25, consistent with the results of the current study. The long-term results are unknown due to this study’s short observation time, and further studies are expected to confirm the long-term outcomes.

This retrospective study may be subject to selection bias and have incomplete information on some key variables, affecting the accuracy of observations. Without randomized controlled trials, the conclusions observed are not directly causal but related factors. Moreover, controlling for unmeasured factors (such as patients lifestyle and dietary habits) was difficult, which could potentially impact research results. Additionally, the follow-up time was short; thus, long-term clinical effects could not be observed. Therefore, subsequent research should address all these shortcomings.

In conclusion, LNG-IUS is a feasible and effective treatment option for patients with AUB of childbearing age, especially for those who do not want children, and it often achieves satisfactory treatment results.

Conflict of interest

The authors declare that they have no competing interests.

Acknowledgments

We want to acknowledge the hard and dedicated work of all the staff who implemented the intervention and evaluation components of the study. The datasets analyzed during this study are available from the corresponding author upon reasonable request. 

References

  1. Wouk N, Helton M. Abnormal Uterine Bleeding in Premenopausal Women. Am Fam Physician. 2019; 99: 435-443.
  2. Jewson M, Purohit P, Lumsden MA. Progesterone and abnormal uterine bleeding/menstrual disorders. Best Pract Res Clin Obstet Gynaecol. 2020; 69: 62-73.
  3. Brun JL, Plu-Bureau G, Huchon C, Ah-Kit X, Barral M, Chauvet P, et al. Management of women with abnormal uterine bleeding: Clinical practice guidelines of the French National College of Gynaecologists and Obstetricians (CNGOF). Eur J Obstet Gynecol Reprod Biol. 2023; 288: 90-107.
  4. Vannuccini S, Petraglia F, Carmona F, Calaf J, Chapron C. The modern management of uterine fibroids-related abnormal uterine bleeding. Fertil Steril. 2024; 122: 20-30.
  5. MacGregor B, Munro MG, Lumsden MA. Therapeutic options for the management of abnormal uterine bleeding. Int J Gynaecol Obstet. 2023; 162 Suppl 2: 43-57.
  6. Jensen JT, Lukkari-Lax E, Schulze A, Wahdan Y, Serrani M, Kroll R. Contraceptive efficacy and safety of the 52-mg levonorgestrel intrauterine system for up to 8 years: findings from the Mirena Extension Trial. Am J Obstet Gynecol. 2022; 227: 873.e1-873.e12.
  7. Silver S, Arnold JJ. Levonorgestrel-Releasing Intrauterine System for Regression of Endometrial Hyperplasia. Am Fam Physician. 2021; 104: 26-27.
  8. Elassall GM, Sayed EG, Abdallah NA, El-Zohiry MM, Radwan AA, AlMahdy AM, et al. Levonorgestrel-releasing intrauterine system versus systemic progestins in management of endometrial hyperplasia: A systemic review and meta-analysis. J Gynecol Obstet Hum Reprod. 2022; 51: 102432.
  9. Kim MK, Seong SJ, Kang SB, Bae DS, Kim JW, Nam JH, et al. Six months response rate of combined oral medroxyprogesterone/levonorgestrel-intrauterine system for early-stage endometrial cancer in young women: a Korean Gynecologic-Oncology Group Study. J Gynecol Oncol. 2019; 30: e47.
  10. Gupta A, Gangane N, Dhanvij M, Moharana B, Davile M, Mundle S. The Effect of the Levonorgestrel-Releasing Intrauterine System on Myometrial Blood Flow in Patients With Heavy Menstrual Bleeding. Cureus. 2024; 16: e66712.
  11. Munro MG, Critchley HOD, Fraser IS; FIGO Menstrual Disorders Committee. The two FIGO systems for normal and abnormal uterine bleeding symptoms and classification of causes of abnormal uterine bleeding in the reproductive years: 2018 revisions. Int J Gynaecol Obstet. 2018; 143: 393-408.
  12. Cim N, Soysal S, Sayan S, Yildizhan B, Karaman E, Cetin O, et al. Two Years Follow-Up of Patients with Abnormal Uterine Bleeding after Insertion of the Levonorgestrel-Releasing Intrauterine System. Gynecol Obstet Invest. 2018; 83: 569-575.
  13. Yu Y, Zhou Z, Wang L, Liu J. Effect of Mirena Intrauterine Device on Endometrial Thickness, Quality of Life Score, and Curative Effect in Patients with Perimenopausal Abnormal Uterine Bleeding. Comput Math Methods Med. 2022; 2022: 5648918.
  14. Elshamy E, Nofal A, Ibrrahim D. Postplacental Insertion of Levonorgestrel Intrauterine System Versus Copper Intrauterine Device: A Prospective Study. J Obstet Gynaecol India. 2021; 71: 150-155.
  15. Magalhaes J, Ferreira-Filho ES, Soares-Junior JM, Baracat EC. Uterine volume, menstrual patterns, and contraceptive outcomes in users of the levonorgestrel-releasing intrauterine system: A cohort study with a five-year follow-up. Eur J Obstet Gynecol Reprod Biol. 2022; 276: 56-62.
  16. Fang F, Xu H, Wu L, Hu L, Liu Y, Li Y, et al. NG-IUS combined with progesterone ameliorates endometrial thickness and pregnancy outcomes of patients with early-stage endometrial cancer or atypical hyperplasia. Am J Transl Res. 2021; 13: 5412-5419.
  17. Lebduska E, Beshear D, Spataro BM. Abnormal Uterine Bleeding. Med Clin North Am. 2023; 107: 235-246.
  18. Selmi C, La Marca A. Oral hormonal therapy as treatment option for abnormal uterine bleeding. Eur J Contracept Reprod Health Care. 2023; 28: 285-294.
  19. Abbott JA. Adenomyosis and Abnormal Uterine Bleeding (AUB-A)-Pathogenesis, diagnosis, and management. Best Pract Res Clin Obstet Gynaecol. 2017; 40: 68-81.
  20. Abul R, Selcuki NFT, Karadeniz O, Bahat PY. A comparison of the effects of oral dydrogesterone and levonorgestrel-releasing intrauterine device on quality of life and sexual function in patients with abnormal uterine bleeding. Arch Gynecol Obstet. 2024; 309: 715-719.
  21. Jewson M, Purohit P, Lumsden MA. Progesterone and abnormal uterine bleeding/menstrual disorders. Best Pract Res Clin Obstet Gynaecol. 2020; 69: 62-73.
  22. Bianchi P, Guo SW, Habiba M, Benagiano G. Utility of the Levonorgestrel-Releasing Intrauterine System in the Treatment of Abnormal Uterine Bleeding and Dysmenorrhea: A Narrative Review. J Clin Med. 2022; 11: 5836.
  23. Ilyin AB, Khasanov AA, Suturina LV, Borisova NI, Reshetov ZS, Foidart JM, et al. Comparison of two levonorgestrel-releasing intrauterine systems for the treatment of heavy menstrual bleeding: a randomised, controlled, phase 3 trial. Eur J Contracept Reprod Health Care. 2021; 26: 491-498.
  24. Alves RDMS, Rabelo MM, Andrade VR, Cabral RCS, Merriman JW, Brito MB. The influence of the levonorgestrel-releasing intrauterine system position on bleeding patterns in reproductive age women. Int J Gynaecol Obstet. 2019; 147: 326-331.
  25. Wittmann BZ, Monteiro I, Juliato C, Fernandes A. Consecutive Use of the 52 mg Levonorgestrel-releasing Intrauterine System: Variations in Bleeding Patterns. Rev Bras Ginecol Obstet. 2020; 42: 194-199.