Pathogenetic aspects of decreased ovarian reserve in women of reproductive age (literature review)

Introduction. The incidence of diminished ovarian reserve (DOR) increases with age: up to 10% in women under 35 and up to 25-50% in women over 40. Among patients seeking ART treatment, DOR is a significant proportion and is one of the main reasons for the decreased success of IVF. The etiology of DOR is multifactorial, and the pathogenetic mechanisms of a significant number of idiopathic and exogenous triggers remain poorly understood.
Objective. To conduct a literature review of the PubMed, Crossref, Medline, and Russian Science Citation Index (RSCI) databases on the causes and pathogenesis of decreased ovarian reserve.
Materials and Methods. A literature search covering 18 years was conducted in the PubMed, Crossref, Medline, and RSCI databases using the keywords “infertility,” “decreased ovarian reserve,” “reproductive age,” “assisted reproductive technologies,” “pathogenesis of decreased ovarian reserve,” “causes of decreased ovarian reserve,” and “factors influencing decreased ovarian reserve.”
Results. Forty-four sources were analyzed and included in the study. The literature data demonstrates a variety of causes for decreased ovarian reserve, each with a different pathogenesis.
Conclusion. This study describes the multifactorial causes and pathogenetic mechanisms of decreased ovarian reserve. It is shown that the complexity and multicomponent nature of the pathogenetic patterns of this process determine the feasibility of further clinical and fundamental study

1. Clinical guidelines «Female infertility», year of approval: 2024. (In Russ) https://disuria.ru/_ld/14/1497_kr24N97N98Z31MZ.pdf (дата обращения: 06.05.2024).

2. WHO Team Sexual and Reproductive Health and Research Infertility Prevalence Estimates 1990–2021. https://www.who.int/publications/i/item/978920068315 (accessed on 06.05.2024).

3. Adebisi OY, Singh M, Tobler KJ. Female Infertility. [Updated 2026 Apr 12. In: StatPearls [Internet. Treasure Island (FL): StatPearls Publishing; 2026 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK556033/ (accessed on 06.05.2026)..

4. Hirano M, Onodera T, Takasaki K, Takahashi Y, Ichinose T, Nishida H, Hiraike H, Nagasaka K. Ovarian aging: pathophysiology and recent developments in maintaining ovarian reserve. Front Endocrinol (Lausanne). 2025;16:1619516. https://doi.org/10.3389/fendo.2025.1619516

5. Boyarsky K. Yu. The role of ovarian reserve indicators in the treatment of infertility by IVF and ET. In: Kulakov V. I., Leonov B. V., Kuzmichev L. N., eds. Treatment of female and male infertility (assisted reproductive technologies). Moscow: MIA; 2005: 53–60. (In Russ). https://medkniga.ru/files/book_fragments_files/81int.pdf (дата обращения 06.05.2024)

6. BLOCK E. Quantitative morphological investigations of the follicular system in women; variations at different ages. Acta Anat (Basel). 1952;14(1-2):108-23. https://doi.org/10.1159/000140595

7. Boucher J, Kleinridders A, Kahn CR. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb Perspect Biol. 2014 Jan 1;6(1): a00919. https://doi.org/10.1101/cshperspect.a009191

8. Markström E, Svensson ECh, Shao R, Svanberg B, Billig H. Survival factors regulating ovarian apoptosis dependence on follicle differentiation. Reproduction. 2002; 123(1):23-30. https://doi.org/10.1530/rep.0.1230023

9. Faddy MJ, Gosden RG. A model conforming the decline in follicle numbers to the age of menopause in women. Hum Reprod. 1996;11(7):1484-6. https://doi.org/10.1093/oxfordjournals.humrep.a019422

10. Faddy MJ. Follicle dynamics during ovarian ageing. Mol Cell Endocrinol. 2000;163(1-2):43-8. https://doi.org/10.1016/s0303-7207(99)00238-5

11. Steckler T, Wang J, Bartol FF, Roy SK, Padmanabhan V. Fetal programming: prenatal testosterone treatment causes intrauterine growth retardation, reduces ovarian reserve and increases ovarian follicular recruitment. Endocrinology. 2005;146(7):3185-93. https://doi.org/10.1210/en.2004-1444

12. Fraser A, McNally W, Sattar N, Anderson EL, Lashen H, Fleming R, Lawlor DA, Nelson SM. Prenatal exposures and anti-Mullerian hormone in female adolescents: the Avon Longitudinal Study of Parents and Children. Am J Epidemiol. 2013;178(9):1414-23. https://doi.org/10.1093/aje/kwt137

13. Strohsnitter WC, Hatch EE, Hyer M, Troisi R, Kaufman RH, Robboy SJ, Palmer JR, Titus-Ernstoff L, Anderson D, Hoover RN, Noller KL. The association between in utero cigarette smoke exposure and age at menopause. Am J Epidemiol. 2008;167(6):727-33. https://doi.org/10.1093/aje/kwm351

14. Qiqi L, Junlin H, Xuemei C, Yi H, Fangfang L, Yanqing G, Yan Z, Lamptey J, Zhuxiu C, Fangfei L, Yingxiong W, Xinyi M. Fetal exposure of Aristolochic Acid I undermines ovarian reserve by disturbing primordial folliculogenesis. Ecotoxicol Environ Saf. 2022; 236:113480. https://doi.org/10.1016/j.ecoenv.2022.113480

15. Rostami Dovom M, Noroozzadeh M, Mosaffa N, Piryaei A, Zadeh-Vakili A, Aabdollahifar MA, Rahmati M, FarhadiAzar M, Ramezani Tehrani F. Maternal Exposure to D-galactose Reduces Ovarian Reserve in Female Rat Offspring Later in Life. Int J Endocrinol Metab. 2022;20(2): e123206. https://doi.org/10.5812/ijem-123206

16. Gougeon A. Des follicules dans tous leurs états.. [All about follicles.... Gynecol Obstet Fertil. 2010;38(6):394. (French.) https://doi.org/10.1016/j.gyobfe.2010.04.011

17. Dólleman M, Faddy MJ, van Disseldorp J, van der Schouw YT, Messow CM, Leader B, Peeters PH, McConnachie A, Nelson SM, Broekmans FJ. The relationship between anti-Müllerian hormone in women receiving fertility assessments and age at menopause in subfertile women: evidence from large population studies. J Clin Endocrinol Metab. 2013 May;98(5):1946-53. https://doi.org/10.1210/jc.2013-3105

18. Wallace WH, Kelsey TW. Human ovarian reserve from conception to the menopause. PLoS One. 2010;5(1): e8772. https://doi.org/10.1371/journal.pone.0008772

19. Pelosi E, Forabosco A, Schlessinger D. Genetics of the ovarian reserve. Front Genet. 2015;6:308. https://doi.org/10.3389/fgene.2015.00308

20. Гаспаров А.С., Дубинская Е.Д., Титов Д.С., Лаптева Н.В. Клиническое значение овариального резерва в реализации репродуктивной функции. Акушерство и гинекология. 2014; 4:11-16. [Gasparov A.S., Dubinskaya E.D., Titov D.S., Lapteva N.V. Clinical significance of the ovarian reserve in the implementation of reproductive function. Obstetrics and gynecology. 2014; 4:11-16.( In Russ) https://aig-journal.ru/articles/Klinicheskoe-znachenieovarialnogo-rezerva-v-realizacii-reproduktivnoi-funkcii.html (дата обращения 05.04.2024)

21. Samartzis K, Kathopoulis N, Loutradis D, Protopapas A. Do techniques of surgical management of ovarian endometrioma affect ovarian reserve? A narrative review. J Obstet Gynaecol. 2022;42(5):778-784. https://doi.org/10.1080/01443615.2021.1962817

22. Lu Y, Xia Z. Diminished ovarian reserve is associated with metabolic disturbances and hyperhomocysteinemia in women with infertility. J Obstet Gynaecol. 2023;43(2): 2282722. https://doi.org/10.1080/01443615.2023.2282722

23. Chen W, Dong L, Wei C, Wu H. Role of epigenetic regulation in diminished ovarian reserve. J Assist Reprod Genet. 2025;42(2):389-403. https://doi.org/10.1007/s10815-024-03301-8

24. Holdgate GA, Bardelle C, Lanne A, Read J, O’Donovan DH, Smith JM, Selmi N, Sheppard R. Drug discovery for epigenetics targets. Drug Discov Today. 2022;27(4):1088- 1098. https://doi.org/10.1016/j.drudis.2021.10.020

25. Rutten MGS, Rots MG, Oosterveer MH. Exploiting epigenetics for the treatment of inborn errors of metabolism. J Inherit Metab Dis. 2020;43(1):63-70. https://doi.org/10.1002/jimd.12093

26. Jiao X, Meng T, Zhai Y, Zhao L, Luo W, Liu P, Qin Y. Ovarian Reserve Markers in Premature Ovarian Insufficiency: Within Different Clinical Stages and Different Etiologies. Front Endocrinol (Lausanne). 2021 18;12:601752. https://doi.org/10.3389/fendo.2021.601752

27. Gasparri ML, Di Micco R, Zuber V, Taghavi K, Bianchini G, Bellaminutti S, Meani F, Graffeo R, Candiani M, Mueller MD, Papadia A, Gentilini OD. Ovarian reserve of women with and without BRCA pathogenic variants: A systematic review and meta-analysis. Breast. 2021;60:155-162. https://doi.org/10.1016/j.breast.2021.09.006

28. Hu J, Wang H, Fang J, Jiang R, Kong Y, Zhang T, Yang G, Jin H, Shi S, Song N, Qi L, Huang X, Wu Z, Yao G. Ovarian aging-associated downregulation of GPX4 expression regulates ovarian follicular development by affecting granulosa cell functions and oocyte quality. FASEB J. 2025;39(6):e70469. https://doi.org/10.1096/fj.202401580RR

29. Fan Y, Chang Y, Wei L, Chen J, Li J, Goldsmith S, Silber S, Liang X. Apoptosis of mural granulosa cells is increased in women with diminished ovarian reserve. J Assist Reprod Genet. 2019;36(6):1225-1235. https://doi.org/10.1007/s10815-019-01446-5

30. Alam MH, Miyano T. Interaction between growing oocytes and granulosa cells in vitro. Reprod Med Biol. 2019;19(1):13-23. https://doi.org/10.1002/rmb2.12292

31. Tu J, Cheung AH, Chan CL, Chan WY. The Role of microRNAs in Ovarian Granulosa Cells in Health and Disease. Front Endocrinol (Lausanne). 2019;10:174. https://doi.org/10.3389/fendo.2019.00174

32. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet. 2011;12(12):861-74. https://doi.org/10.1038/nrg3074

33. Hong X, Luense LJ, McGinnis LK, Nothnick WB, Christenson LK. Dicer1 is essential for female fertility and normal development of the female reproductive system. Endocrinology. 2008;149(12):6207-12. https://doi.org/10.1210/en.2008-0294

34. Sinha PB, Tesfaye D, Rings F, Hossien M, Hoelker M, Held E, Neuhoff C, Tholen E, Schellander K, SalilewWondim D. MicroRNA-130b is involved in bovine granulosa and cumulus cells function, oocyte maturation and blastocyst formation. J Ovarian Res. 2017;10(1):37. https://doi.org/10.1186/s13048-017-0336-1

35. Yan G, Zhang L, Fang T, Zhang Q, Wu S, Jiang Y, Sun H, Hu Y. MicroRNA-145 suppresses mouse granulosa cell proliferation by targeting activin receptor IB. FEBS Lett. 2012;586(19):3263-70. https://doi.org/10.1016/j.febslet.2012.06.048

36. Liu J, Yao W, Yao Y, Du X, Zhou J, Ma B, Liu H, Li Q, Pan Z. MiR-92a inhibits porcine ovarian granulosa cell apoptosis by targeting Smad7 gene. FEBS Lett. 2014;588(23):4497- 503. https://doi.org/10.1016/j.febslet.2014.10.021

37. Zhang P, Wang J, Lang H, Wang W, Liu X, Liu H, Tan C, Li X, Zhao Y, Wu X. MicroRNA-205 affects mouse granulosa cell apoptosis and estradiol synthesis by targeting CREB1. J Cell Biochem. 2019;120(5):8466-8474. https://doi.org/10.1002/jcb.28133. Epub 2018. Retraction in: J Cell Biochem. 2024 Oct;125(10):e30553. https://doi.org/10.1002/jcb.30553

38. Cao R, Wu W, Zhou X, Liu K, Li B, Huang X, Zhang Y, Liu H. Let-7g induces granulosa cell apoptosis by targeting MAP3K1 in the porcine ovary. Int J Biochem Cell Biol. 2015;68:148-57. https://doi.org/10.1016/j.biocel.2015.08.011

39. Murri M, Insenser M, Fernández-Durán E, San-Millán JL, Escobar-Morreale HF. Effects of polycystic ovary syndrome (PCOS), sex hormones, and obesity on circulating miRNA-21, miRNA-27b, miRNA-103, and miRNA-155 expression. J Clin Endocrinol Metab. 2013;98(11):E1835-44. https://doi.org/10.1210/jc.2013-2218

40. Sang Q, Yao Z, Wang H, Feng R, Wang H, Zhao X, Xing Q, Jin L, He L, Wu L, Wang L. Identification of microRNAs in human follicular fluid: characterization of microRNAs that govern steroidogenesis in vitro and are associated with polycystic ovary syndrome in vivo. J Clin Endocrinol Metab. 2013;98(7):3068-79. https://doi.org/10.1210/jc.2013-1715

41. Yang X, Zhou Y, Peng S, Wu L, Lin HY, Wang S, Wang H. Differentially expressed plasma microRNAs in premature ovarian failure patients and the potential regulatory function of mir-23a in granulosa cell apoptosis. Reproduction. 2012;144(2):235-44. https://doi.org/10.1530/REP-11-0371

42. Abu-Halima M, Becker LS, Ayesh BM, Baus SL, Hamza A, Fischer U, Hammadeh M, Keller A, Meese E. Characterization of micro-RNA in women with different ovarian reserve. Sci Rep. 2021;11(1):13351. https://doi.org/10.1038/s41598-021-92901-w

43. Huang Y, Cheng Y, Zhang M, Xia Y, Chen X, Xian Y, Lin D, Xie S, Guo X. Oxidative stress and inflammatory markers in ovarian follicular fluid of women with diminished ovarian reserve during in vitro fertilization. J Ovarian Res. 2023;16(1):206. https://doi.org/10.1186/s13048-023-01293-0

44. Yang Q, Chen W, Cong L, Wang M, Li H, Wang H, Luo X, Zhu J, Zeng X, Zhu Z, Xu Y, Lei M, Zhao Y, Wei C, Sun Y. NADase CD38 is a key determinant of ovarian aging. Nat Aging. 2024;4(1):110-128. https://doi.org/10.1038/s43587-023-00532-9