Published September 30, 2025 | Version CC-BY-NC-ND 4.0
Journal article Open

Genetic Predisposition and Pathogenesis in Endometriosis

Creators

  • 1. Department of Genetics and Bioengineering, University International Burch University, Sarajevo, Federation of Bosnia and Herzegovina.

Contributors

Contact person:

Researcher:

  • 1. Department of Genetics and Bioengineering, University International Burch University, Sarajevo, Federation of Bosnia and Herzegovina.
  • 2. Sarajevo Medical School, University Sarajevo School of Science and Technology, Sarajevo, Federation of Bosnia and Herzegovina.

Description

Abstract: Endometriosis is a chronic, estrogen-dependent inflammatory disorder defined by the growth of endometrial-like tissue outside the uterus, leading to pain, infertility, and reduced quality of life. Although retrograde menstruation remains the prevailing theory of pathogenesis, it does not fully explain why only some individuals develop the condition. Accumulating evidence highlights a substantial genetic component, with heritability estimates suggesting that approximately 51% of the risk of endometriosis is genetically driven. Genome-wide association studies (GWAS) have identified more than a dozen risk loci, including WNT4, GREB1, FN1, CDKN2B-AS1, and ESR1, which are involved in reproductive tract development, hormone signalling, immune modulation, and cell adhesion. This review synthesizes findings from genetic, epigenetic, and molecular studies to provide an updated understanding of the pathophysiology of endometriosis. In addition to inherited variants, recent discoveries have included epigenetic alterations, such as DNA methylation and microRNA regulation, which influence gene expression in key pathways related to cell proliferation and differentiation. Moreover, somatic mutations found in eutopic endometrial cells and chromosomal instability within lesions suggest a neoplastic-like progression, especially in advanced stages of the disease. Newly validated GWAS loci and polymorphisms in vascular remodelling and oxidative stressrelated genes (e.g., VEGF, MMPs, NAT2) further underscore the multifactorial nature of endometriosis. The purpose of this review is to investigate how genetic predisposition, somatic alterations, and epigenetic mechanisms interact to contribute to lesion development, persistence, and symptom severity. By examining these interconnected pathways, we highlight the current limitations in diagnosis and treatment, and emphasize the urgent need for personalized approaches in clinical care. These insights pave the way for future research to identify biomarkers for earlier diagnosis and to develop individualized therapeutic strategies. A more comprehensive understanding of endometriosis at the molecular level is crucial for advancing precision medicine and enhancing outcomes for women affected worldwide.

Files

E111305050725.pdf

Files (628.3 kB)

Name Size Download all
md5:9ce77a024e9cf2493dd96791de8f8b3e
628.3 kB Preview Download

Additional details

Identifiers

DOI
10.54105/ijpmh.E1113.05060925
EISSN
2582-7588

Dates

Accepted
2025-09-15
Manuscript received on 30 June 2025 | First Revised Manuscript received on 09 July 2025 | Second Revised Manuscript received on 17 August 2025 | Manuscript Accepted on 15 September 2025 | Manuscript published on 30 September 2025.

References

  • Smolarz, B., Szyłło, K. & Romanowicz, H. Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature). IJMS 22, 10554 (2021). DOI: http://doi.org/10.3390/ijms221910554
  • Allaire, C., Bedaiwy, M. A. & Yong, P. J. Diagnosis and management of endometriosis. CMAJ 195, E363–E371 (2023). DOI: http://doi.org/10.1503/cmaj.220637
  • Falcone, T. & Flyckt, R. Clinical Management of Endometriosis. Obstetrics & Gynaecology 131, 557–571 (2018). DOI: http://doi.org/10.1097/AOG.0000000000002469
  • Chauhan, S., More, A., Chauhan, V. & Kathane, A. Endometriosis: A Review of Clinical Diagnosis, Treatment, and Pathogenesis. Cureus (2022). DOI: http://doi.org/10.7759/cureus.28864
  • Vallvé-Juanico, J., Houshdaran, S. & Giudice, L. C. The Endometrial Immune Environment in Women with Endometriosis. Human Reproduction Update 25, 565–592 (2019). DOI: http://doi.org/10.1093/humupd/dmz018
  • Shigesi, N. et al. The phenotypic and genetic association between endometriosis and immunological diseases. Human Reproduction 40, 1195–1209 (2025) DOI: http://doi.org/10.1093/humrep/deaf062
  • Isidor, B., Latypova, X. & Ploteau, S. Familial deep endometriosis: A rare monogenic disease? European Journal of Obstetrics & Gynaecology and Reproductive Biology 221, 190–193 (2018). DOI: http://doi.org/10.1016/j.ejogrb.2017.11.025
  • Saha, R. et al. Heritability of endometriosis. Fertility and Sterility 104, 947–952 (2015). DOI: http://doi.org/10.1016/j.ejogrb.2017.11.025
  • Lalami, I., Abo, C., Borghese, B., Chapron, C. & Vaiman, D. Genomics of Endometriosis: From Genome Wide Association Studies to Exome Sequencing. IJMS 22, 7297 (2021). DOI: http://doi.org/10.3390/ijms22147297
  • Angioni, S. et al. Genetic Characterization of Endometriosis Patients: Review of the Literature and a Prospective Cohort Study on a Mediterranean Population. IJMS 21, 1765 (2020). DOI: http://doi.org/10.3390/ijms21051765
  • Tao, T., Mo, X., & Zhao, L. Identifying novel potential drug targets for endometriosis via plasma proteome screening. Front. Endocrinol. 15, (2024). DOI: http://doi.org/10.3389/fendo.%202024.1416978
  • 1. Baranov, V., Malysheva, O., & Yarmolinskaya, M. Pathogenomics of Endometriosis Development. IJMS 19, 1852 (2018). DOI: http://doi.org/10.3390/ijms19071852
  • Kattan, S. W. et al. Association of cyclin-dependent kinase inhibitor 2B antisense RNA 1 gene expression and rs2383207 variant with breast cancer risk and survival. Cell Mol Biol Lett 26, (2021). DOI: http://doi.org/10.1186/s11658-021-00258-9
  • Guo, S. Cancer driver mutations in endometriosis: Variations on the significant theme of fibrogenesis. Reprod Medicine & Biology 17, 369– 397 (2018). DOI: http://doi.org/10.1002/rmb2.12221
  • Fung, J. N. et al. Functional evaluation of genetic variants associated with endometriosis near GREB1. Human Reproduction 30, 1263–1275 (2015) DOI: http://doi.org/10.1093/humrep/dev051
  • Neja S. A. Molecular Roles of GREB1 in ER-Positive Breast Cancer. Arch Med. 5(1):2 (2020). DOI: http://dx.doi.org/10.36648/2572-5610.4.4.67
  • Matalliotaki, C. et al. Role of FN1 and GREB1 gene polymorphisms in endometriosis. Mol Med Report (2019). DOI: http://doi.org/10.3892/mmr.2019.10247
  • Cai, X. et al. Down‐regulation of FN1 inhibits colorectal carcinogenesis by suppressing proliferation, migration, and invasion. J of Cellular Biochemistry 119, 4717–4728 (2018). DOI: http://doi.org/10.1002/jcb.26651
  • Adilbayeva, A. & Kunz, J. Pathogenesis of Endometriosis and Endometriosis-Associated Cancers. IJMS 25, 7624 (2024). DOI: http://doi.org/10.3390/ijms25147624
  • Rahmioglu, N. et al. Beyond Endometriosis Genome-Wide Association Study: From Genomics to Phenomics to the Patient. Semin Reprod Med 34, 242–254 (2016). DOI: http://doi.org/10.1055/s-0036-1585408
  • Smolarz, B., Szyłło, K. & Romanowicz, H. Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature). IJMS 22, 10554 (2021). DOI: http://doi.org/10.3390/ijms221910554
  • Ren Y, Cheung HW, Von Maltzhan G, Agrawal A, Cowley GS, Weir BA, et al. Targeted tumour-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4. Sci Transl Med.4(147):147ra112-147ra112 (2024). DOI: http://doi.org/10.1126/scitranslmed.adp2153
  • Du, H. & Taylor, H. S. The Role of Hox Genes in Female Reproductive Tract Development, Adult Function, and Fertility. Cold Spring Harb Perspect Med 6, a023002 (2015). DOI: http://doi.org/10.1101/cshperspect.a023002
  • Cardoso, J. V., Perini, J. A., Machado, D. E., Pinto, R., & Medeiros, R. Systematic review of genome-wide association studies on susceptibility to endometriosis. European Journal of Obstetrics & Gynaecology and Reproductive Biology 255, 74–82 (2020). DOI: http://doi.org/10.1016/j.ejogrb.2020.10.017
  • Zhang, A. et al. THE DIAGNOSTIC VALUE OF SERUM AND PERITONEAL MARKERS IN ENDOMETRIOSIS: A SYSTEMATIC REVIEW. Fertility and Sterility 122, e162 (2024). DOI: http://doi.org/10.1016/j.fertnstert.2024.07.569
  • Kato, T. et al. Interleukin-1/-33 Signalling Pathways as Therapeutic Targets for Endometriosis. Front. Immunol. 10, (2019). http://doi.org/10.3389/fimmu.2019.02021
  • Osiński, M. et al. The assessment of GWAS — identified polymorphisms associated with infertility risk in Polish women with endometriosis. Ginekol Pol 89, 304–310 (2018). DOI: http://doi.org/10.5603/GP.a2018.0052
  • Chou, Y.-C. et al. Integration of genome-wide association study and expression quantitative trait locus mapping for identification of endometriosis-associated genes. Sci Rep 11, (2021). DOI: http://doi.org/10.1038/s41598-020-79515-4
  • Mosaddeghzadeh, N. & Ahmadian, M. R. The RHO Family GTPases: Mechanisms of Regulation and Signalling. Cells 10, 1831 (2021). DOI:http://doi.org/10.3390/cells10071831
  • Matalliotakis, M. et al. The role of gene polymorphisms in endometriosis. Molecular Medicine Reports 16, 5881–5886 (2017). DOI: http://doi.org/10.3892/mmr.2017.7398.
  • Holdsworth-Carson, S. J. et al. Endometrial vezatin and its association with the risk of endometriosis. Hum. Reprod. 31, 999–1013 (2016). DOI: http://doi.org/10.1093/humrep/dew047
  • Feng, S. et al. Ewing Tumour-associated Antigen 1 Interacts with Replication Protein A to Promote Restart of Stalled Replication Forks. Journal of Biological Chemistry 291, 21956–21962 (2016). DOI: http://doi.org/10.1074/jbc.C116.747758
  • Santin, A. et al. Puzzling Out the Genetic Architecture of Endometriosis: Whole-Exome Sequencing and Novel Candidate Gene Identification in a Deeply Clinically Characterised Cohort. Biomedicines 11, 2122 (2023). DOI: http://doi.org/10.3390/biomedicines11082122
  • Bianco, B. et al. Effects of FSHR and FSHB Variants on Hormonal Profile and Reproductive Outcomes of Infertile Women With Endometriosis. Front. Endocrinol. 12, (2021). DOI: http://doi.org/10.3389/fendo.2021.760616
  • Golovchenko, I. et al. Sex Hormone Candidate Gene Polymorphisms Are Associated with Endometriosis. IJMS 23, 13691 (2022). DOI: http://doi.org/10.3390/ijms232213691
  • Veth, V. B. et al. Gonadotropin-releasing hormone analogues for endometriosis. Cochrane Database of Systematic Reviews 2023, (2023). DOI: http://doi.org/10.1002/14651858.CD014788.pub2
  • Findikli, N. et al. The Effects of Endometriosis on Oocyte and Embryo Quality. JCM 14, 2339 (2025). DOI: http://doi.org/10.3390/jcm14072339
  • Ponomarenko, I. et al. Candidate genes for age at menarche are associated with endometrial hyperplasia. Gene 757, 144933 (2020). DOI: http://doi.org/10.1016/j.gene.2020.144933
  • Adewuyi, E. O. et al. Shared Molecular Genetic Mechanisms Underlie the Comorbidity of Endometriosis and Migraine. Genes 11, 268 (2020). DOI: http://doi.org/10.3390/genes11030268
  • McGrath, I. M., Mortlock, S. & Montgomery, G. W. Genetic Regulation of Physiological Reproductive Lifespan and Female Fertility. IJMS 22, 2556 (2021). DOI: http://doi.org/10.3390/ijms22052556
  • Chantalat, E. et al. Estrogen Receptors and Endometriosis. IJMS 21, 2815 (2020). DOI: http://doi.org/10.3390/ijms21082815
  • Zhao, L. et al. Association between oestrogen receptor alpha (ESR1) gene polymorphisms and endometriosis: a meta-analysis of 24 casecontrol studies. Reproductive BioMedicine Online 33, 335–349 (2016). DOI: http://doi.org/10.1016/j.rbmo.2016.06.003
  • Ikhtiyarova, G.A., Aslonova, M., Kurbanova, Z., & Kalimatova, D.M. Promising diagnostic tools for endometriosis given the pathogenic role of genetic factors. Russian Journal of Women and Child Health 4, 12– 16 (2021). DOI: http://doi.org/10.32364/2618-8430-2021-4-1-12-16
  • Montgomery, G. W., Mortlock, S. & Giudice, L. C. Should Genetics Now Be Considered the Pre-eminent Etiologic Factor in Endometriosis? Journal of Minimally Invasive Gynaecology 27, 280–286 (2020). DOI: http://doi.org/10.1016/j.jmig.2019.10.020
  • Borges Garnica, A. The Role of the Molecular Genetic Approach in the Pathogenesis of Endometriosis. Molecular Bases of Endometriosis - The Integration Between Research and Clinical Practice (2019). DOI: http://doi.org/10.5772/intechopen.81598
  • Chen, B., Zhao, L., Yang, R. & Xu, T. New insights about endometriosis-associated ovarian cancer: pathogenesis, risk factors, prediction, diagnosis and treatment. Front. Oncol. 14, (2024). DOI: http://doi.org/10.3389/fonc.2024.1329133
  • Ponomareva, T. A., Altukhova, O. B., Ponomarenko, I. V. & Churnosov, M. I. The role of genetic factors in developing endometrioid lesions. Akušerstvo, ginekologiâ i reprodukciâ 17, 443–454 (2023). DOI: http://doi.org/10.17749/2313-7347/ob.gyn.rep.2023.434
  • Shigesi, N. et al. The phenotypic and genetic association between endometriosis and immunological diseases. Human Reproduction 40, 1195–1209 (2025). DOI: http://doi.org/10.1093/humrep/deaf062
  • Zhang, M. et al. Research advances in endometriosis-related signalling pathways: A review. Biomedicine & Pharmacotherapy 164, 114909 (2023). DOI: http://doi.org/10.1016/j.biopha.2023.114909
  • Chiorean, D. et al. New Insights into Genetics of Endometriosis—A Comprehensive Literature Review. Diagnostics 13, 2265 (2023). DOI: http://doi.org/10.3390/diagnostics13132265
  • Irimia, T. et al. Oxidative-Stress Related Gene Polymorphism in Endometriosis-Associated Infertility. Medicina 58, 1105 (2022). DOI: http://doi.org/10.3390/medicina58081105