J Gynecol Oncol.  2013 Apr;24(2):128-134. 10.3802/jgo.2013.24.2.128.

LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women: a randomized controlled trial

  • 1Department of Obstetrics and Gynecology, Mansoura University, Faculty of Medicine, Mansoura, Egypt. hatem_ah@hotmail.com
  • 2Department of Clinical Pharmacology, Mansoura University, Faculty of Medicine, Mansoura, Egypt.
  • 3Department of Diagnostic Radiology, Mansoura University, Faculty of Medicine, Mansoura, Egypt.


To compare the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUS) and oral norethisterone acetate (NET) for treatment of non-atypical endometrial hyperplasia in perimenopausal women.
One hundred and twenty perimenopausal women with non-atypical endometrial hyperplasia were selected in this randomized controlled trial. Patients received LNG-IUS (n=59) or NET (n=61; 15 mg/day for 3 weeks/cycle) for 3-6 months. Outpatient follow-up with endometrial biopsies were undertaken at 3, 6, and 12 months intervals after treatment. Outcome measures were; the regression rate, the time to regression and hysterectomy rate.
A significantly higher regression rate was noted in the LNG-IUS group than in NET group at the 3rd, 6th and 12th month follow-up visits using intention-to-treat analysis (67.8% vs. 47.5%, relative risk [RR], 1.42; 79.7% vs. 60.7%, RR, 1.31; and 88.1% vs. 55.7%, RR, 1.58, respectively). However, no significant difference was found regarding the median time to regression (3 months). The hysterectomy rate during the follow-up period was significantly higher in the NET group (57.4% vs.22%, p<0.001).
LNG-IUS treatment of non-atypical endometrial hyperplasia in perimenopausal women is more effective than NET for achieving disease regression for the majority within 1 year. Moreover, it can reduce the number of hysterectomies performed.


Abnormal uterine bleeding; Endometrial hyperplasia; Levonorgestrel-releasing intrauterine system; Non-atypical; Norethisterone acetate

MeSH Terms

Endometrial Hyperplasia
Follow-Up Studies
Outcome Assessment (Health Care)


  • Fig. 1 CONSORT flow chart of participants in this trial. ITT, intention-to-treat analysis; LNG-IUS, levonorgestrel-releasing intrauterine system; NET, norethisterone acetate; PPA, per protocol analysis.


1. Gultekin M, Dogan NU, Aksan G, Ozgul N. Management of endometrial hyperplasia. Minerva Ginecol. 2010. 62:433–445.
2. Reed SD, Newton KM, Clinton WL, Epplein M, Garcia R, Allison K, et al. Incidence of endometrial hyperplasia. Am J Obstet Gynecol. 2009. 200:678.e1–678.e6.
3. Anastasiadis PG, Skaphida PG, Koutlaki NG, Galazios GC, Tsikouras PN, Liberis VA. Descriptive epidemiology of endometrial hyperplasia in patients with abnormal uterine bleeding. Eur J Gynaecol Oncol. 2000. 21:131–134.
4. Espindola D, Kennedy KA, Fischer EG. Management of abnormal uterine bleeding and the pathology of endometrial hyperplasia. Obstet Gynecol Clin North Am. 2007. 34:717–737.
5. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia: a long-term study of "untreated" hyperplasia in 170 patients. Cancer. 1985. 56:403–412.
6. Lacey JV Jr, Chia VM. Endometrial hyperplasia and the risk of progression to carcinoma. Maturitas. 2009. 63:39–44.
7. Trimble CL, Kauderer J, Zaino R, Silverberg S, Lim PC, Burke JJ 2nd, et al. Concurrent endometrial carcinoma in women with a biopsy diagnosis of atypical endometrial hyperplasia: a Gynecologic Oncology Group study. Cancer. 2006. 106:812–819.
8. Eddib A, Allaf B, Lee J, Yeh J. Risk for advanced-stage endometrial cancer in surgical specimens from patients with complex endometrial hyperplasia with atypia. Gynecol Obstet Invest. 2012. 73:38–42.
9. Marsden DE, Hacker NF. Optimal management of endometrial hyperplasia. Best Pract Res Clin Obstet Gynaecol. 2001. 15:393–405.
10. Koskas M, Azria E, Walker F, Luton D, Madelenat P, Yazbeck C. Progestin treatment of atypical hyperplasia and well-differentiated adenocarcinoma of the endometrium to preserve fertility. Anticancer Res. 2012. 32:1037–1043.
11. Gunderson CC, Fader AN, Carson KA, Bristow RE. Oncologic and reproductive outcomes with progestin therapy in women with endometrial hyperplasia and grade 1 adenocarcinoma: a systematic review. Gynecol Oncol. 2012. 125:477–482.
12. Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, et al. Management of endometrial precancers. Obstet Gynecol. 2012. 120:1160–1175.
13. Montgomery BE, Daum GS, Dunton CJ. Endometrial hyperplasia: a review. Obstet Gynecol Surv. 2004. 59:368–378.
14. 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. 113:655–662.
15. Ferenczy A, Gelfand M. The biologic significance of cytologic atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol. 1989. 160:126–131.
16. 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. 203:547.e1–547.e10.
17. Haoula ZJ, Walker KF, Powell MC. Levonorgestrel intra-uterine system as a treatment option for complex endometrial hyperplasia. Eur J Obstet Gynecol Reprod Biol. 2011. 159:176–179.
18. Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol (Oxf). 1982. 17:529–536.
19. Phillips V, Graham CT, Manek S, McCluggage WG. The effects of the levonorgestrel intrauterine system (Mirena coil) on endometrial morphology. J Clin Pathol. 2003. 56:305–307.
20. Guttinger A, Critchley HO. Endometrial effects of intrauterine levonorgestrel. Contraception. 2007. 75:6 Suppl. S93–S98.
21. Horn LC, Schnurrbusch U, Bilek K, Hentschel B, Einenkel J. Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment. Int J Gynecol Cancer. 2004. 14:348–353.
22. Bese T, Vural A, Ozturk M, Dagistanli F, Demirkiran F, Tuncdemir M, et al. The effect of long-term use of progesterone therapy on proliferation and apoptosis in simple endometrial hyperplasia without atypia. Int J Gynecol Cancer. 2006. 16:809–813.
23. 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. 139:169–175.
24. Lee SY, Kim MK, Park H, Yoon BS, Seong SJ, Kang JH, et al. The effectiveness of levonorgestrel releasing intrauterine system in the treatment of endometrial hyperplasia in Korean women. J Gynecol Oncol. 2010. 21:102–105.
25. Orbo 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. 111:68–73.
26. Haimovich S, Checa MA, Mancebo G, Fuste P, Carreras R. Treatment of endometrial hyperplasia without atypia in peri- and postmenopausal women with a levonorgestrel intrauterine device. Menopause. 2008. 15:1002–1004.
27. Orbo A, Arnes M, Pettersen I, Larsen K, Hanssen K, Moe B. Down-regulated progesterone receptor A and B coinciding with successful treatment of endometrial hyperplasia by the levonorgestrel impregnated intrauterine system. Acta Obstet Gynecol Scand. 2010. 89:1438–1446.
28. Jensen JT, Nelson AL, Costales AC. Subject and clinician experience with the levonorgestrel-releasing intrauterine system. Contraception. 2008. 77:22–29.
29. Bachmann G, Korner P. Bleeding patterns associated with non-oral hormonal contraceptives: a review of the literature. Contraception. 2009. 79:247–258.
30. Mansour D. The benefits and risks of using a levonorgestrel-releasing intrauterine system for contraception. Contraception. 2012. 85:224–234.
31. Ceci O, Bettocchi S, Pellegrino A, Impedovo L, Di Venere R, Pansini N. Comparison of hysteroscopic and hysterectomy findings for assessing the diagnostic accuracy of office hysteroscopy. Fertil Steril. 2002. 78:628–631.
32. Gallos ID, Ofinran O, Shehmar M, Coomarasamy A, Gupta JK. Current management of endometrial hyperplasia-a survey of United Kingdom consultant gynaecologists. Eur J Obstet Gynecol Reprod Biol. 2011. 158:305–307.
33. American Association of Gynecologic Laparoscopists. AAGL practice report: practice guidelines for the diagnosis and management of endometrial polyps. J Minim Invasive Gynecol. 2012. 19:3–10.
34. Haynes PJ, Hodgson H, Anderson AB, Turnbull AC. Measurement of menstrual blood loss in patients complaining of menorrhagia. Br J Obstet Gynaecol. 1977. 84:763–768.
35. Demirkiran F, Yavuz E, Erenel H, Bese T, Arvas M, Sanioglu C. Which is the best technique for endometrial sampling? Aspiration (pipelle) versus dilatation and curettage (D&C). Arch Gynecol Obstet. 2012. 286:1277–1282.
36. Lee TS, Seong SJ, Kim JW, Ryu HS, Song ES, Nam BH. Management of endometrial hyperplasia with a levonorgestrel-releasing intrauterine system: single arm, prospective multicenter study: Korean Gynecologic Oncology Group Study (KGOG2006). Jpn J Clin Oncol. 2011. 41:817–819.
Full Text Links
  • JGO
export Copy
  • Twitter
  • Facebook
Similar articles
Copyright © 2023 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr