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Endometrial Determinism of Endometriosis: An Unnecessary Adjunct to Retrograde Menstruation

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Abstract

Purpose of Review

The observation that retrograde menstruation is almost universal while only a small proportion of women suffer with endometriosis is among the most quoted challenges to Sampson’s hypothesis. Addressing this challenge has focused on identifying unique features in the endometrium of affected women. The assumption that endometriosis develops from an aberrant endometrium forms the cornerstone of “endometrial determinism.” This review appraises the evidence for endometrial aberrations starting with an appraisal of retrograde menstruation.

Recent Findings

The quantity of endometrial tissue in retrograde menstruation is not well defined and is probably small, variable and its characteristics remain largely unknown. There are well documented differences between the eutopic endometrium in the presence and absence of endometriosis. On the other hand, at least some of the endometrial aberrations in endometriosis are the result of the disease and similar “defects” have been identified in the absence of endometriosis.

Summary

The evidence provided here challenges endometrial determinism as the primum movens in endometriosis. Indeed, it is unclear that the theory is a necessary adjunct to Sampson’s hypothesis. Further research is needed that can further our understanding of the natural history or endometriosis and that can enable the development of novel theories of its pathogenesis.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Sampson JA. The development of the implantation theory for the origin of peritoneal endometriosis. Am J Obstet Gynecol. 1940;40:549–57.

    Article  Google Scholar 

  2. Ulukus M, Cakmak H, Arici A. The role of endometrium in endometriosis. J Soc Gynecol Investig. 2006;13(7):467–76.

    Article  CAS  PubMed  Google Scholar 

  3. Lang JH. Cornerstone of study on endometriosis. Zhonghua Fu Chan Ke Za Zhi. 2005;40:3–4.

    PubMed  Google Scholar 

  4. Liang Y, Li Y, Liu K, Chen P, Wang D. Expression and significance of WNT4 in ectopic and eutopic endometrium of human endometriosis. Reprod Sci. 2016;23(3):379–85.

    Article  CAS  PubMed  Google Scholar 

  5. Guo SW, Habiba M, Benagiano G. From retrograde menstruation to endometrial determinism and a brave new world of “root treatment” of endometriosis: destiny or a fanciful utopia? Biomolecules. 2023;13(2):336.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Blumenkrantz MJ, Gallagher N, Bashore RA, Tenckhoff H. Retrograde menstruation in women undergoing chronic peritoneal dialysis. Obstet Gynecol. 1981;57(5):667–70.

    CAS  PubMed  Google Scholar 

  7. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. 1984;64(2):151–4.

    CAS  PubMed  Google Scholar 

  8. Liu DT, Hitchcock A. Endometriosis: its association with retrograde menstruation, dysmenorrhoea and tubal pathology. Br J Obstet Gynaecol. 1986;93(8):859–62.

    Article  CAS  PubMed  Google Scholar 

  9. Eskenazi B, Warner ML. Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 1997;24(2):235–58.

    Article  CAS  PubMed  Google Scholar 

  10. Moradi Y, Shams-Beyranvand M, Khateri S, Gharahjeh S, Tehrani S, Varse F, Tiyuri A, Najmi Z. A systematic review on the prevalence of endometriosis in women. Indian J Med Res. 2021;154(3):446–54.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod. 2002;17(10):2725–36.

    Article  CAS  PubMed  Google Scholar 

  12. D’Hooghe TM, Debrock S. Evidence that endometriosis results from the dislocation of basal endometrium? Hum Reprod. 2003;18(5):1130–1.

    Article  PubMed  Google Scholar 

  13. Dorning A, Dhami P, Panir K, Hogg C, Park E, Ferguson GD, Hargrove D, Karras J, Horne AW, Greaves E. Bioluminescent imaging in induced mouse models of endometriosis reveals differences in four model variations. Dis Model Mech. 2021;14(8):dmm.049070. https://doi.org/10.1242/dmm.049070.

    Article  Google Scholar 

  14. Donnez O, Van Langendonckt A, Defrère S, Colette S, Van Kerk O, Dehoux JP, Squifflet J, Donnez J. Induction of endometriotic nodules in an experimental baboon model mimicking human deep nodular lesions. Fertil Steril. 2013;99(3):783–9.

    Article  PubMed  Google Scholar 

  15. Donnez O, Soares M, Defrère S, Dehoux JP, van Langendonckt A, Donnez J, Dolmans MM, Colette S. Nerve fiber density in deep nodular endometriotic lesions induced in a baboon experimental model. Fertil Steril. 2013;100(4):1144–50.

    Article  CAS  PubMed  Google Scholar 

  16. Orellana R, García-Solares J, Donnez J, van Kerk O, Dolmans MM, Donnez O. Important role of collective cell migration and nerve fiber density in the development of deep nodular endometriosis. Fertil Steril. 2017;107(4):987–95.

    Article  CAS  PubMed  Google Scholar 

  17. D’Hooghe TM, Debrock S. Endometriosis, retrograde menstruation and peritoneal inflammation in women and in baboons. Hum Reprod Update. 2002;8(1):84–8.

    Article  PubMed  Google Scholar 

  18. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Increased prevalence and recurrence of retrograde menstruation in baboons with spontaneous endometriosis. Hum Reprod. 1996;11(9):2022–5.

    Article  CAS  PubMed  Google Scholar 

  19. Hastings JM, Fazleabas AT. A baboon model for endometriosis: implications for fertility. Reprod Biol Endocrinol. 2006;4(Suppl 1):S7.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Scheenjes E, te Velde ER, Kremer J. Inspection of the ovaries and steroids in serum and peritoneal fluid at various time intervals after ovulation in fertile women: implications for the luteinized unruptured follicle syndrome. Fertil Steril. 1990;54(1):38–41.

    Article  CAS  PubMed  Google Scholar 

  21. Koninckx PR, Ide P, Vandenbroucke W, Brosens IA. New aspects of the pathophysiology of endometriosis and associated infertility. J Reprod Med. 1980;24(6):257–60.

    CAS  PubMed  Google Scholar 

  22. Bartosik D, Jacobs SL, Kelly LJ. Endometrial tissue in peritoneal fluid. Fertil Steril. 1986;46(5):796–800.

    Article  CAS  PubMed  Google Scholar 

  23. Beyth Y, Yaffe H, Levij ISh, Sadovsky E. Retrograde seeding of endometrium: sequela of tubal flushing. Fertil Steril. 1975;26:1094–7.

    Article  CAS  PubMed  Google Scholar 

  24. Nagele F, Wieser F, Deery A, Hart R, Magos A. Endometrial cell dissemination at diagnostic hysteroscopy: a prospective randomized cross-over comparison of normal saline and carbon dioxide uterine distension. Hum Reprod. 1999;14(11):2739–42.

    Article  CAS  PubMed  Google Scholar 

  25. van der Linden PJ, Dunselman GA, de Goeij AF, van der Linden EP, Evers JL, Ramaekers FC. Epithelial cells in peritoneal fluid - of endometrial origin? Am J Obstet Gynecol. 1995;173(2):566–70.

    Article  PubMed  Google Scholar 

  26. Portuondo JA, Herrán C, Echanojauregui AD, Riego AG. Peritoneal flushing and biopsy in laparoscopically diagnosed endometriosis. Fertil Steril. 1982;38(5):538–41.

    Article  CAS  PubMed  Google Scholar 

  27. Badawy SZ, Cuenca V, Marshall L, Munchback R, Rinas AC, Coble DA. Cellular components in peritoneal fluid in infertile patients with and without endometriosis. Fertil Steril. 1984;42(5):704–8.

    Article  CAS  PubMed  Google Scholar 

  28. Goldstein DP, De Cholnoky C, Emans SJ. Adolescent endometriosis. J Adolesc Health Care. 1980;1(1):37–41.

    Article  CAS  PubMed  Google Scholar 

  29. Bokor A, Debrock S, Drijkoningen M, Goossens W, Fülöp V, D’Hooghe T. Quantity and quality of retrograde menstruation: a case control study. Reprod Biol Endocrinol. 2009;7:123.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Sharpe-Timms KL. Haptoglobin expression by shed endometrial tissue fragments found in peritoneal fluid. Fertil Steril. 2005;84(1):22–30.

    Article  CAS  PubMed  Google Scholar 

  31. Kruitwagen RF, Poels LG, Willemsen WN, Jap PH, de Ronde IJ, Hanselaar TG, Rolland R. Immunocytochemical markerprofile of endometriotic epithelial, endometrial epithelial, and mesothelial cells: a comparative study. Eur J Obstet Gynecol Reprod Biol. 1991;41:215–23.

    Article  CAS  PubMed  Google Scholar 

  32. Willemsen WN, Mungyer G, Smets H, Rolland R, Vemer H, Jap P. Behavior of cultured glandular cells obtained by flushing of the uterine cavity. Fertil Steril. 1985;44(1):92–5.

    Article  CAS  PubMed  Google Scholar 

  33. Kruitwagen RF, Poels LG, Willemsen WN, de Ronde IJ, Jap PH, Rolland R. Endometrial epithelial cells in peritoneal fluid during the early follicular phase. Fertil Steril. 1991;55(2):297–303.

    Article  CAS  PubMed  Google Scholar 

  34. D’Hooghe TM, Bambra CS, De Jonge I, Lauweryns JM, Koninckx PR. The prevalence of spontaneous endometriosis in the baboon (Papio anubis, Papio cynocephalus) increases with the duration of captivity. Acta Obstet Gynecol Scand. 1996;75(2):98–101.

    Article  CAS  PubMed  Google Scholar 

  35. D’Hooghe TM, Bambra CS, Raeymaekers BM, Koninckx PR. Development of spontaneous endometriosis in baboons. Obstet Gynecol. 1996;88(3):462–6.

    Article  CAS  PubMed  Google Scholar 

  36. D’Hooghe TM. Clinical relevance of the baboon as a model for the study of endometriosis. Fertil Steril. 1997;68(4):613–25.

    Article  CAS  PubMed  Google Scholar 

  37. Liu X, Long Q, Guo SW. Surgical history and the risk of endometriosis: a hospital-based case-control study. Reprod Sci. 2016;23(9):1217–24.

    Article  PubMed  Google Scholar 

  38. Long Q, Liu X, Guo SW. Surgery accelerates the development of endometriosis in mice. Am J Obstet Gynecol. 2016;215(3):320.e1-320.

    Article  PubMed  Google Scholar 

  39. Dehoux JP, Defrère S, Squifflet J, Donnez O, Polet R, Mestdagt M, Foidart JM, Van Langendonckt A, Donnez J. Is the baboon model appropriate for endometriosis studies? Fertil Steril. 2011;96(3):728–33.

    Article  PubMed  Google Scholar 

  40. te Linde RW, Scott RB. Experimental endometriosis. Am J Obstet Gynecol. 1950;60(5):1147–73.

    Article  Google Scholar 

  41. D’Hooghe TM, Bambra CS, Raeymaekers BM, De Jonge I, Lauweryns JM, Koninckx PR. Intrapelvic injection of menstrual endometrium causes endometriosis in baboons (Papio cynocephalus and Papio anubis). Am J Obstet Gynecol. 1995;173(1):125–34.

    Article  CAS  PubMed  Google Scholar 

  42. Harirchian P, Gashaw I, Lipskind ST, Braundmeier AG, Hastings JM, Olson MR, Fazleabas AT. Lesion kinetics in a non-human primate model of endometriosis. Hum Reprod. 2012;27(8):2341–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Slayden OD, Luo F, Martin DVMLD. A protocol for creating endometriosis in rhesus macaques (Macaca mulatta). J Med Primatol. 2023;52(6):405–13.

    Article  PubMed  Google Scholar 

  44. Vercellini P, Bandini V, Viganò P, Ambruoso D, Cetera GE, Somigliana E. Proposal for targeted, neo-evolutionary-oriented secondary prevention of early-onset endometriosis and adenomyosis. Part II: medical interventions Hum Reprod. 2024;39(1):18–34.

    PubMed  Google Scholar 

  45. Olive DL, Henderson DY. Endometriosis and Müllerian anomalies. Obstet Gynecol. 1987;69(3 Pt 1):412–5.

    CAS  PubMed  Google Scholar 

  46. Matalliotakis M, Goulielmos GN, Matalliotaki C, Trivli A, Matalliotakis I, Arici A. Endometriosis in adolescent and young girls: report on a series of 55 cases. J Pediatr Adolesc Gynecol. 2017;30(5):568–70.

    Article  PubMed  Google Scholar 

  47. Fedele L, Bianchi S, Di Nola G, Franchi D, Candiani GB. Endometriosis and nonobstructive müllerian anomalies. Obstet Gynecol. 1992;79(4):515–7.

    CAS  PubMed  Google Scholar 

  48. Uğur M, Turan C, Mungan T, Kuşçu E, Senöz S, Ağiş HT, Gökmen O. Endometriosis in association with Müllerian anomalies. Gynecol Obstet Invest. 1995;40(4):261–4.

    Article  PubMed  Google Scholar 

  49. Pitot MA, Bookwalter CA, Dudiak KM. Müllerian duct anomalies coincident with endometriosis: a review. Abdom Radiol (NY). 2020;45(6):1723–40.

    Article  PubMed  Google Scholar 

  50. Barbieri RL. Stenosis of the external cervical os: an association with endometriosis in women with chronic pelvic pain. Fertil Steril. 1998;70(3):571–3.

    Article  CAS  PubMed  Google Scholar 

  51. Spechler S, Nieman LK, Premkumar A, Stratton P. The Keeper, a menstrual collection device, as a potential cause of endometriosis and adenomyosis. Gynecol Obstet Invest. 2003;56(1):35–7.

    Article  PubMed  Google Scholar 

  52. Mollazadeh S, Sadeghzadeh Oskouei B, Kamalifard M, Mirghafourvand M, Aminisani N, Jafari SM. Association between sexual activity during menstruation and endometriosis: a case-control study. Int J Fertil Steril. 2019;13(3):230–5.

    PubMed  PubMed Central  Google Scholar 

  53. Filer RB, Wu CH. Coitus during menses. Its effect on endometriosis and pelvic inflammatory disease. J Reprod Med. 1989;34(11):887–90.

    CAS  PubMed  Google Scholar 

  54. Meaddough EL, Olive DL, Gallup P, Perlin M, Kliman HJ. Sexual activity, orgasm and tampon use are associated with a decreased risk for endometriosis. Gynecol Obstet Invest. 2002;53(3):163–9.

    Article  PubMed  Google Scholar 

  55. Arumugam K, Lim JM. Menstrual characteristics associated with endometriosis. Br J Obstet Gynaecol. 1997;104(8):948–50.

    Article  CAS  PubMed  Google Scholar 

  56. Mahmood TA, Templeton AA, Thomson L, Fraser C. Menstrual symptoms in women with pelvic endometriosis. Br J Obstet Gynaecol. 1991;98(6):558–63.

    Article  CAS  PubMed  Google Scholar 

  57. Vercellini P, De Giorgi O, Aimi G, Panazza S, Uglietti A, Crosignani PG. Menstrual characteristics in women with and without endometriosis. Obstet Gynecol. 1997;90(2):264–8.

    Article  CAS  PubMed  Google Scholar 

  58. Cramer DW, Wilson E, Stillman RJ, Berger MJ, Belisle S, Schiff I, Albrecht B, Gibson M, Stadel BV, Schoenbaum SC. The relation of endometriosis to menstrual characteristics, smoking, and exercise. JAMA. 1986;255(14):1904–8.

    Article  CAS  PubMed  Google Scholar 

  59. Treloar SA, Bell TA, Nagle CM, Purdie DM, Green AC. Early menstrual characteristics associated with subsequent diagnosis of endometriosis. Am J Obstet Gynecol. 2010;202(6):534.e1-534.e5346.

    Article  PubMed  Google Scholar 

  60. Smolarz B, Szyłło K, Romanowicz H. Endometriosis: epidemiology, classification, pathogenesis, treatment and genetics (review of literature). Int J Mol Sci. 2021;22(19):10554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Evers JL. Endometriosis does not exist; all women have endometriosis. Hum Reprod. 1994;9(12):2206–9.

    Article  CAS  PubMed  Google Scholar 

  62. Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med. 2014;2014:179515.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Murphy AA, Green WR, Bobbie D, dela Cruz ZC, Rock JA. Unsuspected endometriosis documented by scanning electron microscopy in visually normal peritoneum. Fertil Steril. 1986;46(3):522–4.

    Article  CAS  PubMed  Google Scholar 

  64. Redwine DB. Is “microscopic” peritoneal endometriosis invisible? Fertil Steril. 1988;50(4):665–6.

    Article  CAS  PubMed  Google Scholar 

  65. Nezhat F, Allan CJ, Nezhat C, Martin DC. Nonvisualized endometriosis at laparoscopy. Int J Fertil. 1991;36(6):340–3.

    CAS  PubMed  Google Scholar 

  66. Hopton EN, Redwine DB. Eyes wide shut: the illusory tale of ‘occult’ microscopic endometriosis. Hum Reprod. 2014;29(3):384–7.

    Article  PubMed  Google Scholar 

  67. Khan KN, Fujishita A, Kitajima M, Hiraki K, Nakashima M, Masuzaki H. Occult microscopic endometriosis: undetectable by laparoscopy in normal peritoneum. Hum Reprod. 2014;29(3):462–72.

    Article  PubMed  Google Scholar 

  68. Chopyak VV, Koval HD, Havrylyuk AM, Lishchuk-Yakymovych KA, Potomkina HA, Kurpisz MK. Immunopathogenesis of endometriosis - a novel look at an old problem. Cent Eur J Immunol. 2022;47(1):109–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Villanacci R, Bandini V, Ottolina J, Pagliardini L, Candiani M, Viganò P. The pathogenesis of endometriosis: clues from the immunological evidence. Minerva Obstet Gynecol. 2021;73(3):275–82.

    Article  PubMed  Google Scholar 

  70. Anderson G. Endometriosis pathoetiology and pathophysiology: roles of vitamin A, estrogen, immunity, adipocytes, gut microbiome and melatonergic pathway on mitochondria regulation. Biomol Concepts. 2019;10(1):133–49.

    Article  CAS  PubMed  Google Scholar 

  71. Yamaguchi M, Yoshihara K, Yachida N, Suda K, Tamura R, Ishiguro T, Enomoto T. The new era of three-dimensional histoarchitecture of the human endometrium. J Pers Med. 2021;11(8):713.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Schmidt WA, Karon M. Three-dimensional subgross morphology of the human endometrium. Diagn Gynecol Obstet. 1981;3(3):193–203.

    CAS  PubMed  Google Scholar 

  73. Donnez J, Nisolle M, Casanas-Roux F. Three-dimensional architectures of peritoneal endometriosis. Fertil Steril. 1992;57(5):980–3.

    Article  CAS  PubMed  Google Scholar 

  74. Yamaguchi M, Yoshihara K, Suda K, Nakaoka H, Yachida N, Ueda H, Sugino K, Mori Y, Yamawaki K, Tamura R, Ishiguro T, Motoyama T, Watanabe Y, Okuda S, Tainaka K, Enomoto T. Three-dimensional understanding of the morphological complexity of the human uterine endometrium. iScience. 2021;24(4):102258.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Yamaguchi M, Nakaoka H, Suda K, et al. Spatiotemporal dynamics of clonal selection and diversification in normal endometrial epithelium. Nat Commun. 2022;13(1):943.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fasciani A, Bocci G, Xu J, Bielecki R, Greenblatt E, Leyland N, Casper RF. Three-dimensional in vitro culture of endometrial explants mimics the early stages of endometriosis. Fertil Steril. 2003;80(5):1137–43.

    Article  PubMed  Google Scholar 

  77. Dundon M, Madden O, Comizzoli P. Three-dimensional culture of endometrial cells from domestic cats: a new in vitro platform for assessing plastic toxicity. PLoS ONE. 2019;14(5):e0217365.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Abbas Y, Brunel LG, Hollinshead MS, Fernando RC, Gardner L, Duncan I, Moffett A, Best S, Turco MY, Burton GJ, Cameron RE. Generation of a three-dimensional collagen scaffold-based model of the human endometrium. Interface Focus. 2020;10(2):20190079.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Ahn J, Yoon MJ, Hong SH, Cha H, Lee D, Koo HS, Ko JE, Lee J, Oh S, Jeon NL, Kang YJ. Three-dimensional microengineered vascularised endometrium-on-a-chip. Hum Reprod. 2021;36(10):2720–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Wu Y, Basir Z, Kajdacsy-Balla A, Strawn E, Macias V, Montgomery K, Guo SW. Resolution of clonal origins for endometriotic lesions using laser capture microdissection and the human androgen receptor (HUMARA) assay. Fertil Steril. 2003;79(Suppl 1):710–7.

    Article  PubMed  Google Scholar 

  81. Li L, Antero MF, Zhang M, Chu T, Seckin T, Ayhan A, Pisanic T, Wang TL, Cope L, Segars J, Shih IM. Mutation and methylation profiles of ectopic and eutopic endometrial tissues. J Pathol. 2021;255(4):387–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Yi D, Lang J, Zhu L, Leng J. The present and future of diagnosis and treatment of endometriosis (in Chinese). Sci Sin Vitae. 2021;51:1017–23.

    Article  Google Scholar 

  83. Benagiano G, Brosens I, Habiba M. Structural and molecular features of the endomyometrium in endometriosis and adenomyosis. Hum Reprod Update. 2014;20(3):386–402.

    Article  CAS  PubMed  Google Scholar 

  84. Lawson C, Bourcier N, Al-Akoum M, Maheux R, Naud F, Akoum A. Abnormal interleukin 1 receptor types I and II gene expression in eutopic and ectopic endometrial tissues of women with endometriosis. J Reprod Immunol. 2008;77(1):75–84.

    Article  CAS  PubMed  Google Scholar 

  85. Abu-Asab M, Zhang M, Amini D, Abu-Asab N, Amri H. Endometriosis gene expression heterogeneity and biosignature: a phylogenetic analysis. Obstet Gynecol Int. 2011;2011:719059. https://doi.org/10.1155/2011/719059.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bulun SE, Yildiz S, Adli M, Wei JJ. Adenomyosis pathogenesis: insights from next-generation sequencing. Hum Reprod Update. 2021;27(6):1086–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Yilmaz BD, Bulun SE. Endometriosis and nuclear receptors. Hum Reprod Update. 2019;25(4):473–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Laganà AS, Garzon S, Götte M, Viganò P, Franchi M, Ghezzi F, Martin DC. The pathogenesis of endometriosis: molecular and cell biology insights. Int J Mol Sci. 2019;20(22):5615.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Patel BG, Rudnicki M, Yu J, Shu Y, Taylor RN. Progesterone resistance in endometriosis: origins, consequences and interventions. Acta Obstet Gynecol Scand. 2017;96(6):623–32.

    Article  CAS  PubMed  Google Scholar 

  90. Zhang X, Lu B, Huang X, Xu H, Zhou C, Lin J. Innervation of endometrium and myometrium in women with painful adenomyosis and uterine fibroids. Fertil Steril. 2010;94(2):730–7.

    Article  PubMed  Google Scholar 

  91. Miller EJ, Fraser IS. The importance of pelvic nerve fibers in endometriosis. Womens Health (Lond). 2015;11(5):611–8.

    Article  CAS  PubMed  Google Scholar 

  92. Yadav G, Rao M, Gothwal M, Singh P, Kathuria P, Sharma PP. Detection of nerve fibers in the eutopic endometrium of women with endometriosis, uterine fibroids and adenomyosis. Obstet Gynecol Sci. 2021;64(5):454–61.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Scutiero G, Iannone P, Bernardi G, Bonaccorsi G, Spadaro S, Volta CA, Greco P, Nappi L. Oxidative stress and endometriosis: a systematic review of the literature. Oxid Med Cell Longev. 2017;2017:7265238.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Carvalho LF, Abrão MS, Biscotti C, Sharma R, Nutter B, Falcone T. Oxidative cell injury as a predictor of endometriosis progression. Reprod Sci. 2013;20(6):688–98.

    Article  CAS  PubMed  Google Scholar 

  95. Laschke MW, Menger MD. Basic mechanisms of vascularization in endometriosis and their clinical implications. Hum Reprod Update. 2018;24(2):207–24.

    Article  CAS  PubMed  Google Scholar 

  96. • Walker ER, McGrane M, Aplin JD, Brison DR, Ruane PT. A systematic review of transcriptomic studies of the human endometrium reveals inconsistently reported differentially expressed genes. Reprod Fertil. Published online June 1, 2023. https://doi.org/10.1530/RAF-22-0115. The review reveals important limitations that hinder collation of results of published studies of transcriptomes obtained from the endometrium in endometriosis.

  97. Prašnikar E, Knez J, Kovačič B, Kunej T. Molecular signature of eutopic endometrium in endometriosis based on the multi-omics integrative synthesis. J Assist Reprod Genet. 2020;37(7):1593–611.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Barlow DH, Kennedy S. Endometriosis: new genetic approaches and therapy. Annu Rev Med. 2005;56:345–56.

    Article  CAS  PubMed  Google Scholar 

  99. Di W, Guo SW. The search for genetic variants predisposing women to endometriosis. Curr Opin Obstet Gynecol. 2007;19(4):395–401.

    Article  PubMed  Google Scholar 

  100. Guo SW. Epigenetics of endometriosis. Mol Hum Reprod. 2009;15(10):587–607.

    Article  CAS  PubMed  Google Scholar 

  101. Dyson MT, Roqueiro D, Monsivais D, Ercan CM, Pavone ME, Brooks DC, Kakinuma T, Ono M, Jafari N, Dai Y, Bulun SE. Genome-wide DNA methylation analysis predicts an epigenetic switch for GATA factor expression in endometriosis. PLoS Genet. 2014;10(3):e1004158.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Houshdaran S, Nezhat CR, Vo KC, Zelenko Z, Irwin JC, Giudice LC. Aberrant endometrial DNA methylome and associated gene expression in women with endometriosis. Biol Reprod. 2016;95(5):93. https://doi.org/10.1095/biolreprod.116.140434.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Naqvi H, Ilagan Y, Krikun G, Taylor HS. Altered genome-wide methylation in endometriosis. Reprod Sci. 2014;21(10):1237–43. https://doi.org/10.1177/1933719114532841. Epud.2014 Apr 30. PMID: 2478717; PMCID: PMC5933183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. •• 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. https://doi.org/10.1210/endrev/bnad020. PMID:37409951;PMCID:PMC10638603. This review analyzes the recent evidence of epigenetic contributions to the pathophysiology of endometriosis and how this may impact developments in therapeutics.

    Article  PubMed  Google Scholar 

  105. Wu Y, Strawn E, Basir Z, Halverson G, Guo SW. Aberrant expression of deoxyribonucleic acid methyltransferases DNMT1, DNMT3A, and DNMT3B in women with endometriosis. Fertil Steril. 2007;87(1):24–32.

    Article  CAS  PubMed  Google Scholar 

  106. Szczepanska M, Wirstlein P, Skrzypczak J, Jagodzinski PP. Expression of HOXA11 in the mid-luteal endometrium from women with endometriosis-associated infertility. Reprod Biol Endocrinol. 2012;10(1):1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van Kaam KJ, Delvoux B, Romano A, D’Hooghe T, Dunselman GA, Groothuis PG. Deoxyribonucleic acid methyltransferases and methyl-CpG-binding domain proteins in human endometrium and endometriosis. Fertil Steril. 2011;95(4):1421–7.

    Article  PubMed  Google Scholar 

  108. Roca FJ, Loomans HA, Wittman AT, Creighton CJ, Hawkins SM. Ten-eleven translocation genes are downregulated in endometriosis. Curr Mol Med. 2016;16(3):288–98.

    Article  CAS  PubMed  Google Scholar 

  109. Huang Q, Liu X, Critchley H, Fu Z, Guo SW. How does the extent of fibrosis in adenomyosis lesions contribute to heavy menstrual bleeding? Reprod Med Biol. 2022;21(1):e12442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Naqvi H, Mamillapalli R, Krikun G, Taylor HS. Endometriosis located proximal to or remote from the uterus differentially affects uterine gene expression. Reprod Sci. 2016;23(2):186–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Szczepanska M, Wirstlein P, Zawadzka M, Wender-Ozegowska E, Jagodzinski PP. Alternation of ten-eleven translocation 1, 2, and 3 expression in eutopic endometrium of women with endometriosis-associated infertility. Gynecol Endocrinol. 2018;34(12):1084–90.

    Article  CAS  PubMed  Google Scholar 

  112. Xiao L, Pei T, Huang W, Zhou M, Fu J, Tan J, Liu T, Song Y, Yang S. MicroRNA22–5p targets ten-eleven translocation and regulates estrogen receptor 2 expression in infertile women with minimal/mild endometriosis during implantation window. PLoS ONE. 2020;15(7):e0234086. https://doi.org/10.1371/journal.pone.0234086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Adamczyk M, Rawluszko-Wieczorek AA, Wirstlein P, Nowicki M, Jagodziński PP, Wender-Ozegowska E, Kedzia M. Assessment of TET1 gene expression, DNA methylation and H3K27me3 level of its promoter region in eutopic endometrium of women with endometriosis and infertility. Biomed Pharmacother. 2022;150:112989. https://doi.org/10.1016/j.biopha.2022.112989.

    Article  CAS  PubMed  Google Scholar 

  114. Xiaomeng X, Ming Z, Jiezhi M, Xiaoling F. Aberrant histone acetylation and methylation levels in woman with endometriosis. Arch Gynecol Obstet. 2013;287(3):487–94.

    Article  PubMed  Google Scholar 

  115. Colón-Díaz M, Baez-Vega P, Garcia M, Ruiz A, Monteiro JB, Fourquet J, Bayona M, Alvarez-Garriga C, Achille A, Seto E, Flores I. HDAC1 and HDAC2 are differentially expressed in endometriosis. Reprod Sci. 2012;19(5):483–92.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kim D, Kim KI, Baek SH. Roles of lysine-specific demethylase 1 (LSD1) in homeostasis and diseases. J Biomed Sci. 2021;28(1):41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Yoo JY, Kim TH, Fazleabas AT, Palomino WA, Ahn SH, Tayade C, Schammel DP, Young SL, Jeong JW, Lessey BA. KRAS activation and over- expression of SIRT1/BCL6 contributes to the pathogenesis of endometriosis and progesterone resistance. Sci Rep. 2017;7(1):6765.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Zhang Q, Dong P, Liu X, Sakuragi N, Guo SW. Enhancer of zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis. Sci Rep. 2017;7(1):6804.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Colón-Caraballo M, Torres-Reveron A, Soto-Vargas JL, Young SL, Lessey B, Mendoza A, Urrutia R, Flores I. Effects of histone methyltransferase inhibition in endometriosis. Biol Reprod. 2018;99(2):293–307.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Wen X, Xiong Y, Liu H, Geng T, Jin L, Zhang M, Ma L, Zhang Y. Decreased mixed lineage leukemia 1 is involved in endometriosis-related infertility. J Mol Endocrinol. 2021;66(1):45–57.

    Article  CAS  PubMed  Google Scholar 

  121. Kim TH, Yoo JY, Wang Z, Lydon JP, Khatri S, Hawkins SM, Leach RE, Fazleabas AT, Young SL, Lessey BA, Ku BJ, Jeong JW. ARID1A is essential for endometrial function during early pregnancy. PLoS Genet. 2015;11(9):e1005537.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Rocha-Junior CV, Da Broi MG, Miranda-Furtado CL, Navarro PA, Ferriani RA, Meola J. Progesterone receptor B (PGR-B) is partially methylated in eutopic endometrium from infertile women with endometriosis. Reprod Sci. 2019;26(12):1568–74.

    Article  CAS  PubMed  Google Scholar 

  123. Samadieh Y, Favaedi R, Ramezanali F, Afsharian P, Aflatoonian R, Shahhoseini M. Epigenetic dynamics of HOXA10 gene in infertile women with endometriosis. Reprod Sci. 2019;26(1):88–96.

    Article  CAS  PubMed  Google Scholar 

  124. Wu YU, Zhang M, Zhang X, Xu Z, Jin W. Methylation status and protein expression of RASSF1A in endometriosis. Oncol Lett. 2016;11(6):4107–12. https://doi.org/10.3892/ol.2016.4512.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Wang D, 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. https://doi.org/10.1186/2047-783X-17-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Li Y, An D, Guan YX, Kang S. Aberrant methylation of the E-cadherin gene promoter region in endometrium and ovarian endometriotic cysts of patients with ovarian endometriosis. Gynecol Obstet Invest. 2017;82(1):78–85.

    Article  CAS  PubMed  Google Scholar 

  127. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Xue Q, Xu Y, Yang H, Zhang L, Shang J, Zeng C, Yin P, Bulun SE. Methylation of a novel CpG island of intron 1 is associated with steroidogenic factor 1 expression in endometriotic stromal cells. Reprod Sci. 2014;21(3):395–400.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Zhao J, Wang L, Li Y, Zhao W, Kang S. Hypomethylation of the GSTM1 promoter is associated with ovarian endometriosis. Hum Reprod. 2019;34(5):804–12. https://doi.org/10.1093/humrep/dez039.

    Article  CAS  PubMed  Google Scholar 

  130. Juanqing L, Hailan Y, Xiangwei F, Tao Z, Junyan M, Jianhong Z, Jun L, Jianhua Y. Relationship between the methylation levels of Twist gene and pathogenesis of endometriosis. Cell Mol Biol (Noisy-le-grand). 2019;65(3):94–100. PMID:30942161. Cited in: Ovid MEDLINE(R) at http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=reference&D=med16&NEWS=N&AN=30942161. Accessed 30 Dec 2023.

  131. Zhao W, Kang S, Zhao J, Wang L, Cao S, Li Y. Aberrant methylation of the IL-12B promotor region contributes to the risk of developing ovarian endometriosis. Mol Reprod Dev. 2019;86(6):632–8. https://doi.org/10.1002/mrd.23139,10.1002/mrd.23139.

    Article  CAS  PubMed  Google Scholar 

  132. 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. https://doi.org/10.1177/1933719112451146.

    Article  CAS  PubMed  Google Scholar 

  133. Andersson KL, Bussani C, Fambrini M, Polverino V, Taddei GL, Gemzell-Danielsson K, Scarselli G. DNA methylation of HOXA10 in eutopic and ectopic endometrium. Hum Reprod. 2014;29(9):1906–11. https://doi.org/10.1093/humrep/deu161,10.1093/humrep/deu161.

    Article  CAS  PubMed  Google Scholar 

  134. Amirteimouri S, Ashini M, Ramazanali F, Aflatoonian R, Afsharian P, Shahhoseini M. Epigenetic role of the nuclear factor NF-Y on ID gene family in endometrial tissues of women with endometriosis: a case control study. Reprod Biol Endocrinol. 2019;17(1):32. https://doi.org/10.1186/s12958-019-0476-9.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Tanaka M, Kyo S, Kanaya T, Yatabe N, Nakamura M, Maida Y, Okabe M, Inoue M. Evidence of the monoclonal composition of human endometrial epithelial glands and mosaic pattern of clonal distribution in luminal epithelium. Am J Pathol. 2003;163(1):295–301.

    Article  PubMed  PubMed Central  Google Scholar 

  136. Wu Y, Guo SW. Reconstructing cellular lineages in endometrial cells. Fertil Steril. 2008;89(2):481–4.

    Article  PubMed  Google Scholar 

  137. Suda K, Nakaoka H, Yoshihara K, Ishiguro T, Tamura R, Mori Y, Yamawaki K, Adachi S, Takahashi T, Kase H, Tanaka K, Yamamoto T, Motoyama T, Inoue I, Enomoto T. Clonal expansion and diversification of cancer-associated mutations in endometriosis and normal endometrium. Cell Rep. 2018;24(7):1777–89.

    Article  CAS  PubMed  Google Scholar 

  138. Moore L, Leongamornlert D, Coorens THH, et al. The mutational landscape of normal human endometrial epithelium. Nature. 2020;580(7805):640–6.

    Article  CAS  PubMed  Google Scholar 

  139. Takeda T, Banno K, Kobayashi Y, Adachi M, Yanokura M, Tominaga E, Kosaki K, Aoki D. Mutations of RAS genes in endometrial polyps. Oncol Rep. 2019;42(6):2303–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Hoshiai H, Ishikawa M, Sawatari Y, Noda K, Fukaya T. Laparoscopic evaluation of the onset and progression of endometriosis. Am J Obstet Gynecol. 1993;169(3):714–9.

    Article  CAS  PubMed  Google Scholar 

  141. Thomas EJ, Cooke ID. Impact of gestrinone on the course of asymptomatic endometriosis. Br Med J. 1987;294:272–4.

    Article  CAS  Google Scholar 

  142. Mahmood TA, Templeton A. The impact of treatment on the natural history of endometriosis. Human Reprod. 1990;5:965–70.

    Article  CAS  Google Scholar 

  143. Telimaa S, Puolakka J, Ronnberg L, Kauppila A. Placebo controlled comparison of danazol and high-dose medroxyprogesterone acetate in the treatment of endometriosis. Gynecol Endocrinol. 1987;1:13–23.

    Article  CAS  PubMed  Google Scholar 

  144. Kim JJ, Taylor HS, Lu Z, Ladhani O, Hastings JM, Jackson KS, Wu Y, Guo SW, Fazleabas AT. Altered expression of HOXA10 in endometriosis: potential role in decidualization. Mol Hum Reprod. 2007;13(5):323–32.

    Article  CAS  PubMed  Google Scholar 

  145. Lee B, Du H, Taylor HS. Experimental murine endometriosis induces DNA methylation and altered gene expression in eutopic endometrium. Biol Reprod. 2009;80(1):79–85.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Kim TH, Yoo JY, Choi KC, Shin JH, Leach RE, Fazleabas AT, Young SL, Lessey BA, Yoon HG, Jeong JW. Loss of HDAC3 results in nonreceptive endometrium and female infertility. Sci Transl Med. 2019;11(474):eaaf7533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Sherwin JR, Hastings JM, Jackson KS, Mavrogianis PA, Sharkey AM, Fazleabas AT. The endometrial response to chorionic gonadotropin is blunted in a baboon model of endometriosis. Endocrinology. 2010;151(10):4982–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. • Afshar Y, Hastings J, Roqueiro D, Jeong JW, Giudice LC, Fazleabas AT. Changes in eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio anubis. Biol Reprod. 2013;88(2):44 This article and others cited provides strong evidence that endometriosis rather than inherent defects in the endometrium is the cause of aberrant gene expression in the eutopic endometrium.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Bashir ST, Redden CR, Raj K, Arcanjo RB, Stasiak S, Li Q, Steelman AJ, Nowak RA. Endometriosis leads to central nervous system-wide glial activation in a mouse model of endometriosis. J Neuroinflammation. 2023;20(1):59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

M.H. and G.B. received no financial support for this manuscript. S-W.G. was supported, in part, by grant 82071623 from the National Natural Science Foundation of China and grant SHDC2020CR2062B from Shanghai Shenkang Centre for Hospital Development.

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Authors and Affiliations

  1. Department of Health Sciences, University of Leicester and University Hospitals of Leicester, Leicester, LE1 5WW, UK

    Marwan Habiba

  2. Department of Biochemistry and Molecular Biology, Research Institute, Shanghai Obstetrics and Gynecology Hospital, Fudan University, Shanghai, 200011, China

    Sun-Wei Guo

  3. Faculty of Medicine and Surgery, “Sapienza”, University of Rome, 00161, Rome, Italy

    Giuseppe Benagiano

  4. Geneva Foundation for Medical Education and Research, 1202, Geneva, Switzerland

    Giuseppe Benagiano

  5. Women and Perinatal Services, Leicester Royal Infirmary, Leicester, LE1 5WW, UK

    Marwan Habiba

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M.H., G.B., and S-W.G.: conceptualization; M.H.: methodology; G.B., M.H., and S-W.G.: validation; M.H.: writing—original draft preparation; G.B. and S-W.G.: writing—review and editing. All authors have read and agreed to the published version of the manuscript.

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Habiba, M., Guo, SW. & Benagiano, G. Endometrial Determinism of Endometriosis: An Unnecessary Adjunct to Retrograde Menstruation. Curr Obstet Gynecol Rep 13, 97–107 (2024). https://doi.org/10.1007/s13669-024-00378-x

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