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Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial

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Abstract

In a prior randomized controlled study, patients treated with ulipristal acetate (UPA) or placebo for 3 months had a decrease in leiomyoma size. A total of 10 patients’ tissue samples (5 placebo and 5 treated with 10 mg/d UPA) that underwent hysterectomy and tissue preservation were identified from this study. Quantitative real-time reverse transcriptase polymerase chain reaction and Western blotting were used to assess fold gene and protein expression of extracellular membrane (ECM) proteins: collagen IA (COLI A), fibronectin (FNI), and versican (VCAN) of the samples. Confirmatory immunohistochemical analysis was performed. Changes in total matrix collagen were examined using Masson trichrome staining. Multiplex measurement of the matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases was performed. Compared to placebo-treated surgical specimens, 80% of the treated specimens showed decrease in VCAN protein, 60% showed decrease in FNI, but no consistent alteration in COLI A. This effect was also supported by immunohistochemistry where leiomyoma surgical specimens demonstrated decreased amount of FNI and VCAN on UPA treatment. Increased MMP2 and decreased MMP9 in treated patient leiomyomas indicate both degradation of the matrix and inhibition of the pathway involved in matrix production. Treatment with UPA decreased fibroid volume in placebo-controlled, randomized trials. Treatment with UPA decreased gene expression and protein production in leiomyoma tissue, suggesting both an impact on water content and ECM protein concentration as a mechanism of ulipristal-mediated decrease in leiomyoma size.

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References

  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 Obset Gynecol. 2003;188(1):100–107.

    Google Scholar 

  2. Bartels CB, Cayton KC, Chuong FS, et al. An evidence-based approach to the medical management of fibroids: a systematic review. Clin Obstet Gynecol. 2016;59(1):30–52.

    PubMed  Google Scholar 

  3. Walker CL, Stewart EA. Uterine fibroids: the elephant in the room. Science. 2005;308(5728):1589–1592.

    CAS  PubMed  Google Scholar 

  4. Payson M, Leppert P, Segars J. Epidemiology of myomas. Obset Gynecol Clin N Am. 2006;33(1):1–11.

    Google Scholar 

  5. Myers ER, Barber MD, Gustilo-Ashby T, Couchman G, Matchar DB, McCrory DC. Management of uterine leiomyomata: what do we really know? Obstet Gynecol. 2002;100(1):8–17.

    PubMed  Google Scholar 

  6. Levens ED, Potlog-Nahari C, Armstrong AY, et al. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. Obstet Gynecol. 2008;111(5):1129–1136.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Nieman LK, Blocker W, Nansel T, et al. Efficacy and tolerability of CDB-2914 treatment for symptomatic uterine fibroids: a randomized, double-blind, placebo-controlled, phase lib study. Fertil Steril. 2011;95(2):767–772.

    CAS  PubMed  Google Scholar 

  8. Nieman LK. Treatment of uterine fibroids with the selective progesterone receptor modulator CDB-2014. https://clinicaltrials.gov/ct2/show/NCT00290251.

  9. Donnez J, Tatarchuk TF, Bouchard P, et al; PEARL I Study Group. Ulipristal acetate versus placebo for fibroid treatment before surgery. N Engl J Med. 2012;366(5):409–420.

    CAS  PubMed  Google Scholar 

  10. Donnez J, Tomaszewski J, Vazquez F, et al; PEARL II Study Group. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N EnglJ Med. 2012;366(5):421–432.

    CAS  Google Scholar 

  11. Donnez J, Hudecek R, Donnez O, et al. Efficacy and safety of repeated use of ulipristal acetate in uterine fibroids. Fertil Steril. 2015;103(2):519–527.

    CAS  PubMed  Google Scholar 

  12. Malik M, Britten J, Cox J, Patel A, Catherino WH. Gonadotropin-releasing hormone analogues inhibit leiomyoma extracellular matrix despite presence of gonadal hormones. Fertil Steril. 2016;105(1):214–224.

    CAS  PubMed  Google Scholar 

  13. Patel A, Malik M, Britten J, Cox J, Catherino WH. Mifepristone inhibits extracellular matrix formation in uterine leiomyoma. Fer-til Steril. 2016;105(4):1102–1110.

    CAS  Google Scholar 

  14. Rosato E, Farris M, Bastianelli C. Mechanism of action of ulipristal acetate for emergency contraception: a systematic review. Front Pharmacol. 2016;6:315.

    PubMed  PubMed Central  Google Scholar 

  15. Leppert PC, Catherino WH, Segars JH. A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays. Am J Obset Gynecol. 2006;195(2):415–420.

    CAS  Google Scholar 

  16. 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. Sent Reprod Med. 2010;28(3):169–179.

    Google Scholar 

  17. Chegini N. Proinflammatory and profibrotic mediators: principal effectors of leiomyoma development as a fibrotic disorder. Semin Reprod Med. 2010;28(3):180–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Norian JM, Malik M, Parker CY, et al. Transforming growth factor beta3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas. Reprod Sci. 2009;16(12):1153–1164.

    CAS  PubMed  Google Scholar 

  19. Fujisawa C, Castellot J Jr. Matrix production and remodeling as therapeutic targets for uterine leiomyoma. J Cell Commun Signal. 2014;8(3):179–194.

    PubMed  PubMed Central  Google Scholar 

  20. Xu Q, Ohara N, Liu J, et al. Progesterone receptor modulator CDB-2914 induces extracellular matrix metalloproteinase inducer in cultured human uterine leiomyoma cells. Mol Hum Reprod. 2008;14(3):181–191.

    CAS  PubMed  Google Scholar 

  21. Xu Q, Ohara N, Chen W, et al. Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells. Hum Reprod. 2006;21(9):2408–2416.

    CAS  PubMed  Google Scholar 

  22. Xu Q, Takekida S, Ohara N, et al. Progesterone receptor modulator CDB-2914 down-regulates proliferative cell nuclear antigen and Bc1-2 protein expression and up-regulates caspase-3 and poly(adenosine 5’-diphosphate-ribose) polymerase expression in cultured human uterine leiomyoma cells. J Clin Endocrinol Metab. 2005;90(2):953–961.

    CAS  PubMed  Google Scholar 

  23. Malik M, Catherino WH. Novel method to characterize primary cultures of leiomyoma and myometrium with the use of confirmatory biomarker gene arrays. Fertil Steril. 2007;87(5):1166–1172.

    CAS  PubMed  Google Scholar 

  24. Pay son M, Malik M, Siti-Nur Morris S, Segars JH, Chason R, Catherino WH. Activating transcription factor 3 gene expression suggests that tissue stress plays a role in leiomyoma development. Fertil Steril. 2009;92(2):748–755.

    CAS  Google Scholar 

  25. Malik M, Britten J, Segars J, Catherino WH. Leiomyoma cells in 3-dimensional cultures demonstrate an attenuated response to fas-udil, a rho-kinase inhibitor, when compared to 2-dimensional cultures. Reprod Sci. 2014;21(9):1126–1138.

    PubMed  PubMed Central  Google Scholar 

  26. Catherino W, Salama A, Potlog-Nahari C, Leppert P, Tsibris J, Segars J. Gene expression studies in leiomyomata: new directions for research. Semin Reprod Med. 2004;22(2):83–90.

    CAS  PubMed  Google Scholar 

  27. Barker NM, Carrino DA, Caplan Al, et al. Proteoglycans in leiomyoma and normal myometrium: abundance, steroid hormone control, and implications for pathophysiology. Reprod Sci. 2016;23(3):302–309.

    CAS  PubMed  Google Scholar 

  28. Flake GP, Moore AB, Sutton D, 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.

    Google Scholar 

  29. Bouchard P, Chabbert-Buffet N, Fauser B. Selective progeter-one receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety. Fertil Steril. 2011;96(5):1175–1189.

    CAS  PubMed  Google Scholar 

  30. Melis GB, Piras B, Marotto MF, et al. Pharmacokinetic evaluation of ulipristal acetate for uterine leiomyoma treatment. Expert Opin Drug Metab Toxicol. 2012;8(7):901–908.

    CAS  PubMed  Google Scholar 

  31. 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(3):423–438.

    CAS  PubMed  Google Scholar 

  32. Courtoy GE, Donnez J, Marbaix E, Dolmans MM. In vivo mechanisms of uterine myoma volume reduction with ulipristal acetate treatment. Fertil Steril. 2015;104(2):426–434.el.

    CAS  PubMed  Google Scholar 

  33. Dou Q, Tarnuzzer RW, Williams RS, Schultz GS, Chegini N. Differential expression of matrix metalloproteinases and their tissue inhibitors in leiomyomata: a mechanism for gonadotrophin releasing hormone agonist-induced tumour regression. Mol Hum Reprod. 1997;3(11):1005–1014.

    CAS  PubMed  Google Scholar 

  34. Palmer SS, Haynes-Johnson D, Diehl T, Nowak RA. Increased expression of stromelysin 3 mRNA in leiomyomas (uterine fibroids) compared with myometrium. J Soc Gynecol Investig. 1998;5(4):203–209.

    CAS  PubMed  Google Scholar 

  35. Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, Jakimiuk AJ, Rechberger T. Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium. Gynecol Endocrinol. 2007;23(9):541–546.

    CAS  PubMed  Google Scholar 

  36. Korompelis P, Piperi C, Adamopoulos C, et al. Expression of vascular endothelial factor-A, gelatinases (MMP-2, MMP-9) and TIMP-1 in uterine leiomyomas. Clin Chem Lab Med. 2015;53(9):1415–1424.

    CAS  PubMed  Google Scholar 

  37. Wolahska M, Sobolewski K, Bahkowski E, Jaworski S. Matrix metalloproteinases of human leiomyoma in various stages of tumor growth. Gynecol Obstet Invest. 2004;58(1):14–18.

    Google Scholar 

  38. Haider SK, Osteen KG. Al-Hendy A. Vitamin D3 inhibits expression and activities of matrix metalloproteinase-2 and -9 in human uterine fibroid cells. Hum Reprod. 2013;28(9):2407–2416.

    Google Scholar 

  39. Giannandrea M, Parks WC. Diverse functions of matrix metalloproteinases during fibrosis. Dis Model Mech. 2014;7(2):193–203.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Parks WC, Wilson CL. Lopez-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol. 2004;4(8):617–629.

    CAS  PubMed  Google Scholar 

  41. Zuo F, Kaminski N, Eugui E, et al. Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci U S A. 2002;99(9):6292–6297.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yu Q, Stamenkovic I. Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. Genes Dev. 2000;14(2):163–176.

    PubMed  PubMed Central  Google Scholar 

  43. Dayer C, Stamenkovic I. Recruitment of matrix metalloproteinase-9 (MMP-9) to the fibroblast cell surface by lysyl hydroxylase 3 (LH3) triggers transforming growth factor-P (TGF-P) activation and fibroblast differentiation. J Biol Chem. 2015;290(22):13763–13778.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Ciarmela P, Carrarelli P, Islam MS, et al. Ulipristal acetate modulates the expression and functions of activin a in leiomyoma cells. Reprod Sci. 2014;21(9):1120–1125.

    PubMed  Google Scholar 

  45. McCarthy-Keith D, Malik M, Britten J, Segars J, Catherino W. Gonadotropin-releasing hormone agonist increases expression of osmotic response genes in leiomyoma cells. Fertil Steril. 2011;95(7):2383–2387.

    CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Building A, Room 3078, 4301 Jones Bridge Road, Bethesda, MD, 20814, USA

    Jeris Cox MD, Minnie Malik PhD, Joy Britten MD, Terrence Lewis MD & William H. Catherino MD, PhD

  2. Fort Belvoir Community Hospital, Fort Belvoir, VA, USA

    Jeris Cox MD

  3. Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD, USA

    Terrence Lewis MD & William H. Catherino MD, PhD

Authors
  1. Jeris Cox MD
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  2. Minnie Malik PhD
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  3. Joy Britten MD
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  4. Terrence Lewis MD
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  5. William H. Catherino MD, PhD
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Correspondence to William H. Catherino MD, PhD.

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Cox, J., Malik, M., Britten, J. et al. Ulipristal Acetate and Extracellular Matrix Production in Human Leiomyomas In Vivo: A Laboratory Analysis of a Randomized Placebo Controlled Trial. Reprod. Sci. 25, 198–206 (2018). https://doi.org/10.1177/1933719117728802

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