Obstetrics and GynecologyObstetrics and GynecologyАкушерство и гинекология0300-90922412-5679Bionika Media62791010.18565/aig.2023.241ReviewsОбзорыReview ArticleEtiopathogenetic mechanisms of uterine fibroids developmentЭтиопатогенетические механизмы развития миомы маткиhttps://orcid.org/0009-0009-0312-0829PonomarenkoMarina S.ПономаренкоМарина Сергеевна
Russian Federation

graduate student of the Department of Biomedical Disciplines

аспирант кафедры медико-биологических дисциплин медицинского института

ponomarenkomc@yandex.ruhttps://orcid.org/0000-0002-5429-6666ReshetnikovEvgeny A.РешетниковЕвгений Александрович
Russian Federation

Dr. Bio. Sci., Professor of the Department of Medical and Biological Disciplines

доктор биологических наук, профессор кафедры медико-биологических дисциплин медицинского института

reshetnikov@bsu.edu.ruhttps://orcid.org/0000-0002-5652-0166PonomarenkoIrina V.ПономаренкоИрина Васильевна
Russian Federation

Dr. Med. Sci., Professor of the Department of Medical and Biological Disciplines

доктор медицинских наук, профессор кафедры медико-биологических дисциплин медицинского института

ponomarenko_i@bsu.edu.ruhttps://orcid.org/0000-0003-1254-6134ChurnosovMikhail I.ЧурносовМихаил Иванович
Russian Federation

Dr. Med. Sci., Head of the Department of Medical and Biological Disciplines

доктор медицинских наук, профессор, заведующий кафедрой медико-биологических дисциплин медицинского института

churnosov@bsu.edu.ruBelgorod State National Research UniversityФГАОУ ВО «Белгородский государственный национальный исследовательский университет»31012024134410103202401032024Copyright ©; 2024, Bionika MediaCopyright ©; 2024, ООО «Бионика Медиа»2024Bionika MediaООО «Бионика Медиа»https://journals.eco-vector.com/0300-9092/article/view/627910

Uterine fibroids are the most common benign tumors in women. However, despite the high incidence of uterine fibroids among reproductive-aged women, its negative impact on a woman’s quality of life, and health care costs for the treatment of patients with uterine tumors, there is currently no unified understanding of the etiopathogenesis of this disease. The modern data on the causes and mechanisms of uterine fibroids development are considered in the article. Uterine fibroids have a complex, multifactorial nature. Genetic, epigenetic factors, dysregulation of key signaling pathways involved in cell proliferation, apoptosis, extracellular matrix proliferation, as well as reactions to steroid hormones play an important role in the development and growth of myoma nodes.

Conclusion: Modern views on the etiopathogenesis of uterine fibroids indicate that this disease has a complex, multifactorial nature. The development of this disease involves genetic and epigenetic mechanisms, reactions to steroid hormones, dysregulation of key signaling pathways, etc. However, in spite of significant progress in understanding of uterine fibroids pathophysiology, today there are still more questions than answers.

Миома матки представляет собой наиболее распространенную доброкачественную опухоль у женщин. Однако, несмотря на высокую частоту встречаемости миомы матки среди женщин репродуктивного возраста, ее негативное влияние на качество жизни женщины, а также затраты здравоохранения на лечение пациенток с опухолью матки, на сегодняшний день нет единого представления об этиопатогенезе данного заболевания. В статье рассмотрены современные данные о причинах и механизмах развития миомы матки.

Миома матки имеет сложную, многофакторную природу. Важную роль в формировании и росте миоматозных узлов играют генетические, эпигенетические факторы, нарушения регуляции ключевых сигнальных путей, участвующих в клеточной пролиферации, апоптозе, разрастании внеклеточного матрикса, а также реакции на стероидные гормоны.

Заключение: Современные представления об этиопатогенезе миомы матки свидетельствуют о том, что данное заболевание имеет сложную, многофакторную природу, в развитии задействованы генетические и эпигенетические механизмы, реакции на стероидные гормоны, нарушения регуляции ключевых сигнальных путей и др. Однако, несмотря на существенный прогресс в понимании патофизиологии миомы матки, на сегодняшний день остается больше вопросов, чем ответов.

uterine fibroidsetiologypathogenesisмиома маткиэтиологияпатогенезYang Q., Ciebiera M., Bariani M.V., Ali M., Elkafas H., Boyer T.G., Al-Hendy A. Comprehensive review of uterine fibroids: developmental origin, pathogenesis, and treatment. Endocr. Rev. 2022;43(4):678-719. https://dx.doi.org/10.1210/endrev/bnab039.Ali M., Ciebiera M., Vafaei S., Alkhrait S., Chen H.-Yu., Chiang Yi-F. et al. Progesterone signaling and uterine fibroid pathogenesis; molecular mechanisms and potential therapeutics. Cells. 2023;12(8):1117. https://dx.doi.org/10.3390/cells12081117.Koltsova A.S., Efimova O.A., Pendina A.A. A view on uterine leiomyoma genesis through the prism of genetic, epigenetic and cellular heterogeneity. Int. J. Mol. Sci. 2023;24(6):5752. https://dx.doi.org/10.3390/ijms24065752.Stewart E.A., Nowak R.A. Uterine fibroids: hiding in plain sight. Physiology (Bethesda). 2022;37(1):16-27. https://dx.doi.org/10.1152/physiol.00013.2021.Lou Z., Huang Y., Li S., Luo Z., Li C., Chu K. et al. Global, regional, and national time trends in incidence, prevalence, years lived with disability for uterine fibroids, 1990-2019: an age-period-cohort analysis for the global burden of disease 2019 study. BMC Public Health. 2023;23(1):916. https://dx.doi:10.1186/s12889-023-15765-x.Shih V., Banks E., Bonine N.G., Harrington A., Stafkey-Mailey D., Yue B. et al. Healthcare resource utilization and costs among women diagnosed with uterine fibroids compared to women without uterine fibroids. Curr. Med. Res. Opin. 2019;35(11):1925-35. https://dx.doi.org/10.1080/ 03007995.2019.1642186.Baranov V.S., Osinovskaya N.S., Yarmolinskaya M.I. Pathogenomics of uterine fibroids development. Int. J. Mol. Sci. 2019;20(24):6151. https://dx.doi.org/10.3390/ijms20246151.Machado-Lopez A., Simón C., Mas A. Molecular and cellular insights into the development of uterine fibroids. Int. J. Mol. Sci. 2021;22(16):8483. https://dx.doi.org/10.3390/ijms22168483.Пономаренко И.В., Чурносов М.И. Современные представления об этиопатогенезе и факторах риска лейомиомы матки. Акушерство и гинекология. 2018;8:27-32. [Ponomarenko I.V., Churnosov M.I. Current views on the etiopathogenesis and risk factors of uterine leiomyoma. Obstetrics and Gynecology. 2018;(8):27-32. (in Russian)]. https://dx.doi.org/10.18565/aig.2018.8.27-32.Salas A., Beltrán-Flores S., Évora C., Reyes R., Montes de Oca F., Delgado A., Almeida T.A. Stem cell growth and differentiation in organ culture: new insights for uterine fibroid treatment. Biomedicines. 2022;10(7):1542. https://dx.doi.org/10.3390/biomedicines10071542.Sefah N., Ndebele S., Prince L., Korasare E., Agbleke M., Nkansah A. et al. Uterine fibroids - causes, impact, treatment, and lens to the African perspective. Front. Pharmacol. 2023;13:1045783. https://dx.doi.org/10.3389/fphar.2022.1045783.Buyukcelebi K., Chen X., Abdula F., Duval A., Ozturk H., Seker-Polat F. et al. Engineered MED12 mutations drive uterine fibroid-like transcriptional and metabolic programs by altering the 3D genome compartmentalization. Res. Sq. [Preprint]. 2023;rs.3.rs-2537075. https://dx.doi.org/10.21203/rs.3.rs-2537075/v1.He Ch., Nelson W., Li H., Xu Y.-D., Dai X.-J., Wang Y.-X. et al. Frequency of MED12 mutation in relation to tumor and patient's clinical characteristics: a meta-analysis. Reprod. Sci. 2022;9(2):357-65. https://dx.doi.org/10.1007/s43032-021-00473-x.Äyräväinen A., Pasanen A., Ahvenainen T., Heikkinen T., Pakarinen P., Härkki P., Vahteristo P. Systematic molecular and clinical analysis of uterine leiomyomas from fertile-aged women undergoing myomectomy. Hum. Reprod. 2020;35(10):2237-44. https://dx.doi.org/10.1093/humrep/deaa187.Maekawa R., Sato S., Tamehisa T., Sakai T., Kajimura T., Sueoka K., Sugino N. Different DNA methylome, transcriptome and histological features in uterine fibroids with and without MED12 mutations. Sci. Rep. 2022;12(1):8912. https://dx.doi.org/10.1038/s41598-022-12899-7.Kirschen G.W., AlAshqar A., Miyashita-Ishiwata M., Reschke L., El Sabeh M., Borahay M.A. Vascular biology of uterine fibroids: connecting fibroids and vascular disorders. Reproduction. 2021;162(2):R1-R18. https://dx.doi.org/10.1530/REP-21-0087.Chang H.Y., Koh V.C.Y., Md Nasir N.D., Ng C.C.Y., Guan P., Thike A.A. et al. MED12, TERT and RARA in fibroepithelial tumours of the breast. J. Clin. Pathol. 2020;73(1):51-6. https://dx.doi.org/10.1136/jclinpath-2019-206208.Heikkinen T., Äyräväinen A., Hänninen J., Ahvenainen T., Bützow R., Pasanen A., Vahteristo P. MED12 mutations and fumarate hydratase inactivation in uterine adenomyomas. Hum. Reprod. Open. 2018;4:hoy020. https://dx.doi.org/10.1093/hropen/hoy020Ferrero H. HMGA2 involvement in uterine leiomyomas development through angiogenesis activation. Fertil. Steril. 2020;114(5):974-5. https://dx.doi.org/10.1016/j.fertnstert.2020.07.044Li Y., Qiang W., Griffin B.B., Gao T., Chakravarti D., Bulun S. et al. HMGA2-mediated tumorigenesis through angiogenesis in leiomyoma. Fertil. Steril. 2020;114(5):1085-96. https://dx.doi.org/10.1016/j.fertnstert.2020.05.036Unachukwu U., Chada K., D’Armiento J. High Mobility Group AT-Hook 2 (HMGA2) oncogenicity in mesenchymal and epithelial neoplasia. Int. J. Mol. Sci. 2020;21:3151. https://dx.doi.org/10.3390/ ijms21093151.Galindo L.J., Hernández-Beeftink T., Salas A., Jung Y., Reyes R., de Oca F.M. et al. HMGA2 and MED12 alterations frequently co-occur in uterine leiomyomas. Gynecol. Oncol. 2018;150(3):562-8. https://dx.doi.org/10.1016/ j.ygyno.2018.07.007.Zyla R.E., Hodgson A.J. Gene of the month: FH. J. Clin. Pathol. 2021;74(10):615-9. https://dx.doi.org/10.1136/jclinpath-2021-207830.Schmidt C., Sciacovelli M., Frezza C. Fumarate hydratase in cancer: A multifaceted tumour suppressor. Semin. Cell Dev. Biol. 2020;98:15-25. https://dx.doi.org/10.1016/j.semcdb.2019.05.002.Gregová M., Hojný J., Němejcová K., Bártů M., Mára M., Boudová B. et al. Leiomyoma with bizarre nuclei: a study of 108 cases focusing on clinicopathological features, morphology, and fumarate hydratase alterations. Pathol. Oncol. Res. 2020;26(3):1527-37. https://dx.doi.org/10.1007/ s12253-019-00739-5.Sciacovelli M., Gonçalves E., Johnson T.I., Zecchini V.R., da Costa A.S., Gaude E. et al. Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature. 2016;537(7621):544-7. https://dx.doi.org/10.1038/nature19353.Punjabi L.S., Thomas A. The Waldo of fibroids under the microscope: fumarate hydratase-deficient leiomyomata. F. S. Rep. 2022;3(2):172-3. https://dx.doi.org/10.1016/j.xfre.2022.03.008.Garg K., Rabban J. Hereditary leiomyomatosis and renal cell carcinoma syndrome associated uterine smooth muscle tumors: bridging morphology and clinical screening. Genes. Chromosomes Cancer. 2021;60:210-6. https://dx.doi.org/10.1002/gcc.22905.Zhao Z., Wang W., You Y., Zhu L., Feng F. Novel FH mutation associated with multiple uterine leiomyomas in Chinese siblings. Mol. Genet. Genomic Med. 2020;8(1):e1068. https://dx.doi.org/10.1002/mgg3.1068.Пономаренко И.В., Полоников А.В., Чурносов М.И. Полиморфные локусы гена LHCGR, ассоциированные с развитием миомы матки. Акушерство и гинекология. 2018;10:86-91. [Ponomarenko I.V., Polonikov A.V., Churnosov M.I. Polymorphic LHCGR gene loci associated with the development of uterine fibroids. Obstetrics and Gynecology. 2018;(10):86-91. (in Russian)]. https://dx.doi.org/10.18565/ aig.2018.10.86-91.Ponomarenko I., Reshetnikov E., Polonikov A., Verzilina I., Sorokina I., Yermachenko A. et al. Candidate genes for age at menarche are associated with uterine leiomyoma Front. Genet. 2021;11:512940. https://dx.doi.org/10.3389/fgene.2020.512940.Liu S., Yin P., Xu J., Dotts A.J., Kujawa S.A., Coon V.J.S. et al. Targeting DNA methylation depletes uterine leiomyoma stem cell-enriched population by stimulating their differentiation. Endocrinology. 2020;161(10):bqaa143. https://dx.doi.org/10.1210/endocr/bqaa143Ali M., Esfandyari S., Al-Hendy A. Evolving role of microRNAs in uterine fibroid pathogenesis: filling the gap! Fertil. Steril. 2020;113(6):1167-8. https://dx.doi.org/10.1016/j.fertnstert.2020.04.011Ciebiera M., Włodarczyk M., Zgliczyński S., Łoziński T., Walczak K., Czekierdowski A. The role of miRNA and related pathways in pathophysiology of uterine fibroids-from bench to bedside. Int. J. Mol. Sci. 2020;21(8):3016. https://dx.doi.org/10.3390/ijms21083016.Peng X., Mo Y., Liu J., Liu H., Wang S. Identification and validation of miRNA-TF-mRNA regulatory networks in uterine fibroids. Front. Bioeng. Biotechnol. 2022;10:856745. https://dx.doi.org/10.3389/fbioe.2022.856745.Kim M., Kang D., Kwon M.Y., Lee H.J., Kim M.J. MicroRNAs as potential indicators of the development and progression of uterine leiomyoma. PloS One. (2022);17(5):e0268793. https://dx.doi.org/10.1371/journal.pone.0268793.Falahati Z., Mohseni-Dargah M., Mirfakhraie R. Emerging roles of long non-coding RNAs in uterine leiomyoma pathogenesis: a review. Reprod. Sci. 2022;29:1086-101. https://dx.doi.org/10.1007/s43032-021-00571-w.Cao T., Jiang Y., Wang Z., Zhang N., Al-Hendy A., Mamillapalli R. et al. H19 LncRNA identified as a master regulator of genes that drive uterine leiomyomas. Oncogene. 2019;38:5356-66. https://dx.doi.org/10.1038/s41388-019-0808-4.Chuang T.D., Quintanilla D., Boos D., Khorram O. Long noncoding RNA MIAT modulates the extracellular matrix deposition in leiomyomas by sponging MiR-29 family. Endocrinology. 2021;162(11):bqab186. https://dx.doi.org/10.1210/endocr/bqab186.Zhou W., Wang G., Li B., Qu J., Zhang Y. LncRNA APTR promotes uterine leiomyoma cell proliferation by targeting ERα to activate the Wnt/β-Catenin pathway. Front. Oncol. 2021;11:536346. https://dx.doi.org/10.3389/fonc.2021.536346.Ulin M., Ali M., Chaudhry Z. T., Al-Hendy A., Yang Q. Uterine fibroids in menopause and perimenopause. Menopause. 2020;27(2):238-42. https://dx.doi.org/10.1097/GME.0000000000001438.Omar M., Laknaur A., Al-Hendy A., Yang Q. Myometrial progesterone hyper-responsiveness associated with increased risk of human uterine fibroids. BMC Womens Health. 2019;19(1):92. https://dx.doi.org/10.1186/s12905-019-0795-1Borahay M.A., Asoglu M.R., Mas A., Adam S., Kilic G.S., Al-Hendy A. Estrogen receptors and signaling in fibroids: role in pathobiology and therapeutic implications. Reprod. Sci. 2017;24:1235-44. https://dx.doi.org/10.1177/1933719116678686.Khan K.N., Fujishita A., Koshiba A., Ogawa K., Mori T., Ogi H. et al. Expression profiles of E/P receptors and fibrosis in GnRHa-treated and -untreated women with different uterine leiomyomas. PloS One. 2020;15(11):e0242246. https://dx.doi.org/10.1371/journal.pone.0242246.Головченко И.О. Генетические детерминанты уровня половых гормонов у больных эндометриозом. Научные результаты биомедицинских исследований. 2023;9(1):5-21. [Golovchenko I.O. Genetic determinants of sex hormone levels in endometriosis patients. Research Results in Biomedicine. 2023;9(1):5-21. (in Russian)]. https://dx.doi.org/10.18413/ 2658-6533-2023-9-1-0-1.Alsudairi H.N., Alrasheed A.T., Dvornyk V. Estrogens and uterine fibroids: an integrated view. Research Results in Biomedicine. 2021;7(2):156-63. https://dx.doi.org/10.18413/2658-6533-2021-7-2-0-6.Xing C., Zhang J., Zhao H., He B. Effect of sex hormone-binding globulin on polycystic ovary syndrome: mechanisms, manifestations, genetics, and treatment. Int. J. Womens Health. 2022;14:91-105. https://dx.doi.org/10.2147/IJWH.S344542.Balogh A., Karpati E., Schneider A.E., Hetey S., Szilagyi A., Juhasz K. et al. Sex hormone-binding globulin provides a novel entry pathway for estradiol and influences subsequent signaling in lymphocytes via membrane receptor. Sci. Rep. 2019;9(1):4. https://dx.doi.org/10.1038/s41598-018-36882-3.Hammond G.L. Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action. J. Endocrinol. 2016;230(1):R13-25. https://dx.doi.org/10.1530/JOE-16-0070.Soave I., Marci R. From obesity to uterine fibroids: an intricate network. Curr. Med. Res. Opin. 2018;34(11):1877-9. https://dx.doi.org/ 10.1080/03007995.2018.1505606Mozzachio K., Moore A.B., Kissling G.E., Dixon D. Immunoexpression of steroid hormone receptors and proliferation markers in uterine leiomyoma and normal myometrial tissues from the miniature pig, sus scrofa. Toxicol. Pathol. 2016;44:450-7. https://dx.doi.org/10.1177/ 0192623315621414Ali M., Al-Hendy A. Selective progesterone receptor modulators for fertility preservation in women with symptomatic uterine fibroids. Biol. Reprod. 2017;97(3):337-52. https://dx.doi.org/10.1093/biolre/iox094.Stewart E.A. Gonadotropins and the uterus: is there a gonad-independent pathway? J. Soc. Gynecol. Investig. 2001;8(6):319-26.Baird D.D., Kesner J.S., Dunson D.B. Luteinizing hormone in premenopausal women may stimulate uterine leiomyomata development. J. Soc. Gynecol. Investig. 2006;13(2):130-5. https://dx.doi.org/10.1016/j.jsgi.2005.12.001.DiMauro A., Seger C., Minor B., Amitrano A.M., Okeke I., Taya M. et al. Prolactin is expressed in uterine leiomyomas and promotes signaling and fibrosis in myometrial cells. Reprod. Sci. 2022;29(9):2525-35. https://dx.doi.org/10.1007/s43032-021-00741-w.Cetin E., Al-Hendy A., Ciebiera M. Non-hormonal mediators of uterine fibroid growth. Curr. Opin. Obstet. Gynecol. 2020;32(5):361-70. https://dx.doi.org/ 10.1097/GCO.0000000000000650.Радзинский В.Е., Алтухова О.Б. Молекулярно-генетические детерминанты бесплодия при генитальном эндометриозе. Научные результаты биомедицинских исследований. 2018;4(3):28-37. [Radzinsky V.E., Altuchova O.B. Molecular-genetic determinants of infertility in genital endometryosis. Research Results in Biomedicine. 2018;4(3):28-37. (in Russian)]. https://dx.doi.org/10.18413/2313-8955-2018-4-3-0-3.Ciebiera M., Włodarczyk M., Wrzosek M., Słabuszewska-Jóźwiak A., Nowicka G., Jakiel G. Ulipristal acetate decreases transforming growth factor β3 serum and tumor tissue concentrations in patients with uterine fibroids. Fertil. Steril. 2018;109(3):501-7.e2. https://dx.doi.org/10.1016/j.fertnstert.2017.11.023.Yang Q., Al-Hendy A. Update on the role and regulatory mechanism of extracellular matrix in the pathogenesis of uterine fibroids. Int. J. Mol. Sci. 2023;24(6):5778. https://dx.doi.org/10.3390/ijms24065778.Ciebiera M., Włodarczyk M., Wrzosek M., Męczekalski B., Nowicka G., Łukaszuk K. et al. Role of transforming growth factor β in uterine fibroid biology. Int. J. Mol. Sci. 2017;18(11):2435. https://dx.doi.org/10.3390/ijms18112435.Ciebiera M., Włodarczyk M., Wrzosek M., Wojtyła C., Błażej M., Nowicka G. et al. TNF-α serum levels are elevated in women with clinically symptomatic uterine fibroids. Int. J. Immunopathol. Pharmacol. 2018;32:2058738418779461. https://dx.doi.org/10.1177/2058738418779461.Демакова Н.А. Молекулярно-генетические характеристики пациенток с гиперплазией и полипами эндометрия. Научные результаты биомедицинских исследований. 2018;4(2):26-39. [Demakova N.A. Molecular and genetic characteristics of patients with hyperplasia and endometric polyps. Research Results in Biomedicine. 2018;4(2):26-39. (in Russian)]. https://dx.doi.org/10.18413/2313-8955-2018-4-2-0-4.Navarro A., Bariani M.V., Yang Q., Al-Hendy A. Understanding the impact of uterine fibroids on human endometrium function. Front. Cell Dev. Biol. 2021;25(9):633180. https://dx.doi.org/10.3389/fcell.2021.633180.Ciebiera M., Włodarczyk M., Zgliczyńska M., Łukaszuk K., Męczekalski B., Kobierzycki C. et al. The role of tumor necrosis factor α in the biology of uterine fibroids and the related symptoms. Int. J. Mol. Sci. 2018;19(12):3869. https://dx.doi.org/10.3390/ijms19123869.K V.K., Bhat R.G., Rao B.K., R A.P. The gut microbiota: a novel player in the pathogenesis of uterine fibroids. Reprod. Sci. 2023;30(12):3443-55. https://dx.doi.org/10.1007/s43032-023-01289-7.