The role of epigenetic modification in pathogenesis of diminished ovarian reserve

DOI

https://dx.doi.org/10.18565/aig.2025.169

Patskova P.O., Amyan T.S., Krasnova N.A., Timofeeva A.V., Gavisova A.A.
Academician V.I. Kulakov National Medical Research Centre for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia

Diminished ovarian reserve (DOR) is characterized by a decrease in the number and quality of oocytes. The pathogenesis of DOR remains unclear, which makes this condition one of the most challenging problems in the field of infertility treatment and assisted reproductive technologies. The development of the oocyte is directly dependent on its “molecular dialog” with granulosa cells; therefore, studies of the epigenetic mechanisms underlying DOR are primarily focused on detailing, clarifying, and identifying epigenetic changes induced by hormones and other extracellular molecules not only in oocytes but also in ovarian granulosa cells.
This review provides a detailed analysis of various factors that play a role in the pathogenesis of DOR, including epigenetic modifications such as DNA methylation, N6-methyladenosine (m6A) modifications and changes in the expression levels of long non-coding RNAs and microRNAs in granulosa cells and oocytes in DOR. These epigenetic changes affect the biological functions of cells by controlling the expression of protein-coding genes and thus all intracellular signaling pathways responsible for oocyte development. This review examines the role of epigenetic alterations in DOR, providing new insights into its pathogenesis and clinical diagnosis. In addition, the article discusses the possibility of potential application of targeting epigenetic modifications for the therapeutic correction of DOR.
Conclusion: The data presented in the review make it possible to clarify the characteristics of DOR pathogenesis and the impact of epigenetic modifications on the processes of folliculogenesis and oogenesis. The study of epigenetic regulation has been gaining the attention of more and more scientists around the world. This suggests that future research will identify new epigenetic factors related to DOR. Epigenetic modifications may become new diagnostic markers for assessing ovarian function, and their analogues or inhibitors may be used as targeted therapies in the future.

Authors’ contributions: Patskova P.O., Amyan T.S., Krasnova N.A. – search and analysis of literature, writing the text of the article; Timofeeva A.V., Gavisova А.А. – editing and final approval of the article.
Conflicts of interest: The authors declare that there are no conflicts of interest.
Funding: The research was carried out with the financial support of the Ministry of Health of the Russian Federation within the framework of the state assignment 125022002648-0 on the subject: “Assessment of the blastocyst ploidy and its implantation potential by the level of extracellular piwiRNAs in the culture medium”.
For citation: Patskova P.O., Amyan T.S., Krasnova N.A., Timofeeva A.V., Gavisova A.A.
The role of epigenetic modification in pathogenesis of diminished ovarian reserve.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2025; (11): 23-29 (in Russian)
https://dx.doi.org/10.18565/aig.2025.169

diminished ovarian reserve

epigenetic modification

reproductive medicine

Full text (in Russian)

Li L., Sun B., Wang F., Zhang Y., Sun Y. Which factors are associated with reproductive outcomes of DOR patients in ART cycles: an eight-year retrospective study. Front. Endocrinol. (Lausanne). 2022;.13:.796199. https://dx.doi.org/10.3389/fendo.2022.796199
Parasar P., Ozcan P., Terry K.L. Endometriosis: epidemiology, diagnosis and clinical management. Curr. Obs. Gynecol. Rep. 2017; 6(1): 34-41. https://dx.doi.org/10.1007/s13669-017-0187-1
Wilkinson A.L., Zorzan I., Rugg-Gunn P.J. Epigenetic regulation of early human embryo development. Cell Stem Cell. 2023; 30(12): 1569-84. https://dx.doi.org/10.1016/j.stem.2023.09.010.
Wang J., Sun X., Yang Z., Li S., Wang Y., Ren R. et al. Epigenetic regulation in premature ovarian failure: a literature review. Front. Physiol. 2023; 13: 998424. https://dx.doi.org/10.3389/fphys.2022.998424
Stringer J.M., Alesi L.R., WinshipK A.L., Hutt J. Beyond apoptosis: Evidence of other regulated cell death pathways in the ovary throughout development and life. Hum. Reprod. Update. 2023; 29(4): 434-56. https://dx.doi.org/10.1093/humupd/dmad005
Miranda-Furtado C.L., Luchiari H.R., Chielli Pedroso D.C., Kogure G.S., Caetano L.C., Santana B.A. et al. Skewed X-chromosome inactivation and shorter telomeres associate with idiopathic premature ovarian insufficiency. Fertil. Steril. 2018; 110(3): 476-85.e1. https://dx.doi.org/10.1016/j.fertnstert.2018.04.017
Howard J.A., Hart K.N., Thompson T.B. Molecular mechanisms of AMH signaling. Front. Endocrinol. (Lausanne). 2022; 13: 927824. https://dx.doi.org/10.3389/fendo.2022.927824
Omrizadeh M., Mokhtari P., Eftekhari-Yazdi P., ChekiniA Z., Meybodi M. Altered expression of GDF9 and BMP15 genes in Granulosa cells of diminished ovarian reserve patients: a case-control study. Cell J. 2022; 24(9): 540-5. https://dx.doi.org/10.22074/cellj.2022.8077
Alberico H.C., Woods D.C. Role of granulosa cells in the aging ovarian landscape: a focus on mitochondrial and metabolic function. Front. Physiol. 2022; 12: 800739. https://dx.doi.org/10.3389/fphys.2021.800739
Boucret L., Chao de la Barca J.M., Moriniere C., Desquiret V., Ferre-L'Hotellier V., Descamps P. et al. Relationship between diminished ovarian reserve and mitochondrial biogenesis in cumulus cells. Hum. Reprod. 2015; 30(7): 1653-64. https://dx.doi.org/10.1093/humrep/dev114
Chen X., Tang Z., Guan H., Xia H., Gu C., Xu Y. et al. Rapamycin maintains the primordial follicle pool and protects ovarian reserve against cyclophosphamide-induced damage. J. Reprod. Dev. 2022; 68(4): 287-94. https://dx.doi.org/10.1262/jrd.2022-001
Niu W., Spradling A.C. Two distinct pathways of pregranulosa cell differentiation support follicle formation in the mouse ovary. Proc. Natl. Acad. Sci. USA. 2020; 117(33): 20015-26. https://dx.doi.org/10.1073/pnas.2005570117
Liu A., Shen H., Li Q., He J., Wang B., Du W. et al. Determination of tryptophan and its indole metabolites in follicular fluid of women with diminished ovarian reserve. Sci. Rep. 2023; 13(1): 17124. https://dx.doi.org/10.1038/s41598-023-44335-9
Kelley N., Jeltema D., Duan Y., He Y. The NLRP3 inflammasome: an overview of mechanisms of activation and regulation. Int. J. Mol. Sci. 2019; 20(13): 3328. https://dx.doi.org/10.3390/ijms20133328
Navarro-Pando J.M., Alcocer-Gómez E., Castejón-Vega B., Navarro-Villarán E., Condés-Hervás M., Mundi-Roldan M. et al. Inhibition of the NLRP3 inflammasome prevents ovarian aging. Sci. Adv. 2021; 7(1): eabc7409. https://dx.doi.org/10.1126/sciadv.abc7409
Lliberos C., Liew S.H., Mansell A., Hutt K.J. The inflammasome contributes to depletion of the ovarian reserve during aging in mice. Front. Cell Dev. Biol. 2020; 8: 628473. https://dx.doi.org/10.3389/fcell.2020.628473
Сыркашева А.Г., Долгушина Н.В., Яроцкая Е.Л. Влияние антропогенных химических веществ на репродукцию. Акушерство и гинекология. 2018; 3: 16-21. [Syrkasheva A.G., Dolgushina N.V., Yarotskaya E.L. The effect of anthropogenic chemicals on reproduction. Obstetrics and Gynecology. 2018; (3): 16-21 (in Russian). https://dx.doi.org/10.18565/aig.2018.3.16-21
Сыркашева А.Г., Киндышева С.В., Стародубцева Н.Л., Франкевич В.Е., Долгушина Н.В. Бисфенол А в организме пациенток с бесплодием: влияние на результаты программ вспомогательных репродуктивных технологий. Акушерство и гинекология. 2021; 5: 113-20. [Syrkasheva A.G., Kindysheva S.V., Starodubtseva N.L., Frankevich V.E., Dolgushina N.V. Bisphenol A in infertile patients: impact on assisted reproductive technologies outcomes. Obstetrics and Gynecology. 2021; (5): 113-20 (in Russian)]. https://dx.doi.org/10.18565/aig.2021.5.113-120
Buratini J., Dellaqua T.T., Dal Canto M., Marca A.L., Carone D., Mignini Renzini M. et al. The putative roles of FSH and AMH in the regulation of oocyte developmental competence: from fertility prognosis to mechanisms underlying age-related subfertility. Hum. Reprod. Update. 2022; 28(2): 232-54. https://dx.doi.org/10.1093/humupd/dmab044
Olsen K.W., Castillo-Fernandez J., Chan A.C., la Cour Freiesleben N., Zedeler A., Bungum M. et al. Identification of a unique epigenetic profile in women with diminished ovarian reserve. Fertil. Steril. 2021; 115(3): 732-41. https://dx.doi.org/10.1016/j.fertnstert.2020.09.009
Yilmaz B., Terekeci H., Sandal S., Kelestimur F. Endocrine disrupting chemicals: exposure, effects on human health, mechanism of action, models for testing and strategies for prevention. Rev. Endocr. Metab. Disord. 2020; 21(1): 127-47. https://dx.doi.org/10.1007/s11154-019-09521-z
Chen Y., Sun Y., Zhao A., Cai X., Yu A., Xu Q. et al. Arsenic exposure diminishes ovarian follicular reserve and induces abnormal steroidogenesis by DNA methylation. Ecotoxicol. Environ. Saf. 2022; 241(Pt.3): 113816. https://dx.doi.org/10.1016/j.ecoenv.2022.113816
Hughes C.H.K., Smith O.E., Meinsohn M.C., Brunelle M., Gévry N., Murphy B.D. Steroidogenic factor 1 (SF-1; Nr5a1) regulates the formation of the ovarian reserve. Proc. Natl. Acad. Sci. USA. 2023; 120(32): e2220849120. https://dx.doi.org/10.1073/pnas.2220849120
Uehara R., Au Yeung W.K., Toriyama K., Ohishi H., Kubo N., Toh H. et al. The DNMT3A ADD domain is requireed for efficient de novo DNA methylation and maternal imprinting in mouse oocytes. PLOS Genet. 2023; 19(8): e1010855. https://dx.doi.org/10.1371/journal.pgen.1010855
Uysal F., Sukur G., Bozdemir N., Cinar O. Unveiling the impact of DNA methylation machinery: Dnmt1 and Dnmt3a in orchestrating oocyte development and cellular homeostasis. Genesis. 2024; 62(1): e23579. https://dx.doi.org/10.1002/dvg.23579
Qian Y., Tu J., Tang N.L., Kong G.W., Chung J.P., Chan W.Y. et al. Dynamic changes of DNA epigenetic marks in mouse oocytes during natural and accelerated aging. Int. J. Biochem. Cell Biol. 2015; 67: 121-7. https://dx.doi.org/10.1016/j.biocel.2015.05.005
Zhang X.J., Han B.B., Shao Z.Y., Yan R., Gao J., Liu T. et al. Auto-suppression of Tet dioxygenases protects the mouse oocyte genome from oxidative demethylation. Nat. Struct. Mol. Biol. 2024; 31(1): 42-53. https://dx.doi.org/10.1038/s41594-023-01125-1
Hou G.Q., Sun Y. Maternal ageing causes changes in DNA methylation and gene expression profiles in mouse oocytes. Zygote. 2020; 1-7. https://dx.doi.org/10.1017/S0967199420000143
Iyer M.K., Niknafs Y.S., Malik R., Singhal U., Sahu A., Hosono Y. et al. The landscape of long noncoding RNAs in the human transcriptome. Nat. Genet. 2015; 47(3): 199-208. https://dx.doi.org/10.1038/ng.3192
Wang Y.L., Chen L. Organization and function of paraspeckles. Essays Biochem. 2020; 64(6): 875-82. https://dx.doi.org/10.1042/EBC20200010
Elias-Lopez A.L., Vazquez-Mena O., Sferruzzi-Perri A.N. Mitochondrial dysfunction in the offspring of obese mothers and it’s transmission through damaged oocyte mitochondria: Integration of mechanisms. Biochim. Biophys. Acta Mol. Basis. Dis. 2023; 1869(7): 166802. https://dx.doi.org/10.1016/j.bbadis.2023.166802
Zhao M., Liu S., Wang Y., Lv K., Lou P., Zhou P. et al. The mitochondria–paraspeckle axis regulates the survival of transplanted stem cells under oxidative stress conditions. Theranostics. 2024; 14(4): 1517-33. https://dx.doi.org/10.7150/thno.88764
Adu-Gyamfi E.A., Cheeran E.A., Salamah J., Lee B.K. Long noncoding RNA H19 in ovarian biology and placenta development. Cell Biochem. Funct. 2024; 42(1): e3907. https://dx.doi.org/10.1002/cbf.3907
Qin C., Xia X., Fan Y., Jiang Y., Chen Y., Zhang N. et al. A novel, noncoding-RNA-mediated, post-transcriptional mechanism of anti-mullerian hormone regulation by the H19/let-7 axis. Biol. Reprod. 2019; 100(1): 101-11. https://dx.doi.org/10.1093/biolre/ioy172
Zhang T., Zhang J., Yang G., Hu J., Wang H., Jiang R. et al. Long non-coding RNA PWRN1 affects ovarian follicular development by regulating the function of granulosa cells. Reprod. Biomed. Online. 2024; 48(5): 103697. https://dx.doi.org/10.1016/j.rbmo.2023.103697
Lu T.X., Rothenberg M.E. MicroRNA. J. Allergy Clin. Immunol. 2018; 141(4): 1202-7. https://dx.doi.org/10.1016/j.jaci.2017.08.034
Hong L., Peng S., Li Y., Fang Y., Wang Q., Klausen C. et al. miR-106a increases granulosa cell viability and is downregulated in women with diminished ovarian reserve. J. Clin. Endocrinol. Metab. 2018; 103(6): 2157-66. https://dx.doi.org/10.1210/jc.2017-02344
Ju W., Zhao S., Wu H., Yu Y., Li Y., Liu D. et al. miR-6881-3p contributes to diminished ovarian reserve by regulating granulosa cell apoptosis by targeting SMAD4. Reprod. Biol. Endocrinol. 2024; 22(1): 17. https://dx.doi.org/10.1186/s12958-024-01189-8
Wei C., Xiang S., Yu Y., Song J., Zheng M., Lian F. miR-221-3p regulates apoptosis of ovarian granulosa cells via targeting FOXO1 in older women with diminished ovarian reserve (DOR). Mol. Reprod. Dev. 2021; 88(4): 251-60. https://dx.doi.org/10.1002/mrd.23457
Li H., Wang X., Mu H., Mei Q., Liu Y., Min Z. et al. miR-484 contributes to diminished ovarian reserve by regulating granulosa cell function via YAP1-mediated mitochondrial function and apoptosis. Int. J. Biol. Sci. 2022; 18(3): 1008-21. https://dx.doi.org/10.7150/ijbs.68028
Шамина М.А., Тимофеева А.В., Калинина Е.А. Малые некодирующие РНК и их потенциальная роль в оценке фертильности супружеской пары в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2019; 11: 33-9. [Shamina M.A., Timofeeva A.V., Kalinina E.A. Small non-coding RNAs and their potential role in assessing the fertility of a married couple in assisted reproductive technology programs. Obstetrics and Gynecology. 2019; 11: 33-9 (in Russian)]. https://dx.doi.org/10.1856/aig.2019.11.33-39
Liu C., Li L., Yang B., Zhao Y., Dong X., Zhu L. et al. Transcriptome-wide N6-methyladenine methylation in granulosa cells of women with decreased ovarian reserve. BMC Genomics. 2022; 23(1): 240. https://dx.doi.org/10.1186/s12864-022-08462-3
Zhang J.N., Wang R.T., Klinger F.G., Cheng S.F., Shen W., Sun X.F. RNA m6A dynamic modification mediated by nucleus-localized FTO is involved in follicular reserve. Zool. Res. 2024; 45(2): 415-28. https://dx.doi.org/10.24272/j.issn.2095-8137.2023.236
Gan X., Dai Z., Ge C., Yin H., Wang Y., Tan J. et al. FTO promotes liver inflammation by suppressing m6A mRNA methylation of IL-17RA. Front. Oncol. 2022; 12: 989353. https://dx.doi.org/10.3389/fonc.2022.989353
Li B., Du M., Sun Q., Cao Z., He H. m⁶ A demethylase Fto regulates the TNF-α-induced inflammatory response in cementoblasts. Oral Dis. 2023; 29(7):2806-15. https://dx.doi.org/10.1111/odi.14396
Huang B., Ding C., Zou Q., Wang W., Li H. Cyclophosphamide regulates N6-Methyladenosine and m6A RNA enzyme levels in human granulosa cells and in ovaries of a premature ovarian aging mouse model. Front. Endocrinol. (Lausanne). 2019; 10: 415. https://dx.doi.org/10.3389/fendo.2019.00415

Received 24.06.2025

Accepted 13.11.2025

Polina O. Patskova, PhD student, 1st Gynecological Departament of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(915)639-66-06, p_patskova@oparina4.ru,
https://orcid.org/0009-0005-6805-2944
Tatiana S. Amyan, PhD, gynaecologist, 1st Gynecological Departament of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(926)163-28-33, t_amyan@oparina4.ru,
https://orcid.org/0009-0004-3772-2346
Natalia A. Krasnova, PhD, Associate Professor at the Department of Obstetrics, Gynecology, Perinatology and Reproductology, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia; gynaecologist at the 1st Gynecological Departament of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(915)355-42-03,
n_krasnova@oparina4.ru
Angelika V. Timofeeva, PhD (Bio), Head of the Laboratory of Applied Transcriptomics, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, +7(917)516-51-67, v_timofeeva@oparina4.ru,
https://orcid.org/0000-0003-2324-9653
Alla A. Gavisova, Dr. Med. Sci., Head of the 1st Gynecological Departament of the Institute of Reproductive Medicine, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology, and Perinatology, Ministry of Health of Russia, 117997, Russia, Moscow, Ac. Oparin str., 4, a_gavisova@oparina4.ru,
https://orcid.org/0000-0003-4700-2786

The role of epigenetic modification in pathogenesis of diminished ovarian reserve

Patskova P.O., Amyan T.S., Krasnova N.A., Timofeeva A.V., Gavisova A.A.

Keywords

References

About the Authors

Similar Articles