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Research Article
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The efficacy of levonorgestrel intrauterine device, medroxyprogesterone acetate, and norethisterone acetate in the treatment of endometrial hyperplasia without atypia

Year 2024, Volume: 2 Issue: 3, 93 - 98, 25.09.2024
https://doi.org/10.61678/bursamed.1528905

Abstract

Objectives: Pregestational treatments, which trigger apoptosis and suppress endometrium, are the gold standard therapy for endometrial hyperplasia without atypia. The levonorgestrel-intrauterine device is the first choice in current guidelines due to its low dose. Still, oral progestins have no clear evidence due to their lower regression rates and side effects. Here, we aimed to compare the regression rates, hysterectomy requirement, and the occurrence of side effects in the sixth month between the levonorgestrel-intrauterine device, norethisterone acetate, and medroxyprogesterone acetate treatment.
Methods: A total of 60 patients were included. The study group was divided into three groups: levonorgestrel-intrauterine device group (n=20), norethisterone acetate group (n=20), and medroxyprogesterone acetate group (n=20). Demographic findings, body mass index, gravida, parity, comorbid diseases, regression, hysterectomy requirement, patient desire to continue treatment, and side effects such as amenorrhea, headache, weight gain, intermenstrual spotting, nausea, and breast tenderness were compared between three groups.
Results: There was no statistically significant difference between the three groups regarding headache, weight gain, intermenstrual spotting, and breast tenderness. Regression rates were significantly higher in the levonorgestrel intrauterine device group compared to medroxyprogesterone acetate (p=0.044) and norethisterone acetate group (p=0.020). Similarly, hysterectomy rates were significantly lower in the levonorgestrel intrauterine device group compared to medroxyprogesterone acetate (p=0.031) and norethisterone acetate group (p=0.028). Amenorrhea was significantly more common in the levonorgestrel intrauterine device group than in other groups (p=0.020 for both), whereas nausea was rarer in the levonorgestrel intrauterine device group (p=0.047 for both). According to the patient’s satisfaction, the levonorgestrel intrauterine device was the most satisfactory treatment compared to medroxyprogesterone acetate and norethisterone acetate (p=0.028 and p=0.031). No significant difference was found between the medroxyprogesterone acetate and norethisterone acetate groups in terms of regression rates, hysterectomy requirements, amenorrhea, nausea, and patient satisfaction.
Conclusion: Considering low hysterectomy requirement, high regression rates, and patient satisfaction, the levonorgestrel intrauterine device should be the first choice for endometrial hyperplasia without atypia as compared to oral progestins. Thus, patients must be informed about side effects and offered levonorgestrel intrauterine devices before oral progestins for endometrial hyperplasia without atypia.

Ethical Statement

The present study was approved by the University of Health Sciences, BursaYuksek Ihtisas Research and Training Hospital'S.local ethics committee (decision number of 2024-TBEK 2024/07-08

Supporting Institution

None

References

  • Hannemann MM, Alexander MH, Cope JN, Acheson N, Phillips A. Endometrial hyperplasia: a clinician’s review. Obstet Gynecol Reprod Med 2010;20(4):116-20.
  • Girbash EF, Sherif HE, Radwan AM, Abdeldayem HM. Dienogest versus norethisterone acetate in management of endometrial hyperplasia without atypia. Arch Gynecol Obstet 2023;308(3):947-52. doi: 10.1007/s00404-023-07015-7.
  • El Behery MM, Saleh HS, Ibrahiem MA, Kamal EM, Kassem GA, Mohamed Mel S. Levonorgestrel-releasing intrauterine device versus dydrogesterone for management of endometrial hyperplasia without atypia. Reprod Sci 2015;22(3):329-34. doi: 10.1177/1933719114542014.
  • Varma R, Soneja H, Bhatia K, Ganesan R, Rollason T, Clark TJ, et al. The effectiveness of a levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of endometrial hyperplasia-a long-term follow-up study. Eur J Obstet Gynecol Reprod Biol 2008;139(2):169-75. doi: 10.1016/j.ejogrb.2008.02.022.
  • Li L, Zhu L; Group for Chinese Guidelines On The Management Of Endometrial Hyperplasia. Chinese guidelines on the management of endometrial hyperplasia. Eur J Surg Oncol 2024;50(7):108391. doi: 10.1016/j.ejso.2024.108391.
  • Wildemeersch D, Janssens D, Pylyser K, De Wever N, Verbeeck G, Dhont M, et al. Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up. Maturitas 2007;57(2):210-3. doi: 10.1016/j.maturitas.2006.12.004.
  • Amezcua CA, Lu JJ, Felix JC, Stanczyk FZ, Zheng W. Apoptosis may be an early event of progestin therapy for endometrial hyperplasia. Gynecol Oncol 2000;79(2):169-76. doi: 10.1006/gyno.2000.5955.
  • Rattanachaiyanont M, Angsuwathana S, Techatrisak K, Tanmahasamut P, Indhavivadhana S, Leerasiri P. Clinical and pathological responses of progestin therapy for non-atypical endometrial hyperplasia: a prospective study. J Obstet Gynaecol Res 2005;31(2):98-106. doi: 10.1111/j.1447-0756.2005.00253.x.
  • Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivelä A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291(12):1456-63. doi: 10.1001/jama.291.12.1456.
  • Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203(6):547.e1-10. doi: 10.1016/j.ajog.2010.07.037.
  • Shen Y, Fang H, Zhang Y, Du Y, Cai R, Zhao M, et al. Comparison of the effectiveness of the levonorgestrel-intrauterine device and oral progestogens on regression of endometrial hyperplasia without atypia. Heliyon 2022;8(12):e12150. doi: 10.1016/j.heliyon.2022.e12150.
  • Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985;56(2):403-12. doi.org/10.1002/1097-0142(19850715)56:2<403::aid-cncr2820560233>3.0.co;2-x.
  • Terakawa N, Kigawa J, Taketani Y, Yoshikawa H, Yajima A, Noda K, et al. The behavior of endometrial hyperplasia: a prospective study. Endometrial Hyperplasia Study Group. J Obstet Gynaecol Res 1997;23(3):223-30. doi.org/10.1111/j.1447-0756.1997.tb00836.x.
  • Auclair MH, Yong PJ, Salvador S, Thurston J, Colgan TTJ, Sebastianelli A. Guideline no. 390-classification and management of endometrial hyperplasia. J Obstet Gynaecol Can 2019;41(12):1789-800.
  • Mittermeier T, Farrant C, Wise MR. Levonorgestrel-releasing intrauterine system for endometrial hyperplasia. Cochrane Database Syst Rev 2020;9(9):CD012658. doi: 10.1002/14651858.CD012658.pub2.
  • Emarh M. Cyclic versus continuous medroxyprogesterone acetate for treatment of endometrial hyperplasia without atypia: a 2-year observational study. Arch Gynecol Obstet 2015;292(6):1339-43. doi.org/10.1007/s00404-015-3749-3.
  • Sharifzadeh F, Aminimoghaddam S, Kashanian M, Fazaeli M, Sheikhansari N. A comparison between the effects of metformin and megestrol on simple endometrial hyperplasia 2017;33(2):152-5.
  • Hashim HA, Zayed A, Ghayaty E, El Rakhawy M. LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial 2013;24(2):128-34.
  • Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol 2015;213(4):469-78. doi: 10.1016/j.ajog.2015.03.037.
  • Orbo A, Vereide A, Arnes M, Pettersen I, Straume B. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. BJOG 2014;121(4):477-86. doi: 10.1111/1471-0528.12499.
  • Zhang YF, Fan Y, Mu Y, Li JK. Efficacy of Oral Medications or Intrauterine Device-Delivered Progestin in Patients with Endometrial Hyperplasia with or without Atypia: A Network Meta-Analysis. J Clin Med 2023;12(8):2980. doi: 10.3390/jcm12082980.
  • Vereide AB, Arnes M, Straume B, Maltau JM, Orbo A. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol 2003;91(3):526-533. doi: 10.1016/j.ygyno.2003.07.002.
  • Ørbo A, Arnes M, Hancke C, Vereide AB, Pettersen I, Larsen K. Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol 2008;111(1):68-73.
  • Ismail MT, Fahmy DM, Elshmaa NS. Efficacy of levonorgestrel-releasing intrauterine system versus oral progestins in treatment of simple endometrial hyperplasia without atypia. Reprod Sci 2013;20(1):45-50. doi: 10.1177/1933719112459243.
  • Reed SD, Voigt LF, Newton KM, Garcia RH, Allison HK, Epplein M, et al. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol. 2009;113(3):655-62. doi: 10.1097/AOG.0b013e318198a10a.
  • Gezer Ş, Köle E, Aksoy L. Vaginal micronized progesterone versus the levonorgestrel-releasing intrauterine system for treatment of non-atypical endometrial hyperplasia: A randomized controlled trial. Int J Gynaecol Obstet 2023;161(2):661-6. doi: 10.1002/ijgo.14632.
  • Uysal G, Acmaz G, Madendag Y, Cagli F, Akkaya H, Madendag I, et al. The Efficacy of Dienogest in the Treatment of Simple Endometrial Hyperplasia without Atypia. Gynecol Obstet Invest 2018;83(2):151-5. doi: 10.1159/000477618.
  • Tasci Y, Polat OG, Ozdogan S, Karcaaltincaba D, Seckin L, Erkaya S. Comparison of the efficacy of micronized progesterone and lynestrenol in treatment of simple endometrial hyperplasia without atypia. Arch Gynecol Obstet 2014;290(1):83-6. doi: 10.1007/s00404-014-3161-4.
  • Ozdegirmenci O, Kayikcioglu F, Bozkurt U, Akgul MA, Haberal A. Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia. Gynecol Obstet Invest 2011;72(1):10-4. doi: 10.1159/000321390.
  • Karimi-Zarchi M, Dehghani-Firoozabadi R, Tabatabaie A, Dehghani-Firoozabadi Z, Teimoori S, Chiti Z, et al. A comparison of the effect of levonorgestrel IUD with oral medroxyprogesterone acetate on abnormal uterine bleeding with simple endometrial hyperplasia and fertility preservation. Clin Exp Obstet Gynecol 2013;40(3):421-4.
  • Ziller M, Ziller V, Haas G, Rex J, Kostev K. Risk of venous thrombosis in users of hormonal contraceptives in German gynaecological practices: a patient database analysis. Arch Gynecol Obstet 2014;289(2):413-9. doi: 10.1007/s00404-013-2983-9.
  • Sugiura K, Kobayashi T, Ojima T. Risks of thromboembolism associated with hormonal contraceptives related to body mass index and aging in Japanese women. Thromb Res 2016;137:11-16. doi: 10.1016/j.thromres.2015.11.038.
  • Rezk M, Kandil M, Saleh S, Shaheen A. Comparison of levonorgestrel–releasing intrauterine system, medroxyprogesterone and norethisterone for treatment of endometrial hyperplasia without atypia: A randomized clinical trial. Obstet Gynecol Int J. 2016;5:353-6.
Year 2024, Volume: 2 Issue: 3, 93 - 98, 25.09.2024
https://doi.org/10.61678/bursamed.1528905

Abstract

References

  • Hannemann MM, Alexander MH, Cope JN, Acheson N, Phillips A. Endometrial hyperplasia: a clinician’s review. Obstet Gynecol Reprod Med 2010;20(4):116-20.
  • Girbash EF, Sherif HE, Radwan AM, Abdeldayem HM. Dienogest versus norethisterone acetate in management of endometrial hyperplasia without atypia. Arch Gynecol Obstet 2023;308(3):947-52. doi: 10.1007/s00404-023-07015-7.
  • El Behery MM, Saleh HS, Ibrahiem MA, Kamal EM, Kassem GA, Mohamed Mel S. Levonorgestrel-releasing intrauterine device versus dydrogesterone for management of endometrial hyperplasia without atypia. Reprod Sci 2015;22(3):329-34. doi: 10.1177/1933719114542014.
  • Varma R, Soneja H, Bhatia K, Ganesan R, Rollason T, Clark TJ, et al. The effectiveness of a levonorgestrel-releasing intrauterine system (LNG-IUS) in the treatment of endometrial hyperplasia-a long-term follow-up study. Eur J Obstet Gynecol Reprod Biol 2008;139(2):169-75. doi: 10.1016/j.ejogrb.2008.02.022.
  • Li L, Zhu L; Group for Chinese Guidelines On The Management Of Endometrial Hyperplasia. Chinese guidelines on the management of endometrial hyperplasia. Eur J Surg Oncol 2024;50(7):108391. doi: 10.1016/j.ejso.2024.108391.
  • Wildemeersch D, Janssens D, Pylyser K, De Wever N, Verbeeck G, Dhont M, et al. Management of patients with non-atypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: long-term follow-up. Maturitas 2007;57(2):210-3. doi: 10.1016/j.maturitas.2006.12.004.
  • Amezcua CA, Lu JJ, Felix JC, Stanczyk FZ, Zheng W. Apoptosis may be an early event of progestin therapy for endometrial hyperplasia. Gynecol Oncol 2000;79(2):169-76. doi: 10.1006/gyno.2000.5955.
  • Rattanachaiyanont M, Angsuwathana S, Techatrisak K, Tanmahasamut P, Indhavivadhana S, Leerasiri P. Clinical and pathological responses of progestin therapy for non-atypical endometrial hyperplasia: a prospective study. J Obstet Gynaecol Res 2005;31(2):98-106. doi: 10.1111/j.1447-0756.2005.00253.x.
  • Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivelä A, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291(12):1456-63. doi: 10.1001/jama.291.12.1456.
  • Gallos ID, Shehmar M, Thangaratinam S, Papapostolou TK, Coomarasamy A, Gupta JK. Oral progestogens vs levonorgestrel-releasing intrauterine system for endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol 2010;203(6):547.e1-10. doi: 10.1016/j.ajog.2010.07.037.
  • Shen Y, Fang H, Zhang Y, Du Y, Cai R, Zhao M, et al. Comparison of the effectiveness of the levonorgestrel-intrauterine device and oral progestogens on regression of endometrial hyperplasia without atypia. Heliyon 2022;8(12):e12150. doi: 10.1016/j.heliyon.2022.e12150.
  • Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of "untreated" hyperplasia in 170 patients. Cancer 1985;56(2):403-12. doi.org/10.1002/1097-0142(19850715)56:2<403::aid-cncr2820560233>3.0.co;2-x.
  • Terakawa N, Kigawa J, Taketani Y, Yoshikawa H, Yajima A, Noda K, et al. The behavior of endometrial hyperplasia: a prospective study. Endometrial Hyperplasia Study Group. J Obstet Gynaecol Res 1997;23(3):223-30. doi.org/10.1111/j.1447-0756.1997.tb00836.x.
  • Auclair MH, Yong PJ, Salvador S, Thurston J, Colgan TTJ, Sebastianelli A. Guideline no. 390-classification and management of endometrial hyperplasia. J Obstet Gynaecol Can 2019;41(12):1789-800.
  • Mittermeier T, Farrant C, Wise MR. Levonorgestrel-releasing intrauterine system for endometrial hyperplasia. Cochrane Database Syst Rev 2020;9(9):CD012658. doi: 10.1002/14651858.CD012658.pub2.
  • Emarh M. Cyclic versus continuous medroxyprogesterone acetate for treatment of endometrial hyperplasia without atypia: a 2-year observational study. Arch Gynecol Obstet 2015;292(6):1339-43. doi.org/10.1007/s00404-015-3749-3.
  • Sharifzadeh F, Aminimoghaddam S, Kashanian M, Fazaeli M, Sheikhansari N. A comparison between the effects of metformin and megestrol on simple endometrial hyperplasia 2017;33(2):152-5.
  • Hashim HA, Zayed A, Ghayaty E, El Rakhawy M. LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial 2013;24(2):128-34.
  • Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol 2015;213(4):469-78. doi: 10.1016/j.ajog.2015.03.037.
  • Orbo A, Vereide A, Arnes M, Pettersen I, Straume B. Levonorgestrel-impregnated intrauterine device as treatment for endometrial hyperplasia: a national multicentre randomised trial. BJOG 2014;121(4):477-86. doi: 10.1111/1471-0528.12499.
  • Zhang YF, Fan Y, Mu Y, Li JK. Efficacy of Oral Medications or Intrauterine Device-Delivered Progestin in Patients with Endometrial Hyperplasia with or without Atypia: A Network Meta-Analysis. J Clin Med 2023;12(8):2980. doi: 10.3390/jcm12082980.
  • Vereide AB, Arnes M, Straume B, Maltau JM, Orbo A. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol 2003;91(3):526-533. doi: 10.1016/j.ygyno.2003.07.002.
  • Ørbo A, Arnes M, Hancke C, Vereide AB, Pettersen I, Larsen K. Treatment results of endometrial hyperplasia after prospective D-score classification: a follow-up study comparing effect of LNG-IUD and oral progestins versus observation only. Gynecol Oncol 2008;111(1):68-73.
  • Ismail MT, Fahmy DM, Elshmaa NS. Efficacy of levonorgestrel-releasing intrauterine system versus oral progestins in treatment of simple endometrial hyperplasia without atypia. Reprod Sci 2013;20(1):45-50. doi: 10.1177/1933719112459243.
  • Reed SD, Voigt LF, Newton KM, Garcia RH, Allison HK, Epplein M, et al. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol. 2009;113(3):655-62. doi: 10.1097/AOG.0b013e318198a10a.
  • Gezer Ş, Köle E, Aksoy L. Vaginal micronized progesterone versus the levonorgestrel-releasing intrauterine system for treatment of non-atypical endometrial hyperplasia: A randomized controlled trial. Int J Gynaecol Obstet 2023;161(2):661-6. doi: 10.1002/ijgo.14632.
  • Uysal G, Acmaz G, Madendag Y, Cagli F, Akkaya H, Madendag I, et al. The Efficacy of Dienogest in the Treatment of Simple Endometrial Hyperplasia without Atypia. Gynecol Obstet Invest 2018;83(2):151-5. doi: 10.1159/000477618.
  • Tasci Y, Polat OG, Ozdogan S, Karcaaltincaba D, Seckin L, Erkaya S. Comparison of the efficacy of micronized progesterone and lynestrenol in treatment of simple endometrial hyperplasia without atypia. Arch Gynecol Obstet 2014;290(1):83-6. doi: 10.1007/s00404-014-3161-4.
  • Ozdegirmenci O, Kayikcioglu F, Bozkurt U, Akgul MA, Haberal A. Comparison of the efficacy of three progestins in the treatment of simple endometrial hyperplasia without atypia. Gynecol Obstet Invest 2011;72(1):10-4. doi: 10.1159/000321390.
  • Karimi-Zarchi M, Dehghani-Firoozabadi R, Tabatabaie A, Dehghani-Firoozabadi Z, Teimoori S, Chiti Z, et al. A comparison of the effect of levonorgestrel IUD with oral medroxyprogesterone acetate on abnormal uterine bleeding with simple endometrial hyperplasia and fertility preservation. Clin Exp Obstet Gynecol 2013;40(3):421-4.
  • Ziller M, Ziller V, Haas G, Rex J, Kostev K. Risk of venous thrombosis in users of hormonal contraceptives in German gynaecological practices: a patient database analysis. Arch Gynecol Obstet 2014;289(2):413-9. doi: 10.1007/s00404-013-2983-9.
  • Sugiura K, Kobayashi T, Ojima T. Risks of thromboembolism associated with hormonal contraceptives related to body mass index and aging in Japanese women. Thromb Res 2016;137:11-16. doi: 10.1016/j.thromres.2015.11.038.
  • Rezk M, Kandil M, Saleh S, Shaheen A. Comparison of levonorgestrel–releasing intrauterine system, medroxyprogesterone and norethisterone for treatment of endometrial hyperplasia without atypia: A randomized clinical trial. Obstet Gynecol Int J. 2016;5:353-6.
There are 33 citations in total.

Details

Primary Language English
Subjects Clinical Sciences (Other)
Journal Section Research Articles
Authors

Burcu Dinçgez 0000-0002-2697-7501

Gülten Özgen 0000-0002-7888-7583

Levent Özgen 0000-0003-0070-2646

Publication Date September 25, 2024
Submission Date August 6, 2024
Acceptance Date August 14, 2024
Published in Issue Year 2024 Volume: 2 Issue: 3

Cite

EndNote Dinçgez B, Özgen G, Özgen L (September 1, 2024) The efficacy of levonorgestrel intrauterine device, medroxyprogesterone acetate, and norethisterone acetate in the treatment of endometrial hyperplasia without atypia. Journal of Bursa Faculty of Medicine 2 3 93–98.

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