بررسی جامع ابعاد ژنتیکی و اپی‌ژنتیکی اندومتریوز، راهکارهای نوین درمان

نوع مقاله : مقاله مروری

نویسندگان

1 استادیار، گروه زیست‌شناسی سلولی مولکولی و میکروبیولوژی، دانشکده‌ی علوم و فناوری‌های زیستی، دانشگاه اصفهان، اصفهان، ایران

2 دانشجو، گروه زیست‌شناسی سلولی مولکولی و میکروبیولوژی، دانشکده‌ی علوم و فناوری‌های زیستی، دانشگاه اصفهان، اصفهان، ایران

3 استاد، گروه زنان و زایمان، دانشکده‌ی پزشکی، دانشگاه علوم پزشکی اصفهان. اصفهان، ایران

10.48305/jims.v43.i835.1337

چکیده

مقاله مروری




مقدمه: اندومتریوز، یک بیماری خوش‌خیم با علت ژنتیکی نامشخص است و درمان کلاسیک آن کارآمدی لازم را ندارند.
روش‌ها: مقالات مرتبط با ابعاد ژنتیکی و اپی‌ژنتیکی اندومتریوز استخراج شدند. نظریات مرتبط با بروز اندومتریوز مورد واکاوی قرار گرفتند. امیدهای درمان با تکیه بر دو جنبه ژنتیک و اپی‌ژنتیک اندومترویز بررسی شدند.
یافته‌ها: قاعدگی بازگشتی، متاپلازی کولومیک، جنین‌زایی ناقص، اندومتریوز متاستاتیک و مهاجرت سلول‌های بنیادی اندومتر به عنوان علت‌های بروز اندومتریوز مطرح هستند. مطالعات گسترده‌ی ژنوم، فاکتورهای مرتبط با افزایش خطر ابتلا به اندومتریوز را معرفی کردند. تغییرات اپی‌ژنتیک شامل کاهش متیلاسیون پروموتور COX2 می‌تواند از طریق افزایش تولیداستروژن، بر تعداد و عملکرد نوتروفیل‌ها اثر بگذارد و موجب توسعه‌ی اندومتریوز شود. دو مولفه مهم برای شروع و پیشرفت اندومتریوز، فرار ضایعات اندومتریوز از سیستم ایمنی و مقادیر بالای سایتوکاین‌های التهابی هستند. گزینه‌های درمانی نوین اندومتریوز شامل مهارکننده‌های آروماتاز می‌باشند و ترکیب این داروها با ژستاژن‌ها، داروهای ضدبارداری خوراکی یا آگونیست‌های هورمون آزادکننده گنادوتروپین، علاوه بر موثر بودن، باعث کاهش درد، کاهش اندازه‌ی ضایعه خارج رحم و بهبود کیفیت زندگی بیماران می‌شود. مهارکننده‌های هیستون داستیلاز از تکثیر سلول‌های استرومای اندومتریوز جلوگیری می‌کنند و اثرات جانبی بسیار ضعیفی بر سلول‌های استرومای طبیعی دارند.
نتیجه‌گیری: ژنتیک و اپی‌ژنتیک نقش مهمی در بروز اندومتریوز دارند و روش‌های درمان مبتنی بر داروهای تعدیل‌کننده‌ی اپی ژنوم، امیدهای درمانی جدیدی هستند و نسبت به روش‌های درمان سنتی، کارآیی بهتری نشان می‌دهند.

تازه های تحقیق

سید مرتضی جوادی راد: PubMed ,Google Scholar 

یلدا ریاحی: Google Scholar 

فریبا بهنام فر: PubMed ,Google Scholar 

کلیدواژه‌ها

موضوعات


عنوان مقاله [English]

Comprehensive Review of Genetic and Epigenetic Dimensions of Endometriosis, New Treatment Strategies

نویسندگان [English]

  • Seyed Morteza Javadi Rad 1
  • Yalda Riahi 2
  • Fariba Behnamfar 3
1 Assistant Professor, Department of Cell and Molecular Biology and Microbiology, School of Biological Science and Technology, University of Isfahan, Isfahan, Iran
2 Student, Department of Cell and Molecular Biology and Microbiology, School of Biological Science and Technology, University of Isfahan, Isfahan, Iran
3 Professor, Department of Obstetrics and Gynecology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
چکیده [English]

Background: Endometriosis is a benign condition with an unidentified genetic cause, and conventional therapeutic methods are ineffective.
Methods: Articles pertaining to the genetic and epigenetic dimensions of endometriosis were extracted. Theories concerning the etiology of endometriosis were examined. Therapeutic prospects were evaluated considering both genetic and epigenetic factors of endometriosis.
Findings: Retrograde menstruation, coelomic metaplasia, embryonic rest, metastatic endometriosis, and endometrial stem cell recruitment are regarded as etiological factors of endometriosis. Genome-wide investigations have found variables linked to an elevated incidence of endometriosis. Epigenetic modifications, such as diminished COX2 promoter methylation, can influence the quantity and functionality of neutrophils by elevating estrogen synthesis, hence contributing to the onset of endometriosis. Two critical factors in the onset and advancement of endometriosis are the evasion of endometriotic lesions from the immune response and elevated concentrations of inflammatory cytokines. Novel therapeutic alternatives for endometriosis encompass aromatase inhibitors, and their combination with gestagens, oral contraceptives, or gonadotropin-releasing hormone agonists not only demonstrates efficacy but also alleviates pain, diminishes the size of ectopic lesions, and enhances patients' quality of life. Histone deacetylase inhibitors limit the growth of endometriotic stromal cells while exhibiting little negative effects on normal stromal cells.
Conclusion: Genetics and epigenetics significantly influence the development of endometriosis, and therapeutic approaches utilizing epigenome-modulating agents present promising new options, demonstrating superior efficacy compared to conventional treatments.

کلیدواژه‌ها [English]

  • Endometriosis
  • Genetics
  • Epigenetics
  • Treatment
  1. Guo SW. Epigenetics of endometriosis. Mol Hum Reprod 2009; 15(10): 587–607.
  2. Warzecha D, Szymusik I, Wielgos M, Pietrzak B. The impact of endometriosis on the quality of life and the incidence of depression—A cohort study. Int J Environ Res Public Health 2020; 17(10): 3641.
  3. Lamceva J, Uljanovs R, Strumfa I. The main theories on the pathogenesis of endometriosis. Int J Mol Sci 2023; 24(5): 4254.
  4. Yovich JL, Rowlands PK, Lingham S, Sillender M, Srinivasan S. Pathogenesis of endometriosis: Look no further than John Sampson. Reprod Biomed Online 2020; 40(1): 7–11.
  5. Chantalat E, Valera MC, Vaysse C, Noirrit E, Rusidze M, Weyl A, et al. Estrogen receptors and endometriosis. Int J Mol Sci 2020; 21(8): 2815.
  6. Konrad L, Dietze R, Kudipudi PK, Horné F, Meinhold-Heerlein I. Endometriosis in MRKH cases as a proof for the coelomic metaplasia hypothesis? Reproduction 2019; 158(2): R41–R47.
  7. Signorile PG, Viceconte R, Baldi A. New Insights in Pathogenesis of Endometriosis. Front Med (Lausanne) 2022; 9:
  8. Jerman LF, Hey-Cunningham AJ. The role of the lymphatic system in endometriosis: A comprehensive review of the literature. Biol Reprod 2015; 92(3): 64.
  9. Wang Y, Nicholes K, Shih IM. The origin and pathogenesis of endometriosis. Annu Rev Pathol 2020; 15: 71–95.
  10. Djokovic D, Calhaz-Jorge C. Somatic stem cells and their dysfunction in endometriosis. Front Surg 2015; 1: 51.
  11. Sourial S, Tempest N, Hapangama DK. Theories on the Pathogenesis of Endometriosis. Int J Reprod Med 2014; 2014: 179515.
  12. Wyatt J, Fernando SM, Powell SG, Hill CJ, Arshad I, Probert C, et al. The role of iron in the pathogenesis of endometriosis: a systematic review. Hum Reprod Open 2023; 2023(3): hoad033.
  13. Polak G, Barczyński B, Wertel I, Kwaśniewski W, Bednarek W, Derewianka-Polak M, et al. Disrupted iron metabolism in peritoneal fluid may induce oxidative stress in the peritoneal cavity of women with endometriosis. Ann Agric Environ Med 2018; 25(4): 587–92.
  14. Li S, Zhou Y, Huang Q, Fu X, Zhang L, Gao F, et al. Iron overload in endometriosis peritoneal fluid induces early embryo ferroptosis mediated by HMOX1. Cell Death Discov 2021; 7(1): 355.
  15. Liu Y, Wang J, Zhang X. An Update on the Multifaceted Role of NF-kappaB in Endometriosis. Int J Biol Sci 2022; 18(11): 4400–13.
  16. Zubrzycka A, Zubrzycki M, Perdas E, Zubrzycka M. Genetic, epigenetic, and steroidogenic modulation mechanisms in endometriosis. J Clin Med 2020; 9(5): 1309.
  17. Coxhead D, Thomas EJ. Familial inheritance of endometriosis in a british population. A case control study. J Obstet Gynaecol (Lahore) 1993; 13(1): 42–4.
  18. Treloar SA, O’Connor DT, O’Connor VM, Martin NG. Genetic influences on endometriosis in an Australian twin sample. Fertil Steril 1999; 71(4): 701–10.
  19. Treloar S, Hadfield R, Montgomery G, Lambert A, Wicks J, Barlow DH, et al. The International Endogene Study: A collection of families for genetic research in endometriosis. Fertil Steril 2002; 78(4): 679–85.
  20. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020; 382(13): 1244–56.
  21. Vigano P, Somigliana E, Vignali M, Busacca M, Di Blasio AM. Genetics of endometriosis: Current status and prospects. Front Biosci 2007; 12(9): 3247–55.
  22. Watanabe K, Taskesen E, Van Bochoven A, Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat Commun 2017; 8(1): 1826.
  23. Matalliotakis M, Zervou MI, Matalliotaki C, Rahmioglu N, Koumantakis G, Kalogiannidis I, et al. The role of gene polymorphisms in endometriosis. Mol Med Rep 2017; 16(5): 5881–6.
  24. Uno S, Zembutsu H, Hirasawa A, Takahashi A, Kubo M, Akahane T, et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nat Genet 2010; 42(8): 707–10.
  25. Painter JN, Anderson CA, Nyholt DR, MacGregor S, Lin J, Lee SH, et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nat Genet 2011; 43(1): 51–4.
  26. Behnamfar F, Esmaeilian F, Adibi A, Rouholamin S. Comparison of ultrasound and tumor marker CA125 in diagnosis of adnexal mass malignancies. Adv Biomed Res 2022; 11: 18.
  27. Behnamfar F, Zafarbakhsh A, Ahmadian N. Are ROMA and HE4 more accurate than CA-125, in predicting of ovarian epithelial carcinoma? Adv Biomed Res 2023; 12): 156.
  28. Fujimoto J, Hirose R, Sakaguchi H, Tamaya T. Expression of oestrogen receptor-α and -β in ovarian endometriomata. Mol Hum Reprod 1999; 5(8): 742–7.
  29. Pavone ME, Reierstad S, Sun H, Milad M, Bulun SE, Cheng YH. Altered retinoid uptake and action contributes to cell survival in endometriosis. J Clin Endocrinol Metab 2010; 95(11): E300-9.
  30. Cheng YH, Yin P, Xue Q, Yilmaz B, Dawson MI, Bulun SE. Retinoic Acid (RA) regulates 17β-hydroxysteroid dehydrogenase type 2 expression in endometrium: Interaction of RA receptors with Specificity Protein (SP) 1/SP3 for estradiol metabolism. J Clin Endocrinol Metab2008; 93(5): 1915–23.
  31. Kobayashi H, Imanaka S, Nakamura H, Tsuji A. Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review). Mol Med Rep 2014; 9(5): 1483–505.
  32. Gogusev J, Bouquet De Jolinière J, Telvi L, Doussau M, Du Manoir S, Stojkoski A, et al. Genetic abnormalities detected by comparative genomic hybridization in a human endometriosis-derived cell line. Mol Hum Reprod 2000; 6(9): 821–7.
  33. Nyholt DR, Low SK, Anderson CA, Painter JN, Uno S, Morris AP, et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nat Genet 2012; 44(12): 1355–9.
  34. Kobayashi H, Matsubara S, Yoshimoto C, Shigetomi H, Imanaka S. The role of mitochondrial dynamics in the pathophysiology of endometriosis. J Obstet Gynaecol Res 2023; 49(12): 2783–91.
  35. Govatati S, Deenadayal M, Shivaji S, Bhanoori M. Mitochondrial displacement loop alterations are associated with endometriosis. Fertil Steril 2013; 99(7): 1980-6.e9.
  36. Panir K, Schjenken JE, Robertson SA, Louise Hull M. Non-coding RNAs in endometriosis: A narrative review. Hum Reprod Update 2018; 24(4): 497–515.
  37. Dai L, Gu L, Di W. MiR-199a attenuates endometrial stromal cell invasiveness through suppression of the IKKβ/nf-κb pathway and reduced interleukin-8 expression. Mol Hum Reprod 2012; 18(3): 136–45.
  38. Petracco R, Grechukhina O, Popkhadze S, Massasa E, Zhou Y, Taylor HS. MicroRNA 135 regulates HOXA10 expression in endometriosis. J Clin Endocrinol Metab 2011; 96(12): E1925-33.
  39. Bjorkman S, Taylor HS. MicroRNAs in endometriosis: Biological function and emerging biomarker candidates. Biol Reprod 2019; 100(5): 1135–46.
  40. Begum MIA, Chuan L, Hong ST, Chae HS. The Pathological Role of miRNAs in Endometriosis. Biomedicines 2023; 11(11):
  41. Nematian SE, Mamillapalli R, Kadakia TS, Zolbin MM, Moustafa S, Taylor HS. Systemic Inflammation Induced by microRNAs: Endometriosis-Derived Alterations in Circulating microRNA 125b-5p and Let-7b-5p Regulate Macrophage Cytokine Production. J Clin Endocrinol Metab 2018; 103(1): 64–74.
  42. Kiba A, Banno K, Yanokura M, Asada M, Nakayama Y, Aoki D, et al. Differential micro ribonucleic acid expression profiling in ovarian endometrioma with leuprolide acetate treatment. J Obstet Gynaecol Res 2016; 42(12): 1734–43.
  43. Messina S. The RAS oncogene in brain tumors and the involvement of let-7 microRNA. Mol Biol Rep 2024; 51(1): 531.
  44. Yu L, Cao C, Li X, Zhang M, Gu Q, Gao H, et al. Complete loss of miR-200 family induces EMT associated cellular senescence in gastric cancer. Oncogene 2022; 41(1): 26–36.
  45. Rekker K, Saare M, Roost AM, Kaart T, Sõritsa D, Karro H, et al. Circulating miR-200-family micro-RNAs have altered plasma levels in patients with endometriosis and vary with blood collection time. Fertil Steril 2015; 104(4): 938-46.e2.
  46. Zheng L, Sun DF, Tong Y. Exosomal miR-202 derived from leukorrhea as a potential biomarker for endometriosis. J Int Med Res 2023; 51(1): 3000605221147183.
  47. Maged AM, Deeb WS, El Amir A, Zaki SS, El Sawah H, Al Mohamady M, et al. Diagnostic accuracy of serum miR-122 and miR-199a in women with endometriosis. Int J Gynecol Obstet 2018; 141(1): 14–9.
  48. Nothnick WB, Graham A, Holbert J, Weiss MJ. miR-451 deficiency is associated with altered endometrial fibrinogen alpha chain expression and reduced endometriotic implant establishment in an experimental mouse model. PLoS One 2014; 9(6): e100336.
  49. Wang L, Zhang J, Sun H, Ji X, Zhang S. Effect of miR-451 on IVF/ICSI-ET outcome in patient with endometriosis and infertility. Am J Transl Res 2021; 13(11): 13051–8.
  50. Ghafouri-Fard S, Shoorei H, Taheri M. Role of non-coding RNAs in the pathogenesis of endometriosis. Front Oncol 2020; 10: 1370.
  51. Sun PR, Jia SZ, Lin H, Leng JH, Lang JH. Genome-wide profiling of long noncoding ribonucleic acid expression patterns in ovarian endometriosis by microarray. Fertil Steril 2014; 101(4): 1038-46.e7.
  52. Huang H, Zhu Z, Song Y. Downregulation of lncrna uca1 as a diagnostic and prognostic biomarker for ovarian endometriosis. Rev Assoc Med Bras 2019; 65(3): 336–41.
  53. Cai H, Zhu X, Li Z, Zhu Y, Lang J. IncRNA/mRNA profiling of endometriosis rat uterine tissues during the implantation window. Int J Mol Med 2019; 44(6): 2145–60.
  54. Wang WT, Sun YM, Huang W, He B, Zhao YN, Chen YQ. Genome-wide Long Non-coding RNA Analysis Identified Circulating LncRNAs as Novel Non-invasive Diagnostic Biomarkers for Gynecological Disease. Sci Rep 2016; 6: 23343.
  55. Lin D, Huang Q, Wu R, Dai S, Huang Z, Ren L, et al. Long non-coding RNA AFAP1-AS1 promoting epithelial-mesenchymal transition of endometriosis is correlated with transcription factor ZEB1. Am J Reprod Immunol 2019; 81(1): e13074.
  56. Zhang P, Wang G. Progesterone Resistance in Endometriosis: Current Evidence and Putative Mechanisms. Int J Mol Sci 2023; 24(8):
  57. Marquardt RM, Tran DN, Lessey BA, Rahman MS, Jeong JW. Epigenetic Dysregulation in Endometriosis: Implications for Pathophysiology and Therapeutics. Endocr Rev 2023; 44(6): 1074–95.
  58. Wang L, Zhao J, Li Y, Wang Z, Kang S. Genome-wide analysis of DNA methylation in endometriosis using Illumina Human Methylation 450 K BeadChips. Mol Reprod Dev 2019; 86(5): 491–501.
  59. Xue Q, Lin Z, Cheng YH, Huang CC, Marsh E, Yin P, et al. Promoter methylation regulates estrogen receptor 2 in human endometrium and endometriosis. Biol Reprod 2007; 77(4): 681–7.
  60. Bulun SE, Cheng YH, Pavone ME, Xue Q, Attar E, Trukhacheva E, et al. Estrogen receptor-β, Estrogen receptor-α, and progesterone resistance in endometriosis. Semin Reprod Med 2010; 28(1): 36–43.
  61. Koukoura O, Sifakis S, Spandidos DA. DNA methylation in endometriosis (Review). Mol Med Rep 2016; 13(4): 2939–48.
  62. Koukoura O, Spandidos DA, Daponte A, Sifakis S. DNA methylation profiles in ovarian cancer: Implication in diagnosis and therapy (Review). Mol Med Rep 2014; 10(1): 3–9.
  63. Ayhan A, Mao TL, Seckin T, Wu CH, Guan B, Ogawa H, et al. Loss of ARID1A expression is an early molecular event in tumor progression from ovarian endometriotic cyst to clear cell and endometrioid carcinoma. Int J Gynecol Cancer 2012; 22(8): 1310–5.
  64. Jones S, Li M, Williams Parsons D, Zhang X, Wesseling J, Kristel P, et al. Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. Hum Mutat 2012; 33(1): 100–3.
  65. Guan B, Wang TL, Shih IM. ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. Cancer Res 2011; 71(21): 6718–27.
  66. Dyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, et al. Genome-Wide DNA Methylation Analysis Predicts an Epigenetic Switch for GATA Factor Expression in Endometriosis. PLoS Genet 2014; 10(3): e1004158.
  67. Zanatta A, Rocha AM, Carvalho FM, Pereira RMA, Taylor HS, Motta ELA, et al. The role of the Hoxa10/HOXA10 gene in the etiology of endometriosis and its related infertility: A review. J Assist Reprod Genet 2010; 27(12): 701–10.
  68. Lu H, Yang X, Zhang Y, Lu R, Wang X. Epigenetic disorder may cause downregulation of HOXA10 in the eutopic endometrium of fertile women with endometriosis. Reprod Sci 2013; 20(1): 78–84.
  69. Zanatta A, Pereira RMA, Da Rocha AM, Cogliati B, Baracat EC, Taylor HS, et al. The relationship among HOXA10, estrogen receptor α, progesterone receptor, and progesterone receptor B proteins in rectosigmoid endometriosis: A tissue microarray study. Reprod Sci 2015; 22(1): 31–7.
  70. Bulun SE, Cheng YH, Pavone ME, Yin P, Imir G, Utsunomiya H, et al. 17-Hydroxysteroid dehydrogenase-2 deficiency and progesterone resistance in endometriosis. Semin Reprod Med 2010; 28(1): 44–50.
  71. Huhtinen K, Desai R, Stah̊le M, Salminen A, Handelsman DJ, Perheentupa A, et al. Endometrial and endometriotic concentrations of estrone and estradiol are determined by local metabolism rather than circulating levels. J Clin Endocrinol Metab 2012; 97(11): 4228–35.
  72. Yilmaz BD, Bulun SE. Endometriosis and nuclear receptors. Hum Reprod Update 2019; 25(4): 473–85.
  73. Xue Q, Zhou YF, Zhu SN, Bulun SE. Hypermethylation of the CpG island spanning from exon II to intron III is associated with steroidogenic factor 1 expression in stromal cells of endometriosis. Reprod Sci 2011; 18(11): 1080–4.
  74. Bernardi LA, Dyson MT, Tokunaga H, Sison C, Oral M, Robins JC, et al. The essential role of GATA6 in the activation of estrogen synthesis in endometriosis. Reprod Sci 2019; 26(1): 60–9.
  75. Hsiao KY, Wu MH, Chang N, Yang SH, Wu CW, Sun HS, et al. Coordination of AUF1 and miR-148a destabilizes DNA methyltransferase 1 mRNA under hypoxia in endometriosis. Mol Hum Reprod 2015; 21(12): 894–904.
  76. Arosh JA, Lee JH, Starzinski-Powitz A, Banu SK. Selective inhibition of prostaglandin E2 receptors EP2 and EP4 modulates DNA methylation and histone modification machinery proteins in human endometriotic cells. Mol Cell Endocrinol 2015; 409: 51–8.
  77. Wang DB, Chen Q, Zhang C, Ren F, Li T. DNA hypomethylation of the COX-2 gene promoter is associated with up-regulation of its mRNA expression in eutopic endometrium of endometriosis. Eur J Med Res 2012; 17(1): 12.
  78. Lai ZZ, Yang HL, Ha SY, Chang KK, Mei J, Zhou WJ, et al. Cyclooxygenase-2 in endometriosis. Int J Biol Sci 2019; 15(13): 2783–97.
  79. Gujral P, Mahajan V, Lissaman AC, Ponnampalam AP. Histone acetylation and the role of histone deacetylases in normal cyclic endometrium. Reprod Biol Endocrinol 2020; 18(1): 84.
  80. Hayashi A, Horiuchi A, Kikuchi N, Hayashi T, Fuseya C, Suzuki A, et al. Type-specific roles of histone deacetylase (HDAC) overexpression in ovarian carcinoma: HDAC1 enhances cell proliferation and HDAC3 stimulates cell migration with downregulation of E-cadherin. Int J Cancer 2010; 127(6): 1332–46.
  81. Colón-Díaz M, Báez-Vega P, García M, Ruiz A, Monteiro JB, Fourquet J, et al. HDAC1 and HDAC2 are differentially expressed in endometriosis. Reprod Sci 2012; 19(5): 483–92.
  82. Ito M, Yu RN, Jameson JL. Steroidogenic factor-1 contains a carboxy-terminal transcriptional activation domain that interacts with steroid receptor coactivator-1. Mol Endocrinol 1998; 12(2): 290–301.
  83. Attar E, Tokunaga H, Imir G, Yilmaz MB, Redwine D, Putman M, et al. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. J Clin Endocrinol Metab 2009; 94(2): 623–31.
  84. Kawano Y, Nasu K, Li H, Tsuno A, Abe W, Takai N, et al. Application of the histone deacetylase inhibitors for the treatment of endometriosis: Histone modifications as pathogenesis and novel therapeutic target. Hum Reprod 2011; 26(9): 2486–98.
  85. Chen S, Liu Y, Zhong Z, Wei C, Liu Y, Zhu X. Peritoneal immune microenvironment of endometriosis: Role and therapeutic perspectives. Front Immunol 2023; 14:
  86. Laganà AS, Salmeri FM, Ban Frangež H, Ghezzi F, Vrtačnik-Bokal E, Granese R. Evaluation of M1 and M2 macrophages in ovarian endometriomas from women affected by endometriosis at different stages of the disease. Gynecol Endocrinol 2020; 36(5): 441–4.
  87. Nie MF, Xie Q, Wu YH, He H, Zou LJ, She XL, et al. Serum and ectopic endometrium from women with endometriosis modulate macrophage M1/M2 polarization via the Smad2/Smad3 pathway. J Immunol Res 2018; 2018: 6285813.
  88. Abramiuk M, Grywalska E, Małkowska P, Sierawska O, Hrynkiewicz R, Niedźwiedzka-Rystwej P. The role of the Immune System in the Development of Endometriosis. Cells 2022; 11(13):
  89. Hoogstad-Van Evert J, Paap R, Nap A, van der Molen R. The promises of natural killer cell therapy in endometriosis. Int J Mol Sci 2022; 23(10):
  90. Sikora J, Mielczarek-Palacz A, Kondera-Anasz Z. Role of Natural Killer Cell Activity in the Pathogenesis of Endometriosis. Curr Med Chem 2011; 18(2): 200–8.
  91. Oală IE, Mitranovici MI, Chiorean DM, Irimia T, Crișan AI, Melinte IM, et al. Endometriosis and the Role of Pro-Inflammatory and Anti-Inflammatory Cytokines in Pathophysiology: A Narrative Review of the Literature. Diagnostics (Basel) 2024; 14(3): 312.
  92. Sotiropoulou PA, Perez SA, Gritzapis AD, Baxevanis CN, Papamichail M. Interactions between human mesenchymal stem cells and natural killer cells. Stem Cells 2006; 24(1): 74–85.
  93. Wang X, Jia Y, Li D, Guo X, Zhou Z, Qi M, et al. The abundance and function of neutrophils in the endometriosis systemic and pelvic microenvironment. Mediators Inflamm 2023; 2023: 1481489.
  94. Gardella B, Dominoni M, Gritti A, Arrigo A, Antonucci S, Carletti GV, et al. Endometriosis pain and epithelial neutrophil activating peptide-78 levels. Sci Rep 2022; 12(1): 3227.
  95. Milewski Ł, Dziunycz P, Barcz E, Radomski D, Roszkowski PI, Korczak-Kowalska G, et al. Increased levels of human neutrophil peptides 1, 2, and 3 in peritoneal fluid of patients with endometriosis: Association with neutrophils, T cells and IL-8. J Reprod Immunol 2011; 91(1–2): 64–70.
  96. Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, Taketani Y. Lymphocytes in Endometriosis. Am J Reprod Immunol 2011; 65(1): 1–10.
  97. Shi JL, Zheng ZM, Chen M, Shen HH, Li MQ, Shao J. IL-17: an important pathogenic factor in endometriosis. Int J Med Sci 2022; 19(4): 769–78.
  98. Osuga Y, Hirota Y, Hirata T, Takamura M, Urata Y, Harada M, et al. Th2 cells and Th17 cells in the development of endometriosis – possible roles of interleukin-4 and interleukin-17A. J Endometr 2016; 8(4): 136–40.
  99. Chang LY, Shan J, Hou XX, Li DJ, Wang XQ. Synergy between Th1 and Th2 responses during endometriosis: A review of current understanding. J Reprod Immunol 2023; 158: 103975.
  100. Suen JL, Chang Y, Shiu YS, Hsu CY, Sharma P, Chiu CC, et al. IL-10 from plasmacytoid dendritic cells promotes angiogenesis in the early stage of endometriosis. J Pathol 2019; 249(4): 485–97.
  101. Javadirad SM, Shishebor E, Behnamfar F. Decreased Expression of PSMB9 Gene in Patients with Endometrial Carcinoma [in Persian] J Isfahan Med Sch 2024; 41(745): 1045–51.
  102. García-Gómez E, Vázquez-Martínez ER, Reyes-Mayoral C, Cruz-Orozco OP, Camacho-Arroyo I, Cerbón M. Regulation of Inflammation Pathways and Inflammasome by Sex Steroid Hormones in Endometriosis. Front Endocrinol (Lausanne) 2020; 10: 935.
  103. Anastasiu CV, Moga MA, Neculau AE, Bălan A, Scârneciu I, Dragomir RM, et al. Biomarkers for the noninvasive diagnosis of endometriosis: State of the art and future perspectives. Int J Mol Sci 2020; 21(5): 1750.
  104. Laganà AS, Garzon S, Götte M, Viganò P, Franchi M, Ghezzi F, et al. The pathogenesis of endometriosis: Molecular and cell biology insights. Int J Mol Sci 2019; 20(22): 5615.
  105. Hon JX, Wahab NA, Karim AKA, Mokhtar NM, Mokhtar MH. MicroRNAs in Endometriosis: Insights into Inflammation and Progesterone Resistance. Int J Mol Sci 2023; 24(19):
  106. Behnamfar F, Ghahiri A, Tavakoli M. Levonorgestrel-releasing intrauterine system (mirena) in compare to medroxyprogesterone acetate as a therapy for endometrial hyperplasia. J Res Med Sci 2014; 19(8): 686–90.
  107. Ghaemmaghami F, Behnamfar F, Saberi H. Immediate grafting of transected obturator nerve during radical hysterectomy. Int J Surg 2009; 7(2): 168–9.
  108. Biswas S, Rao CM. Epigenetic tools (The Writers, The Readers and The Erasers) and their implications in cancer therapy. Eur J Pharmacol 2018; 837: 8–24.
  109. Ganesan A, Arimondo PB, Rots MG, Jeronimo C, Berdasco M. The timeline of epigenetic drug discovery: From reality to dreams. Clin Epigenetics 2019; 11(1): 174.
  110. Szukiewicz D. Epigenetic regulation and T-cell responses in endometriosis – something other than autoimmunity. Front Immunol 2022; 13: 943839.
  111. Smolarz B, Szyłło K, Romanowicz H. Endometriosis: Epidemiology, classification, pathogenesis, treatment and genetics (review of literature). Int J Mol Sci 2021; 22(19): 10554.
  112. Patwardhan S, Nawathe A, Yates D, Harrison GR, Khan KS. Systematic review of the effects of aromatase inhibitors on pain associated with endometriosis. BJOG An Int J Obstet Gynaecol 2008; 115(7): 818–22.
  113. Słopień R, Mȩczekalski B. Aromatase inhibitors in the treatment of endometriosis. Prz Menopauzalny 2016; 15(1): 43–7.
  114. Krasenska M. Treatment with Aromatase Inhibitors in Postmenopausal Women with Breast Cancer and the Possibility of Influencing Side Effects. Klin Onkol 2016; 29(Suppl 3): 3S39–49.
  115. Psilopatis I, Vrettou K, Fleckenstein FN, Theocharis S. The Impact of Histone Modifications in Endometriosis Highlights New Therapeutic Opportunities. Cells 2023; 12(9): 1227.
  116. Qiu L, Burgess A, Fairlie DP, Leonard H, Parsons PG, Gabrielli BG. Histone deacetylase inhibitors trigger a G2 checkpoint in normal cells that is defective in tumor cells. Mol Biol Cell 2000; 11(6): 2069–83.
  117. Li X, Liu X, Guo SW. Histone deacetylase inhibitors as therapeutics for endometriosis. Expert Rev Obstet Gynecol 2012; 7(5): 451–66.
  118. Wu Y, Guo SW. Histone deacetylase inhibitors trichostatin A and valproic acid induce cell cycle arrest and p21 expression in immortalized human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol 2008; 137(2): 198–203.
  119. Wu Y, Guo SW. Suppression of IL-1β-induced COX-2 expression by trichostatin A (TSA) in human endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol [Internet]. 2007;135(1):88–93. Available from: https://www.sciencedirect.com/science/article/pii/S0301211506004507
  120. Lu Y, Nie J, Liu X, Zheng Y, Guo SW. Trichostatin A, a histone deacetylase inhibitor, reduces lesion growth and hyperalgesia in experimentally induced endometriosis in mice. Hum Reprod. 2010 Apr;25(4):1014–25.
  121. Nasu K, Kawano Y, Kai K, Aoyagi Y, Abe W, Okamoto M, et al. Aberrant histone modification in endometriosis. Front Biosci - Landmark. 2014 Jun;19(8):1202–14.
  122. Zhang A, Wang G, Jia L, Su T, Zhang L. Exosome-mediated microRNA-138 and vascular endothelial growth factor in endometriosis through inflammation and apoptosis via the nuclear factor-κB signaling pathway. Int J Mol Med. 2018;
  123. Fu J-L, Hsiao K-Y, Lee H-C, Li W-N, Chang N, Wu M-H, et al. Suppression of COUP-TFII upregulates angiogenin and promotes angiogenesis in endometriosis. Hum Reprod. 2018 Dec;33(8):1517–27.
  124. Sahin C, Mamillapalli R, Yi KW, Taylor HS. microRNA Let-7b: A Novel treatment for endometriosis. J Cell Mol Med. 2018;22(11):5346–53.
  125. Yang WW, Hong L, Xu XX, Wang Q, Huang JL, Jiang L. Regulation of miR-33b on endometriosis and expression of related factors. Eur Rev Med Pharmacol Sci. 2017;21(9):2027–33.
  126. Zhang Z, Li H, Zhao Z, Gao B, Meng L, Feng X. miR-146b level and variants is associated with endometriosis related macrophages phenotype and plays a pivotal role in the endometriotic pain symptom. Taiwan J Obstet Gynecol. 2019;58(3):401–8.
  127. Wu M, Zhang Y. MiR-182 inhibits proliferation, migration, invasion and inflammation of endometrial stromal cells through deactivation of NF-κB signaling pathway in endometriosis. Mol Cell Biochem. 2021;476(3):1575–88.
  128. Schneider C, Kässens N, Greve B, Hassan H, Schüring AN, Starzinski-Powitz A, et al. Targeting of syndecan-1 by micro-ribonucleic acid miR-10b modulates invasiveness of endometriotic cells via dysregulation of the proteolytic milieu and interleukin-6 secretion. Fertil Steril. 2013;99(3):871-881.e1.
  129. Marí-Alexandre J, Barceló-Molina M, Belmonte-López E, García-Oms J, Estellés A, Braza-Boïls A, et al. Micro-RNA profile and proteins in peritoneal fluid from women with endometriosis: their relationship with sterility. Fertil Steril. 2018;109(4):675-684.e2.
  130. Joshi NR, Miyadahira EH, Afshar Y, Jeong JW, Young SL, Lessey BA, et al. Progesterone resistance in endometriosis is modulated by the altered expression of MicroRNA-29c and FKBP4. J Clin Endocrinol Metab 2017; 102(1): 141–9.
  131. Zhou M, Fu J, Xiao L, Yang S, Song Y, Zhang X, et al. miR-196a overexpression activates the MEK/ERK signal and represses the progesterone receptor and decidualization in eutopic endometrium from women with endometriosis. Hum Reprod 2016; 31(11): 2598–608.
  132. Pei T, Liu C, Liu T, Xiao L, Luo B, Tan J, et al. MiR-194-3p represses the progesterone receptor and decidualization in eutopic endometrium from women with endometriosis. Endocrinology 2018; 159(7): 2554–62.
  133. Li M, Peng J, Shi Y, Sun P. miR-92a promotes progesterone resistance in endometriosis through PTEN/AKT pathway. Life Sci 2020; 242: 117190.
  134. Liu T, Xiao L, Pei T, Luo B, Tan J, Long Y, et al. miR-297 inhibits expression of progesterone receptor and decidualization in eutopic endometria of endometriosis. J Obstet Gynaecol Res 2023; 49(3): 956–65.
  135. Lin S-C, Li W-N, Lin S-C, Hou H-T, Tsai Y-C, Lin T-C, et al. Targeting YAP1 ameliorates progesterone resistance in endometriosis. Hum Reprod 2023; 38(6): 1124–34.
  136. Hawkins SM, Creighton CJ, Han DY, Zariff A, Anderson ML, Gunaratne PH, et al. Functional microRNA involved in endometriosis. Mol Endocrinol 2011; 25(5): 821–32.
  137. Long M, Wan X, La X, Gong X, Cai X. MiR-29c is downregulated in the ectopic endometrium and exerts its effects on endometrial cell proliferation, apoptosis and invasion by targeting c-Jun. Int J Mol Med 2015; 35(4): 1119–25.
  138. Yang H, Hu T, Hu P, Qi C, Qian L. miR‑143‑3p inhibits endometriotic stromal cell proliferation and invasion by inactivating autophagy in endometriosis. Mol Med Rep 2021; 23(5): 356.
  139. Li N, Yi K, Li X, Wang Y, Jing J, Hu J, et al. MiR-143-3p facilitates motility and invasiveness of endometriotic stromal cells by targeting VASH1/TGF-β signaling. Reprod Biol 2022; 22(1): 100592.