DOI: https://doi.org/10.18370/2309-4117.2018.40.23-32

Uterine myoma: еtiology and morphogenesis

Н. В. Косей

Abstract


Uterine myoma is the most common tumor of female genital organs. Despite the significant achievements of modern science and the many studies devoted to this benign tumor, its initiating factors remain unknown. To investigate etiological factors and features of the morphogenesis of uterine leiomyoma for further development of the tactics of its prevention and treatment, the literature data and the results of our original studies, including results of submicroscopic studies, were analyzed. It was revealed that among important etiological factors are African-American ethnic group, nutrition rich in meat, high blood pressure, age, inflammation and stress.

Different clinical and pathogenetic variants of development of uterine myomas have been identified: isolated and combined with dyshormonal diseases of the mammary glands. At the ultrastructural level, the development of isolated uterine myoma was accompanied by significant changes in the organelles of a degenerative-destructive nature along with significant pericellular fibrosis, while the combined variant of uterine leiomyoma was characterized by activation of nuclear structures and an increase in the number of energy and plastic organelles, which indicates intensification of metabolic processes in them and an increase in the proliferative potential.

It was shown that the tumor develops from a single stem cell of the myometrium and grows, moving aside normal uterine tissues and creating around itself pseudocapsule – a site of compressed myometrium at the border of healthy tissue and fibroids, rich in collagen fibers, neurofibrils and blood vessels, which provides regeneration and restoration of myometrium functionality after myomectomy.

The frequency of recurrence of the tumor is significantly higher in the presence of multiple myomas, which should be taken into account when planning conservative myomectomy. When planning the treatment of uterine leiomyoma, it is also necessary to take into account the clinical and pathogenetic variant of its development. In the presence of an isolated variant, the first stage is necessary to perform anti-inflammatory therapy and correction of local factors, after which it is possible to perform specific treatment for fibroids, and in combination with other dyshormonal pathology – first of all to correct systemic disorders and then plan the treatment of fibroids.


Keywords


uterine leiomyoma; myoma; ethiology; morphogenesis; ultrastructure; submicroscopic; clinic-pathogenetic variants; isolated myoma; combined with dishormonal diseases of mammary glands

References


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Ahrendt, H.-J., et al. “Prevalence of uterine myomas in women in Germany: data of an epidemiological study.” Arch Gynecol Obstet (2015). DOI: 10.1007/s00404

Sato, F., Mori, M., Nishi, M., et al. “Familial aggregation of uterine myomas in Japanese women.” J Epidemiol 12 (2002): 249–53.

Ross, R., Pike, M., Vessey, M., et al. “Risk factors for uterine fibroids: reduced risk associated with oral contraceptives.” BMJ 293 (1986): 359–61.

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Hanafi, M. “Predictors of leiomyoma recurrence after myomectomy.” Obstet Gynecol 105 (2005): 877–81.

Chen, C., Buck, G., Courey, N., et al. “Risk factors for uterine fibroids among women undergoing tubal sterilization.” Am J Epidemiol 153 (2001): 20–6.

Boynton-Jarrett, R., Rich-Edwards, J., Malspeis, S., et al. “A prospective study of hypertension and risk of uterine leiomyomata.” Am J Epidemiol 161 (2005): 628–38.

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Torry, R.J., Rongish, B.J. “Angiogenesis in the uterus: potential regulation and relation to tumor angiogenesis.” Am J Reprod Immunol 27.3–4 (1992: 171–9.

Fraser, H.M., Lunn, S.F. “Angiogenesis and its control in the female reproductive system.” Br Med Bull 56.3 (2000): 787–97.

Smith, S.K. “Angiogenesis, vascular endothelial growth factor and the endometrium.” Hum Reprod Update 4.5 (1998): 509–19.

Jaffe, R.B. “Importance of angiogenesis in reproductive physiology.” Semin Perinatol 24.1 (2000): 79–81.

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Hyder, S.M., Stancel, G.M. “Regulation of VEGF in the reproductive tract by sex-steroid hormones.” Histol Histopathol 15.1 (2000): 325–34.

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Dixon, D., He, H., Haseman, J.K. “Immunohistochemical localization of growth factors and their receptors in uterine leiomyomas and matched myometrium.” Environ Health Perspect 108.5 (2000): 795–802.

Mangrulkar, R.S., Ono, M., Ishikawa, M., et al. “Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium.” Biol Reprod 53.3 (1995): 636–46.

Nowak, R.A. “Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors.” Environ Health Perspect 108.5 (2000): 849–53.

Sanci, M., Dikis, C., Inan, S., et al. “Immunolocalization of VEGF, VEGF receptors, EGF-R and Ki-67 in leiomyoma, cellular leiomyoma and leiomyosarcoma.” Acta Histochem 113.3 (2011): 317–25.

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Xu, Q., Ohara, N., Chen, W., et al. “Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells.” Hum Reprod 21.9 (2006): 2408–16.

Walocha, J.A., Litwin, J.A., Miodonski, A.J. “Vascular system of intramural leiomyomata revealed by corrosion casting and scanning electron microscopy.” Hum Reprod 18 (2003): 1088–93.

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Lametschwandtner, A., Lametschwandtner, U., Weiger, T. “Scanning electron microscopy of vascular corrosion casts – technique and applications: updated review.” Scanning Microsc 4 (1990): 889–941.

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Mayer, A., Hoeckel, M., von Wallbrunn, A., et al. “HIF-mediated hypoxic response is missing in severely hypoxic uterine leiomyomas.” Adv Exp Med Biol 662 (2010): 399–405.

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GOST Style Citations


1. Baird, D., Dunson, D., Hill, M., et al. “High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence.” Am J Obstet Gynecol 188 (2003): 100–7.

2. Aboyeji, A., Ijaiya, M. “Uterine fibroids: a ten-year clinical review in Ilorin Nigeria.” Niger J Med 11 (2002): 16–9.

3. Ahrendt, H.-J., et al. “Prevalence of uterine myomas in women in Germany: data of an epidemiological study.” Arch Gynecol Obstet (2015). DOI: 10.1007/s00404

4. Sato, F., Mori, M., Nishi, M., et al. “Familial aggregation of uterine myomas in Japanese women.” J Epidemiol 12 (2002): 249–53.

5. Ross, R., Pike, M., Vessey, M., et al. “Risk factors for uterine fibroids: reduced risk associated with oral contraceptives.” BMJ 293 (1986): 359–61.

6. DeWaay, D., Syrop, C., Nygaard, I., et al. “Natural history of uterine polyps and leiomyomata.” Obstet Gynecol 100 (2002): 3–7.

7. Hanafi, M. “Predictors of leiomyoma recurrence after myomectomy.” Obstet Gynecol 105 (2005): 877–81.

8. Chen, C., Buck, G., Courey, N., et al. “Risk factors for uterine fibroids among women undergoing tubal sterilization.” Am J Epidemiol 153 (2001): 20–6.

9. Boynton-Jarrett, R., Rich-Edwards, J., Malspeis, S., et al. “A prospective study of hypertension and risk of uterine leiomyomata.” Am J Epidemiol 161 (2005): 628–38.

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14. Linder, D., Gartler, S.M. “Glucose-6-phosphate dehydrogenase mosaicism: utilization as a cell marker in the study of leiomyomas.” Science 150 (1965): 67–9.

15. Arango, N.A., Szotek, P.P., Manganaro, T.F., et al. “Conditional deletion of beta-catenin in the mesenchyme of the developing mouse uterus results in a switch to adipogenesis in the myometrium.” Dev Biol 288 (2005): 276–83.

16. Szotek, P.P., Chang, H.L., Zhang, L., et al. “Adult mouse myometrial label-retaining cells divide in response to gonadotropin stimulation.” Stem Cells 25 (2007): 1317–25.

17. 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 USA 104 (2007): 18700–5.

18. Chang, H.L., Senaratne, T.N., Zhang, L., et al. “Uterine leiomyomas exhibit fewer stem/progenitor cell characteristics when compared with corresponding normal myometrium.” Reproductive Sci 17 (2010): 158–67.

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20. Leppert, P.C., Catherino, W.H., Segars, J.H. “A new hypothesis about the origin of uterine fibroids based on gene expression profiling with microarrays.” Am J Obstet Gynecol 195 (2006): 415–20.

21. Peddada, S.D., Laughlin, S.K., Miner, K., et al. “Growth of uterine leiomyomata among premenopausal black and white women.” Proc Natl Acad Sci USA 105 (2008): 19887–92.

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25. Sampson, J.A. “The blood supply of uterine myomata.” Surg Gynecol Obstet XIV (1912): 15–234.

26. Faulkner, R.L. “The blood vessels of the myomatous uterus.” Am J Obstet Gynecol 47 (1944): 185–97.

27. Farrer-Brown, G., Beilby, J.O., Tarbit, M.H. “The vascular patterns in myomatous uteri.” J Obstet Gynaecol Br Common W 77 (1970): 967–75.

28. Mayer, A., Hockel, M., Wree, A., et al. “Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia.” Cancer Res 68 (2008): 4719–26.

29. Torry, R.J., Rongish, B.J. “Angiogenesis in the uterus: potential regulation and relation to tumor angiogenesis.” Am J Reprod Immunol 27.3–4 (1992: 171–9.

30. Fraser, H.M., Lunn, S.F. “Angiogenesis and its control in the female reproductive system.” Br Med Bull 56.3 (2000): 787–97.

31. Smith, S.K. “Angiogenesis, vascular endothelial growth factor and the endometrium.” Hum Reprod Update 4.5 (1998): 509–19.

32. Jaffe, R.B. “Importance of angiogenesis in reproductive physiology.” Semin Perinatol 24.1 (2000): 79–81.

33. Reynolds, L.P., Grazul-Bilska, A.T., Redmer, D.A. “Angiogenesis in the female reproductive organs: pathological implications.” Int J Exp Pathol 83.4 (2002): 151–63.

34. Hyder, S.M., Stancel, G.M. “Regulation of VEGF in the reproductive tract by sex-steroid hormones.” Histol Histopathol 15.1 (2000): 325–34.

35. Reynolds, L.P., Redmer, D.A. “Angiogenesis in the placenta.” Biol Reprod 64.4 (2001): 1033–40.

36. Fraser, H.M., Duncan, W.C.; SRB Reproduction, Fertility and Development Award Lecture 2008. “Regulation and manipulation of angiogenesis in the ovary and endometrium.” Reprod Fertil Dev 21.3 (2009): 377–92.

37. 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 56.5 (1991): 997–1000.

38. Dixon, D., He, H., Haseman, J.K. “Immunohistochemical localization of growth factors and their receptors in uterine leiomyomas and matched myometrium.” Environ Health Perspect 108.5 (2000): 795–802.

39. Mangrulkar, R.S., Ono, M., Ishikawa, M., et al. “Isolation and characterization of heparin-binding growth factors in human leiomyomas and normal myometrium.” Biol Reprod 53.3 (1995): 636–46.

40. Nowak, R.A. “Novel therapeutic strategies for leiomyomas: targeting growth factors and their receptors.” Environ Health Perspect 108.5 (2000): 849–53.

41. Sanci, M., Dikis, C., Inan, S., et al. “Immunolocalization of VEGF, VEGF receptors, EGF-R and Ki-67 in leiomyoma, cellular leiomyoma and leiomyosarcoma.” Acta Histochem 113.3 (2011): 317–25.

42. Pekonen, F., Nyman, T., Rutanen, E.M. “Differential expression of keratinocyte growth factor and its receptor in the human uterus.” Mol Cell Endocrinol 95.1–2 (1993): 43–9.

43. Anania, C.A., Stewart, E.A., Quade, B.J., et al. “Expression of the fibroblast growth factor receptor in women with leiomyomas and abnormal uterine bleeding.” Mol Hum Reprod 3.8 (1997): 685–91.

44. Boehm, K.D., Daimon, M., Gorodeski, I.G., et al. “Expression of the insulin-like and platelet-derived growth factor genes in human uterine tissues.” Mol Reprod Dev 27.2 (1990): 93–101.

45. Chegini, N., Zhao, Y., Williams, R.S., Flanders, K.C. “Human uterine tissue throughout the menstrual cycle expresses transforming growth factor-beta 1 (TGF beta 1), TGF beta 2, TGF beta 3, and TGF beta type II receptor messenger ribonucleic acid and protein and contains [125I]TGF beta 1-binding sites.” Endocrinology 135.1 (1994): 439–49.

46. Tang, X.M., Dou, Q., Zhao, Y., et al. “The expression of transforming growth factor-beta s and TGF-beta receptor mRNA and protein and the effect of TGF-beta s on human myometrial smooth muscle cells in vitro.” Mol Hum Reprod 3.3 (1997): 233–40.

47. Hague, S., Zhang, L., Oehler, M.K., et al.

“Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density.” Clin Cancer Res 6.7 (2000): 2808–14.

48. Xu, Q., Ohara, N., Chen, W., et al. “Progesterone receptor modulator CDB-2914 down-regulates vascular endothelial growth factor, adrenomedullin and their receptors and modulates progesterone receptor content in cultured human uterine leiomyoma cells.” Hum Reprod 21.9 (2006): 2408–16.

49. Walocha, J.A., Litwin, J.A., Miodonski, A.J. “Vascular system of intramural leiomyomata revealed by corrosion casting and scanning electron microscopy.” Hum Reprod 18 (2003): 1088–93.

50. Aitken, E., Khaund, A., Hamid, S.A., et al. “The normal human myometrium has a vascular spatial gradient absent in small fibroids.” Hum Reprod 21 (2006): 2669–78.

51. Lametschwandtner, A., Lametschwandtner, U., Weiger, T. “Scanning electron microscopy of vascular corrosion casts – technique and applications: updated review.” Scanning Microsc 4 (1990): 889–941.

52. Tsiligiannis, S.E., Zaitseva, M., Coombs, P.R., et al. “Fibroid-associated heavy menstrual bleeding: correlation between clinical features, Doppler ultrasound assessment of vasculature, and tissue gene expression profiles.” Reprod Sci 20 (2013): 361–70.

53. Carmeliet, P. “Angiogenesis in health and disease.” Nat Med 9 (2003): 653–60.

54. Mayer, A., Hockel, M., Wree, A., et al. “Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia.” Cancer Res 68 (2008): 4719–26.

55. Vincent, K.A., Feron, O., Kelly, R.A. “Harnessing the response to tissue hypoxia: HIF-1 alpha and therapeutic angiogenesis.” Trends Cardiovasc Med 12 (2002): 362–7.

56. Mayer, A., Hoeckel, M., von Wallbrunn, A., et al. “HIF-mediated hypoxic response is missing in severely hypoxic uterine leiomyomas.” Adv Exp Med Biol 662 (2010): 399–405.

57. Carmeliet, P., Dor, Y., Herbert, J.M., et al. “Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis.” Nature 394 (1998): 485–90.

58. Levy, G., Hill, M.J., Beall, S., et al. “Leiomyoma: genetics, assisted reproduction, pregnancy and therapeutic advances.” J Assist Reprod Genet 29 (2012): 703–12.

59. Yamagata, Y., Maekawa, R., Asada, H., et al. “Aberrant DNA methylation status in human uterine leiomyoma.” Mol Hum Reprod 15 (2009): 259–67.

60. Kamphaus, G.D., Colorado, P.C., Panka, D.J., et al. “Canstatin, a novel matrix-derived inhibitor of angiogenesis and tumor growth.” J Biol Chem 275 (2000): 1209–15.

61. Weston, G., Trajstman, A.C., Gargett, C.E., et al. “Fibroids display an anti-angiogenic gene expression profile when compared with adjacent myometrium.” Mol Hum Reprod 9 (2003): 541–9.

62. Maisonpierre, P.C., Suri, C., Jones, P.F., et al. “Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.” Science 277 (1997): 55–60.

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