PDF herunterladen
Semin Reprod Med 2017; 35(06): 494-498
DOI: 10.1055/s-0037-1607240
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Uterine Fibroids: Bridging Genomic Defects and Chronic Inflammation

Abdeljabar El Andaloussi
1   Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia
,
Zuni Chaudhry
3   Saint James School of Medicine, St. Vincent, Caribbean
,
Ayman Al-Hendy
1   Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta University, Augusta, Georgia
,
Nahed Ismail
2   Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
03. November 2017 (online)

    Lizenzen und Reprints

Abstract

Uterine fibroids (UF; aka leiomyoma, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70 to 80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pelvic bulk symptoms, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 34 billion dollars annually in the United States alone. Recently, somatic mutations in exons 1 and 2 of Med12 gene emerged as common UF driver mutations. Unfortunately, the detailed etiology of UF is not fully realized. Particularly, very little is known about possible dysregulation of inflammatory and immune processes and their possible contribution to UF pathogenesis. The notion on possible impact of altered estrogen and progesterone signaling in UF on inflammatory responses and DNA repair machinery that can conceivably lead to tumor-specific somatic mutation is indeed an intriguing concept which has some foundation in available observation in other hormonally responsive tissues. This review highlights and summarizes our current knowledge on the convergence of such pathways and their relevance for UF pathogenesis.

Keywords

inflammation - progesterone - cytokines - immune cells - Estrogen - Med12
 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Kim JJ, Sefton EC. The role of progesterone signaling in the pathogenesis of uterine leiomyoma. Mol Cell Endocrinol 2012; 358 (02) 223-231
    CrossrefPubMedGoogle Scholar
  • 3 Bulun SE. Uterine fibroids. N Engl J Med 2013; 369 (14) 1344-1355
    CrossrefPubMedGoogle Scholar
  • 4 Kozma N, Halasz M, Polgar B. , et al. Progesterone-induced blocking factor activates STAT6 via binding to a novel IL-4 receptor. J Immunol 2006; 176 (02) 819-826
    CrossrefPubMedGoogle Scholar
  • 5 Hughes GC. Progesterone and autoimmune disease. Autoimmun Rev 2012; 11 (6-7): A502-A514
    CrossrefPubMedGoogle Scholar
  • 6 Miyaura H, Iwata M. Direct and indirect inhibition of Th1 development by progesterone and glucocorticoids. J Immunol 2002; 168 (03) 1087-1094
    CrossrefPubMedGoogle Scholar
  • 7 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
    CrossrefPubMedGoogle Scholar
  • 8 Kawaguchi K, Fujii S, Konishi I. , 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 (04) 309-315
    CrossrefPubMedGoogle Scholar
  • 9 Tan H, Yi L, Rote NS, Hurd WW, Mesiano S. Progesterone receptor-A and -B have opposite effects on proinflammatory gene expression in human myometrial cells: implications for progesterone actions in human pregnancy and parturition. J Clin Endocrinol Metab 2012; 97 (05) E719-E730
    CrossrefPubMedGoogle Scholar
  • 10 Palomba S, Sena T, Noia R, Di Carlo C, Zullo F, Mastrantonio P. Transdermal hormone replacement therapy in postmenopausal women with uterine leiomyomas. Obstet Gynecol 2001; 98 (06) 1053-1058
    PubMedGoogle Scholar
  • 11 Ito A, Imada K, Sato T, Kubo T, Matsushima K, Mori Y. Suppression of interleukin 8 production by progesterone in rabbit uterine cervix. Biochem J 1994; 301 (Pt 1): 183-186
    CrossrefPubMedGoogle Scholar
  • 12 Yellon SM, Ebner CA, Elovitz MA. Medroxyprogesterone acetate modulates remodeling, immune cell census, and nerve fibers in the cervix of a mouse model for inflammation-induced preterm birth. Reprod Sci 2009; 16 (03) 257-264
    CrossrefPubMedGoogle Scholar
  • 13 Kyurkchiev D, Ivanova-Todorova E, Kyurkchiev SD. New target cells of the immunomodulatory effects of progesterone. Reprod Biomed Online 2010; 21 (03) 304-311
    CrossrefPubMedGoogle Scholar
  • 14 Tabiasco J, Rabot M, Aguerre-Girr M. , et al. Human decidual NK cells: unique phenotype and functional properties -- a review. Placenta 2006; 27 (Suppl A): S34-S39
    PubMedGoogle Scholar
  • 15 Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO. Steroid receptor expression in uterine natural killer cells. J Clin Endocrinol Metab 2003; 88 (01) 440-449
    PubMedGoogle Scholar
  • 16 Barber EM, Pollard JW. The uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol 2003; 171 (01) 37-46
    CrossrefPubMedGoogle Scholar
  • 17 Okada H, Nakajima T, Sanezumi M, Ikuta A, Yasuda K, Kanzaki H. Progesterone enhances interleukin-15 production in human endometrial stromal cells in vitro. J Clin Endocrinol Metab 2000; 85 (12) 4765-4770
    PubMedGoogle Scholar
  • 18 Verma S, Hiby SE, Loke YW, King A. Human decidual natural killer cells express the receptor for and respond to the cytokine interleukin 15. Biol Reprod 2000; 62 (04) 959-968
    CrossrefPubMedGoogle Scholar
  • 19 Brakta S, Diamond JS, Al-Hendy A, Diamond MP, Halder SK. Role of vitamin D in uterine fibroid biology. Fertil Steril 2015; 104 (03) 698-706
    CrossrefPubMedGoogle Scholar
  • 20 Mittal P, Shin YH, Yatsenko SA, Castro CA, Surti U, Rajkovic A. Med12 gain-of-function mutation causes leiomyomas and genomic instability. J Clin Invest 2015; 125 (08) 3280-3284
    CrossrefPubMedGoogle Scholar
  • 21 Yang Q, Diamond MP, Al-Hendy A. Early life adverse environmental exposures increase the risk of uterine fibroid development: role of epigenetic regulation. Front Pharmacol 2016; 7: 40
    PubMedGoogle Scholar
  • 22 Tagashira Y, Taniguchi F, Harada T, Ikeda A, Watanabe A, Terakawa N. Interleukin-10 attenuates TNF-alpha-induced interleukin-6 production in endometriotic stromal cells. Fertil Steril 2009; 91 (05, Suppl): 2185-2192
    CrossrefPubMedGoogle Scholar
  • 23 Nair S, Al-Hendy A. Adipocytes enhance the proliferation of human leiomyoma cells via TNF-α proinflammatory cytokine. Reprod Sci 2011; 18 (12) 1186-1192
    CrossrefPubMedGoogle Scholar
  • 24 Hunt JS, Miller L, Roby KF, Huang J, Platt JS, DeBrot BL. Female steroid hormones regulate production of pro-inflammatory molecules in uterine leukocytes. J Reprod Immunol 1997; 35 (02) 87-99
    CrossrefPubMedGoogle Scholar
  • 25 Plewka A, Madej P, Plewka D. , et al. Immunohistochemical localization of selected pro-inflammatory factors in uterine myomas and myometrium in women of various ages. Folia Histochem Cytobiol 2013; 51 (01) 73-83
    CrossrefPubMedGoogle Scholar
  • 26 Straub RH. The complex role of estrogens in inflammation. Endocr Rev 2007; 28 (05) 521-574
    CrossrefPubMedGoogle Scholar
  • 27 Sternberg EM. Neuroendocrine regulation of autoimmune/inflammatory disease. J Endocrinol 2001; 169 (03) 429-435
    CrossrefPubMedGoogle Scholar
  • 28 Heldring N, Pike A, Andersson S. , et al. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007; 87 (03) 905-931
    CrossrefPubMedGoogle Scholar
  • 29 Glatstein IZ, Yeh J. Ontogeny of the estrogen receptor in the human fetal uterus. J Clin Endocrinol Metab 1995; 80 (03) 958-964
    PubMedGoogle Scholar
  • 30 Murphy AJ, Guyre PM, Pioli PA. Estradiol suppresses NF-kappa B activation through coordinated regulation of let-7a and miR-125b in primary human macrophages. J Immunol 2010; 184 (09) 5029-5037
    CrossrefPubMedGoogle Scholar
  • 31 Stice JP, Mbai FN, Chen L, Knowlton AA. Rapid activation of nuclear factor κB by 17β-estradiol and selective estrogen receptor modulators: pathways mediating cellular protection. Shock 2012; 38 (02) 128-136
    CrossrefPubMedGoogle Scholar
  • 32 Xing D, Oparil S, Yu H. , et al. Estrogen modulates NFκB signaling by enhancing IκBα levels and blocking p65 binding at the promoters of inflammatory genes via estrogen receptor-β. PLoS One 2012; 7 (06) e36890
    CrossrefPubMedGoogle Scholar
  • 33 Dodel RC, Du Y, Bales KR, Gao F, Paul SM. Sodium salicylate and 17beta-estradiol attenuate nuclear transcription factor NF-kappaB translocation in cultured rat astroglial cultures following exposure to amyloid A beta(1-40) and lipopolysaccharides. J Neurochem 1999; 73 (04) 1453-1460
    PubMedGoogle Scholar
  • 34 Wen Y, Yang S, Liu R. , et al. Estrogen attenuates nuclear factor-kappa B activation induced by transient cerebral ischemia. Brain Res 2004; 1008 (02) 147-154
    CrossrefPubMedGoogle Scholar
  • 35 Solar P, Velasquez L. Consequences of nongenomic actions of estradiol on pathogenic genital tract response. J Mol Signal 2013; 8 (01) 1
    CrossrefPubMedGoogle Scholar
  • 36 Liu CJ, Lo JF, Kuo CH. , et al. Akt mediates 17beta-estradiol and/or estrogen receptor-alpha inhibition of LPS-induced tumor necrosis factor-alpha expression and myocardial cell apoptosis by suppressing the JNK1/2-NFkappaB pathway. J Cell Mol Med 2009; 13 (9B): 3655-3667
    CrossrefPubMedGoogle Scholar
  • 37 Maia Jr H, Pimentel K, Casoy J. , et al. Aromatase expression in the eutopic endometrium of myomatous uteri: the influence of the menstrual cycle and oral contraceptive use. Gynecol Endocrinol 2007; 23 (06) 320-324
    CrossrefPubMedGoogle Scholar
  • 38 Poligone B, Baldwin AS. Positive and negative regulation of NF-kappaB by COX-2: roles of different prostaglandins. J Biol Chem 2001; 276 (42) 38658-38664
    CrossrefPubMedGoogle Scholar
  • 39 Danforth Jr DN, Sgagias MK. Tumour necrosis factor-alpha modulates oestradiol responsiveness of MCF-7 breast cancer cells in vitro. J Endocrinol 1993; 138 (03) 517-528
    CrossrefPubMedGoogle Scholar
  • 40 Lin L, DeMartino GN, Greene WC. Cotranslational biogenesis of NF-kappaB p50 by the 26S proteasome. Cell 1998; 92 (06) 819-828
    CrossrefPubMedGoogle Scholar
  • 41 Roberts AB, Flanders KC, Heine UI. , et al. Transforming growth factor-beta: multifunctional regulator of differentiation and development. Philos Trans R Soc Lond B Biol Sci 1990; 327 (1239): 145-154
    CrossrefPubMedGoogle Scholar
  • 42 Klimp AH, Hollema H, Kempinga C, van der Zee AG, de Vries EG, Daemen T. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in human ovarian tumors and tumor-associated macrophages. Cancer Res 2001; 61 (19) 7305-7309
    PubMedGoogle Scholar
  • 43 Ozel E, Peştereli HE, Simşek T, Erdoğan G, Karaveli FS. Expression of cyclooxygenase-2 and inducible nitric oxide synthase in ovarian surface epithelial carcinomas: is there any correlation with angiogenesis or clinicopathologic parameters?. Int J Gynecol Cancer 2006; 16 (02) 549-555
    PubMedGoogle Scholar
  • 44 Ali-Fehmi R, Semaan A, Sethi S. , et al. Molecular typing of epithelial ovarian carcinomas using inflammatory markers. Cancer 2011; 117 (02) 301-309
    CrossrefPubMedGoogle Scholar
  • 45 Rogers R, Norian J, Malik M. , et al. Mechanical homeostasis is altered in uterine leiomyoma. Am J Obstet Gynecol 2008; 198 (04) 474.e1-474.e11
    CrossrefPubMedGoogle Scholar
  • 46 Manta L, Suciu N, Toader O, Purcărea RM, Constantin A, Popa F. The etiopathogenesis of uterine fibromatosis. J Med Life 2016; 9 (01) 39-45
    PubMedGoogle Scholar
  • 47 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
    CrossrefPubMedGoogle Scholar
  • 48 Scheibl P, Zerbe H. Effect of progesterone on the immune system in consideration of bovine placental retention [in German]. Dtsch Tierarztl Wochenschr 2000; 107 (06) 221-227
    PubMedGoogle Scholar
  • 49 Giannoni E, Guignard L, Knaup Reymond M. , et al. Estradiol and progesterone strongly inhibit the innate immune response of mononuclear cells in newborns. Infect Immun 2011; 79 (07) 2690-2698
    CrossrefPubMedGoogle Scholar
  • 50 Hardy DB, Janowski BA, Corey DR, Mendelson CR. Progesterone receptor plays a major antiinflammatory role in human myometrial cells by antagonism of nuclear factor-kappaB activation of cyclooxygenase 2 expression. Mol Endocrinol 2006; 20 (11) 2724-2733
    CrossrefPubMedGoogle Scholar
  • 51 Edwards J, Lorenz KT, Remington BA. , et al. Laser-driven plasma loader for shockless compression and acceleration of samples in the solid state. Phys Rev Lett 2004; 92 (07) 075002
    CrossrefPubMedGoogle Scholar
  • 52 Hoekstra AV, Sefton EC, Berry E. , et al. Progestins activate the AKT pathway in leiomyoma cells and promote survival. J Clin Endocrinol Metab 2009; 94 (05) 1768-1774
    CrossrefPubMedGoogle Scholar
  • 53 Kovács KA, Lengyel F, Környei JL. , et al. Differential expression of Akt/protein kinase B, Bcl-2 and Bax proteins in human leiomyoma and myometrium. J Steroid Biochem Mol Biol 2003; 87 (4-5): 233-240
    CrossrefPubMedGoogle Scholar
  • 54 Yang Q, Laknaur A, Elam L. , et al. Identification of Polycomb group protein EZH2-mediated DNA mismatch repair gene MSH2 in human uterine fibroids. Reprod Sci 2016; 23 (10) 1314-1325
    CrossrefPubMedGoogle Scholar
  • 55 Yang Q, Nair S, Laknaur A, Ismail N, Diamond MP, Al-Hendy A. The Polycomb group protein EZH2 impairs DNA damage repair gene expression in human uterine fibroids. Biol Reprod 2016; 94 (03) 69
    PubMedGoogle Scholar
  • 56 Bertsch E, Qiang W, Zhang Q. , et al. MED12 and HMGA2 mutations: two independent genetic events in uterine leiomyoma and leiomyosarcoma. Mod Pathol 2014; 27 (08) 1144-1153
    CrossrefPubMedGoogle Scholar
  • 57 Mäkinen N, Vahteristo P, Kämpjärvi K, Arola J, Bützow R, Aaltonen LA. MED12 exon 2 mutations in histopathological uterine leiomyoma variants. Eur J Hum Genet 2013; 21 (11) 1300-1303
    CrossrefPubMedGoogle Scholar
  • 58 Tsutsui T, Fukasawa R, Shinmyouzu K. , et al. Mediator complex recruits epigenetic regulators via its two cyclin-dependent kinase subunits to repress transcription of immune response genes. J Biol Chem 2013; 288 (29) 20955-20965
    CrossrefPubMedGoogle Scholar
  • 59 Natsuka S, Akira S, Nishio Y. , et al. Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6. Blood 1992; 79 (02) 460-466
    PubMedGoogle Scholar
  • 60 Yamamoto S, Hagihara T, Horiuchi Y. , et al. Mediator cyclin-dependent kinases upregulate transcription of inflammatory genes in cooperation with NF-κB and C/EBPβ on stimulation of Toll-like receptor 9. Genes Cells 2017; 22 (03) 265-276
    CrossrefPubMedGoogle Scholar
  • 61 El Andaloussi A, Sonabend AM, Han Y, Lesniak MS. Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors. Glia 2006; 54 (06) 526-535
    CrossrefPubMedGoogle Scholar