Obstet Gynecol Sci.  2018 Mar;61(2):192-201. 10.5468/ogs.2018.61.2.192.

Current medical treatment of uterine fibroids

• Sohn GS
• Cho S
• Kim YM
• Cho CH
• Kim MR
• Lee SR
• for the Working Group of Society of Uterine Leiomyoma

• KMID: 2420172
• DOI: http://doi.org/10.5468/ogs.2018.61.2.192

Abstract

Uterine fibroids (leiomyomas or myomas), benign monoclonal tumors, are the most common benign tumors in women. Heavy or prolonged menstrual bleeding, abnormal uterine bleeding, resultant anemia, pelvic pain, infertility, and/or recurrent pregnancy loss are generally associated with uterine fibroids. Although curative treatment of this tumor relies on surgical therapies, medical treatments are considered the first-line treatment to preserve fertility and avoid or delay surgery. The aim of this review is to provide available and emerging medical treatment options for symptomatic uterine fibroids. Literature review and consensus of expert opinion. Many uterine fibroids are asymptomatic and require no intervention, although it is advisable to follow-up patients to document stability in size and growth. Fibroid-associated symptoms include heavy menstrual bleeding and pain or pelvic discomfort. The association between infertility and fibroids increases with age. Treatment options for symptomatic uterine fibroids "” include medical, surgical, and radiologically guided interventions. Various medical therapies are now available for women with uterine fibroids, although each therapy has its own advantages and disadvantages. Currently, gonadotrophin-releasing hormone (GnRH) agonists and selective progesterone receptor modulators (SPRMs) are the most effective medical therapies, with the most evidence to support their reduction of fibroid volume and symptomatic improvement in menstrual bleeding. The choice of treatment depends on the patient's personal treatment goals, as well as efficacy and need for repeated interventions.

Keyword

Uterine fibroids; GnRH receptor

MeSH Terms

Anemia
Consensus
Expert Testimony
Female
Fertility
Follow-Up Studies
Hemorrhage
Humans
Infertility
Leiomyoma*
Pelvic Pain
Pregnancy
Receptors, LHRH
Receptors, Progesterone
Uterine Hemorrhage
Receptors, LHRH
Receptors, Progesterone

Reference

1. Baird DD, Dunson DB, Hill MC, Cousins D, Schectman JM. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence. Am J Obstet Gynecol. 2003; 188:100–107.

2. Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science. 2005; 308:1589–1592.

3. Myers SL, Baird DD, Olshan AF, Herring AH, Schroeder JC, Nylander-French LA, et al. Self-report versus ultrasound measurement of uterine fibroid status. J Womens Health (Larchmt). 2012; 21:285–293.

4. Ryan GL, Syrop CH, Van Voorhis BJ. Role, epidemiology, and natural history of benign uterine mass lesions. Clin Obstet Gynecol. 2005; 48:312–324.

5. Zimmermann A, Bernuit D, Gerlinger C, Schaefers M, Geppert K. Prevalence, symptoms and management of uterine fibroids: an international internet-based survey of 21,746 women. BMC Womens Health. 2012; 12:6.

6. Marshall LM, Spiegelman D, Barbieri RL, Goldman MB, Manson JE, Colditz GA, et al. Variation in the incidence of uterine leiomyoma among premenopausal women by age and race. Obstet Gynecol. 1997; 90:967–973.

7. Linder D, Gartler SM. Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas. Science. 1965; 150:67–69.

8. Holdsworth-Carson SJ, Zaitseva M, Vollenhoven BJ, Rogers PA. Clonality of smooth muscle and fibroblast cell populations isolated from human fibroid and myometrial tissues. Mol Hum Reprod. 2014; 20:250–259.

9. Tamaya T, Nioka S, Furuta N, Shimura T, Boku S, Okada H. Progesterone receptor in human endometrium of leiomyoma uteri. Endocrinol Jpn. 1977; 24:523–528.

10. Maruo T. Progesterone and progesterone receptor modulator in uterine leiomyoma growth. Gynecol Endocrinol. 2007; 23:186–187.

11. Ishikawa H, Ishi K, Serna VA, Kakazu R, Bulun SE, Kurita T. Progesterone is essential for maintenance and growth of uterine leiomyoma. Endocrinology. 2010; 151:2433–2442.

12. Peddada SD, Laughlin SK, Miner K, Guyon JP, Haneke K, Vahdat HL, et al. Growth of uterine leiomyomata among premenopausal black and white women. Proc Natl Acad Sci USA. 2008; 105:19887–19892.

13. Radin RG, Rosenberg L, Palmer JR, Cozier YC, Kumanyika SK, Wise LA. Hypertension and risk of uterine leiomyomata in US black women. Hum Reprod. 2012; 27:1504–1509.

14. Wise LA, Radin RG, Palmer JR, Rosenberg L. Association of intrauterine and early life factors with uterine leiomyomata in black women. Ann Epidemiol. 2012; 22:847–854.

15. Baird DD, Hill MC, Schectman JM, Hollis BW. Vitamin d and the risk of uterine fibroids. Epidemiology. 2013; 24:447–453.

16. Paffoni A, Somigliana E, Viganó P, Benaglia L, Cardellicchio L, Pagliardini L, et al. Vitamin D status in women with uterine leiomyomas. J Clin Endocrinol Metab. 2013; 98:E1374–8.

17. Gupta S, Jose J, Manyonda I. Clinical presentation of fibroids. Best Pract Res Clin Obstet Gynaecol. 2008; 22:615–626.

18. Jayakrishnan K, Menon V, Nambiar D. Submucous fibroids and infertility: effect of hysteroscopic myomectomy and factors influencing outcome. J Hum Reprod Sci. 2013; 6:35–39.

19. Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review of the evidence. Fertil Steril. 2009; 91:1215–1223.

20. Zepiridis LI, Grimbizis GF, Tarlatzis BC. Infertility and uterine fibroids. Best Pract Res Clin Obstet Gynaecol. 2016; 34:66–73.

21. Marret H, Fritel X, Ouldamer L, Bendifallah S, Brun JL, De Jesus I, et al. Therapeutic management of uterine fibroid tumors: updated French guidelines. Eur J Obstet Gynecol Reprod Biol. 2012; 165:156–164.

22. Qin J, Yang T, Kong F, Zhou Q. Oral contraceptive use and uterine leiomyoma risk: a meta-analysis based on cohort and case-control studies. Arch Gynecol Obstet. 2013; 288:139–148.

23. Hoffman BL, Williams JW. Williams gynecology. 2nd ed. New York (NY): McGraw-Hill Medical;2012.

24. American College of Obstetricians and Gynecologists. ACOG committee opinion no. 557: management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013; 121:891–896.

25. Sayed GH, Zakherah MS, El-Nashar SA, Shaaban MM. A randomized clinical trial of a levonorgestrel-releasing intrauterine system and a low-dose combined oral contraceptive for fibroid-related menorrhagia. Int J Gynaecol Obstet. 2011; 112:126–130.

26. American College of Obstetricians and Gynecologists. ACOG practice bulletin. Alternatives to hysterectomy in the management of leiomyomas. Obstet Gynecol. 2008; 112:387–400.

27. Venkatachalam S, Bagratee JS, Moodley J. Medical management of uterine fibroids with medroxyprogesterone acetate (Depo Provera): a pilot study. J Obstet Gynaecol. 2004; 24:798–800.

28. Ichigo S, Takagi H, Matsunami K, Suzuki N, Imai A. Beneficial effects of dienogest on uterine myoma volume: a retrospective controlled study comparing with gonadotropin-releasing hormone agonist. Arch Gynecol Obstet. 2011; 284:667–670.

29. Socolov D, Blidaru I, Tamba B, Miron N, Boiculese L, Socolov R. Levonorgestrel releasing-intrauterine system for the treatment of menorrhagia and/or frequent irregular uterine bleeding associated with uterine leiomyoma. Eur J Contracept Reprod Health Care. 2011; 16:480–487.

30. Zapata LB, Whiteman MK, Tepper NK, Jamieson DJ, Marchbanks PA, Curtis KM. Intrauterine device use among women with uterine fibroids: a systematic review. Contraception. 2010; 82:41–55.

31. Jiang W, Shen Q, Chen M, Wang Y, Zhou Q, Zhu X, et al. Levonorgestrel-releasing intrauterine system use in premenopausal women with symptomatic uterine leiomyoma: a systematic review. Steroids. 2014; 86:69–78.

32. 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.

33. Islam MS, Protic O, Giannubilo SR, Toti P, Tranquilli AL, Petraglia F, et al. Uterine leiomyoma: available medical treatments and new possible therapeutic options. J Clin Endocrinol Metab. 2013; 98:921–934.

34. De Leo V, Morgante G, La Marca A, Musacchio MC, Sorace M, Cavicchioli C, et al. A benefit-risk assessment of medical treatment for uterine leiomyomas. Drug Saf. 2002; 25:759–779.

35. Singh SS, Belland L. Contemporary management of uterine fibroids: focus on emerging medical treatments. Curr Med Res Opin. 2015; 31:1–12.

36. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2000; CD000547.

37. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001; CD000547.

38. Palomba S, Affinito P, Di Carlo C, Bifulco G, Nappi C. Long-term administration of tibolone plus gonadotropin-releasing hormone agonist for the treatment of uterine leiomyomas: effectiveness and effects on vasomotor symptoms, bone mass, and lipid profiles. Fertil Steril. 1999; 72:889–895.

39. Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Nappi C, et al. Raloxifene administration in women treated with gonadotropin-releasing hormone agonist for uterine leiomyomas: effects on bone metabolism. J Clin Endocrinol Metab. 2002; 87:4476–4481.

40. Sabry M, Al-Hendy A. Innovative oral treatments of uterine leiomyoma. Obstet Gynecol Int. 2012; 2012:943635.

41. Reissmann T, Diedrich K, Comaru-Schally AM, Schally AV. Introduction of LHRH-antagonists into the treatment of gynaecological disorders. Hum Reprod. 1994; 9:769.

42. Kettel LM, Murphy AA, Morales AJ, Rivier J, Vale W, Yen SS. Rapid regression of uterine leiomyomas in response to daily administration of gonadotropin-releasing hormone antagonist. Fertil Steril. 1993; 60:642–646.

43. Gonzalez-Barcena D, Alvarez RB, Ochoa EP, Cornejo IC, Comaru-Schally AM, Schally AV, et al. Treatment of uterine leiomyomas with luteinizing hormone-releasing hormone antagonist Cetrorelix. Hum Reprod. 1997; 12:2028–2035.

44. Britten JL, Malik M, Levy G, Mendoza M, Catherino WH. Gonadotropin-releasing hormone (GnRH) agonist leuprolide acetate and GnRH antagonist cetrorelix acetate directly inhibit leiomyoma extracellular matrix production. Fertil Steril. 2012; 98:1299–1307.

45. Flierman PA, Oberyé JJ, van der Hulst VP, de Blok S. Rapid reduction of leiomyoma volume during treatment with the GnRH antagonist ganirelix. BJOG. 2005; 112:638–642.

46. Maruo T, Ohara N, Matsuo H, Xu Q, Chen W, Sitruk-Ware R, et al. Effects of levonorgestrel-releasing IUS and progesterone receptor modulator PRM CDB-2914 on uterine leiomyomas. Contraception. 2007; 75:S99–S103.

47. Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H, Mori T. Mitotic activity in uterine leiomyomas during the menstrual cycle. Am J Obstet Gynecol. 1989; 160:637–641.

48. Kawaguchi K, Fujii S, Konishi I, Iwai T, Nanbu Y, Nonogaki H, et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy. Virchows Arch A Pathol Anat Histopathol. 1991; 419:309–315.

49. Segaloff A, Weed JC, Sternberg WH, Parson W. The progesterone therapy of human uterine leiomyomas. J Clin Endocrinol Metab. 1949; 9:1273–1291.

50. Tsigkou A, Reis FM, Lee MH, Jiang B, Tosti C, Centini G, et al. Increased progesterone receptor expression in uterine leiomyoma: correlation with age, number of leiomyomas, and clinical symptoms. Fertil Steril. 2015; 104:170–175.e1.

51. Friedman AJ, Daly M, Juneau-Norcross M, Gleason R, Rein MS, LeBoff M. Long-term medical therapy for leiomyomata uteri: a prospective, randomized study of leuprolide acetate depot plus either oestrogen-progestin or progestin ‘add-back’ for 2 years. Hum Reprod. 1994; 9:1618–1625.

52. Kim JJ, Sefton EC. The role of progesterone signaling in the pathogenesis of uterine leiomyoma. Mol Cell Endocrinol. 2012; 358:223–231.

53. Chwalisz K, Perez MC, Demanno D, Winkel C, Schubert G, Elger W. Selective progesterone receptor modulator development and use in the treatment of leiomyomata and endometriosis. Endocr Rev. 2005; 26:423–438.

54. Feng C, Meldrum S, Fiscella K. Improved quality of life is partly explained by fewer symptoms after treatment of fibroids with mifepristone. Int J Gynaecol Obstet. 2010; 109:121–124.

55. Kulshrestha V, Kriplani A, Agarwal N, Sareen N, Garg P, Hari S, et al. Low dose mifepristone in medical management of uterine leiomyoma - an experience from a tertiary care hospital from north India. Indian J Med Res. 2013; 137:1154–1162.

56. Shen Q, Hua Y, Jiang W, Zhang W, Chen M, Zhu X. Effects of mifepristone on uterine leiomyoma in premenopausal women: a meta-analysis. Fertil Steril. 2013; 100:1722–1726. 1726.e1–1726.e10.

57. Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS. Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metab. 1993; 76:513–517.

58. Reinsch RC, Murphy AA, Morales AJ, Yen SS. The effects of RU 486 and leuprolide acetate on uterine artery blood flow in the fibroid uterus: a prospective, randomized study. Am J Obstet Gynecol. 1994; 170:1623–1627.

59. Eisinger SH, Bonfiglio T, Fiscella K, Meldrum S, Guzick DS. Twelve-month safety and efficacy of low-dose mifepristone for uterine myomas. J Minim Invasive Gynecol. 2005; 12:227–233.

60. Tristan M, Orozco LJ, Steed A, Ramírez-Morera A, Stone P. Mifepristone for uterine fibroids. Cochrane Database Syst Rev. 2012; CD007687.

61. Carbonell JL, Acosta R, Pérez Y, Marrero AG, Trellez E, Sánchez C, et al. Safety and effectiveness of different dosage of mifepristone for the treatment of uterine fibroids: a double-blind randomized clinical trial. Int J Womens Health. 2013; 5:115–124.

62. Biglia N, Carinelli S, Maiorana A, D'Alonzo M, Lo Monte G, Marci R. Ulipristal acetate: a novel pharmacological approach for the treatment of uterine fibroids. Drug Des Devel Ther. 2014; 8:285–292.

63. Courtoy GE, Donnez J, Marbaix E, Dolmans MM. In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment. Fertil Steril. 2015; 104:426–434.e1.

64. Nieman LK, Blocker W, Nansel T, Mahoney S, Reynolds J, Blithe D, et al. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase IIb study. Fertil Steril. 2011; 95:767–772. 772.e1–772.e2.

65. Luyckx M, Squifflet JL, Jadoul P, Votino R, Dolmans MM, Donnez J. First series of 18 pregnancies after ulipristal acetate treatment for uterine fibroids. Fertil Steril. 2014; 102:1404–1409.

66. Donnez J, Tatarchuk TF, Bouchard P, Puscasiu L, Zakharenko NF, Ivanova T, et al. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012; 366:409–420.

67. Donnez J, Tomaszewski J, Vázquez F, Bouchard P, Lemieszczuk B, Baró F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med. 2012; 366:421–432.

68. Donnez J, Vázquez F, Tomaszewski J, Nouri K, Bouchard P, Fauser BC, et al. Long-term treatment of uterine fibroids with ulipristal acetate XMLLink_XYZ. Fertil Steril. 2014; 101:1565–1573. 1573.e1–1573.e18.

69. Donnez J, Hudecek R, Donnez O, Matule D, Arhendt HJ, Zatik J, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril. 2015; 103:519–527.e3.

70. Donnez J, Donnez O, Matule D, Ahrendt HJ, Hudecek R, Zatik J, et al. Long-term medical management of uterine fibroids with ulipristal acetate. Fertil Steril. 2016; 105:165–173.e4.

71. Donnez J, Donnez O, Courtoy GE, Dolmans MM. The place of selective progesterone receptor modulators in myoma therapy. Minerva Ginecol. 2016; 68:313–320.

72. Mutter GL, Bergeron C, Deligdisch L, Ferenczy A, Glant M, Merino M, et al. The spectrum of endometrial pathology induced by progesterone receptor modulators. Mod Pathol. 2008; 21:591–598.

73. Williams AR, Bergeron C, Barlow DH, Ferenczy A. Endometrial morphology after treatment of uterine fibroids with the selective progesterone receptor modulator, ulipristal acetate. Int J Gynecol Pathol. 2012; 31:556–569.

74. Dutertre M, Smith CL. Molecular mechanisms of selective estrogen receptor modulator (SERM) action. J Pharmacol Exp Ther. 2000; 295:431–437.

75. Liu J, Matsuo H, Xu Q, Chen W, Wang J, Maruo T. Concentration-dependent effects of a selective estrogen receptor modulator raloxifene on proliferation and apoptosis in human uterine leiomyoma cells cultured in vitro . Hum Reprod. 2007; 22:1253–1259.

76. Deng L, Wu T, Chen XY, Xie L, Yang J. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev. 2012; 10:CD005287.

77. Lingxia X, Taixiang W, Xiaoyan C. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev. 2007; CD005287.

78. Wu T, Chen X, Xie L. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev. 2007; CD005287.

79. Palomba S, Orio F Jr, Morelli M, Russo T, Pellicano M, Zupi E, et al. Raloxifene administration in premenopausal women with uterine leiomyomas: a pilot study. J Clin Endocrinol Metab. 2002; 87:3603–3608.

80. Ishikawa H, Reierstad S, Demura M, Rademaker AW, Kasai T, Inoue M, et al. High aromatase expression in uterine leiomyoma tissues of African-American women. J Clin Endocrinol Metab. 2009; 94:1752–1756.

81. Duhan N, Madaan S, Sen J. Role of the aromatase inhibitor letrozole in the management of uterine leiomyomas in premenopausal women. Eur J Obstet Gynecol Reprod Biol. 2013; 171:329–332.

82. Hilário SG, Bozzini N, Borsari R, Baracat EC. Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients. Fertil Steril. 2009; 91:240–243.

83. Brito LG, Candido-dos-Reis FJ, Magario FA, Sabino-de-Freitas MM. Effect of the aromatase inhibitor anastrozole on uterine and leiomyoma Doppler blood flow in patients scheduled for hysterectomy: a pilot study. Ultrasound Obstet Gynecol. 2012; 40:119–120.

84. Parsanezhad ME, Azmoon M, Alborzi S, Rajaeefard A, Zarei A, Kazerooni T, et al. A randomized, controlled clinical trial comparing the effects of aromatase inhibitor (letrozole) and gonadotropin-releasing hormone agonist (triptorelin) on uterine leiomyoma volume and hormonal status. Fertil Steril. 2010; 93:192–198.

85. Song H, Lu D, Navaratnam K, Shi G. Aromatase inhibitors for uterine fibroids. Cochrane Database Syst Rev. 2013; CD009505.