MEDICAL TREATMENT OF LEIOMYOMAS

Abstract

Leiomyomlar, reprodüktif çağda en sık görülen jinekolojik tümörlerdir. Leiomyomlar çoğu kadında bulunmakla beraber, bazı kadınlarda semptomatik hale gelmektedir. Genetik veya hormonal kökenli olabilirler. Leiomyomların üzerinde östrojen ve progesteron reseptörleri olması, onları hormona duyarlı hale getirmektedir. Leiomyomların ana tedavisi cerrahi olmakla beraber, cerrahi istemeyen veya fertilitesini korumak isteyen kadınlarda medikal tedaviler gündeme gelmektedir. Medikal tedavilerin çıkış noktası, leiomyomların hormona duyarlı olmasıdır. Medikal tedavi seçenekleri arasında gonadotropin-releasing-3 hormon analogları ve antagonistleri, aromataz inhibitörleri ve selektif progesteron reseptör modülatörleri yer almaktadır. Bu tedaviler kanama kontrolünün yanında leiomyom volümünde de küçülme sağlamaktadır. Bu derlemede bu tedavi yöntemlerine değinilecektir.

Keywords

• Leiomyoma,abnormal uterine bleeding,selective progesterone receptor modulators,ulipristal acetate,anemia

LEİOMYOMLARIN MEDİKAL TEDAVİSİ

Abstract

Leiomyomlar, reprodüktif çağda en sık görülen jinekolojik tümörlerdir. Leiomyomlar çoğu kadında bulunmakla beraber, bazı kadınlarda semptomatik hale gelmektedir. Genetik veya hormonal kökenli olabilirler. Leiomyomların üzerinde östrojen ve progesteron reseptörleri olması, onları hormona duyarlı hale getirmektedir. Leiomyomların ana tedavisi cerrahi olmakla beraber, cerrahi istemeyen veya fertilitesini korumak isteyen kadınlarda medikal tedaviler gündeme gelmektedir. Medikal tedavilerin çıkış noktası, leiomyomların hormona duyarlı olmasıdır. Medikal tedavi seçenekleri arasında gonadotropin-releasing-3 hormon analogları ve antagonistleri, aromataz inhibitörleri ve selektif progesteron reseptör modülatörleri yer almaktadır. Bu tedaviler kanama kontrolünün yanında leiomyom volümünde de küçülme sağlamaktadır. Bu derlemede bu tedavi yöntemlerine değinilecektir.

Keywords

• Leiomyom,anormal uterin kanama,selektif progesteron reseptör modülatörleri,ulipristal asetat,anemi

References

1. 1. Evans P, Brunsell S. Uterine fibroid tumors: diagnosis and treatment. Am Fam Physician 2007;75(10):1503-8.
2. 2. Parker WH. Etiology, symptomatology, and diagnosis of uterine myomas. Fertil Steril 2007;87(4):725-36.
3. 3. 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(1):100-7.
4. 4. Donnez J, Jadoul P. What are the implications of myomas on fertility? A need for a debate? Hum Reprod 2002;17(6):1424-30.
5. 5. Munro MG, Critchley HOD, Broder MS, Fraser IS; for the FIGO working group on menstrual disorders. FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynecol Obstet 2011;113(1):3-13.
6. 6. Wamsteker K, Emanuel MH, de Kruif JH. Transcervical hysteroscopic resection of submucous fibroids for abnormal uterine bleeding: results regarding the degree of intramural extension. Obstet Gynecol 1993;82(5):736-40.
7. 7. Cakmak H, Taylor HS. Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update 2011;17(2):242-53.
8. 8. Sinclair DC, Mastroyannis A, Taylor HS. Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-beta3. J Clin Endocrinol Metabol 2011;96(2):412-21.

9. 9. Malik M, Norian J, McCarthy-Keith D, Britten J, Catherino WH. Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women. Semin Reprod Med 2010;28(3):169-79.
10. 10. Kim JJ, Kurita T, Bulun SE. Progesterone action in endometrial cancer, endometriosis, uterine fibroids, and breast cancer. Endocr Rev 2013;34(1):130-62.
11. 11. Flake GP, Moore AB, Sutton D, Kissling GE, Horton J, Wicker B, et al. The natural history of uterine leiomyomas: light and electron microscopic studies of fibroid phases, interstitial ischemia, inanosis, and reclamation. Obstet Gynecol Int 2013;2013:528376.
12. 12. Moravek MB, Bulun SE. Endocrinology of uterine fibroids: steroid hormones, stem cells, and genetic contribution. Curr Opin Obstet Gynecol 2015;27(4):276-83.
13. 13. Bulun SE, Simpson ER, Word RA. Expression of the CYP19 gene and its product aromatase cytochrome P450 in human uterine leiomyoma tissues and cells in culture. J Clin Endocrinol Metabol 1994;78(3):736-43.
14. 14. Andersen J, DyReyes VM, Barbieri RL, Coachman DM, Miksicek RJ. Leiomyoma primary cultures have elevated transcriptional response to estrogen compared with autologous myometrial cultures. J Soc Gynecol Investig 1995;2(3):542-51.
15. 15. Li S, McLachlan JA. Estrogen-associated genes in uterine leiomyoma. Ann New York Acad Sci 2001;948:112-20.
16. 16. Brandon DD, Bethea CL, Strawn EY, Novy MJ, Burry KA, Harrington MS, et al. Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas. Am J Obstet Gynecol 1993;169(1):78-85 17. . 18. Englund K, Blanck A, Gustavsson I, Lundkvist U, Sjöblom P, Norgren A, et al. Sex steroid receptors in human myometrium and fibroids: changes during the menstrual cycle and gonadotropin-releasing hormone treatment. J Clin Endocrinol Metabol 1998;83(11):4092-6.
17. 19. Nisolle M, Gillerot S, Casanas-Roux F, Squifflet J, Berliere M, Donnez J. Immunohistochemical study of the proliferation index, oestrogen receptors and progesterone receptors A and B in leiomyomata and normal myometrium during the menstrual cycle and under gonadotrophin-releasing hormone agonist therapy. Hum Reprod 1999;14(11):2844-50.
18. 20. Chegini N, Kornberg L. Gonadotropin releasing hormone analogue therapy alters signal transduction pathways involving mitogen-activated protein and focal adhesion kinases in leiomyoma. J Soc Gynecol Investig 2003;10(1):21-6.
19. 21. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev 2001:CD000547.
20. 22. Kamat MS, Kalampokas EE, Kalampokas TE. Use of GnRH analogues pre-operatively for hysteroscopic resection of submucous fibroids: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2014;177:11-8.
21. 23. Donnez J, Tomaszewski J, Vazquez F, Bouchard P, Lemieszczuk B, Baro F, et al. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012;366(5):421-32.
22. 24. Flierman PA, OberyéJJ, van der Hulst VP, de Blok S. Rapid reduction of leiomyoma volume during treatment with the GnRH antagonist ganirelix. BJOG 2005;112(5):638.
23. 25. Felberbaum RE, Küpker W, Krapp M, Gehl B, Ludwig M, Diedrich K. Preoperative reduction of uterine fibroids in only 16 days by administration of a gonadotrophin-releasing hormone antagonist (Cetrotide). Reprod Biomed Online 2001;3(1):14.
24. 26. Chumsri S, Howes T, Bao T, Sabnis G, Brodie A. Aromatase, aromatase inhibitors, and breast cancer. J Steroid Biochem Mol Biol 2011;125(1-2):13-22.
25. 27. Michaud LB, Buzdar AU. Risks and benefits of aromatase inhibitors in postmenopausal breast cancer. Drug Safety 1999;21(4):297-309.
26. 28. 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(1):192-8.
27. 29. Varelas FK, Papanicolaou AN, Vavatsi-Christaki N, Makedos GA, Vlassis GD. The effect of anastrozole on symptomatic uterine leiomyomata. Obstet Gynecol 2007;110(3):643-9.
28. 30. Hilario SG, Bozzini N, Borsari R, Baracat EC. Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients. Fertil Steril 2009;91(1):240-3.
29. 31. 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(2):329-32.
30. 32. Lonning PE, Eikesdal HP. Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved. Endocr Related Cancer 2013;20(4):R183-201.
31. 33. Chabbert-Buffet N, Meduri G, Bouchard P, Spitz IM. Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications. Hum Reprod Update 2005;11(3):293-307.
32. 34. Xu Q, Ohara N, Liu J, Nakabayashi K, DeManno D, Chwalisz K, et al. Selective progesterone receptor modulator asoprisnil induces endoplasmic reticulum stress in cultured human uterine leiomyoma cells. Am J Physiol Endocrinol Metab 2007;293(4):E1002-11.
33. 35. Chen W, Ohara N, Wang J, Xu Q, Liu J, Morikawa A, et al. A novel selective progesterone receptor modulator asoprisnil (J867) inhibits proliferation and induces apoptosis in cultured human uterine leiomyoma cells in the absence of comparable effects on myometrial cells. J Clin Endocrinol Metab 2006;91(4):1296-304.
34. 36. 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(Suppl 6):S99-103.
35. 37. Murphy AA, Kettel LM, Morales AJ, Roberts VJ, Yen SS. Regression of uterine leiomyomata in response to the antiprogesterone RU 486. J Clin Endocrinol Metabol 1993;76(2):513-7.
36. 38. Carbonell Esteve JL, Acosta R, Heredia B, Pérez Y, Castañeda MC, Hernández AV. Mifepristone for the treatment of uterine leiomyomas: a randomized controlled trial. Obstet Gynecol 2008;112(5):1029-36.
37. 39. Eisinger SH, Fiscella J, Bonfiglio T, Meldrum S, Fiscella K. Open-label study of ultra low-dose mifepristone for the treatment of uterine leiomyomata. Eur J Obstet Gynecol Reprod Biol 2009;146(2):215-8.
38. 40. Tristan M1, Orozco LJ, Steed A, Ramírez-Morera A, Stone P. Mifepristone for uterine fibroids. Cochrane Database Syst Rev 2012;8:CD007687.
39. 41. Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel CA. A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata. Fertil Steril 2007;87(6):1399-12.
40. 42. Wilkens J, Chwalisz K, Han C, Walker J, Cameron IT, Ingamells S, et al. Effects of the selective progesterone receptor modulator asoprisnil on uterine artery blood flow, ovarian activity, and clinical symptoms in patients with uterine leiomyomata scheduled for hysterectomy. J Clin Endocrinol Metabol 2008;93(12):4664-71.
41. 43. Madauss KP, Grygielko ET, Deng SJ, Sulpizio AC, Stanley TB, Wu C, et al. A structural and in vitro characterization of asoprisnil: a selective progesterone receptor modulator. Mol Endocrinol 2007;21(5):1066-81.
42. 44. Bouchard P, Chabbert-Buffet N, Fauser BC. Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety. Fertil Steril 2011;96(5):1175-89.
43. 45. 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(5):409-20.
44. 46. 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(2):519-27.
45. 47. 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(1):165-73.
46. 48. Fiscella J, Bonfiglio T, Winters P, Eisinger SH, Fiscella K. Distinguishing features of endometrial pathology after exposure to the progesterone receptor modulator mifepristone. Hum Pathol 2011;42(7):947-53.
47. 49. 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(5):591-8.
48. 50. 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(6):556-69. 51. Donnez J, Vazquez F, Tomaszewski J, Nouri K, Bouchard P, Fauser BC, et al. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil Steril 2014;101(6):1565-73.e1-18.51. Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Rajaratnam V, Al-Hendy A. Antiproliferative and proapoptotic effects of epigallocatechin gallate on human leiomyoma cells. Fertil Steril 2009;94(5):1887-93.
49. 52. Zhang D, Al-Hendy M, Richard-Davis G, Montgomery-Rice V, Sharan C, Rajaratnam V, et al. Green tea extract inhibits proliferation of uterine leiomyoma cells in vitro and in nude mice. Am J Obstet Gynecol 2010;202(3):289.e1-9.
50. 53. Lee BS, Margolin SB, Nowak RA. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production. J Clin Endocrinol Metab 1998;83(1):219-23.
51. 54. Liu JP, Yang H, Xia Y, Cardini F. Herbal preparations for uterine fibroids. Cochrane Database Syst Rev 2013;(4):CD005292.