Uterine leiomyomas (fibroids or myomas) are benign tumors of uterus and clinically apparent in a large part of reproductive aged women. Clinically, they present with a variety of symptoms: excessive menstrual bleeding, dysmenorrhoea and intermenstrual bleeding, chronic pelvic pain, and pressure symptoms such as a sensation of bloatedness, increased urinary frequency, and bowel disturbance. In addition, they may compromise reproductive functions, possibly contributing to subfertility, early pregnancy loss, and later pregnancy complications. Despite the prevalence of this condition, myoma research is underfunded compared to other nonmalignant diseases. To date, several pathogenetic factors such as genetics, microRNA, steroids, growth factors, cytokines, chemokines, and extracellular matrix components have been implicated in the development and growth of leiomyoma. This paper summarizes the available literature regarding the ultimate relative knowledge on pathogenesis of uterine fibroids and their interactions with endometrium and subendometrial myometrium. 1. Introduction Leiomyomas are benign uterine tumors of unknown aetiology. These kinds of lesions seem to arise from myometrial transformation as a result of specific physiological and pathological conditions. The majority of these monoclonal estrogen-dependent uterine neoformations [1] afflict mostly women during reproductive age, and 80% of them suffer from this during their whole lifetime [2]. In the past, most women with fibroids remained undiagnosed, because they were asymptomatic. Analyses based on clinical diagnosis or diagnostic tests underestimate the true incidence; in fact, they take only into account symptomatic patients. Cramer and Patel [3] estimated the prevalence of uterine fibroids based on clinical assessment at 33%, ultrasound scan at 50%, and histological examination of hysterectomy specimens at 77%. The reported frequency of the disease varies widely due to differences in study design. In fact, to determine the exact prevalence of fibroids, a correct clinical research should apply ultrasound scanning in a randomly sampled population [4]. Nowadays, conflicting data about the pathogenesis of leiomyomas coexist in the literature. The development of uterine myomas can be linked to predisposing risk factors, initiators and genetic mechanisms, promoters, and effectors. The aim of this work is to discuss the latest knowledge on the pathogenesis of uterine fibroids and their interactions with the endometrium and subendometrial myometrium. 2. Pathogenesis of Uterine Leiomyoma 2.1. Risk
References
[1]
W. Bowden, J. Skorupski, E. Kovanci, and A. Rajkovic, “Detection of novel copy number variants in uterine leiomyomas using high-resolution SNP arrays,” Molecular Human Reproduction, vol. 15, no. 9, pp. 563–568, 2009.
[2]
S. K. Laughlin, J. C. Schroeder, and D. D. Baird, “New directions in the epidemiology of uterine fibroids,” Seminars in Reproductive Medicine, vol. 28, no. 3, pp. 204–217, 2010.
[3]
S. F. Cramer and A. Patel, “The frequency of uterine leiomyomas,” American Journal of Clinical Pathology, vol. 94, no. 4, pp. 435–438, 1990.
[4]
M. Payson, P. Leppert, and J. Segars, “Epidemiology of myomas,” Obstetrics and Gynecology Clinics of North America, vol. 33, no. 1, pp. 1–11, 2006.
[5]
S. D. Peddada, S. K. Laughlin, K. Miner et al., “Growth of uterine leiomyomata among premenopausal black and white women,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 50, pp. 19887–19892, 2008.
[6]
M. K. Lobel, P. Somasundaram, and C. C. Morton, “The genetic heterogeneity of uterine leiomyomata,” Obstetrics and Gynecology Clinics of North America, vol. 33, no. 1, pp. 13–39, 2006.
[7]
J. Wei, L. Chiriboga, A. A. Arslan, J. Melamed, H. Yee, and K. Mittal, “Ethnic differences in expression of the dysregulated proteins in uterine leiomyomata,” Human Reproduction, vol. 21, no. 1, pp. 57–67, 2006.
[8]
J. Wei, L. Chiriboga, and K. Mittal, “Expression profile of the tumorigenic factors associated with tumor size and sex steroid hormone status in uterine leiomyomata,” Fertility and Sterility, vol. 84, no. 2, pp. 474–484, 2005.
[9]
M. Wolańska and E. Bańkowski, “Transforming growth factor β and platelet-derived growth factor in human myometrium and in uterine leiomyomas at various stages of tumour growth,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 130, no. 2, pp. 238–244, 2007.
[10]
T. Wang, X. Zhang, L. Obijuru et al., “A micro-RNA signature associated with race, tumor size, and target gene activity in human uterine leiomyomas,” Genes Chromosomes and Cancer, vol. 46, no. 4, pp. 336–347, 2007.
[11]
L. M. Marshall, D. Spiegelman, R. L. Barbieri et al., “Variation in the incidence of uterine leiomyoma among premenopausal women by age and race,” Obstetrics and Gynecology, vol. 90, no. 6, pp. 967–973, 1997.
[12]
K. H. Kjerulff, P. Langenberg, J. D. Seidman, P. D. Stolley, and G. M. Guzinski, “Uterine leiomyomas: racial differences in severity, symptoms and age at diagnosis,” Journal of Reproductive Medicine for the Obstetrician and Gynecologist, vol. 41, no. 7, pp. 483–490, 1996.
[13]
G. P. Flake, J. Andersen, and D. Dixon, “Etiology and pathogenesis of uterine leiomyomas: a review,” Environmental Health Perspectives, vol. 111, no. 8, pp. 1037–1054, 2003.
[14]
W. H. Parker, “Etiology, symptomatology, and diagnosis of uterine myomas,” Fertility and Sterility, vol. 87, no. 4, pp. 725–736, 2007.
[15]
D. D. Baird, M. C. Hill, J. M. Schectman, and B. W. Hollis, “Vitamin D and the risk of uterine fibroids,” Epidemiology, vol. 24, pp. 447–453, 2013.
[16]
M. Sabry, S. K. Halder, A. S. Allah, E. Roshdy, V. Rajaratnam, and A. Al-Hendy, “Serum vitamin D3 level inversely correlates with uterine fibroid volume in different ethnic groups: a cross-sectional observational study,” International Journal of Women's Health, vol. 5, pp. 93–100, 2013.
[17]
P. C. Leppert, W. H. Catherino, and J. H. Segars, “A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays,” American Journal of Obstetrics and Gynecology, vol. 195, no. 2, pp. 415–420, 2006.
[18]
S. M. Schwartz, L. M. Marshall, and D. D. Baird, “Epidemiologic contributions to understanding the etiology of uterine leiomyomata,” Environmental Health Perspectives, vol. 108, supplement 5, pp. 821–827, 2000.
[19]
E. M. Vikhlyaeva, “Familial predisposition to uterine leiomyomas,” International Journal of Gynecology and Obstetrics, vol. 51, no. 2, pp. 127–131, 1995.
[20]
T. M. Saldana, M. Moshesh, and D. D. Baird, “Self-reported family history of leiomyoma: not a reliable marker of high risk,” Annals of Epidemiology, vol. 23, no. 5, pp. 286–290, 2013.
[21]
R. K. Ross, M. C. Pike, and M. P. Vessey, “Risk factors for uterine fibroids: reduced risk associated with oral contraceptives,” The British Medical Journal, vol. 293, no. 6543, pp. 359–362, 1986.
[22]
S. A. Shikora, J. M. Niloff, B. R. Bistrian, R. A. Forse, and G. L. Blackburn, “Relationship between obesity and uterine leiomyomata,” Nutrition, vol. 7, no. 4, pp. 251–255, 1991.
[23]
S. Nair and A. Al-Hendy, “Adipocytes enhance the proliferation of human leiomyoma cells via TNF-α proinflammatory cytokine,” Reproductive Sciences, vol. 18, no. 12, pp. 1186–1192, 2011.
[24]
F. Chiaffarino, F. Parazzini, C. La Vecchia, L. Chatenoud, E. Di Cintio, and S. Marsico, “Diet and uterine myomas,” Obstetrics and Gynecology, vol. 94, no. 3, pp. 395–398, 1999.
[25]
G. Wyshak, R. E. Frisch, and N. L. Albright, “Lower prevalence of benign diseases of the breast and benign tumours of the reproductive system among former college athletes compared to non-athletes,” British Journal of Cancer, vol. 54, no. 5, pp. 841–845, 1986.
[26]
R. L. Barbieri, P. M. McShane, and K. J. Ryan, “Constituents of cigarette smoke inhibit human granulosa cell aromatase,” Fertility and Sterility, vol. 46, no. 2, pp. 232–236, 1986.
[27]
J. J. Michnovicz, R. J. Hershcopf, and H. Naganuma, “Increased 2-hydroxylation of estradiol as a possible mechanism for the anti-estrogenic effect of cigarette smoking,” The New England Journal of Medicine, vol. 315, no. 21, pp. 1305–1309, 1986.
[28]
M. Daniel, A. D. Martin, and D. T. Drinkwater, “Cigarette smoking, steroid hormones, and bone mineral density in young women,” Calcified Tissue International, vol. 50, no. 4, pp. 300–305, 1992.
[29]
A. J. Tiltman, “The effect of progestins on the mitotic activity of uterine fibromyomas,” International Journal of Gynecological Pathology, vol. 4, no. 2, pp. 89–96, 1985.
[30]
F. Parazzini, E. Negri, C. La Vecchia, L. Chatenoud, E. Ricci, and P. Guarnerio, “Reproductive factors and risk of uterine fibroids,” Epidemiology, vol. 7, no. 4, pp. 440–442, 1996.
[31]
P. Lumbiganon, S. Rugpao, S. Phandhu-fung, M. Laopaiboon, N. Vudhikamraksa, and Y. Werawatakul, “Protective effect of depot-medroxyprogesterone acetate on surgically treated uterine leiomyomas: a multicentre case-control study,” British Journal of Obstetrics and Gynaecology, vol. 103, no. 9, pp. 909–914, 1996.
[32]
D. D. Baird and D. B. Dunson, “Why is parity protective for uterine fibroids?” Epidemiology, vol. 14, no. 2, pp. 247–250, 2003.
[33]
S. Palomba, T. Sena, M. Morelli, R. Noia, F. Zullo, and P. Mastrantonio, “Effect of different doses of progestin on uterine leiomyomas in postmenopausal women,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 102, no. 2, pp. 199–201, 2002.
[34]
D. W. Cramer, “Epidemiology of myomas,” Seminars in Reproductive Endocrinology, vol. 10, no. 4, pp. 320–324, 1992.
[35]
M. S. Rein, “Advances in uterine leiomyoma research: the progesterone hypothesis,” Environmental Health Perspectives, vol. 108, no. 5, pp. 791–793, 2000.
[36]
P. A. Richards and A. J. Tiltman, “Anatomical variation of the oestrogen receptor in the non-neoplastic myometrium of fibromyomatous uteri,” Virchows Archiv, vol. 428, no. 6, pp. 347–351, 1996.
[37]
E. A. Stewart and R. A. Nowak, “Leiomyoma-related bleeding: a classic hypothesis updated for the molecular era,” Human Reproduction Update, vol. 2, no. 4, pp. 295–306, 1996.
[38]
D. Dixon, G. P. Flake, A. B. Moore et al., “Cell proliferation and apoptosis in human uterine leiomyomas and myometria,” Virchows Archiv, vol. 441, no. 1, pp. 53–62, 2002.
[39]
V. Lindner and M. A. Reidy, “Proliferation of smooth muscle cells after vascular injury is inhibited by an antibody against basic fibroblast growth factor,” Proceedings of the National Academy of Sciences of the United States of America, vol. 88, no. 9, pp. 3739–3743, 1991.
[40]
R. S. Mangrulkar, M. Ono, M. Ishikawa, S. Takashima, M. Klagsbrun, and R. A. Nowak, “Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium,” Biology of Reproduction, vol. 53, no. 3, pp. 636–646, 1995.
[41]
K. L. Gross and C. C. Morton, “Genetics and the development of fibroids,” Clinical Obstetrics and Gynecology, vol. 44, pp. 335–349, 2001.
[42]
J. C. Hodge, K. T. Cuenco, K. L. Huyck et al., “Uterine leiomyomata and decreased height: a common HMGA2 predisposition allele,” Human Genetics, vol. 125, no. 3, pp. 257–263, 2009.
[43]
G. J. Gattas, B. J. Quade, R. A. Nowak, and C. C. Morton, “HMGIC expression in human adult and fetal tissues and in uterine leiomyomata,” Genes, Chromosomes and Cancer, vol. 25, pp. 316–322, 1999.
[44]
D. N. Markowski, B. M. Helmke, G. Belge et al., “HMGA2 and p14Arf: major roles in cellular senescence of fibroids and therapeutic implications,” Anticancer Research, vol. 31, no. 3, pp. 753–761, 2011.
[45]
S. Sudarshan, P. A. Pinto, L. Neckers, and W. M. Linehan, “Mechanisms of disease: hereditary leiomyomatosis and renal cell cancer—a distinct form of hereditary kidney cancer,” Nature Clinical Practice Urology, vol. 4, no. 2, pp. 104–110, 2007.
[46]
V. Uliana, E. Marcocci, M. Mucciolo et al., “Alport syndrome and leiomyomatosis: the first deletion extending beyond COL4A6 intron 2,” Pediatric Nephrology, vol. 26, no. 5, pp. 717–724, 2011.
[47]
P. Cha, A. Takahashi, N. Hosono et al., “A genome-wide association study identifies three loci associated with susceptibility to uterine fibroids,” Nature Genetics, vol. 43, no. 5, pp. 447–451, 2011.
[48]
R. Rogers, J. Norian, M. Malik et al., “Mechanical homeostasis is altered in uterine leiomyoma,” American Journal of Obstetrics and Gynecology, vol. 198, no. 4, pp. 474.e1–474.e11, 2008.
[49]
N. M？kinen, M. Mehine, J. Tolvanen et al., “MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas,” Science, vol. 334, no. 6053, pp. 252–255, 2011.
[50]
E. M. Je, M. R. Kim, K. O. Min, N. J. Yoo, and S. H. Lee, “Mutational analysis of MED12 exon 2 in uterine leiomyoma and other common tumors,” International Journal of Cancer, vol. 131, no. 6, pp. E1044–E1047, 2012.
[51]
G. Pérot, S. Croce, A. Ribeiro et al., “MED12 alterations in both human benign and malignant uterine soft tissue tumors,” PLoS One, vol. 7, no. 6, Article ID e40015, 2012.
[52]
S. Kim, X. Xu, A. Hecht, and T. G. Boyer, “Mediator is a transducer of Wnt/β-catenin signaling,” The Journal of Biological Chemistry, vol. 281, no. 20, pp. 14066–14075, 2006.
[53]
P. P. Rocha, M. Scholze, W. Blei？, and H. Schrewe, “Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling,” Development, vol. 137, no. 16, pp. 2723–2731, 2010.
[54]
J. Zavadil, H. Ye, Z. Liu et al., “Profiling and functional analyses of microRNAs and their target gene products in human uterine leiomyomas,” PLoS ONE, vol. 5, no. 8, Article ID e12362, 2010.
[55]
S. Lin, W. Xia, J. C. Wang et al., “β-catenin, a novel prognostic marker for breast cancer: its roles in cyclin D1 expression and cancer progression,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 8, pp. 4262–4266, 2000.
[56]
Q. Qiao, M. Ramadani, S. Gansauge, et al., “Reduced membranous and ectopic cytoplasmic expression of beta-catenin correlate with cyclin D1 overexpression and poor prognosis in pancreatic cancer,” International Journal of Cancer, vol. 95, pp. 194–197, 2001.
[57]
E. A. Kogan, V. E. Ignatova, T. N. Rukhadze, E. A. Kudrina, and A. I. Ischenko, “A role of growth factors in development of various histological types of uterine leiomyoma,” Arkhiv Patologii, vol. 67, no. 3, pp. 34–38, 2005.
[58]
J. M. Norian, M. Malik, C. Y. Parker et al., “Transforming Growth Factor β3 regulates the versican variants in the extracellular matrix-rich uterine leiomyomas,” Reproductive Sciences, vol. 16, no. 12, pp. 1153–1164, 2009.
[59]
M. Malik, J. Webb, and W. H. Catherino, “Retinoic acid treatment of human leiomyoma cells transformed the cell phenotype to one strongly resembling myometrial cells,” Clinical Endocrinology, vol. 69, no. 3, pp. 462–470, 2008.
[60]
J. M. Norian, C. M. Owen, J. Taboas et al., “Characterization of tissue biomechanics and mechanical signaling in uterine leiomyoma,” Matrix Biology, vol. 31, no. 1, pp. 57–65, 2012.
[61]
H. Asada, Y. Yamagata, T. Taketani et al., “Potential link between estrogen receptor-α gene hypomethylation and uterine fibroid formation,” Molecular Human Reproduction, vol. 14, no. 9, pp. 539–545, 2008.
[62]
Y. Yamagata, R. Maekawa, H. Asada et al., “Aberrant DNA methylation status in human uterine leiomyoma,” Molecular Human Reproduction, vol. 15, no. 4, pp. 259–267, 2009.
[63]
D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004.
[64]
E. A. Miska, “How microRNAs control cell division, differentiation and death,” Current Opinion in Genetics and Development, vol. 15, no. 5, pp. 563–568, 2005.
[65]
E. E. Marsh, Z. Lin, P. Yin, M. Milad, D. Chakravarti, and S. E. Bulun, “Differential expression of microRNA species in human uterine leiomyoma versus normal myometrium,” Fertility and Sterility, vol. 89, no. 6, pp. 1771–1776, 2008.
[66]
C. Benassayag, M. J. Leroy, V. Rigourd et al., “Estrogen receptors (ERα/ERβ) in normal and pathological growth of the human myometrium: pregnancy and leiomyoma,” American Journal of Physiology, vol. 276, no. 6, pp. E1112–E1118, 1999.
[67]
K. A. Kovács, A. Oszter, P. M. G？cze, J. L. K？rnyei, and I. Szabó, “Comparative analysis of cyclin D1 and oestrogen receptor (α and β) levels in human leiomyoma and adjacent myometrium,” Molecular Human Reproduction, vol. 7, no. 11, pp. 1085–1091, 2001.
[68]
A. Olmos Grings, V. Lora, G. Dias Ferreira, I. Simoni Brum, H. Von Eye Corleta, and E. Capp, “Protein expression of estrogen receptors α and β and aromatase in myometrium and uterine leiomyoma,” Gynecologic and Obstetric Investigation, vol. 73, no. 2, pp. 113–117, 2012.
[69]
H. Ishikawa, K. Ishi, V. Ann Serna, R. Kakazu, S. E. Bulun, and T. Kurita, “Progesterone is essential for maintenance and growth of uterine leiomyoma,” Endocrinology, vol. 151, no. 6, pp. 2433–2442, 2010.
[70]
H. Ishikawa, K. Ishi, V. Ann Serna, R. Kakazu, S. E. Bulun, and T. Kurita, “Progesterone is essential for maintenance and growth of uterine leiomyoma,” Endocrinology, vol. 151, no. 6, pp. 2433–2442, 2010.
[71]
A. Barbarisi, O. Petillo, A. Di Lieto et al., “17-beta estradiol elicits an autocrine leiomyoma cell proliferation: evidence for a stimulation of protein kinase-dependent pathway,” Journal of Cellular Physiology, vol. 186, no. 3, pp. 414–424, 2001.
[72]
P. Ciarmela, E. Bloise, P. C. Gray et al., “Activin-A and myostatin response and steroid regulation in human myometrium: disruption of their signalling in uterine fibroid,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 3, pp. 755–765, 2011.
[73]
Y. Shimomura, H. Matsuo, T. Samoto, and T. Maruo, “Up-regulation by progesterone of proliferating cell nuclear antigen and epidermal growth factor expression in human uterine leiomyoma,” Journal of Clinical Endocrinology and Metabolism, vol. 83, no. 6, pp. 2192–2198, 1998.
[74]
H. Matsuo, T. Maruo, and T. Samoto, “Increased expression of Bcl-2 protein in human uterine leiomyoma and its up-regulation by progesterone,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 1, pp. 293–299, 1997.
[75]
E. N. Nierth-Simpson, M. M. Martin, T. Chiang et al., “Human uterine smooth muscle and leiomyoma cells differ in their rapid 17/J-estradiol signaling: implications for proliferation,” Endocrinology, vol. 150, no. 5, pp. 2436–2445, 2009.
[76]
S. Park, S. Ramachandran, S. Kwon et al., “Upregulation of ATP-sensitive potassium channels for estrogen-mediated cell proliferation in human uterine leiomyoma cells,” Gynecological Endocrinology, vol. 24, no. 5, pp. 250–256, 2008.
[77]
P. Kastner, A. Krust, B. Turcotte et al., “Two distinct estrogen-regulated promoters generate transcripts encoding the two functionally different human progesterone receptor forms A and B,” The EMBO Journal, vol. 9, no. 5, pp. 1603–1614, 1990.
[78]
T. Maruo, N. Ohara, S. Yoshida et al., “Translational research with progesterone receptor modulator motivated by the use of levonorgestrel-releasing intrauterine system,” Contraception, vol. 82, no. 5, pp. 435–441, 2010.
[79]
J. J. Kim and E. C. Sefton, “The role of progesterone signaling in the pathogenesis of uterine leiomyoma,” Molecular and Cellular Endocrinology, vol. 358, no. 2, pp. 223–231, 2011.
[80]
O. Sadan, B. Van Iddekinge, and C. J. Van Gelderen, “Oestrogen and progesterone receptor concentrations in leiomyoma and normal myometrium,” Annals of Clinical Biochemistry, vol. 24, no. 3, pp. 263–267, 1987.
[81]
G. Marelli, A. M. Codegoni, and A. Bizzi, “Estrogen and progesterone receptors in leiomyomas and normal uterine tissues during reproductive life,” Acta Europaea Fertilitatis, vol. 20, no. 1, pp. 19–22, 1989.
[82]
D. D. Brandon, C. L. Bethea, E. Y. Strawn et al., “Progesterone receptor messenger ribonucleic acid and protein are overexpressed in human uterine leiomyomas,” American Journal of Obstetrics and Gynecology, vol. 169, no. 1, pp. 78–85, 1993.
[83]
B. Viville, D. S. Charnock-Jones, A. M. Sharkey, B. Wetzka, and S. K. Smith, “Distribution of the A and B forms of the progesterone receptor messenger ribonucleic acid and protein in uterine leiomyomata and adjacent myometrium,” Human Reproduction, vol. 12, no. 4, pp. 815–822, 1997.
[84]
Z. Ying and Z. Weiyuan, “Dual actions of progesterone on uterine leiomyoma correlate with the ratio of progesterone receptor A:B,” Gynecological Endocrinology, vol. 25, no. 8, pp. 520–523, 2009.
[85]
J. Fujimota, R. Hirose, S. Ichigo, H. Sakaguchi, Y. Li, and T. Tamaya, “Expression of progesterone receptor form A and B mRNAs in uterine leiomyoma,” Tumor Biology, vol. 19, no. 2, pp. 126–131, 1998.
[86]
A. Arici and I. Sozen, “Transforming growth factor-β3 is expressed at high levels in leiomyoma where it stimulates fibronectin expression and cell proliferation,” Fertility and Sterility, vol. 73, no. 5, pp. 1006–1011, 2000.
[87]
O. Kurachi, H. Matsuo, T. Samoto, and T. Maruo, “Tumor necrosis factor-α expression in human uterine leiomyoma and its down-regulation by progesterone,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 5, pp. 2275–2280, 2001.
[88]
P. Yin, Z. Lin, Y. Cheng et al., “Progesterone receptor regulates Bcl-2 gene expression through direct binding to its promoter region in uterine leiomyoma cells,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 11, pp. 4459–4466, 2007.
[89]
X. Luo, P. Yin, S. Reierstad et al., “Progesterone and mifepristone regulate L-type amino acid transporter 2 and 4F2 heavy chain expression in uterine leiomyoma cells,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 11, pp. 4533–4539, 2009.
[90]
P. Yin, Z. Lin, S. Reierstad et al., “Transcription factor KLF11 integrates progesterone receptor signaling and proliferation in uterine leiomyoma cells,” Cancer Research, vol. 70, no. 4, pp. 1722–1730, 2010.
[91]
P. Ciarmela, M. S. Islam, F. M. Reis et al., “Growth factors and myometrium: biological effects in uterine fibroid and possible clinical implications,” Human Reproduction Update, vol. 17, no. 6, Article ID dmr031, pp. 772–790, 2011.
[92]
C. A. Anania, E. A. Stewart, B. J. Quade, J. A. Hill, and R. A. Nowak, “Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding,” Molecular Human Reproduction, vol. 3, no. 8, pp. 685–691, 1997.
[93]
T. Hong, Y. Shimada, S. Uchida et al., “Expression of angiogenic factors and apoptotic factors in leiomyosarcoma and leiomyoma,” International Journal of Molecular Medicine, vol. 8, no. 2, pp. 141–148, 2001.
[94]
S. Arita, F. Kikkawa, H. Kajiyama et al., “Prognostic importance of vascular endothelial growth factor and its receptors in the uterine sarcoma,” International Journal of Gynecological Cancer, vol. 15, no. 2, pp. 329–336, 2005.
[95]
M. J. Rossi, N. Chegini, and B. J. Masterson, “Presence of epidermal growth factor, platelet-derived growth factor, and their receptors in human myometrial tissue and smooth muscle cells: their action in smooth muscle cells in vitro,” Endocrinology, vol. 130, no. 3, pp. 1716–1727, 1992.
[96]
Y. Ren, H. Yin, R. Tian et al., “Different effects of epidermal growth factor on smooth muscle cells derived from human myometrium and from leiomyoma,” Fertility and Sterility, vol. 96, no. 4, pp. 1015.e1–1020.e1, 2011.
[97]
Y. M. Fayed, J. C. M. Tsibris, P. W. Langenberg, and A. L. Robertson Jr., “Human uterine leiomyoma cells: binding and growth responses to epidermal growth factor, platelet-derived growth factor, and insulin,” Laboratory Investigation, vol. 60, no. 1, pp. 30–37, 1989.
[98]
A. Arici and I. Sozen, “Expression, menstrual cycle-dependent activation, and bimodal mitogenic effect of transforming growth factor-β1 in human myometrium and leiomyoma,” American Journal of Obstetrics and Gynecology, vol. 188, no. 1, pp. 76–83, 2003.
[99]
M. Liang, H. Wang, Y. Zhang, S. Lu, and Z. Wang, “Expression and functional analysis of platelet-derived growth factor in uterine leiomyomata,” Cancer Biology and Therapy, vol. 5, no. 1, pp. 28–33, 2006.
[100]
G. Suo, Y. Jiang, B. Cowan, and J. Y. J. Wang, “Platelet-derived growth factor C is upregulated in human uterine fibroids and regulates uterine smooth muscle cell growth,” Biology of Reproduction, vol. 81, no. 4, pp. 749–758, 2009.
[101]
D. S. Joseph, M. Malik, S. Nurudeen, and W. H. Catherino, “Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor β-3,” Fertility and Sterility, vol. 93, no. 5, pp. 1500–1508, 2010.
[102]
L. Ding, J. Xu, X. Luo, and N. Chegini, “Gonadotropin releasing hormone and transforming growth factor β 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,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 11, pp. 5549–5557, 2004.
[103]
L. Yu, K. Saile, C. D. Swartz et al., “Differential expression of receptor tyrosine kinases (RTKs) and IGF-I pathway activation in human uterine leiomyomas,” Molecular Medicine, vol. 14, no. 5-6, pp. 264–275, 2008.
[104]
Z. Gao, H. Matsuo, Y. Wang, S. Nakago, and T. Maruo, “Up-regulation by IGF-I of proliferating cell nuclear antigen and Bcl-2 protein expression in human uterine leiomyoma cells,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 11, pp. 5593–5599, 2001.
[105]
P. Ciarmela, E. Wiater, and W. Vale, “Activin-A in myometrium: characterization of the actions on myometrial cells,” Endocrinology, vol. 149, no. 5, pp. 2506–2516, 2008.
[106]
P. Ciarmela, E. Wiater, S. M. Smith, and W. Vale, “Presence, actions, and regulation of myostatin in rat uterus and myometrial cells,” Endocrinology, vol. 150, no. 2, pp. 906–914, 2009.
[107]
E. C. Weir, D. L. Goad, A. G. Daifotis, W. J. Burtis, B. E. Dreyer, and R. A. Nowak, “Relative overexpression of the parathyroid hormone-related protein gene in human leiomyomas,” Journal of Clinical Endocrinology and Metabolism, vol. 78, no. 3, pp. 784–789, 1994.
[108]
M. Yoshida, A. Ohtsuru, T. Samejima et al., “Involvement of parathyroid hormone-related peptide in cell proliferation activity of human uterine leiomyomas,” Endocrine Journal, vol. 46, no. 1, pp. 81–90, 1999.
[109]
B. Gellersen, A. Bonhoff, N. Hunt, and H. G. Bohnet, “Decidual-type prolactin expression by the human myometrium,” Endocrinology, vol. 129, no. 1, pp. 158–168, 1991.
[110]
D. J. Austin, R. A. Nowak, and E. A. Stewart, “Onapristone suppresses prolactin production in explant cultures of leiomyoma,” Gynecologic and Obstetric Investigation, vol. 47, no. 4, pp. 268–271, 1999.
[111]
F. Pekonen, T. Nyman, and E.-M. Rutanen, “Differential expression of mRNAs for endothelin-related proteins in human endometrium, myometrium and leiomyoma,” Molecular and Cellular Endocrinology, vol. 103, no. 1-2, pp. 165–170, 1994.
[112]
P. Robin, S. Chouayekh, C. Bole-Feysot, D. Leiber, and Z. Tanfin, “Contribution of phospholipase D in endothelin-1-mediated extracellular signal-regulated kinase activation and proliferation in rat uterine leiomyoma cells,” Biology of Reproduction, vol. 72, no. 1, pp. 69–77, 2005.
[113]
A. Horiuchi, T. Nikaido, T. Yoshizawa et al., “HCG promotes proliferation of uterine leiomyomal cells more strongly than that of myometrial smooth muscle cells in vitro,” Molecular Human Reproduction, vol. 6, no. 6, pp. 523–528, 2000.
[114]
S.-J. Tsai, S.-J. Lin, Y.-M. Cheng, H.-M. Chen, and L.-Y. C. Wing, “Erratum: Expression and functional analysis of pituitary tumor transforming growth factor-1 in uterine leiomyomas (The Journal of Clinical Endocrinology and Metabolism (2005) 90 (3715-3723)),” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 9, p. 5233, 2005.
[115]
M. Suzuki, S. Takamizawa, K. Nomaguchi et al., “Erythropoietin synthesis by tumour tissues in a patient with uterine myoma and erythrocytosis,” British Journal of Haematology, vol. 113, no. 1, pp. 49–51, 2001.
[116]
P. Hatthachote and J. I. Gillespie, “Complex interactions between sex steroids and cytokines in the human pregnant myometrium: evidence for an autocrine signaling system at term,” Endocrinology, vol. 140, no. 6, pp. 2533–2540, 1999.
[117]
K. V. Litovkin, V. P. Domenyuk, V. V. Bubnov, and V. N. Zaporozhan, “Interleukin-6-174G/C polymorphism in breast cancer and uterine leiomyoma patients: a population-based case control study,” Experimental Oncology, vol. 29, no. 4, pp. 295–298, 2007.
[118]
T. L. Bonfield, J. R. Panuska, M. W. Konstan et al., “Inflammatory cytokines in cystic fibrosis lungs,” American Journal of Respiratory and Critical Care Medicine, vol. 152, no. 6 I, pp. 2111–2118, 1995.
[119]
B. Mehrad, M. P. Keane, and R. M. Strieter, “Chemokines as mediators of angiogenesis,” Thrombosis and Haemostasis, vol. 97, no. 5, pp. 755–762, 2007.
[120]
H. E. Broxmeyer, “Chemokines in hematopoiesis,” Current Opinion in Hematology, vol. 15, no. 1, pp. 49–58, 2008.
[121]
I. Sozen, D. L. Olive, and A. Arici, “Expression and hormonal regulation of monocyte chemotactic protein-1 in myometrium and leiomyomata,” Fertility and Sterility, vol. 69, no. 6, pp. 1095–1102, 1998.
[122]
L. M. Senturk, I. Sozen, L. Gutierrez, and A. Arici, “Interleukin 8 production and interleukin 8 receptor expression in human myometrium and leiomyoma,” American Journal of Obstetrics and Gynecology, vol. 184, no. 4, pp. 559–566, 2001.
[123]
S. F. Cramer, P. M. Newcomb, and T. A. Bonfiglio, “Myometrial dysplasia (atypical myometrial hyperplasia),” Human Pathology, vol. 38, no. 4, pp. 652–655, 2007.
[124]
S. F. Cramer and A. L. Robertson Jr, “The origin of uterine leiomyomas,” in The Extracellular Matrix of the Uterus, Cervix, and Fetal Membranes, P. C. Leppert and J. F. Woessner, Eds., pp. 213–223, Perinatology Press, Ithaca, NY, USA, 1991.
[125]
M. Malik, J. Norian, D. McCarthy-Keith, J. Britten, and W. H. Catherino, “Why leiomyomas are called fibroids: the central role of extracellular matrix in symptomatic women,” Seminars in Reproductive Medicine, vol. 28, no. 3, pp. 169–179, 2010.
[126]
M. Wolańska, K. Sobolewski, M. Drozdzewicz, and E. Bańkowski, “Extracellular matrix components in uterine leiomyoma and their alteration during the tumour growth,” Molecular and Cellular Biochemistry, vol. 189, no. 1-2, pp. 145–152, 1998.
[127]
A. G. A. Berto, S. M. Oba, Y. M. Michelacci, and L. O. Sampaio, “Galactosaminoglycans from normal myometrium and leiomyoma,” Brazilian Journal of Medical and Biological Research, vol. 34, no. 5, pp. 633–637, 2001.
[128]
B. Bodner-Adler, K. Bodner, O. Kimberger, K. Czerwenka, S. Leodolter, and K. Mayerhofer, “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,” Journal of the Society for Gynecologic Investigation, vol. 11, no. 3, pp. 182–186, 2004.
[129]
M. Bogusiewicz, M. Stryjecka-Zimmer, K. Postawski, A. J. Jakimiuk, and T. Rechberger, “Activity of matrix metalloproteinase-2 and -9 and contents of their tissue inhibitors in uterine leiomyoma and corresponding myometrium,” Gynecological Endocrinology, vol. 23, no. 9, pp. 541–546, 2007.
[130]
H. Hricak, C. Alpers, L. E. Crooks, and P. E. Sheldon, “Magnetic resonance imaging of the female pelvis: initial experience,” American Journal of Roentgenology, vol. 141, no. 6, pp. 1119–1128, 1983.
[131]
A. Tocci, E. Greco, and F. M. Ubaldi, “Adenomyosis and endometrial-subendometrial myometrium unit disruption disease are two different entities,” Reproductive BioMedicine Online, vol. 17, no. 2, pp. 285–291, 2008.
[132]
J. J. Brosens, F. G. Barker, and N. M. DeSouza, “Myometrial zonal differentiation and uterine junctional zone hyperplasia in the non-pregnant uterus,” Human Reproduction Update, vol. 4, no. 5, pp. 496–502, 1998.
[133]
Practice Committee of the American Society for Reproductive Medicine, “Myomas and reproductive function,” Fertility and Sterility, vol. 82, 1, pp. S111–S116, 2004.
[134]
V. C. Buttram Jr. and R. C. Reiter, “Uterine leiomyomata: etiology, symptomatology, and management,” Fertility and Sterility, vol. 36, no. 4, pp. 433–445, 1981.
[135]
J. M. Berman, “Intrauterine adhesions,” Seminars in Reproductive Medicine, vol. 26, no. 4, pp. 349–355, 2008.
[136]
C. Davies, M. Gibson, E. M. Holt, and E. P. H. Torrie, “Amenorrhoea secondary to endometrial ablation and Asherman's syndrome following uterine artery embolization,” Clinical Radiology, vol. 57, no. 4, pp. 317–318, 2002.
[137]
A. A. Hare and K. S. Olah, “Pregnancy following endometrial ablation: a review article,” Journal of Obstetrics and Gynaecology, vol. 25, no. 2, pp. 108–114, 2005.
[138]
A. Magos, “Hysteroscopic treatment of Asherman's syndrome,” Reproductive BioMedicine Online, vol. 4, 3, pp. 46–51, 2002.
[139]
S. F. Cramer, L. Mann, E. Calianese, J. Daley, and K. Williamson, “Association of seedling myomas with myometrial hyperplasia,” Human Pathology, vol. 40, no. 2, pp. 218–225, 2009.
[140]
L. M. Scoutt, S. D. Flynn, D. J. Luthringer, T. R. McCauley, and S. M. McCarthy, “Junctional zone of the uterus: correlation of MR imaging and histologic examination of hysterectomy specimens,” Radiology, vol. 179, no. 2, pp. 403–407, 1991.
[141]
C. Bulletti, D. De Ziegler, V. Polli, and C. Flamigni, “The role of leiomyomas in infertility,” Journal of the American Association of Gynecologic Laparoscopists, vol. 6, no. 4, pp. 441–445, 1999.
[142]
P. A. Richards, P. D. G. Richards, and A. J. Tiltman, “The ultrastructure of fibromyomatous myometrium and its relationship to infertility,” Human Reproduction Update, vol. 4, no. 5, pp. 520–525, 1998.
[143]
O. Yoshino, T. Hayashi, Y. Osuga et al., “Decreased pregnancy rate is linked to abnormal uterine peristalsis caused by intramural fibroids,” Human Reproduction, vol. 25, no. 10, pp. 2475–2479, 2010.
[144]
T. Inoue, H. Kanzaki, M. Iwai et al., “Tumour necrosis factor α inhibits in-vitro decidualization of human endometrial stromal cells,” Human Reproduction, vol. 9, no. 12, pp. 2411–2417, 1994.
[145]
M. Kariya, H. Kanzaki, K. Takakura et al., “Interleukin-1 inhibits in Vitro decidualization of human endometrial stromal cells,” Journal of Clinical Endocrinology and Metabolism, vol. 73, no. 6, pp. 1170–1174, 1991.
[146]
N. Inagaki, L. Ung, T. Otani, D. Wilkinson, and A. Lopata, “Uterine cavity matrix metalloproteinases and cytokines in patients with leiomyoma, adenomyosis or endometrial polyp,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 111, no. 2, pp. 197–203, 2003.
[147]
S. Matsuzaki, M. Canis, C. Darcha, J. Pouly, and G. Mage, “HOXA-10 expression in the mid-secretory endometrium of infertile patients with either endometriosis, uterine fibromas or unexplained infertility,” Human Reproduction, vol. 24, no. 12, pp. 3180–3187, 2009.
[148]
B. C. Paria, J. Reese, S. K. Das, and S. K. Dey, “Deciphering the cross-talk of implantation: advances and challenges,” Science, vol. 296, no. 5576, pp. 2185–2188, 2002.
[149]
B. W. Rackow and H. S. Taylor, “Submucosal uterine leiomyomas have a global effect on molecular determinants of endometrial receptivity,” Fertility and Sterility, vol. 93, no. 6, pp. 2027–2034, 2010.
[150]
D. C. Sinclair, A. Mastroyannis, and H. S. Taylor, “Leiomyoma simultaneously impair endometrial BMP-2-mediated decidualization and anticoagulant expression through secretion of TGF-β3,” Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 2, pp. 412–421, 2011.
[151]
K. Y. Lee, J. Jeong, J. Wang et al., “Bmp2 is critical for the murine uterine decidual response,” Molecular and Cellular Biology, vol. 27, no. 15, pp. 5468–5478, 2007.
[152]
E. B. Morosova, A. B. Chukhlovin, N. V. Kulagina, N. V. Kipich, and A. A. Totolian, “Functional gene polymorphism of matrix metalloproteinase-1 is associated with benign hyperplasia of myo- and endometrium in the Russian population,” Genetic Testing and Molecular Biomarkers, vol. 16, no. 9, pp. 1032–1037, 2012.
