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DOI: 10.1055/s-0037-1606303
New and Emerging Therapies for Uterine Fibroids
Publikationsverlauf
Publikationsdatum:
03. November 2017 (online)
![](https://www.thieme-connect.de/media/srm/201706/lookinside/thumbnails/10-1055-s-0037-1606303_001088-1.jpg)
Abstract
The pain, bleeding, and anemia associated with uterine fibroids debilitate many women. In addition to limited efficacy, the side effects of the currently used medical therapies prevent long-term use and nearly all pregnancies. Thus, women hoping to achieve pregnancy have limited options and usually opt for myomectomy. Once completed childbearing, many patients proceed with hysterectomy despite its risks and costs. Thus, there is a clear need for a new medical treatment for fibroids that is safe and effective. To this end, researchers have investigated several new treatments over the recent years, including both hormonal and nonhormonal ones. Some examples include selective progesterone receptor modulators, vitamin D, aromatase inhibitors, gene therapy, simvastatin, nanoparticles, epigallocatechin gallate, and intratumor collagenase injections. The aim of this article is to review and critically analyze the evidence (both laboratory and clinical) for these emerging therapies. We will discuss strengths and weaknesses of studies, areas where further evidence is needed, and finally deliberate on novel targets potentially amenable for development of future therapeutics.
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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 Obstet Gynecol 2003; 188 (01) 100-107
- 2 Sunkara SK, Khairy M, El-Toukhy T, Khalaf Y, Coomarasamy A. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Hum Reprod 2010; 25 (02) 418-429
- 3 Cardozo ER, Clark AD, Banks NK, Henne MB, Stegmann BJ, Segars JH. The estimated annual cost of uterine leiomyomata in the United States. Am J Obstet Gynecol 2012; 206 (03) 211.e1-211.e9
- 4 Friedman AJ, Barbieri RL, Doubilet PM, Fine C, Schiff I. A randomized, double-blind trial of a gonadotropin releasing-hormone agonist (leuprolide) with or without medroxyprogesterone acetate in the treatment of leiomyomata uteri. Fertil Steril 1988; 49 (03) 404-409
- 5 Lethaby A, Vollenhoven B, Sowter M. Efficacy of pre-operative gonadotrophin hormone releasing analogues for women with uterine fibroids undergoing hysterectomy or myomectomy: a systematic review. BJOG 2002; 109 (10) 1097-1108
- 6 Wright JD, Herzog TJ, Tsui J. , et al. Nationwide trends in the performance of inpatient hysterectomy in the United States. Obstet Gynecol 2013; 122 (2, Pt 1): 233-241
- 7 Sabry M, Al-Hendy A. Innovative oral treatments of uterine leiomyoma. Obstet Gynecol Int 2012; 2012: 943635
- 8 Borahay MA, Al-Hendy A, Kilic GS, Boehning D. Signaling pathways in leiomyoma: understanding pathobiology and implications for therapy. Mol Med 2015; 21: 242-256
- 9 Borahay MA, Asoglu MR, Mas A, Adam S, Kilic GS, Al-Hendy A. Estrogen receptors and signaling in fibroids: role in pathobiology and therapeutic implications. Reprod Sci 2016; ; pii: 1933719116678686 [Epub ahead of print]
- 10 Matsuo H, Maruo T, Samoto T. Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone. J Clin Endocrinol Metab 1997; 82 (01) 293-299
- 11 Chen W, Ohara N, Wang J. , 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 (04) 1296-1304
- 12 Lamminen S, Rantala I, Helin H, Rorarius M, Tuimala R. Proliferative activity of human uterine leiomyoma cells as measured by automatic image analysis. Gynecol Obstet Invest 1992; 34 (02) 111-114
- 13 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 (03) 637-641
- 14 Tiltman AJ. The effect of progestins on the mitotic activity of uterine fibromyomas. Int J Gynecol Pathol 1985; 4 (02) 89-96
- 15 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 (06) 2433-2442
- 16 Luo X, Yin P, Coon V JS, Cheng YH, Wiehle RD, Bulun SE. The selective progesterone receptor modulator CDB4124 inhibits proliferation and induces apoptosis in uterine leiomyoma cells. Fertil Steril 2010; 93 (08) 2668-2673
- 17 Bouchard P, Chabbert-Buffet N, Fauser BC. Selective progesterone receptor modulators in reproductive medicine: pharmacology, clinical efficacy and safety. Fertil Steril 2011; 96 (05) 1175-1189
- 18 Horne FM, Blithe DL. Progesterone receptor modulators and the endometrium: changes and consequences. Hum Reprod Update 2007; 13 (06) 567-580
- 19 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 (05) 409-420
- 20 Donnez J, Tomaszewski J, Vázquez F. , et al; PEARL II Study Group. Ulipristal acetate versus leuprolide acetate for uterine fibroids. N Engl J Med 2012; 366 (05) 421-432
- 21 Donnez J, Vázquez F, Tomaszewski J. , et al; PEARL III and PEARL III Extension Study Group. Long-term treatment of uterine fibroids with ulipristal acetate. Fertil Steril 2014; 101 (06) 1565-73.e1 , 18
- 22 Sumitani H, Shozu M, Segawa T. , et al. In situ estrogen synthesized by aromatase P450 in uterine leiomyoma cells promotes cell growth probably via an autocrine/intracrine mechanism. Endocrinology 2000; 141 (10) 3852-3861
- 23 Shozu M, Murakami K, Segawa T, Kasai T, Inoue M. Successful treatment of a symptomatic uterine leiomyoma in a perimenopausal woman with a nonsteroidal aromatase inhibitor. Fertil Steril 2003; 79 (03) 628-631
- 24 Hilário SG, Bozzini N, Borsari R, Baracat EC. Action of aromatase inhibitor for treatment of uterine leiomyoma in perimenopausal patients. Fertil Steril 2009; 91 (01) 240-243
- 25 Varelas FK, Papanicolaou AN, Vavatsi-Christaki N, Makedos GA, Vlassis GD. The effect of anastrazole on symptomatic uterine leiomyomata. Obstet Gynecol 2007; 110 (03) 643-649
- 26 Parsanezhad ME, Azmoon M, Alborzi S. , 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 (01) 192-198
- 27 Hadji P, Body JJ, Aapro MS. , et al. Practical guidance for the management of aromatase inhibitor-associated bone loss. Ann Oncol 2008; 19 (08) 1407-1416
- 28 Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357 (03) 266-281
- 29 Catherino WH, Eltoukhi HM, Al-Hendy A. Racial and ethnic differences in the pathogenesis and clinical manifestations of uterine leiomyoma. Semin Reprod Med 2013; 31 (05) 370-379
- 30 Halder SK, Osteen KG, Al-Hendy A. 1,25-dihydroxyvitamin d3 reduces extracellular matrix-associated protein expression in human uterine fibroid cells. Biol Reprod 2013; 89 (06) 150
- 31 Halder 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 (09) 2407-2416
- 32 Halder SK, Goodwin JS, Al-Hendy A. 1,25-Dihydroxyvitamin D3 reduces TGF-beta3-induced fibrosis-related gene expression in human uterine leiomyoma cells. J Clin Endocrinol Metab 2011; 96 (04) E754-E762
- 33 Halder SK, Sharan C, Al-Hendy A. 1,25-dihydroxyvitamin D3 treatment shrinks uterine leiomyoma tumors in the Eker rat model. Biol Reprod 2012; 86 (04) 116
- 34 Sharan C, Halder SK, Thota C, Jaleel T, Nair S, Al-Hendy A. Vitamin D inhibits proliferation of human uterine leiomyoma cells via catechol-O-methyltransferase. Fertil Steril 2011; 95 (01) 247-253
- 35 Paffoni A, Somigliana E, Vigano' P. , et al. Vitamin D status in women with uterine leiomyomas. J Clin Endocrinol Metab 2013; 98 (08) E1374-E1378
- 36 Sabry M, Halder SK, Allah AS, Roshdy E, Rajaratnam V, Al-Hendy A. Serum vitamin D3 level inversely correlates with uterine fibroid volume in different ethnic groups: a cross-sectional observational study. Int J Womens Health 2013; 5: 93-100
- 37 Baird DD, Hill MC, Schectman JM, Hollis BW. Vitamin D and the risk of uterine fibroids. Epidemiology 2013; 24 (03) 447-453
- 38 Seeger H, Wallwiener D, Mueck AO. Statins can inhibit proliferation of human breast cancer cells in vitro. Exp Clin Endocrinol Diabetes 2003; 111 (01) 47-48
- 39 Martirosyan A, Clendening JW, Goard CA, Penn LZ. Lovastatin induces apoptosis of ovarian cancer cells and synergizes with doxorubicin: potential therapeutic relevance. BMC Cancer 2010; 10: 103
- 40 Hoque A, Chen H, Xu XC. Statin induces apoptosis and cell growth arrest in prostate cancer cells. Cancer Epidemiol Biomarkers Prev 2008; 17 (01) 88-94
- 41 Oktem M, Esinler I, Eroglu D, Haberal N, Bayraktar N, Zeyneloglu HB. High-dose atorvastatin causes regression of endometriotic implants: a rat model. Hum Reprod 2007; 22 (05) 1474-1480
- 42 Borahay MA, Kilic GS, Yallampalli C. , et al. Simvastatin potently induces calcium-dependent apoptosis of human leiomyoma cells. J Biol Chem 2014; 289 (51) 35075-35086
- 43 Borahay MA, Vincent K, Motamedi M. , et al. Novel effects of simvastatin on uterine fibroid tumors: in vitro and patient-derived xenograft mouse model study. Am J Obstet Gynecol 2015; 213 (02) 196.e1-196.e8
- 44 Borahay MA, Fang X, Baillargeon JG, Kilic GS, Boehning DF, Kuo YF. Statin use and uterine fibroid risk in hyperlipidemia patients: a nested case-control study. Am J Obstet Gynecol 2016; 215 (06) 750.e1-750.e8
- 45 Costantine MM, Cleary K. ; Eunice Kennedy Shriver National Institute of Child Health and Human Development Obstetric--Fetal Pharmacology Research Units Network. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 2013; 121 (2, Pt 1): 349-353
- 46 Al-Hendy A, Salama S. Gene therapy and uterine leiomyoma: a review. Hum Reprod Update 2006; 12 (04) 385-400
- 47 Ince BA, Zhuang Y, Wrenn CK, Shapiro DJ, Katzenellenbogen BS. Powerful dominant negative mutants of the human estrogen receptor. J Biol Chem 1993; 268 (19) 14026-14032
- 48 Al-Hendy A, Lee EJ, Wang HQ, Copland JA. Gene therapy of uterine leiomyomas: adenovirus-mediated expression of dominant negative estrogen receptor inhibits tumor growth in nude mice. Am J Obstet Gynecol 2004; 191 (05) 1621-1631
- 49 Hassan MH, Salama SA, Zhang D. , et al. Gene therapy targeting leiomyoma: adenovirus-mediated delivery of dominant-negative estrogen receptor gene shrinks uterine tumors in Eker rat model. Fertil Steril 2010; 93 (01) 239-250
- 50 Nair S, Curiel DT, Rajaratnam V, Thota C, Al-Hendy A. Targeting adenoviral vectors for enhanced gene therapy of uterine leiomyomas. Hum Reprod 2013; 28 (09) 2398-2406
- 51 Salama SA, Kamel M, Christman G, Wang HQ, Fouad HM, Al-Hendy A. Gene therapy of uterine leiomyoma: adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir treatment inhibits growth of human and rat leiomyoma cells in vitro and in a nude mouse model. Gynecol Obstet Invest 2007; 63 (02) 61-70
- 52 Barchiesi F, Jackson EK, Fingerle J, Gillespie DG, Odermatt B, Dubey RK. 2-Methoxyestradiol, an estradiol metabolite, inhibits neointima formation and smooth muscle cell growth via double blockade of the cell cycle. Circ Res 2006; 99 (03) 266-274
- 53 Salama SA, Nasr AB, Dubey RK, Al-Hendy A. Estrogen metabolite 2-methoxyestradiol induces apoptosis and inhibits cell proliferation and collagen production in rat and human leiomyoma cells: a potential medicinal treatment for uterine fibroids. J Soc Gynecol Investig 2006; 13 (08) 542-550
- 54 Salama SA, Kamel MW, Botting S. , et al. Catechol-O-methyltransferase expression and 2-methoxyestradiol affect microtubule dynamics and modify steroid receptor signaling in leiomyoma cells. PLoS One 2009; 4 (10) e7356
- 55 Hassan MH, Fouad H, Bahashwan S, Al-Hendy A. Towards non-surgical therapy for uterine fibroids: catechol-O-methyl transferase inhibitor shrinks uterine fibroid lesions in the Eker rat model. Hum Reprod 2011; 26 (11) 3008-3018
- 56 Ali H, Kilic G, Vincent K, Motamedi M, Rytting E. Nanomedicine for uterine leiomyoma therapy. Ther Deliv 2013; 4 (02) 161-175
- 57 Shalaby SM, Khater MK, Perucho AM. , et al. Magnetic nanoparticles as a new approach to improve the efficacy of gene therapy against differentiated human uterine fibroid cells and tumor-initiating stem cells. Fertil Steril 2016; 105 (06) 1638-1648.e8
- 58 Mouridsen H, Palshof T, Patterson J, Battersby L. Tamoxifen in advanced breast cancer. Cancer Treat Rev 1978; 5 (03) 131-141
- 59 Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM. Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 1994; 86 (07) 527-537
- 60 Becker C. Another selective estrogen-receptor modulator for osteoporosis. N Engl J Med 2010; 362 (08) 752-754
- 61 Fuchs-Young R, Glasebrook AL, Short LL. , et al. Raloxifene is a tissue-selective agonist/antagonist that functions through the estrogen receptor. Ann N Y Acad Sci 1995; 761: 355-360
- 62 Fuchs-Young R, Howe S, Hale L, Miles R, Walker C. Inhibition of estrogen-stimulated growth of uterine leiomyomas by selective estrogen receptor modulators. Mol Carcinog 1996; 17 (03) 151-159
- 63 Zbucka M, Miltyk W, Bielawski T, Surazynski A, Palka J, Wolczynski S. Mechanism of collagen biosynthesis up-regulation in cultured leiomyoma cells. Folia Histochem Cytobiol 2007; 45 (Suppl. 01) S181-S185
- 64 Porter KB, Tsibris JC, Porter GW. , et al. Effects of raloxifene in a guinea pig model for leiomyomas. Am J Obstet Gynecol 1998; 179 (05) 1283-1287
- 65 Deng L. , et al. Selective estrogen receptor modulators (SERMs) for uterine leiomyomas. Cochrane Database Syst Rev 2012; 10: CD005287
- 66 Jirecek S, Lee A, Pavo I, Crans G, Eppel W, Wenzl R. Raloxifene prevents the growth of uterine leiomyomas in premenopausal women. Fertil Steril 2004; 81 (01) 132-136
- 67 Palomba S, Orio Jr F, Morelli M. , et al. Raloxifene administration in premenopausal women with uterine leiomyomas: a pilot study. J Clin Endocrinol Metab 2002; 87 (08) 3603-3608
- 68 Palomba S, Russo T, Orio Jr F. , et al. Effectiveness of combined GnRH analogue plus raloxifene administration in the treatment of uterine leiomyomas: a prospective, randomized, single-blind, placebo-controlled clinical trial. Hum Reprod 2002; 17 (12) 3213-3219
- 69 Palomba S, Sammartino A, Di Carlo C, Affinito P, Zullo F, Nappi C. Effects of raloxifene treatment on uterine leiomyomas in postmenopausal women. Fertil Steril 2001; 76 (01) 38-43
- 70 Palomba S, Orio Jr F, Russo T. , et al. Antiproliferative and proapoptotic effects of raloxifene on uterine leiomyomas in postmenopausal women. Fertil Steril 2005; 84 (01) 154-161
- 71 Pusztai L, Lewis CE, Lorenzen J, McGee JO. Growth factors: regulation of normal and neoplastic growth. J Pathol 1993; 169 (02) 191-201
- 72 Ciarmela P, Islam MS, Reis FM. , et al. Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications. Hum Reprod Update 2011; 17 (06) 772-790
- 73 Yeh J, Rein M, Nowak R. Presence of messenger ribonucleic acid for epidermal growth factor (EGF) and EGF receptor demonstrable in monolayer cell cultures of myometria and leiomyomata. Fertil Steril 1991; 56 (05) 997-1000
- 74 Shushan A, Rojansky N, Laufer N. , et al. The AG1478 tyrosine kinase inhibitor is an effective suppressor of leiomyoma cell growth. Hum Reprod 2004; 19 (09) 1957-1967
- 75 Shushan A, Ben-Bassat H, Mishani E, Laufer N, Klein BY, Rojansky N. Inhibition of leiomyoma cell proliferation in vitro by genistein and the protein tyrosine kinase inhibitor TKS050. Fertil Steril 2007; 87 (01) 127-135
- 76 Strawn Jr EY, Novy MJ, Burry KA, Bethea CL. Insulin-like growth factor I promotes leiomyoma cell growth in vitro. Am J Obstet Gynecol 1995; 172 (06) 1837-1843 , discussion 1843–1844
- 77 Yu L, Saile K, Swartz CD. , et al. Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas. Mol Med 2008; 14 (5-6): 264-275
- 78 Cohen O, Schindel B, Homburg R. Uterine leiomyomata--a feature of acromegaly. Hum Reprod 1998; 13 (07) 1945-1946
- 79 De Leo V, la Marca A, Morgante G, Severi FM, Petraglia F. Administration of somatostatin analogue reduces uterine and myoma volume in women with uterine leiomyomata. Fertil Steril 2001; 75 (03) 632-633
- 80 Feelders RA, Hofland LJ, van Aken MO. , et al. Medical therapy of acromegaly: efficacy and safety of somatostatin analogues. Drugs 2009; 69 (16) 2207-2226
- 81 Chen C, Wu D, Guo Z. , et al. Discovery of sodium R-(+)-4-2-[5-(2-fluoro-3-methoxyphenyl)-3-(2-fluoro-6-[trifluoromethyl]benzyl)-4-methyl-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-yl]-1-phenylethylaminobutyrate (elagolix), a potent and orally available nonpeptide antagonist of the human gonadotropin-releasing hormone receptor. J Med Chem 2008; 51 (23) 7478-7485
- 82 Struthers RS, Nicholls AJ, Grundy J. , et al. Suppression of gonadotropins and estradiol in premenopausal women by oral administration of the nonpeptide gonadotropin-releasing hormone antagonist elagolix. J Clin Endocrinol Metab 2009; 94 (02) 545-551
- 83 Diamond MP, Carr B, Dmowski WP. , et al. Elagolix treatment for endometriosis-associated pain: results from a phase 2, randomized, double-blind, placebo-controlled study. Reprod Sci 2014; 21 (03) 363-371
- 84 Carr B, Dmowski WP, O'Brien C. , et al. Elagolix, an oral GnRH antagonist, versus subcutaneous depot medroxyprogesterone acetate for the treatment of endometriosis: effects on bone mineral density. Reprod Sci 2014; 21 (11) 1341-1351
- 85 Alessandro P, Luigi N, Felice S, Maria PA, Benedetto MG, Stefano A. Research development of a new GnRH antagonist (Elagolix) for the treatment of endometriosis: a review of the literature. Arch Gynecol Obstet 2017; 295 (04) 827-832
- 86 Lin JK, Liang YC, Lin-Shiau SY. Cancer chemoprevention by tea polyphenols through mitotic signal transduction blockade. Biochem Pharmacol 1999; 58 (06) 911-915
- 87 Tang Y, Zhao DY, Elliott S. , et al. Epigallocatechin-3 gallate induces growth inhibition and apoptosis in human breast cancer cells through survivin suppression. Int J Oncol 2007; 31 (04) 705-711
- 88 Nakazato T, Ito K, Miyakawa Y. , et al. Catechin, a green tea component, rapidly induces apoptosis of myeloid leukemic cells via modulation of reactive oxygen species production in vitro and inhibits tumor growth in vivo. Haematologica 2005; 90 (03) 317-325
- 89 Chen C, Yu R, Owuor ED, Kong AN. Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. Arch Pharm Res 2000; 23 (06) 605-612
- 90 Ahmad N, Feyes DK, Nieminen AL, Agarwal R, Mukhtar H. Green tea constituent epigallocatechin-3-gallate and induction of apoptosis and cell cycle arrest in human carcinoma cells. J Natl Cancer Inst 1997; 89 (24) 1881-1886
- 91 Gupta S, Ahmad N, Nieminen AL, Mukhtar H. Growth inhibition, cell-cycle dysregulation, and induction of apoptosis by green tea constituent (-)-epigallocatechin-3-gallate in androgen-sensitive and androgen-insensitive human prostate carcinoma cells. Toxicol Appl Pharmacol 2000; 164 (01) 82-90
- 92 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 2010; 94 (05) 1887-1893
- 93 Zhang D, Al-Hendy M, Richard-Davis G. , et al. Green tea extract inhibits proliferation of uterine leiomyoma cells in vitro and in nude mice. Am J Obstet Gynecol 2010; 202 (03) 289.e1-289.e9
- 94 Roshdy E, Rajaratnam V, Maitra S, Sabry M, Allah AS, Al-Hendy A. Treatment of symptomatic uterine fibroids with green tea extract: a pilot randomized controlled clinical study. Int J Womens Health 2013; 5: 477-486
- 95 Liu S, Li H, Chen L. , et al. (-)-Epigallocatechin-3-gallate inhibition of Epstein-Barr virus spontaneous lytic infection involves ERK1/2 and PI3-K/Akt signaling in EBV-positive cells. Carcinogenesis 2013; 34 (03) 627-637
- 96 Leppert PC, Baginski T, Prupas C, Catherino WH, Pletcher S, Segars JH. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium. Fertil Steril 2004; 82 (Suppl. 03) 1182-1187
- 97 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 (03) 169-179
- 98 Taylor DK, Leppert PC. Treatment for uterine fibroids: searching for effective drug therapies. Drug Discov Today Ther Strateg 2012; 9 (01) e41-e49
- 99 Brunengraber LN, Jayes FL, Leppert PC. Injectable Clostridium histolyticum collagenase as a potential treatment for uterine fibroids. Reprod Sci 2014; 21 (12) 1452-1459
- 100 Taylor DK, Holthouser K, Segars JH, Leppert PC. Recent scientific advances in leiomyoma (uterine fibroids) research facilitates better understanding and management. F1000 Res 2015; 4 (F1000 Faculty Rev): 183
- 101 Ono M, Qiang W, Serna VA. , et al. Role of stem cells in human uterine leiomyoma growth. PLoS One 2012; 7 (05) e36935
- 102 Cervelló I, Mas A, Gil-Sanchis C. , et al. Reconstruction of endometrium from human endometrial side population cell lines. PLoS One 2011; 6 (06) e21221
- 103 Ono M, Maruyama T, Masuda H. , et al. Side population in human uterine myometrium displays phenotypic and functional characteristics of myometrial stem cells. Proc Natl Acad Sci U S A 2007; 104 (47) 18700-18705
- 104 Smalley MJ, Clarke RB. The mammary gland “side population”: a putative stem/progenitor cell marker?. J Mammary Gland Biol Neoplasia 2005; 10 (01) 37-47
- 105 Yin P, Ono M, Moravek MB. , et al. Human uterine leiomyoma stem/progenitor cells expressing CD34 and CD49b initiate tumors in vivo. J Clin Endocrinol Metab 2015; 100 (04) E601-E606
- 106 Mas A, Nair S, Laknaur A, Simón C, Diamond MP, Al-Hendy A. Stro-1/CD44 as putative human myometrial and fibroid stem cell markers. Fertil Steril 2015; 104 (01) 225-34.e3
- 107 Mas A, Cervelló I, Gil-Sanchis C. , et al. Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells. Fertil Steril 2012; 98 (03) 741-751.e6
- 108 Yang Q, Diamond MP, Al-Hendy A. Converting of myometrial stem cells to tumor-initiating cells: mechanism of uterine fibroid development. Cell Stem Cells Regen Med 2016; 2 (01) e103
- 109 Mas A, Stone L, O'Connor PM. , et al. Developmental exposure to endocrine disruptors expands murine myometrial stem cell compartment as a prerequisite to leiomyoma tumorigenesis. Stem Cells 2017; 35 (03) 666-678
- 110 Esteller M, Herman JG. Cancer as an epigenetic disease: DNA methylation and chromatin alterations in human tumours. J Pathol 2002; 196 (01) 1-7
- 111 Moore SD, Herrick SR, Ince TA. , et al. Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Cancer Res 2004; 64 (16) 5570-5577
- 112 Asada H, Yamagata Y, Taketani T. , et al. Potential link between estrogen receptor-alpha gene hypomethylation and uterine fibroid formation. Mol Hum Reprod 2008; 14 (09) 539-545
- 113 Maekawa R, Sato S, Yamagata Y. , et al. Genome-wide DNA methylation analysis reveals a potential mechanism for the pathogenesis and development of uterine leiomyomas. PLoS One 2013; 8 (06) e66632
- 114 Morelli C, Garofalo C, Sisci D. , et al. Nuclear insulin receptor substrate 1 interacts with estrogen receptor alpha at ERE promoters. Oncogene 2004; 23 (45) 7517-7526
- 115 Esposito DL, Aru F, Lattanzio R. , et al. The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer. PLoS One 2012; 7 (04) e36190
- 116 Reiss K, Del Valle L, Lassak A, Trojanek J. Nuclear IRS-1 and cancer. J Cell Physiol 2012; 227 (08) 2992-3000
- 117 Wei LH, Torng PL, Hsiao SM, Jeng YM, Chen MW, Chen CA. Histone deacetylase 6 regulates estrogen receptor alpha in uterine leiomyoma. Reprod Sci 2011; 18 (08) 755-762
- 118 Sant'Anna GD, Brum IS, Branchini G, Pizzolato LS, Capp E, Corleta HV. Ovarian steroid hormones modulate the expression of progesterone receptors and histone acetylation patterns in uterine leiomyoma cells. Gynecol Endocrinol 2017; 33 (08) 629-633
- 119 Egger G, Liang G, Aparicio A, Jones PA. Epigenetics in human disease and prospects for epigenetic therapy. Nature 2004; 429 (6990): 457-463
- 120 Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov 2006; 5 (01) 37-50
- 121 Du T, Zamore PD. microPrimer: the biogenesis and function of microRNA. Development 2005; 132 (21) 4645-4652
- 122 Esquela-Kerscher A, Slack FJ. Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006; 6 (04) 259-269
- 123 Marsh EE, Lin Z, Yin P, Milad M, Chakravarti D, Bulun SE. Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium. Fertil Steril 2008; 89 (06) 1771-1776
- 124 Fitzgerald JB, Chennathukuzhi V, Koohestani F, Nowak RA, Christenson LK. Role of microRNA-21 and programmed cell death 4 in the pathogenesis of human uterine leiomyomas. Fertil Steril 2012; 98 (03) 726-734.e2
- 125 Zavadil J. , et al. Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas. PLoS One 2017; 5 (08) e12362
- 126 Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov 2017; 16 (03) 203-222
- 127 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 (03) 227-233
- 128 Fiscella K, Eisinger SH, Meldrum S, Feng C, Fisher SG, Guzick DS. Effect of mifepristone for symptomatic leiomyomata on quality of life and uterine size: a randomized controlled trial. Obstet Gynecol 2006; 108 (06) 1381-1387
- 129 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 (05) 1029-1036
- 130 Bagaria M, Suneja A, Vaid NB, Guleria K, Mishra K. Low-dose mifepristone in treatment of uterine leiomyoma: a randomised double-blind placebo-controlled clinical trial. Aust N Z J Obstet Gynaecol 2009; 49 (01) 77-83
- 131 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 (02) 215-218
- 132 Engman M, Granberg S, Williams AR, Meng CX, Lalitkumar PG, Gemzell-Danielsson K. Mifepristone for treatment of uterine leiomyoma. A prospective randomized placebo controlled trial. Hum Reprod 2009; 24 (08) 1870-1879
- 133 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 (02) 121-124
- 134 Levens ED, Potlog-Nahari C, Armstrong AY. , et al. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial. Obstet Gynecol 2008; 111 (05) 1129-1136
- 135 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 IIb study. Fertil Steril 2011; 95 (02) 767-72.e1 , 2
- 136 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 (06) 1399-1412
- 137 Wilkens J, Chwalisz K, Han C. , 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 Metab 2008; 93 (12) 4664-4671