• Molecular and biological genetic inductors of change mucous endometrium at external genital endometriosis

Molecular and biological genetic inductors of change mucous endometrium at external genital endometriosis

HEALTH OF WOMAN. 2017.3(119):103–109

Veropotvelyan P. N., Tsehmistrenko I. S., Bondarenko A. A., Osadchuk E. G., Zhuravleva S. A. 
Interregional Center of Medical Genetics and Prenatal Diagnosis, Krivoy Rog
Perinatal Center, Kiev
Center for Family Planning and Human Reproduction, Krivoy Rog

The main theories of the pathogenesis of endometriosis are described. A modern approach is presented concerning the eutopic endometrium of patients with endometriosis and endometrioid heterotopia, including changes in the expression of inducers of adhesion, invasion, angiogenesis, hormonal inducers, receptivity and inducers of immunity.

Differences in healthy endometrium, endometrium of patients with endometriosis and endometrioid heterotopia have been determined. These studies contribute to increasing knowledge of the pathogenesis of endometriosis, the timely identification of possible therapeutic targets and, in addition, realize the effectiveness of methods for early diagnosis and prediction of the course of this pathology.

Key words: endometriosis, ectopic endometrium, hormonal inducers, eutopic endometrium, receptivity.


1. Margarit L, Taylor A, Roberts MH, Hopkins L, Davies C, Brenton AG et al. 2010. MUC1 as a discriminator between endometrium from fertile and infertile patients with PCOS and endometriosis. J. Clin. Endocrinol. Metab. 95(12):5320-9. https://doi.org/10.1210/jc.2010-0603; PMid:20826587

2. Jones CJ, Nardo LG, Litta P, Fazleabas AT. 2009. Peritoneal ectopic lesions from women with endometriosis show abnormalities in progesterone-dependent glycan expression. Fertil. Steril. 91(4, Suppl.):1608-10. https://doi.org/10.1016/j.fertnstert.2008.11.032; PMid:19131060 PMCid:PMC2742333

3. Colette S, Defrиre S, Van Kerk O, Van Langendonckt A, Dolmans MM, Donnez J. 2013. Differential expression of steroidogenic enzymes according to endometriosis type. Fertil. Steril. 100(6):1642-9. https://doi.org/10.1016/j.fertnstert.2013.08.003; PMid:24012197

4. Yu X, Ren H, Liu T, Yong M, Zhong H. 2016. Expression and significance of ERв and TrkB in endometriosis. Clin. Exp. Obstet. Gynecol. 43(1):75-81. PMid:27048022

5. Chishima F, Hayakawa S, Yamamoto T, Sugitani M, Karasaki-Suzuki M, Sugita K, Nemoto N. 2007. Expression of inducible microsomal prostaglandin E synthase in local lesions of endometriosis patients. Am. J. Reprod. Immunol. 57(3):218-26. https://doi.org/10.1111/j.1600-0897.2006.00466.x; PMid:17295901

6. Santulli P, Borghese B, Noлl JC, Fayt I, Anaf V, de Ziegler D et al. 2014. Hormonal therapy deregulates prostaglandin-endoperoxidase synthase 2 (PTGS2) expression in endometriotic tissues. J. Clin. Endocrinol. Metab. 99(3):881-90. https://doi.org/10.1210/jc.2013-2950; PMid:24423291

7. Wölfler MM, Küppers M, Rath W, Buck VU, Meinhold-Heerlein I, Classen-Linke I. 2016. Altered expression of progesterone receptor isoforms A and B in human eutopic endometrium in endometriosis patients. Ann. Anat. 206:1-6. https://doi.org/10.1016/j.aanat.2016.03.004; PMid:27050108

8. Carrarelli P, Rocha AL, Belmonte G, Zupi E, Abrгo MS, Arcuri F et al. 2014. Increased expression of antimьllerian hormone and its receptor in endometriosis. Fertil Steril. 101(5):1353-8. https://doi.org/10.1016/j.fertnstert.2014.01.052; PMid:24613539

9. Adamyan LV, Spitsyn VA, Andreyeva EN. 2008. Genetic aspects of gynecologic diseases. M, GEOTAR-media: 215.

10. Adamyan LV, Aznaurova YaB. 2015. Molecular aspects of pathogenesis of endometriosis. Reproduction problems 21(2):67-77.

11. Tikhonchuk EYu, Asaturova AV, Adamyan LV. 2016. Molecular and biological changes of endometrium at women with external genital endometriosis. Obstetrics and gynecology 11:42-48.

12. Gao X, Yeh YC, Outley J, Simon J, Botteman M, Spalding J. 2006. Health-related quality of life burden of women with endometriosis: a literature review. Curr. Med. Res. Opin. 22(9):1787-97. https://doi.org/10.1185/030079906X121084; PMid:16968582

13. Practice Committee of the American Society for Reproductive Medicine. Treatment of pelvic pain associated with endometriosis: a committee opinion. 2014. The Practice Committee. Fertil. Steril. 101(4):927-35. PMid:24630080

14. Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I et al. 2012. The burden оf endometriosis: costs and quality of life of women with endometriosis and treated in referral centrеs. Hum. Reprod. 27(5):1292-9.

15. Augoulea A, Alexandrou A, Creatsa M, Vrachnis N, Lambrinoudaki I. 2012. Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch. Gynecol. Obstet. 286(1):99-103. https://doi.org/10.1007/s00404-012-2357-8; PMid:22546953

16. Sourial S, Tempest N, Hapangama D. 2014. Theories on the pathogenesis of endometriosis. Int. J. Reprod. Med. 2014:179515. https://doi.org/10.1155/2014/179515; PMid:25763392 PMCid:PMC4334056

17. Osuga Y, Koga K, Hirota Y, Hirata T, Yoshino O, Taketani Y. 2011. Lymphocytes in endometriosis. Am. J. Reprod. Immunol. 65(1):1-10. https://doi.org/10.1111/j.1600-0897.2010.00887.x; PMid:20584009

18. Laschke MW, Giebels C, Menger MD. 2011. Vasculogenesis: a new piece of the endometriosis puzzle. Hum. Reprod. Update. 17(5):628-36. https://doi.org/10.1093/humupd/dmr023; PMid:21586449

19. Taniguchi F, Kaponis A, Izawa M, Kiyama T, Deura I, Ito M et al. 2011. Apoptosis and endometriosis. Front. Biosci. (Elite Ed). 3:648-62. https://doi.org/10.2741/e277

20. Albertsen HM, Chettier R, Farrington P, Ward K. 2013. Genome-wide association study link novel loci to endometriosis. PLoS One 8(3):e58257. https://doi.org/10.1371/journal.pone.0058257; PMid:23472165 PMCid:PMC3589333

21. Nasu K, Yuge A, Tsuno A, Nishida M, Narahara H. 2009. Involvement of resistance to apoptosis in the pathogenesis of endometriosis. Histol. Histopathol. 24(9):1181-92. PMid:19609865

22. Takebayashi A, Kimura F, Kishi Y, Ishida M, Takahashi A, Yamanaka A et al. 2014. The association between endometriosis and chronic endometritis. PLoS One. 9(2):e88354. https://doi.org/10.1371/journal.pone.0088354; PMid:24558386 PMCid:PMC3928198

23. Johnston-MacAnanny EB, Hartnett J, Engmann LL, Nulsen JC, Sanders MM, Benadiva CA. 2010. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil. Steril. 93(2):437-41. https://doi.org/10.1016/j.fertnstert.2008.12.131; PMid:19217098

24. Tong JL, Lang JH, Zhu L, Feng RE, Cui QC. 2012. Study on pathological characteristics of eutopic endometrium in endometriosis. Zhonghua Fu Chan Ke Za Zhi. 47(11):829-32. PMid:23302123

25. Billington BP. 1956. Gastric cancer; relationships between ABO blood-groups, site, and epidemiology. Lancet. 271:859–862. https://doi.org/10.1016/S0140-6736(56)91038-8

26. Burney RO, Giudice LC. 2012. Pathogenesis and pathophysiology of endometriosis. Fertil. Steril. 98(3):511-9. https://doi.org/10.1016/j.fertnstert.2012.06.029; PMid:22819144 PMCid:PMC3836682

27. Escobar-Morreale HF, Luque-Ramirez M, San Millan JL. 2005. The molecular-genetic basis of functional hyperandrogenism and the-polycystic ovary syndrome. Endocr. Rev. 26:251–282. https://doi.org/10.1210/er.2004-0004; PMid:15561799

28. He C, Song Y, He X, Zhang W, Liao L. 2006. No association of endometriosis with galactose-1-phosphate uridyl transferase mutations in a Chinese population. Environ. Mol. Mutagen. 47:307–309. https://doi.org/10.1002/em.20200; PMid:16416427

29. Trabert B, Schwartz SM, Peters U et al. 2011. Genetic variation inthe sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes. Fertil. Steril. 96(6):1401–1406. https://doi.org/10.1016/j.fertnstert.2011.09.004; PMid:21958689 PMCid:PMC3228888

30. Baranova H, Canis M, Ivaschenko T et al. 1999. Possible involvement of arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1 genes in the development of endometriosis. Mol. Hum. Reprod. 5(7):636–641. https://doi.org/10.1093/molehr/5.7.636; PMid:10381818

31. Fakis G, Boukouvala S, Kawamura A. 2007. Description of a novel polymorphic gene encoding for arylamine N-acetyltransferase in the rhesus macaque (Macaca mulatta), a model animal for endometriosis. Pharmacogenet. Genomics. 17(3):181–188. https://doi.org/10.1097/FPC.0b013e328011e3ad

32. Huang PC, Tsai EM, Li WF. 2010. Association between phthalate expo sure and glutathione S-transferase M1 polymorphism in adenomyosis, leiomyoma and endometriosis. Hum. Reprod. 25(4):986–994. https://doi.org/10.1093/humrep/deq015; PMid:20147336

33. Guo SW. 2006. The association of endometriosis risk and genetic polymorphisms involving dioxin detoxification enzymes: a systematic review. Eur. J. Obstet. Gynecol. Reprod. Biol. 124(2):134–143. https://doi.org/10.1016/j.ejogrb.2005.10.002; PMid:16289302

34. Matsuzaka Y, Kikuti YY, Goya K et al. 2012. Lack of an association human dioxin detoxification gene polymorphisms with endometriosis in Japanese women: results of a pilot study. Environ. Health Prev. Med. 17(6):512–517. https://doi.org/10.1007/s12199-012-0281-y

35. Babu KA, Rao KL, Reddy NG et al. 2004. N-acetyl transferase 2 polymorphism and advanced stages of endometriosis in South Indian women. Reprod. Biomed. Online. 9(5):533–540. https://doi.org/10.1016/S1472-6483(10)61638-0

36. Ivashchenko TE, Shved NIu, Kramareva NA et al. 2003. Analysis of the polymorphic alleles of genes encoding phase 1 and phase 2 detoxication enzymes in patients with endometriosis. Genetika. 39(4):525–529. PMid:12760253

37. Boyarskii KYu, Gaidukov SN, Chinchaladze AS. 2009. Zhurnal akusherstva i zhenskikh boleznei – Journal of obstetrics and women’s diseases. 58(2):65–71.

38. Roya R, Baludu GS, Reddy S. 2009. Possible aggravating impact of gene polymorphism in women with endometriosis. Indian J. Med. Res. 129:395–400. PMid:19535834

39. Sonova MM. 2009. Vestnik novykh meditsinskikh tekhnologii – Journal of new medical technologies. 16(1):79–80. 

40. Jana SK, Banerjee P, Mukherjee R, Chakravarty B, Chaudhury K. 2013. HOXA-11 mediated dysregulation of matrix remodeling during implantation window in women with endometriosis. J. Assist. Reprod. Genet. 30(11):1505-12.

41. Forte A, Cipollaro M, Galderisi U. 2014. Genetic, epigenetic and stem cell alterations in endometriosis: new insights and potential therapeutic perspectives. Clin. Sci. (London). 126(2):123-38. https://doi.org/10.1042/CS20130099

42. Meola J, Dentillo DB, Rosa e Silva JC, Hidalgo Gdos S, Paz CC, Ferriani RA. 2013. RHOC: a key gene for endometriosis. Reprod. Sci. 20(8):998-1002.

43. Mafra FA, Christofolini DM, Cavalcanti V, Vilarino FL, André GM, Kato P et al. 2014. Aberrant telomerase expression in the endometrium of infertile women with deep endometriosis. Arch. Med. Res. 45(1):31-5.

44. Locci R, Nisolle M, Angioni S, Foidart JM, Munaut C. 2013. Expression of the gamma 2 chain of laminin-332 in eutopic and ectopic endometrium of patients with endometriosis. Reprod. Biol. Endocrinol. 11:94.

45. Sundqvist J, Andersson KL, Scarselli G, Gemzell-Danielsson K, Lalitkumar PG. 2012. Expression of adhesion, attachment and invasion markers in eutopic and ectopic endometrium: a link to the aetiology of endometriosis. Hum. Reprod. 27(9):2737-46. https://doi.org/10.1093/humrep/des220

46. Li X, Zhang Y, Zhao L, Wang L, Wu Z, Mei Q et al. 2014. Whole-exome sequencing of endometriosis identifies frequent alterations in genes involved in cell adhesion and chromatin-remodeling complexes. Hum. Mol. Genet. 23(22):6008-21.

47. Timologou A, Zafrakas M, Grimbizis G, Miliaras D, Kotronis K, Stamatopoulos P, Tarlatzis BC. 2016. Immunohistochemical expression pattern of metastasis suppressors KAI1 and KISS1 in endometriosis and normal endometrium. Eur. J. Obstet. Gynecol. Reprod. Biol. 199:110-5.

48. Huang Y, Shen L, Cai A, Xiao J. 2015. Effect of warming Yang and removing blood stasis method on matrix metalloproteinases / tissue inhibitor metalloproteinases levels secreted by cultured endometrial cells from patients with endometriosis. J. Tradit. Chin. Med. 35(5):571-6.

49. Trovу de Marqui AB. 2012. Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling. Rev. Assoc. Med. Bras. 58(5):620-32.

50. Noël JC, Borghese B, Vaiman D, Fayt I, Anaf V, Chapron C. 2010. Steroidogenic factor-1 expression in ovarian endometriosis. Appl. Immunohistochem. Mol. Morphol. 18(3):258-61.

51. Cho S, Choi YS, Jeon YE, Im KJ, Choi YM, Yim SY et al. 2012. Expression of vascular endothelial growth factor (VEGF) and its soluble receptor-1 in endometriosis. Microvasc. Res. 83(2):237-42.

52. Saliminejad K, Memariani T, Ardekani AM, Kamali K, Edalatkhah H, Pahlevanzadeh Z, Khorram Khorshid HR. 2013. Association study of the TNF-б -1031T/C and VEGF+450G/C polymorphisms with susceptibility to endometriosis. Gynecol. Endocrinol. 29(11):974-7.

53. Laudanski P, Charkiewicz R, Kuzmicki M, Szamatowicz J, Świątecka J, Mroczko B, Niklinski J. 2014. Profiling of selected angiogenesis-related genes in proliferative eutopic endometrium of women with endometriosis. Eur. J. Obstet. Gynecol. Reprod. Biol. 172:85-92.

54. Harada T, Taniguchi F, Izawa M, Ohama Y, Takenaka Y, Tagashira Y et al. 2007. Apoptosis and endometriosis. Front. Biosci. 12:3140-51.

55. Xue Q, Zhou YF, Zhu SN, Bulun SE. 2011. 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. 18(11):1080-4. https://doi.org/10.1177/1933719111404614

56. Xue Q, Xu Y, Yang H, Zhang L, Shang J, Zeng C et al. 2014. Methylation of a novel CpG island of intron 1 is associated with steroidogenic factor 1 expression in endometriotic stromal cells. Reprod. Sci. 21(3):395-400. https://doi.org/10.1177/1933719113497283

57. Kitawaki J, Kado N, Ishihara H, Koshiba H, Kitaoka Y, Honjo H. 2002. Endometriosis: the pathophysiology as an estrogen dependent disease. J. Steroid Biochem. Mol. Biol. 83:149-55.

58. Dassen H, Punyadeera C, Kamps R, Delvoux B, Van Langendonckt A, Donnez J et al. 2007. Estrogen metabolizing enzymes in endometrium and endometriosis. Hum. Reprod. 22(12):3148-58.

59. Kogan EA, Kalinina EA, Kolotovkina AV, Fayzulina NM, Adamyan LV. 2014. Morfologichesky and molecular substratum of violation of a retseptivnost of endometrium at infertile patients with external and genital endometriosis. Obstetrics and gynecology 8:71-5.

60. Zayratyants OV, Adamyan LV, Somova MM, Borzenkova IP, Opalenov KV, Barsanova TG, Movtayev XP. 2008. An expression of an aromataza of R-450 cytochrome in ektopichesky and eutopichesky endometrium at endometriosis. Archive of pathology 70(5):16-20.

61. Akhmetov JB. 2012. Morphological criteria of the diagnosis of chronic endometritis. Scientific-Practical Journal of Medicine, «Vestnik KazNMU».

62. Johnson NP et al. 2017. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 32(2):315-324. https://doi.org/10.1093/humrep/dew293; PMid:27920089

63. Management to a practical training on gynecology: The education guidanceю 2007. / Under the editorship of VE Radzinsky: 600: silt.

Содержание журнала Full text of article