Download PDF
Semin Reprod Med 2010; 28(3): 169-179
DOI: 10.1055/s-0030-1251475
Published in 2010 by Thieme Medical Publishers

Why Leiomyomas Are Called Fibroids: The Central Role of Extracellular Matrix in Symptomatic Women

Minnie Malik1 , John Norian1 , 2 , Desirée McCarthy-Keith1 , 2 , Joy Britten1 , William H. Catherino1 , 2
  • 1Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, Bethesda, Maryland
  • 2Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland
Further Information

Publication History

Publication Date:
22 April 2010 (online)

    Permissions and Reprints

ABSTRACT

Uterine leiomyomas are highly prevalent and symptomatic tumors of women in their reproductive years. The morbidity caused by these tumors is directly related to increasing size. Leiomyoma cells do not rapidly proliferate; instead, the tumors grow primarily due to excessive production of disorganized extracellular matrix (ECM). The aberrant ECM results from excessive production of collagen subtypes and proteoglycans, increased profibrotic cytokines including transforming growth factors β1 and β3, and decreased or disrupted matrix metalloproteinases. These alterations result in the development of an ECM that is exceptionally stable. As a result, therapeutic interventions must redirect leiomyoma cells toward extracellular matrix dissolution, rather than solely inhibiting cell proliferation. Gonadotropin-releasing hormone analogues and selective progesterone receptor modulators with demonstrated clinical efficacy provide such a change in abnormal extracellular matrix formation by leiomyoma cells, inhibiting and reversing the fibrotic process. Novel therapies using pathways distinct from gonadal hormones, including antifibrotics, retinoic acid, peroxisome-proliferator-activated receptor γ ligands, and curcumin, provide promise for a future with improved therapeutic options for women suffering from uterine leiomyomas.

KEYWORDS

Uterine leiomyoma - extracellular matrix - collagen - proteoglycan - transforming growth factor (TGF)

REFERENCES

  • 1 Selo-Ojeme D, Lawal O, Shah J et al.. The incidence of uterine leiomyoma and other pelvic ultrasonographic findings in 2,034 consecutive women in a north London hospital.  J Obstet Gynaecol. 2008;  28(4) 421-423
    CrossrefPubMedGoogle Scholar
  • 2 Borgfeldt C, Andolf E. Transvaginal ultrasonographic findings in the uterus and the endometrium: low prevalence of leiomyoma in a random sample of women age 25–40 years.  Acta Obstet Gynecol Scand. 2000;  79(3) 202-207
    CrossrefPubMedGoogle Scholar
  • 3 Marino J L, Eskenazi B, Warner M et al.. Uterine leiomyoma and menstrual cycle characteristics in a population-based cohort study.  Hum Reprod. 2004;  19(10) 2350-2355
    CrossrefPubMedGoogle Scholar
  • 4 Eskenazi B, Warner M, Samuels S et al.. Serum dioxin concentrations and risk of uterine leiomyoma in the Seveso Women's Health Study.  Am J Epidemiol. 2007;  166(1) 79-87
    CrossrefPubMedGoogle Scholar
  • 5 Baird D D, Dunson D B, Hill M C, Cousins D, Schectman J M. Association of physical activity with development of uterine leiomyoma.  Am J Epidemiol. 2007;  165(2) 157-163
    CrossrefPubMedGoogle Scholar
  • 6 Day Baird D, Dunson D B, Hill M C, Cousins D, Schectman J M. High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence.  Am J Obstet Gynecol. 2003;  188(1) 100-107
    CrossrefPubMedGoogle Scholar
  • 7 Chen C R, Buck G M, Courey N G, Perez K M, Wactawski-Wende J. Risk factors for uterine fibroids among women undergoing tubal sterilization.  Am J Epidemiol. 2001;  153(1) 20-26
    CrossrefPubMedGoogle Scholar
  • 8 Kjerulff K H, Langenberg P, Seidman J D, Stolley P D, Guzinski G M. Uterine leiomyomas. Racial differences in severity, symptoms and age at diagnosis.  J Reprod Med. 1996;  41(7) 483-490
    PubMedGoogle Scholar
  • 9 Peddada S D, Laughlin S K, Miner K et al.. Growth of uterine leiomyomata among premenopausal black and white women.  Proc Natl Acad Sci U S A. 2008;  105(50) 19887-19892
    CrossrefPubMedGoogle Scholar
  • 10 Pron G, Cohen M, Soucie J et al.. The Ontario Uterine Fibroid Embolization Trial. Part 1. Baseline patient characteristics, fibroid burden, and impact on life.  Fertil Steril. 2003;  79 112-119
    CrossrefPubMedGoogle Scholar
  • 11 Buttram Jr V C, Reiter R C. Uterine leiomyomata: etiology, symptomatology, and management.  Fertil Steril. 1981;  36(4) 433-445
    PubMedGoogle Scholar
  • 12 Olufowobi O, Sharif K, Papaionnou S, Neelakantan D, Mohammed H, Afnan M. Are the anticipated benefits of myomectomy achieved in women of reproductive age? A 5-year review of the results at a UK tertiary hospital.  J Obstet Gynaecol. 2004;  24(4) 434-440
    CrossrefPubMedGoogle Scholar
  • 13 Pritts E A, Parker W H, Olive D L. Fibroids and infertility: an updated systematic review of the evidence.  Fertil Steril. 2009;  91 1215-1223
    CrossrefPubMedGoogle Scholar
  • 14 Bulletti C, DE Ziegler D, Levi Setti P, Cicinelli E, Polli V, Stefanetti M. Myomas, pregnancy outcome, and in vitro fertilization.  Ann N Y Acad Sci. 2004;  1034 84-92
    CrossrefPubMedGoogle Scholar
  • 15 Qidwai G I, Caughey A B, Jacoby A F. Obstetric outcomes in women with sonographically identified uterine leiomyomata.  Obstet Gynecol. 2006;  107(2 Pt 1) 376-382
    CrossrefPubMedGoogle Scholar
  • 16 Sheiner E, Bashiri A, Levy A, Hershkovitz R, Katz M, Mazor M. Obstetric characteristics and perinatal outcome of pregnancies with uterine leiomyomas.  J Reprod Med. 2004;  49(3) 182-186
    PubMedGoogle Scholar
  • 17 Szamatowicz J, Laudanski T, Bulkszas B, Akerlund M. Fibromyomas and uterine contractions.  Acta Obstet Gynecol Scand. 1997;  76(10) 973-976
    CrossrefPubMedGoogle Scholar
  • 18 Salvig J D, Petersen K R, Møller B R. Acute abdominal pain caused by torsion of an enlarged non-pregnant uterus.  J Obstet Gynaecol. 2005;  25(1) 81-82
    CrossrefPubMedGoogle Scholar
  • 19 Ilbey O, Apaydin E, Gürsan A, Cikili N. Bladder leiomyoma: a rare cause of urinary stress incontinence.  Arch Ital Urol Androl. 2000;  72(2) 85-87
    PubMedGoogle Scholar
  • 20 Catherino W H, Leppert P C, Stenmark M H et al.. Reduced dermatopontin expression is a molecular link between uterine leiomyomas and keloids.  Genes Chromosomes Cancer. 2004;  40(3) 204-217
    CrossrefPubMedGoogle Scholar
  • 21 Leppert P C, Baginski T, Prupas C, Catherino W H, Pletcher S, Segars J H. Comparative ultrastructure of collagen fibrils in uterine leiomyomas and normal myometrium.  Fertil Steril. 2004;  82(suppl 3) 1182-1187
    CrossrefPubMedGoogle Scholar
  • 22 Kramar C, Baud C A, Lagier R. Presumed calcified leiomyoma of the uterus. Morphologic and chemical studies of a calcified mass dating from the Neolithic period.  Arch Pathol Lab Med. 1983;  107(2) 91-93
    PubMedGoogle Scholar
  • 23 Wolańska M, Sobolewski K, Drozdzewicz M, Bańkowski E. Extracellular matrix components in uterine leiomyoma and their alteration during the tumour growth.  Mol Cell Biochem. 1998;  189(1-2) 145-152
    CrossrefPubMedGoogle Scholar
  • 24 Berto A G, Oba S M, Michelacci Y M, Sampaio L O. Galactosaminoglycans from normal myometrium and leiomyoma.  Braz J Med Biol Res. 2001;  34(5) 633-637
    PubMedGoogle Scholar
  • 25 Berto A G, Sampaio L O, Franco C R, Cesar Jr R M, Michelacci Y M. A comparative analysis of structure and spatial distribution of decorin in human leiomyoma and normal myometrium.  Biochim Biophys Acta. 2003;  1619(1) 98-112
    PubMedGoogle Scholar
  • 26 Norian J M, Malik M, Parker C Y et al.. Transforming growth factor β3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas.  Reprod Sci. 2009;  16(12) 1153-1164
    CrossrefPubMedGoogle Scholar
  • 27 Bornstein P, Agah A, Kyriakides T R. The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury.  Int J Biochem Cell Biol. 2004;  36(6) 1115-1125
    CrossrefPubMedGoogle Scholar
  • 28 Behera M A, Feng L, Yonish B, Catherino W, Jung S H, Leppert P. Thrombospondin-1 and thrombospondin-2 mRNA and TSP-1 and TSP-2 protein expression in uterine fibroids and correlation to the genes COL1A1 and COL3A1 and to the collagen cross-link hydroxyproline.  Reprod Sci. 2007;  14(8, suppl) 63-76
    CrossrefPubMedGoogle Scholar
  • 29 Vincenti M P. The matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) genes. Transcriptional and posttranscriptional regulation, signal transduction and cell-type-specific expression.  Methods Mol Biol. 2001;  151 121-148
    PubMedGoogle Scholar
  • 30 Inagaki N, Ung L, Otani T, Wilkinson D, Lopata A. Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp.  Eur J Obstet Gynecol Reprod Biol. 2003;  111(2) 197-203
    CrossrefPubMedGoogle Scholar
  • 31 Bodner-Adler B, Bodner K, Kimberger O, Czerwenka K, Leodolter S, Mayerhofer K. Expression of matrix metalloproteinases in patients with uterine smooth muscle tumors: an immunohistochemical analysis of MMP-1 and MMP-2 protein expression in leiomyoma, uterine smooth muscle tumor of uncertain malignant potential, and leiomyosarcoma.  J Soc Gynecol Investig. 2004;  11(3) 182-186
    CrossrefPubMedGoogle Scholar
  • 32 Wolańska M, Sobolewski K, Bańkowski E, Jaworski S. Matrix metalloproteinases of human leiomyoma in various stages of tumor growth.  Gynecol Obstet Invest. 2004;  58(1) 14-18
    CrossrefPubMedGoogle Scholar
  • 33 Bogusiewicz M, Stryjecka-Zimmer M, Postawski K, Jakimiuk A J, 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
    CrossrefPubMedGoogle Scholar
  • 34 Willis B C, Borok Z. TGF-beta-induced EMT: mechanisms and implications for fibrotic lung disease.  Am J Physiol Lung Cell Mol Physiol. 2007;  293(3) L525-L534
    CrossrefPubMedGoogle Scholar
  • 35 Liu Y. Renal fibrosis: new insights into the pathogenesis and therapeutics.  Kidney Int. 2006;  69(2) 213-217
    CrossrefPubMedGoogle Scholar
  • 36 Yata Y, Gotwals P, Koteliansky V, Rockey D C. Dose-dependent inhibition of hepatic fibrosis in mice by a TGF-beta soluble receptor: implications for antifibrotic therapy.  Hepatology. 2002;  35(5) 1022-1030
    CrossrefPubMedGoogle Scholar
  • 37 Verrecchia F, Mauviel A, Farge D. Transforming growth factor-beta signaling through the Smad proteins: role in systemic sclerosis.  Autoimmun Rev. 2006;  5(8) 563-569
    CrossrefPubMedGoogle Scholar
  • 38 Bonniaud P, Margetts P J, Ask K, Flanders K, Gauldie J, Kolb M. TGF-beta and Smad3 signaling link inflammation to chronic fibrogenesis.  J Immunol. 2005;  175(8) 5390-5395
    PubMedGoogle Scholar
  • 39 Ding L, Xu J, Luo X, Chegini N. Gonadotropin releasing hormone and transforming growth factor beta activate mitogen-activated protein kinase/extracellularly regulated kinase and differentially regulate fibronectin, type I collagen, and plasminogen activator inhibitor-1 expression in leiomyoma and myometrial smooth muscle cells.  J Clin Endocrinol Metab. 2004;  89(11) 5549-5557
    CrossrefPubMedGoogle Scholar
  • 40 Lee B S, Nowak R A. Human leiomyoma smooth muscle cells show increased expression of transforming growth factor-beta 3 (TGF beta 3) and altered responses to the antiproliferative effects of TGF beta.  J Clin Endocrinol Metab. 2001;  86(2) 913-920
    CrossrefPubMedGoogle Scholar
  • 41 Arici A, Sozen I. Transforming growth factor-beta3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation.  Fertil Steril. 2000;  73(5) 1006-1011
    CrossrefPubMedGoogle Scholar
  • 42 Derynck R, Lindquist P B, Lee A et al.. A new type of transforming growth factor-beta, TGF-beta 3.  EMBO J. 1988;  7(12) 3737-3743
    PubMedGoogle Scholar
  • 43 Joseph D S, Malik M, Nurudeen S, Catherino W H. Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor beta-3.  Fertil Steril. 2009;  , March 26 (Epub ahead of print)
    PubMedGoogle Scholar
  • 44 Moench G L. The etiology of adenomyositis and uterine fibromyoma: an hypothesis.  Am J Obstet Gynecol. 1929;  18 682-688
    PubMedGoogle Scholar
  • 45 Friedman A J, Rein M S, Harrison-Atlas D, Garfield J M, Doubilet P M. A randomized, placebo-controlled, double-blind study evaluating leuprolide acetate depot treatment before myomectomy.  Fertil Steril. 1989;  52(5) 728-733
    PubMedGoogle Scholar
  • 46 Maheux R, Lemay A, Blanchet P, Friede J, Pratt X. Maintained reduction of uterine leiomyoma following addition of hormonal replacement therapy to a monthly luteinizing hormone-releasing hormone agonist implant: a pilot study.  Hum Reprod. 1991;  6(4) 500-505
    PubMedGoogle Scholar
  • 47 Engel J B, Audebert A, Frydman R, Zivny J, Diedrich K. Presurgical short term treatment of uterine fibroids with different doses of cetrorelix acetate: a double-blind, placebo-controlled multicenter study.  Eur J Obstet Gynecol Reprod Biol. 2007;  134(2) 225-232
    CrossrefPubMedGoogle Scholar
  • 48 Kawamura N, Ito F, Ichimura T, Shibata S, Umesaki N, Ogita S. Correlation between shrinkage of uterine leiomyoma treated with buserelin acetate and histopathologic findings of biopsy specimen before treatment.  Fertil Steril. 1997;  68(4) 632-636
    CrossrefPubMedGoogle Scholar
  • 49 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 1) S181-S185
    PubMedGoogle Scholar
  • 50 Hassan M H, Salama S A, Arafa H M, Hamada F M, Al-Hendy A. Adenovirus-mediated delivery of a dominant-negative estrogen receptor gene in uterine leiomyoma cells abrogates estrogen- and progesterone-regulated gene expression.  J Clin Endocrinol Metab. 2007;  92(10) 3949-3957
    CrossrefPubMedGoogle Scholar
  • 51 Chegini N, Ma C, Tang X M, Williams R S. Effects of GnRH analogues, ‘add-back’ steroid therapy, antiestrogen and antiprogestins on leiomyoma and myometrial smooth muscle cell growth and transforming growth factor-beta expression.  Mol Hum Reprod. 2002;  8(12) 1071-1078
    CrossrefPubMedGoogle Scholar
  • 52 Chegini N, Luo X, Ding L, Ripley D. The expression of Smads and transforming growth factor beta receptors in leiomyoma and myometrium and the effect of gonadotropin releasing hormone analogue therapy.  Mol Cell Endocrinol. 2003;  209(1–2) 9-16
    CrossrefPubMedGoogle Scholar
  • 53 Salama S A, Nasr A B, Dubey R K, 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(8) 542-550
    CrossrefPubMedGoogle Scholar
  • 54 Chwalisz K, Larsen L, Mattia-Goldberg C, Edmonds A, Elger W, Winkel C A. A randomized, controlled trial of asoprisnil, a novel selective progesterone receptor modulator, in women with uterine leiomyomata.  Fertil Steril. 2007;  87(6) 1399-1412
    CrossrefPubMedGoogle Scholar
  • 55 Ohara N, Morikawa A, Chen W et al.. Comparative effects of SPRM asoprisnil (J867) on proliferation, apoptosis, and the expression of growth factors in cultured uterine leiomyoma cells and normal myometrial cells.  Reprod Sci. 2007;  14(8, suppl) 20-27
    PubMedGoogle Scholar
  • 56 Morikawa A, Ohara N, Xu Q et al.. Selective progesterone receptor modulator asoprisnil down-regulates collagen synthesis in cultured human uterine leiomyoma cells through up-regulating extracellular matrix metalloproteinase inducer.  Hum Reprod. 2008;  23(4) 944-951
    CrossrefPubMedGoogle Scholar
  • 57 Levens E D, Potlog-Nahari C, Armstrong A Y et al.. CDB-2914 for uterine leiomyomata treatment: a randomized controlled trial.  Obstet Gynecol. 2008;  111(5) 1129-1136
    CrossrefPubMedGoogle Scholar
  • 58 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
    CrossrefPubMedGoogle Scholar
  • 59 Catherino W H, Malik M, Driggers P et al.. Novel orally active selective progesterone receptor modulator CP8947 inhibits leiomyoma cell proliferation and induces apoptosis without adversely affecting endometrium or myometrium.  J Clin Endocrinol Metab. 2009;  , in press
    PubMedGoogle Scholar
  • 60 Azuma A, Nukiwa T, Tsuboi E et al.. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2005;  171(9) 1040-1047
    CrossrefPubMedGoogle Scholar
  • 61 Cho M E, Smith D C, Branton M H, Penzak S R, Kopp J B. Pirfenidone slows renal function decline in patients with focal segmental glomerulosclerosis.  Clin J Am Soc Nephrol. 2007;  2(5) 906-913
    CrossrefPubMedGoogle Scholar
  • 62 Lee B S, Margolin S B, Nowak R A. Pirfenidone: a novel pharmacological agent that inhibits leiomyoma cell proliferation and collagen production.  J Clin Endocrinol Metab. 1998;  83(1) 219-223
    CrossrefPubMedGoogle Scholar
  • 63 Grudzien M, Low P S, Manning P C et al.. The antifibrotic drug halofuginone inhibits proliferation and collagen production by human leiomyoma and myometrial smooth muscle cells.  Fertil Steril. 2009;  , January 8 (Epub ahead of print)
    PubMedGoogle Scholar
  • 64 Zhang C H, Wen Z Q, Li J F et al.. Inhibition of proliferation and transforming growth factor beta3 protein expression by peroxisome proliferators-activated receptor gamma ligands in human uterine leiomyoma cells.  Chin Med J (Engl). 2008;  121(2) 166-171
    PubMedGoogle Scholar
  • 65 Malik M, Webb J, Catherino W H. Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells.  Clin Endocrinol (Oxf). 2008;  69(3) 462-470
    CrossrefPubMedGoogle Scholar
  • 66 Kwon Y, Malik M, Magnuson B A. Inhibition of colonic aberrant crypt foci by curcumin in rats is affected by age.  Nutr Cancer. 2004;  48(1) 37-43
    CrossrefPubMedGoogle Scholar
  • 67 Malik M, Mendoza M, Payson M, Catherino W H. Curcumin, a nutritional supplement with antineoplastic activity, enhances leiomyoma cell apoptosis and decreases fibronectin expression.  Fertil Steril. 2009;  91(5, Suppl) 2177-2184
    CrossrefPubMedGoogle Scholar
  • 68 Malik M, Britten J, Mendoza M et al.. Symptomatic leiomyomas are a 3-dimensional disease: moving from two dimensions to tumor.  Fertil Steril. 2009;  92(3, Suppl) S126-S127
    PubMedGoogle Scholar

William H CatherinoM.D. Ph.D. 

Department of Obstetrics and Gynecology, Building A, Room 3078, Uniformed Services University of the Health Sciences

4301 Jones Bridge Road, Bethesda, MD 20814-4799

Email: wcatherino@usuhs.mil

      >