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The expression pattern of endometrial receptivity genes is desynchronized between endometrium and matched endometriomas

  • Merli Saare
    Correspondence
    Corresponding author.
    Affiliations
    Competence Centre on Health Technologies Tartu, Estonia

    Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia
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  • Ankita Lawarde
    Affiliations
    Competence Centre on Health Technologies Tartu, Estonia

    Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia
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  • Vijayachitra Modhukur
    Affiliations
    Competence Centre on Health Technologies Tartu, Estonia

    Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia
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  • Iveta Mikeltadze
    Affiliations
    Haematology and Oncology Clinic, Department of Oncosurgery, Tartu University Hospital Tartu, Estonia
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  • Helle Karro
    Affiliations
    Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia

    Women's Clinic, Tartu University Hospital Tartu, Estonia
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  • Ave Minajeva
    Affiliations
    Department of Pathological Anatomy and Forensic Medicine, Institute of Biomedicine and Translational Medicine, University of Tartu Tartu, Estonia
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  • Andres Salumets
    Affiliations
    Competence Centre on Health Technologies Tartu, Estonia

    Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia

    Division of Obstetrics and Gynecology, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet Stockholm, Sweden

    Institute of Genomics, University of Tartu Tartu, Estonia
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  • Maire Peters
    Affiliations
    Competence Centre on Health Technologies Tartu, Estonia

    Department of Obstetrics and Gynecology, Institute of Clinical Medicine, University of Tartu Tartu, Estonia
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      Abstract

      Research question

      Are paired samples of endometrium and ovarian endometriomas synchronous with each other throughout the menstrual cycle?

      Design

      The expression levels of 57 endometrial receptivity-associated genes were determined from matched endometrial and endometrioma samples (n=31) collected from women with endometriosis throughout the menstrual cycle.

      Results

      The expression profile of endometrial receptivity genes divided endometrial samples according to their menstrual cycle phase. Endometrioma samples grouped together irrespective of the menstrual cycle phase and formed a cluster distinct from endometrial samples. Pairwise comparison showed 21, 16, 33 and 23 differentially expressed genes (adjusted P < 0.001–0.05) between the lesions and endometria collected in the proliferative, early-secretory, mid-secretory and late-secretory menstrual cycle phases, respectively, confirming the distinct expression profiles of endometrium and endometrioma.

      Conclusions

      No menstrual cycle synchronicity was found between matched eutopic and ectopic endometrium, suggesting that the concept of cycling endometrial tissue inside the endometrioma should be revised.

      Key words

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      References

        • Aghajanova L.
        • Giudice L.C.
        Molecular evidence for differences in endometrium in severe versus mild endometriosis.
        Reprod. Sci. 2011; 18: 229-251https://doi.org/10.1177/1933719110386241
        • Altmäe S.
        • Koel M.
        • Võsa U.
        • Adler P.
        • Suhorutšenko M.
        • Laisk-Podar T.
        • Kukushkina V.
        • Saare M.
        • Velthut-Meikas A.
        • Krjutškov K.
        • Aghajanova L.
        • Lalitkumar P.G.P.G.
        • Gemzell-Danielsson K.
        • Giudice L.
        • Simón C.
        • Salumets A.
        Meta-signature of human endometrial receptivity: A meta-analysis and validation study of transcriptomic biomarkers.
        Sci. Rep. 2017; 7: 10077https://doi.org/10.1038/s41598-017-10098-3
        • ASRM
        Revised American Society for Reproductive Medicine classification of endometriosis: 1996.
        Fertil. Steril. 1997; 67: 817-821
        • Attia G.R.
        • Zeitoun K.
        • Edwards D.
        • Johns A.
        • Carr B.R.
        • Bulun S.E.
        Progesterone receptor isoform A but not B is expressed in endometriosis.
        J. Clin. Endocrinol. Metab. 2000; 85: 2897-2902https://doi.org/10.1210/JCEM.85.8.6739
        • Bedaiwy M.A.
        • Dahoud W.
        • Skomorovska-Prokvolit Y.
        • Yi L.
        • Liu J.H.
        • Falcone T.
        • Hurd W.W.
        • Mesiano S.
        Abundance and Localization of Progesterone Receptor Isoforms in Endometrium in Women With and Without Endometriosis and in Peritoneal and Ovarian Endometriotic Implants.
        Reprod. Sci. 2015; 22: 1153-1161https://doi.org/10.1177/1933719115585145
        • Béliard A.
        • Noël A.
        • Foidart J.M.
        Reduction of apoptosis and proliferation in endometriosis.
        Fertil. Steril. 2004; 82: 80-85https://doi.org/10.1016/J.FERTNSTERT.2003.11.048
        • Brosens I.A.
        Endometriosis—A disease because it is characterized by bleeding.
        Am. J. Obstet. Gynecol. 1997; 176: 263-267https://doi.org/10.1016/S0002-9378(97)70482-4
        • Bulun S.
        • Monsavais D.
        • Pavone M.
        • Dyson M.
        • Xue Q.
        • Attar E.
        • Tokunaga H.
        • Su E.
        Role of Estrogen Receptor-β in Endometriosis.
        Semin. Reprod. Med. 2012; 30: 39-45https://doi.org/10.1055/s-0031-1299596
        • Burney R.O.
        • Giudice L.C.
        Pathogenesis and pathophysiology of endometriosis.
        Fertil. Steril. 2012; 98: 511-519https://doi.org/10.1016/j.fertnstert.2012.06.029
        • Chen M.
        • Zhou Y.
        • Xu H.
        • Hill C.
        • Ewing R.M.
        • He D.
        • Zhang X.
        • Wang Y.
        Bioinformatic analysis reveals the importance of epithelial-mesenchymal transition in the development of endometriosis.
        Sci. Rep. 2020; 10https://doi.org/10.1038/s41598-020-65606-9
        • Cohen A.M.
        • Ye X.Y.
        • Colgan T.J.
        • Greenblatt E.M.
        • Chan C.
        Comparing endometrial receptivity array to histologic dating of the endometrium in women with a history of implantation failure.
        Syst. Biol. Reprod. Med. 2020; 66: 347-354https://doi.org/10.1080/19396368.2020.1824032
        • Colgrave E.M.
        • Bittinger S.
        • Healey M.
        • Dior U.P.
        • Rogers P.A.W.
        • Keast J.R.
        • Girling J.E.
        • Holdsworth-Carson S.J.
        Superficial peritoneal endometriotic lesions are histologically diverse and rarely demonstrate menstrual cycle synchronicity with matched eutopic endometrium.
        Hum. Reprod. 2020; 35: 2701-2714https://doi.org/10.1093/humrep/deaa249
        • Colgrave E.M.
        • Keast J.R.
        • Bittinger S.
        • Healey M.
        • Rogers P.A.W.
        • Holdsworth-Carson S.J.
        • Girling J.E.
        Comparing endometriotic lesions with eutopic endometrium: time to shift focus?.
        Hum. Reprod. 2021; 36: 2814-2823https://doi.org/10.1093/HUMREP/DEAB208
        • Crispi S.
        • Piccolo M.T.
        • D'Avino A.
        • Donizetti A.
        • Viceconte R.
        • Spyrou M.
        • Calogero R.A.
        • Baldi A.
        • Signorile P.G.
        Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects.
        J. Cell. Physiol. 2013; 228: 1927-1934https://doi.org/10.1002/jcp.24358
        • Devesa-Peiro A.
        • Sebastian-Leon P.
        • Pellicer A.
        • Diaz-Gimeno P.
        Guidelines for biomarker discovery in endometrium: correcting for menstrual cycle bias reveals new genes associated with uterine disorders.
        Mol. Hum. Reprod. 2021; 27https://doi.org/10.1093/MOLEHR/GAAB011
        • Eyster K.M.
        • Klinkova O.
        • Kennedy V.
        • Hansen K.A.
        Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium.
        Fertil. Steril. 2007; 88: 1505-1533https://doi.org/10.1016/j.fertnstert.2007.01.056
        • Guo S.
        Fibrogenesis resulting from cyclic bleeding: the Holy Grail of the natural history of ectopic endometrium.
        Hum. Reprod. 2018; 33: 353-356https://doi.org/10.1093/HUMREP/DEY015
        • Hashimoto T.
        • Koizumi M.
        • Doshida M.
        • Toya M.
        • Sagara E.
        • Oka N.
        • Nakajo Y.
        • Aono N.
        • Igarashi H.
        • Kyono K.
        Efficacy of the endometrial receptivity array for repeated implantation failure in Japan: A retrospective, two-centers study.
        Reprod. Med. Biol. 2017; 16: 290-296https://doi.org/10.1002/rmb2.12041
        • Hever A.
        • Roth R.B.
        • Hevezi P.
        • Marin M.E.
        • Acosta J.A.
        • Acosta H.
        • Rojas J.
        • Herrera R.
        • Grigoriadis D.
        • White E.
        • Conlon P.J.
        • Maki R.A.
        • Zlotnik A.
        Human endometriosis is associated with plasma cells and overexpression of B lymphocyte stimulator.
        Proc. Natl. Acad. Sci. USA. 2007; 104: 12451-12456https://doi.org/10.1073/pnas.0703451104
        • Imanaka S.
        • Yamada Y.
        • Kawahara N.
        • Kobayashi H.
        A delicate redox balance between iron and heme oxygenase-1 as an essential biological feature of endometriosis.
        Arch. Med. Res. 2021; 52: 641-647https://doi.org/10.1016/J.ARCMED.2021.03.006
        • Isbister J.L.T.
        ENDOMETRIOMA.
        Med. J. Aust. 1928; 2: 614-616https://doi.org/10.5694/j.1326-5377.1928.tb13710.x
        • Khan M.A.
        • Sengupta J.
        • Mittal S.
        • Ghosh D.
        Genome-wide expressions in autologous eutopic and ectopic endometrium of fertile women with endometriosis.
        Reprod. Biol. Endocrinol. 2012; 10: 84https://doi.org/10.1186/1477-7827-10-84
        • Kusunoki M.
        • Fujiwara Y.
        • Komohara Y.
        • Imamura Y.
        • Honda R.
        • Ohba T.
        • Katabuchi H.
        Hemoglobin-induced continuous activation of macrophages in endometriotic cysts: a potential mechanism of endometriosis development and carcinogenesis.
        Med. Mol. Morphol. 2021; 54: 122-132https://doi.org/10.1007/S00795-020-00272-4
        • Leek J.T.
        • Scharpf R.B.
        • Bravo H.C.
        • Simcha D.
        • Langmead B.
        • Johnson W.E.
        • Geman D.
        • Baggerly K.
        • Irizarry R.A.
        Tackling the widespread and critical impact of batch effects in high-throughput data.
        Nat. Rev. Genet. 2010; 11: 733-739https://doi.org/10.1038/nrg2825
        • Love M.I.
        • Huber W.
        • Anders S.
        Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
        Genome Biol. 2014; 15https://doi.org/10.1186/S13059-014-0550-8
        • Ma J.
        • Zhang L.
        • Zhan H.
        • Mo Y.
        • Ren Z.
        • Shao A.
        • Lin J.
        Single-cell transcriptomic analysis of endometriosis provides insights into fibroblast fates and immune cell heterogeneity.
        Cell Biosci. 2021; 11: 1-19
        • Ma L.
        • Andrieu T.
        • McKinnon B.
        • Duempelmann L.
        • Peng R.W.
        • Wotzkow C.
        • Müller C.
        • Mueller M.D.
        Epithelial-to-mesenchymal transition contributes to the downregulation of progesterone receptor expression in endometriosis lesions.
        J. Steroid Biochem. Mol. Biol. 2021; 212https://doi.org/10.1016/J.JSBMB.2021.105943
      1. Meltsov, A., Saare, M., Teder, H., Paluoja, P., Arffman, R., Piltonen, T., Laudanski, P., Wielgoś, M., Gianaroli, L., Koel, M., Peters, M., Salumets, A., Palta, P., Krjutškov, K., 2022. Targeted gene expression profiling for accurate endometrial receptivity testing. medRxiv 2022.06.13.22276318. https://doi.org/10.1101/2022.06.13.22276318

        • Murray M.J.
        • Meyer W.R.
        • Zaino R.J.
        • Lessey B.A.
        • Novotny D.B.
        • Ireland K.
        • Zeng D.
        • Fritz M.A.
        A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women.
        Fertil. Steril. 2004; 81: 1333-1343https://doi.org/10.1016/J.FERTNSTERT.2003.11.030
        • Noyes R.W.
        • Hertig A.T.
        • Rock J.
        Dating the endometrial biopsy.
        Am. J. Obstet. Gynecol. 1975; 122: 262-263
        • Core Team R
        R: A language and environment for Computing [WWW Document].
        R Found Stat. Comput, Vienna, Austria2020 (URL)
        • Rekker K.
        • Saare M.
        • Eriste E.
        • Tasa T.
        • Kukuškina V.
        • Roost A.M.
        • Anderson K.
        • Samuel K.
        • Karro H.
        • Salumets A.
        • Peters M.
        • Mari Roost A.
        • Anderson K.
        • Samuel K.
        • Karro H.
        • Salumets A.
        • Peters M.
        High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium.
        Reproduction. 2017; 154: 93-100https://doi.org/10.1530/REP-17-0092
        • Robinson M.
        • McCarthy D.
        • Smyth G.
        edgeR: a Bioconductor package for differential expression analysis of digital gene expression data.
        Bioinformatics. 2010; 26: 139-140https://doi.org/10.1093/BIOINFORMATICS/BTP616
        • Saare M.
        • Laisk T.
        • Teder H.
        • Paluoja P.
        • Palta P.
        • Koel M.
        • Kirss F.
        • Karro H.
        • Sõritsa D.
        • Salumets A.
        • Krjutškov K.
        • Peters M.
        A molecular tool for menstrual cycle phase dating of endometrial samples in endometriosis transcriptome studies†.
        Biol. Reprod. 2019; 101: 1-3https://doi.org/10.1093/biolre/ioz072
        • Saare M.
        • Rekker K.
        • Laisk-Podar T.
        • Sõritsa D.
        • Roost A.M.A.A.M.
        • Simm J.
        • Velthut-Meikas A.
        • Samuel K.K.
        • Metsalu T.
        • Karro H.
        • Sõritsa A.
        • Salumets A.
        • Peters M.
        High-throughput sequencing approach uncovers the miRNome of peritoneal endometriotic lesions and adjacent healthy tissues.
        PLoS One. 2014; 9e112630https://doi.org/10.1371/journal.pone.0112630
        • Sanchez A.M.
        • Vigano P.
        • Somigliana E.
        • Cioffi R.
        • Panina-Bordignon P.
        • Candiani M.
        The Endometriotic Tissue Lining the Internal Surface of Endometrioma: Hormonal, Genetic, Epigenetic Status, and Gene Expression Profile.
        Reprod. Sci. 2015; 22: 391-401https://doi.org/10.1177/1933719114529374
        • Scheenjes E.
        • Thijssen J.H.H.
        • Te Velde E.R.
        • Blankenstein M.A.
        • Krenier J.
        The origin of estrogens, progesterone, androgens and sex hormone binding globulin in peritoneal fluid in the immediate postovulatory period in normal ovulating women.
        Gynecol. Endocrinol. 1991; 5: 157-166https://doi.org/10.3109/09513599109028437
        • Schweppe K.
        • Wynn R.
        Ultrastructural changes in endometriotic implants during the menstrual cycle.
        Obstet. Gynecol. 1981; 58: 465-473
        • Talbi S.
        • Hamilton A.E.
        • Vo K.C.
        • Tulac S.
        • Overgaard M.T.
        • Dosiou C.
        • Le Shay N.
        • Nezhat C.N.
        • Kempson R.
        • Lessey B.A.
        • Nayak N.R.
        • Giudice L.C.
        Molecular phenotyping of human endometrium distinguishes menstrual cycle phases and underlying biological processes in normo-ovulatory women.
        Endocrinology. 2006; 147: 1097-1121https://doi.org/10.1210/en.2005-1076
        • Teder H.
        • Koel M.
        • Paluoja P.
        • Jatsenko T.
        • Rekker K.
        • Laisk-Podar T.
        • Kukuškina V.
        • Velthut-Meikas A.
        • Fjodorova O.
        • Peters M.
        • Kere J.
        • Salumets A.
        • Palta P.
        • Krjutškov K.
        TAC-seq: targeted DNA and RNA sequencing for precise biomarker molecule counting.
        NPJ genomic Med. 2018; 3: 34https://doi.org/10.1038/s41525-018-0072-5
        • Tomassetti C.
        • Johnson N.P.
        • Petrozza J.
        • Abrao M.S.
        • Einarsson J.I.
        • Horne A.W.
        • Lee T.T.M.
        • Missmer S.
        • Vermeulen N.
        • Zondervan K.T.
        • Grimbizis G.
        • De Wilde R.L.
        An international terminology for endometriosis, 2021.
        Hum. Reprod. Open. 2021; 2021https://doi.org/10.1093/hropen/hoab029
        • Vasquez G.
        • Cornillie F.
        • Brosens I.A.
        Peritoneal endometriosis: Scanning electron microscopy and histology of minimal pelvic endometriotic lesions.
        Fertil. Steril. 1984; 42: 696-703https://doi.org/10.1016/S0015-0282(16)48193-8
        • Young S.L.
        Oestrogen and progesterone action on endometrium: a translational approach to understanding endometrial receptivity.
        Reprod. Biomed. Online. 2013; 27: 497-505https://doi.org/10.1016/J.RBMO.2013.06.010

      Biography

      Merli Saare works as a Researcher in Reproductive Medicine at the University of Tartu, Estonia. Her research focuses on the molecular profiling of endometriotic lesions and endometrium to understand the genetic background of endometriosis. Her research interests also include female infertility and the molecular basis of endometrial receptivity.
      Key message
      Gene expression profiling revealed no menstrual cycle synchronicity between endometrium and matched endometrioma samples. The results suggest that endometriotic lesions should be considered as separate entities and drawing parallels between these two separate tissues does not help to find disease-related molecular markers for endometriosis diagnostics or treatment.