Obstet Gynecol Sci.  2013 Mar;56(2):67-75. 10.5468/OGS.2013.56.2.67.

Clinical applications of levonorgestrel-releasing intrauterine system to gynecologic diseases

• Kim ML
• Seong SJ

• KMID: 1425653
• DOI: http://doi.org/10.5468/OGS.2013.56.2.67

Abstract

The levonorgestrel-releasing intrauterine system (LNG-IUS), originally designed for contraception, has since been applied to various gynecologic diseases. This article summarizes the current status of clinical applications of LNG-IUS to the treatment of gynecologic diseases such as heavy menstrual bleeding, endometriosis, leiomyoma, adenomyosis, endometrial hyperplasia, and early-stage endometrial cancer.

Keyword

Adenomyosis; Endometrial cancer; Endometrial hyperplasia; Endometriosis; Leiomyoma; Levonorgestrel-releasing intrauterine system; Menorrhagia

MeSH Terms

Adenomyosis
Contraception
Endometrial Hyperplasia
Endometrial Neoplasms
Endometriosis
Female
Genital Diseases, Female
Hemorrhage
Leiomyoma
Menorrhagia

Reference

1. Salem RM. New attention to the IUD: expanding women's contraceptive options to meet their needs. Popul Rep B. 2006; 1–26. PMID: 16671535.

2. Mirena [Internet]. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc.;c2013. cited 2013 Feb 15. Available from: http://berlex.bayerhealthcare.com/html/products/pi/Mirena_PI.pdf.

3. Perino A, Quartararo P, Catinella E, Genova G, Cittadini E. Treatment of endometrial hyperplasia with levonorgestrel releasing intrauterine devices. Acta Eur Fertil. 1987; 18:137–140. PMID: 3115027.

4. Inki P. Long-term use of the levonorgestrel-releasing intrauterine system. Contraception. 2007; 75:S161–S166. PMID: 17531611.

5. Heikinheimo O, Gemzell-Danielsson K. Emerging indications for the levonorgestrel-releasing intrauterine system (LNG-IUS). Acta Obstet Gynecol Scand. 2012; 91:3–9. PMID: 22007693.

6. Hurskainen R, Teperi J, Rissanen P, Aalto AM, Grenman S, Kivela 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; 291:1456–1463. PMID: 15039412.

7. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005; (4):CD002126. PMID: 16235297.

8. Gupta J, Kai J, Middleton L, Pattison H, Gray R, Daniels J, et al. Levonorgestrel intrauterine system versus medical therapy for menorrhagia. N Engl J Med. 2013; 368:128–137. PMID: 23301731.

9. ESHRE Capri Workshop Group. Intrauterine devices and intrauterine systems. Hum Reprod Update. 2008; 14:197–208. PMID: 18400840.

10. Espey E. Levonorgestrel intrauterine system: first-line therapy for heavy menstrual bleeding. N Engl J Med. 2013; 368:184–185. PMID: 23301736.

11. Gruppoitaliano per lo studio dell'endometriosi. Prevalence and anatomical distribution of endometriosis in women with selected gynaecological conditions: results from a multicentric Italian study. Hum Reprod. 1994; 9:1158–1162. PMID: 7962393.

12. Ajossa S, Mais V, Guerriero S, Paoletti AM, Caffiero A, Murgia C, et al. The prevalence of endometriosis in premenopausal women undergoing gynecological surgery. Clin Exp Obstet Gynecol. 1994; 21:195–197. PMID: 7923803.

13. Evers JL, Dunselman GA, Land JA, Bouckaert PX. Is there a solution for recurrent endometriosis? Br J Clin Pract Suppl. 1991; 72:45–50. PMID: 1807361.

14. Guo SW. Recurrence of endometriosis and its control. Hum Reprod Update. 2009; 15:441–461. PMID: 19279046.

15. Cheong Y, Tay P, Luk F, Gan HC, Li TC, Cooke I. Laparoscopic surgery for endometriosis: how often do we need to re-operate? J Obstet Gynaecol. 2008; 28:82–85. PMID: 18259906.

16. Park HJ, Koo YA, Yoon BK, Choi D. Postoperative long-term maintenance therapy with oral contraceptives after gonadotropin-releasing hormone analog treatment in women with ovarian endometrioma. J Minim Invasive Gynecol. 2009; 16:34–39. PMID: 18976968.

17. Prentice A, Deary AJ, Goldbeck-Wood S, Farquhar C, Smith SK. Gonadotrophin-releasing hormone analogues for pain associated with endometriosis. Cochrane Database Syst Rev. 2000; (2):CD000346. PMID: 10796530.

18. Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev. 2004; (3):CD003678. PMID: 15266496.

19. Abou-Setta AM, Al-Inany HG, Farquhar CM. Levonorgestrel-releasing intrauterine device (LNG-IUD) for symptomatic endometriosis following surgery. Cochrane Database Syst Rev. 2006; (4):CD005072. PMID: 17054236.

20. Parazzini F, Fedele L, Busacca M, Falsetti L, Pellegrini S, Venturini PL, et al. Postsurgical medical treatment of advanced endometriosis: results of a randomized clinical trial. Am J Obstet Gynecol. 1994; 171:1205–1207. PMID: 7977520.

21. Busacca M, Somigliana E, Bianchi S, De Marinis S, Calia C, Candiani M, et al. Post-operative GnRH analogue treatment after conservative surgery for symptomatic endometriosis stage III-IV: a randomized controlled trial. Hum Reprod. 2001; 16:2399–2402. PMID: 11679528.

22. Nilsson CG, Luukkainen T, Arko H. Endometrial morphology of women using a d-norgestrel-releasing intrauterine device. Fertil Steril. 1978; 29:397–401. PMID: 648644.

23. Hurskainen R, Salmi A, Paavonen J, Teperi J, Rutanen E. Expression of sex steroid receptors and Ki-67 in the endometria of menorrhagic women: effects of intrauterine levonorgestrel. Mol Hum Reprod. 2000; 6:1013–1018. PMID: 11044464.

24. Luukkainen T. The levonorgestrel intrauterine system: therapeutic aspects. Steroids. 2000; 65:699–702. PMID: 11108879.

25. Maruo T, Laoag-Fernandez JB, Pakarinen P, Murakoshi H, Spitz IM, Johansson E. Effects of the levonorgestrel-releasing intrauterine system on proliferation and apoptosis in the endometrium. Hum Reprod. 2001; 16:2103–2108. PMID: 11574499.

26. Ramey JW, Archer DF. Peritoneal fluid: its relevance to the development of endometriosis. Fertil Steril. 1993; 60:1–14. PMID: 8513924.

27. Kupker W, Schultze-Mosgau A, Diedrich K. Paracrine changes in the peritoneal environment of women with endometriosis. Hum Reprod Update. 1998; 4:719–723. PMID: 10027625.

28. McLaren J, Prentice A, Charnock-Jones DS, Millican SA, Muller KH, Sharkey AM, et al. Vascular endothelial growth factor is produced by peritoneal fluid macrophages in endometriosis and is regulated by ovarian steroids. J Clin Invest. 1996; 98:482–489. PMID: 8755660.

29. Vercellini P, Aimi G, Panazza S, De Giorgi O, Pesole A, Crosignani PG. A levonorgestrel-releasing intrauterine system for the treatment of dysmenorrhea associated with endometriosis: a pilot study. Fertil Steril. 1999; 72:505–508. PMID: 10519624.

30. Vercellini P, Frontino G, De Giorgi O, Aimi G, Zaina B, Crosignani PG. Comparison of a levonorgestrel-releasing intrauterine device versus expectant management after conservative surgery for symptomatic endometriosis: a pilot study. Fertil Steril. 2003; 80:305–309. PMID: 12909492.

31. Tanmahasamut P, Rattanachaiyanont M, Angsuwathana S, Techatraisak K, Indhavivadhana S, Leerasiri P. Postoperative levonorgestrel-releasing intrauterine system for pelvic endometriosis-related pain: a randomized controlled trial. Obstet Gynecol. 2012; 119:519–526. PMID: 22314873.

32. Petta CA, Ferriani RA, Abrao MS, Hassan D, Rosa ESJC, Podgaec S, et al. Randomized clinical trial of a levonorgestrel-releasing intrauterine system and a depot GnRH analogue for the treatment of chronic pelvic pain in women with endometriosis. Hum Reprod. 2005; 20:1993–1998. PMID: 15790607.

33. Bayoglu Tekin Y, Dilbaz B, Altinbas SK, Dilbaz S. Postoperative medical treatment of chronic pelvic pain related to severe endometriosis: levonorgestrel-releasing intrauterine system versus gonadotropin-releasing hormone analogue. Fertil Steril. 2011; 95:492–496. PMID: 20883991.

34. Kjerulff KH, Langenberg P, Seidman JD, Stolley PD, Guzinski GM. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis. J Reprod Med. 1996; 41:483–490. PMID: 8829060.

35. Stewart EA. Uterine fibroids. Lancet. 2001; 357:293–298. PMID: 11214143.

36. Magalhaes J, Aldrighi JM, de Lima GR. Uterine volume and menstrual patterns in users of the levonorgestrel-releasing intrauterine system with idiopathic menorrhagia or menorrhagia due to leiomyomas. Contraception. 2007; 75:193–198. PMID: 17303488.

37. Soysal S, Soysal ME. The efficacy of levonorgestrel-releasing intrauterine device in selected cases of myoma-related menorrhagia: a prospective controlled trial. Gynecol Obstet Invest. 2005; 59:29–35. PMID: 15377823.

38. Grigorieva V, Chen-Mok M, Tarasova M, Mikhailov A. Use of a levonorgestrel-releasing intrauterine system to treat bleeding related to uterine leiomyomas. Fertil Steril. 2003; 79:1194–1198. PMID: 12738516.

39. Mercorio F, De Simone R, Di Spiezio Sardo A, Cerrota G, Bifulco G, Vanacore F, et al. The effect of a levonorgestrel-releasing intrauterine device in the treatment of myoma-related menorrhagia. Contraception. 2003; 67:277–280. PMID: 12684148.

40. Gunes M, Ozdegirmenci O, Kayikcioglu F, Haberal A, Kaplan M. The effect of levonorgestrel intrauterine system on uterine myomas: a 1-year follow-up study. J Minim Invasive Gynecol. 2008; 15:735–738. PMID: 18971138.

41. Murat Naki M, Tekcan C, Ozcan N, Cebi M. Levonorgestrel-releasing intrauterine device insertion ameliorates leiomyoma-dependent menorrhagia among women of reproductive age without a significant regression in the uterine and leiomyoma volumes. Fertil Steril. 2010; 94:371–374. PMID: 19896649.

42. Sivin I, Stern J. International Committee for Contraception Research (ICCR). Health during prolonged use of levonorgestrel 20 micrograms/d and the copper TCu 380Ag intrauterine contraceptive devices: a multicenter study. Fertil Steril. 1994; 61:70–77. PMID: 8293847.

43. Kriplani A, Awasthi D, Kulshrestha V, Agarwal N. Efficacy of the levonorgestrel-releasing intrauterine system in uterine leiomyoma. Int J Gynaecol Obstet. 2012; 116:35–38. PMID: 21959070.

44. Backman T, Huhtala S, Luoto R, Tuominen J, Rauramo I, Koskenvuo M. Advance information improves user satisfaction with the levonorgestrel intrauterine system. Obstet Gynecol. 2002; 99:608–613. PMID: 12039121.

45. Ikomi A, Mansell E, Spence-Jones C, Singer A. Treatment of menorrhagia with the levonorgestrel intrauterine system: can we learn from our failures? J Obstet Gynaecol. 2000; 20:630–631. PMID: 15512683.

46. Rosa e Silva JC, de Sa Rosa e Silva AC, Candido dos Reis FJ, Manetta LA, Ferriani RA, Nogueira AA. Use of a levonorgestrel-releasing intrauterine device for the symptomatic treatment of uterine myomas. J Reprod Med. 2005; 50:613–617. PMID: 16220768.

47. Rabinovici J, Stewart EA. New interventional techniques for adenomyosis. Best Pract Res Clin Obstet Gynaecol. 2006; 20:617–636. PMID: 16934530.

48. Takebayashi T, Fujino Y, Umesaki N, Ogita S. Danazol suspension injected into the uterine cervix of patients with adenomyosis and myoma: preliminary study. Gynecol Obstet Invest. 1995; 39:207–211. PMID: 7789919.

49. Nelson JR, Corson SL. Long-term management of adenomyosis with a gonadotropin-releasing hormone agonist: a case report. Fertil Steril. 1993; 59:441–443. PMID: 8425643.

50. Fedele L, Bianchi S, Raffaelli R, Portuese A, Dorta M. Treatment of adenomyosis-associated menorrhagia with a levonorgestrel-releasing intrauterine device. Fertil Steril. 1997; 68:426–429. PMID: 9314908.

51. Wood C. Surgical and medical treatment of adenomyosis. Hum Reprod Update. 1998; 4:323–336. PMID: 9825848.

52. Benagiano G, Brosens I, Carrara S. Adenomyosis: new knowledge is generating new treatment strategies. Womens Health (Lond Engl). 2009; 5:297–311. PMID: 19392615.

53. Phillips DR. Endometrial ablation for postmenopausal uterine bleeding induced by hormone replacement therapy. J Am Assoc Gynecol Laparosc. 1995; 2:389–393. PMID: 9050590.

54. Englander MJ. Uterine artery embolization for the treatment of adenomyosis. Semin Intervent Radiol. 2008; 25:387–393. PMID: 21326580.

55. Yoon SW, Kim KA, Cha SH, Kim YM, Lee C, Na YJ, et al. Successful use of magnetic resonance-guided focused ultrasound surgery to relieve symptoms in a patient with symptomatic focal adenomyosis. Fertil Steril. 2008; 90:2018.e13–2018.e15. PMID: 18692791.

56. Bragheto AM, Caserta N, Bahamondes L, Petta CA. Effectiveness of the levonorgestrel-releasing intrauterine system in the treatment of adenomyosis diagnosed and monitored by magnetic resonance imaging. Contraception. 2007; 76:195–199. PMID: 17707716.

57. Cho S, Nam A, Kim H, Chay D, Park K, Cho DJ, et al. Clinical effects of the levonorgestrel-releasing intrauterine device in patients with adenomyosis. Am J Obstet Gynecol. 2008; 198:373.e1–373.e7. PMID: 18177833.

58. Sheng J, Zhang WY, Zhang JP, Lu D. The LNG-IUS study on adenomyosis: a 3-year follow-up study on the efficacy and side effects of the use of levonorgestrel intrauterine system for the treatment of dysmenorrhea associated with adenomyosis. Contraception. 2009; 79:189–193. PMID: 19185671.

59. Ozdegirmenci O, Kayikcioglu F, Akgul MA, Kaplan M, Karcaaltincaba M, Haberal A, et al. Comparison of levonorgestrel intrauterine system versus hysterectomy on efficacy and quality of life in patients with adenomyosis. Fertil Steril. 2011; 95:497–502. PMID: 21074150.

60. Whiteman MK, Zapata LB, Tepper NK, Marchbanks PA, Curtis KM. Use of contraceptive methods among women with endometrial hyperplasia: a systematic review. Contraception. 2010; 82:56–63. PMID: 20682143.

61. 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. PMID: 4005805.

62. Tabata T, Yamawaki T, Yabana T, Ida M, Nishimura K, Nose Y. Natural history of endometrial hyperplasia. Study of 77 patients. Arch Gynecol Obstet. 2001; 265:85–88. PMID: 11409481.

63. 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. PMID: 16400639.

64. Clark TJ, Neelakantan D, Gupta JK. The management of endometrial hyperplasia: an evaluation of current practice. Eur J Obstet Gynecol Reprod Biol. 2006; 125:259–264. PMID: 16246481.

65. Trimble CL, Method M, Leitao M, Lu K, Ioffe O, Hampton M, et al. Management of endometrial precancers. Obstet Gynecol. 2012; 120:1160–1175. PMID: 23090535.

66. Marsden DE, Hacker NF. Optimal management of endometrial hyperplasia. Best Pract Res Clin Obstet Gynaecol. 2001; 15:393–405. PMID: 11476561.

67. 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; 57:210–213. PMID: 17270370.

68. 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. PMID: 18684496.

69. 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. PMID: 18440693.

70. Vereide AB, Kaino T, Sager G, Arnes M, Orbo A. Effect of levonorgestrel IUD and oral medroxyprogesterone acetate on glandular and stromal progesterone receptors (PRA and PRB), and estrogen receptors (ER-alpha and ER-beta) in human endometrial hyperplasia. Gynecol Oncol. 2006; 101:214–223. PMID: 16325240.

71. 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; 91:526–533. PMID: 14675671.

72. 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. PMID: 20934679.

73. 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. PMID: 20613900.

74. 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. PMID: 21478178.

75. Surveillance epidemiology and end results. SEER Stat fact sheets: corpus and uterus, NOS [Internet][. Bethesda, MD: US National Cancer Institute;cited 2013 Feb 15. Available from: http://seer.cancer.gov/statfacts/html/corp.html.

76. Elit L, Hirte H. Current status and future innovations of hormonal agents, chemotherapy and investigational agents in endometrial cancer. Curr Opin Obstet Gynecol. 2002; 14:67–73. PMID: 11801879.

77. Gallup DG, Stock RJ. Adenocarcinoma of the endometrium in women 40 years of age or younger. Obstet Gynecol. 1984; 64:417–420. PMID: 6462572.

78. Soliman PT, Oh JC, Schmeler KM, Sun CC, Slomovitz BM, Gershenson DM, et al. Risk factors for young premenopausal women with endometrial cancer. Obstet Gynecol. 2005; 105:575–580. PMID: 15738027.

79. Creasman WT, Odicino F, Maisonneuve P, Quinn MA, Beller U, Benedet JL, et al. Carcinoma of the corpus uteri. FIGO 26th annual report on the results of treatment in gynecological cancer. Int J Gynaecol Obstet. 2006; 95(Suppl 1):S105–S143. PMID: 17161155.

80. Benshushan A. Endometrial adenocarcinoma in young patients: evaluation and fertility-preserving treatment. Eur J Obstet Gynecol Reprod Biol. 2004; 117:132–137. PMID: 15541846.

81. Rose PG. Endometrial carcinoma. N Engl J Med. 1996; 335:640–649. PMID: 8692240.

82. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987; 60:2035–2041. PMID: 3652025.

83. Leitao MM, Barakat RR. Advances in the management of endometrial carcinoma. Gynecol Oncol. 2011; 120:489–492. PMID: 21215997.

84. Randall TC, Kurman RJ. Progestin treatment of atypical hyperplasia and well-differentiated carcinoma of the endometrium in women under age 40. Obstet Gynecol. 1997; 90:434–440. PMID: 9277658.

85. Ramirez PT, Frumovitz M, Bodurka DC, Sun CC, Levenback C. Hormonal therapy for the management of grade 1 endometrial adenocarcinoma: a literature review. Gynecol Oncol. 2004; 95:133–138. PMID: 15385122.

86. Kim YB, Holschneider CH, Ghosh K, Nieberg RK, Montz FJ. Progestin alone as primary treatment of endometrial carcinoma in premenopausal women. Report of seven cases and review of the literature. Cancer. 1997; 79:320–327. PMID: 9010105.

87. Kaku T, Yoshikawa H, Tsuda H, Sakamoto A, Fukunaga M, Kuwabara Y, et al. Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome. Cancer Lett. 2001; 167:39–48. PMID: 11323097.

88. Gotlieb WH, Beiner ME, Shalmon B, Korach Y, Segal Y, Zmira N, et al. Outcome of fertility-sparing treatment with progestins in young patients with endometrial cancer. Obstet Gynecol. 2003; 102:718–725. PMID: 14551001.

89. Saegusa M, Okayasu I. Progesterone therapy for endometrial carcinoma reduces cell proliferation but does not alter apoptosis. Cancer. 1998; 83:111–121. PMID: 9655300.

90. Gallos ID, Yap J, Rajkhowa M, Luesley DM, Coomarasamy A, Gupta JK. Regression, relapse, and live birth rates with fertility-sparing therapy for endometrial cancer and atypical complex endometrial hyperplasia: a systematic review and metaanalysis. Am J Obstet Gynecol. 2012; 207:266.e1–266.e12. PMID: 23021687.

91. Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol. 2002; 186:651–657. PMID: 11967486.

92. Cade TJ, Quinn MA, Rome RM, Neesham D. Progestogen treatment options for early endometrial cancer. BJOG. 2010; 117:879–884. PMID: 20394609.

93. Kim MK, Yoon BS, Park H, Seong SJ, Chung HH, Kim JW, et al. Conservative treatment with medroxyprogesterone acetate plus levonorgestrel intrauterine system for early-stage endometrial cancer in young women: pilot study. Int J Gynecol Cancer. 2011; 21:673–677. PMID: 21546871.

94. Kim MK, Seong SJ, Lee TS, Kim JW, Nam BH, Hong SR, et al. Treatment with medroxyprogesterone acetate plus levonorgestrel-releasing intrauterine system for early-stage endometrial cancer in young women: single-arm, prospective multicenter study: Korean gynecologic oncology group study (KGOG2009). Jpn J Clin Oncol. 2012; 42:1215–1218. PMID: 23071290.