Prospects of treating infertility in women over 40 using assisted reproductive technology with autologous oocytes

Khachatryan L.V., Makarova N.P., Kalinin A.P., Smolnikova V.Yu.

1) I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), Moscow, Russia; 2) Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, Moscow, Russia; 3) N.I. Pirogov Russian National Research Medical University, Ministry of Health of Russia, Moscow, Russia
Today, childbearing in women of late reproductive age is not only a pressing clinical problem but also a social one. In couples in this age group, the pathogenesis of infertility is extremely complex, representing a combination of several factors that often require tailored treatment for individual patients.
This review presents data on the role of genetic factors and oxidative stress signaling pathways in the pathogenetic mechanisms underlying ovarian aging. The authors summarized various controlled ovarian stimulation protocols and approaches for the optimization of assisted reproductive technology in patients of late reproductive age. This article provides information about experimental studies that will expand our understanding of the prospects for treating infertility in patients of this age category.
Conclusion: The study of pathogenetic mechanisms of ovarian aging is one of the key directions for the optimization of infertility treatment in women of late reproductive age using ART with autologous oocytes and is of scientific interest for the future development of innovative therapeutic approaches for this cohort of patients.

Authors' contributions: Khachatryan L.V., Makarova N.P., Kalinin A.P., Smolnikova V.Yu. – concept of the article, search, review and analysis of relevant literature, manuscript drafting.
Conflicts of interest: The authors have no conflicts of interest to declare.
Funding: There was no funding for this study.
For citation: Khachatryan L.V., Makarova N.P., Kalinin A.P., Smolnikova V.Yu. Prospects of treating infertility in women over 40 using assisted reproductive technology with autologous oocytes. Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2023; (4): 12-19 (in Russian)
https://dx.doi.org/10.18565/aig.2023.34

Keywords

assisted reproductive technology (ART)
optimization of ART programs
late reproductive age
oxidative stress
signaling pathways
ovarian aging

References

1. Yan F., Zhao Q., Li Y., Zheng Z., Kong X., Shu C. et al. The role of oxidative stress in ovarian aging: a review. J. Ovarian Res. 2022; 15(1):100. https://dx.doi.org/10.1186/s13048‑022‑01032‑x.

2. Ubaldi F.M., Cimadomo D., Vaiarelli A., Fabozzi G., Venturella R., Maggiulli R. et al. Advanced maternal age in IVF: still a challenge? The present and the future of its treatment. Front. Endocrinol. (Lausanne). 2019; 10: 94. https://dx.doi.org/10.3389/fendo.2019.00094.

3. Mikwar M., MacFarlane A.J., Marchetti F. Mechanisms of oocyte aneuploidy associated with advanced maternal age. Mutat. Res. Rev. Mutat. Res. 2020; 785: 108320. https://dx.doi.org/10.1016/j.mrrev.2020.108320.

4. Vaiarelli A., Cimadomo D., Ubaldi N., Rienzi L., Ubaldi F.M. What is new in the management of poor ovarian response in IVF? Curr. Opin. Obstet. Gynecol. 2018; 30(3): 155‑62. https://dx.doi.org/10.1097/GCO.0000000000000452.

5. Hassold T., Maylor-Hagen H., Wood A., Gruhn J., Hoffmann E., Broman K.W., Hunt P. Failure to recombine is a common feature of human oogenesis. Am. J. Hum. Genet. 2021; 108(1): 16‑24. https://dx.doi.org/10.1016/ j.ajhg.2020.11.010.

6. Смирнова А.А., Зыряева Н.А., Аншина М.Б. Возрастные изменения и риск хромосомных аномалий в ооцитах человека (обзор лите‑ ратуры). Проблемы репродукции. 2019; 25(2): 16‑26. [Smirnova A.A., Zyryaeva N.A., Anshina M.B. Age‑related changes and the risk of chromosomal adnormalities in human oocytes (literature review). Russian Journal of Human Reproduction. 2019; 25(2): 16‑26. (in Russian)]. https://dx.doi.org/10.17116/ repro20192502116.

7. Mishina T., Tabata N., Hayashi T., Yoshimura M., Umeda M., Mori M. et al. Single‑oocyte transcriptome analysis reveals aging‑associated effects influenced by life stage and calorie restriction. Aging Cell. 2021; 20(8): e13428. https://dx.doi.org/10.1111/acel.13428.

8. Beverley R., Snook M.L., Brieño-Enríquez M.A. Meiotic cohesin and variants associated with human reproductive aging and disease. Front. Cell Dev. Biol. 2021; 9: 710033. https://dx.doi.org/10.3389/fcell.2021.710033.

9. Lee J. Is age‑related increase of chromosome segregation errors in mammalian oocytes caused by cohesin deterioration? Reprod. Med. Biol. 2019; 19(1): 2‑41. https://dx.doi.org/10.1002/rmb2.12299.

10. Ma J.Y., Li S., Chen L.N., Schatten H., Ou X.H., Sun Q.Y. Why is oocyte aneuploidy increased with maternal aging? J. Genet. Genomics. 2020; 47(11): 659‑71. https://dx.doi.org/10.1016/j.jgg.2020.04.003.

11. Blengini C.S., Nguyen A.L., Aboelenain M., Schindler K. Age‑dependent integrity of the meiotic spindle assembly checkpoint in females requires Aurora kinase B. Aging Cell. 2021; 20(11): e13489. https://dx.doi.org/10.1111/acel.13489.

12. Wasielak-Politowska M., Kordowitzki P. Chromosome segregation in the oocyte: what goes wrong during aging. Int. J. Mol. Sci. 2022; 23(5): 2880. https://dx.doi.org/10.3390/ijms23052880.

13. Zielinska A.P., Bellou E., Sharma N., Frombach A.S., Seres K.B., Gruhn J.R. et al. Meiotic kinetochores fragment into multiple lobes upon cohesin loss in aging eggs. Curr. Biol. 2019; 29(22): 3749‑65.e7. https://dx.doi.org/10.1016/ j.cub.2019.09.006.

14. Chiang J.L., Shukla P., Pagidas K., Ahmed N.S., Karri S., Gunn D.D., Hurd W.W., Singh K.K. Mitochondria in ovarian aging and reproductive longevity. Ageing Res. Rev. 2020; 63: 101168. https://dx.doi.org/10.1016/ j.arr.2020.101168.

15. Tesarik J., Galán-Lázaro M., Mendoza-Tesarik R. Ovarian aging: molecular mechanisms and medical management. Int. J. Mol. Sci. 2021; 22(3): 1371. https://dx.doi.org/10.3390/ijms22031371.

16. Wang L., Tang J., Wang L., Tan F., Song H., Zhou J., Li F. Oxidative stress in oocyte aging and female reproduction. J. Cell. Physiol. 2021; 236(12): 7966‑83. https://dx.doi.org/10.1002/jcp.30468.

17. Sies H., Jones D.P. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat. Rev. Mol. Cell Biol. 2020; 21(7): 363‑83. https://dx.doi.org/10.1038/s41580‑020‑0230‑3.

18. Teixeira C.P., Florencio-Silva R., Sasso G.R.S., Carbonel A.A.F., Simões R.S., Simões M.J. Soy isoflavones protect against oxidative stress and diminish apoptosis in ovary of middle‑aged female rats. Gynecol. Endocrinol. 2019; 35(7): 586‑90. https://dx.doi.org/10.1080/09513590.2018.1559287.

19. Yang L., Chen Y., Liu Y., Xing Y., Miao C., Zhao Y. et al. The role of oxidative stress and natural antioxidants in ovarian aging. Front. Pharmacol. 2021; 11: 617843. https://dx.doi.org/10.3389/fphar.2020.617843.

20. Jalouli M., Mofti A., Elnakady Y.A., Nahdi S., Feriani A., Alrezaki A. et al. Allethrin promotes apoptosis and autophagy associated with the oxidative stress‑related PI3K/AKT/mTOR signaling pathway in developing rat ovaries. Int. J. Mol. Sci. 2022; 23(12): 6397. https://dx.doi.org/10.3390/ ijms23126397.

21. Yang X., Wang W., Zhang Y., Wang J., Huang F. Moxibustion improves ovary function by suppressing apoptosis events and upregulating antioxidant defenses in natural aging ovary. Life Sci. 2019; 229: 166‑72. https://dx.doi.org/10.1016/ j.lfs.2019.05.040.

22. Zhang J., Xu Y., Liu H., Pan Z. MicroRNAs in ovarian follicular atresia and granulosa cell apoptosis. Reprod. Biol. Endocrinol. 2019; 17(1): 9. https://dx.doi.org/10.1186/s12958‑018‑0450‑y.

23. Guan Y., Zhang W., Wang X., Cai P., Jia Q., Zhao W. Cell‑free DNA induced apoptosis of granulosa cells by oxidative stress. Clin. Chim. Acta. 2017; 473: 213‑7. https://dx.doi.org/10.1016/j.cca.2016.11.023.

24. He F., Ru X., Wen T. NRF2, a Transcription factor for stress response and beyond. Int. J. Mol. Sci. 2020; 21(13): 4777. https://dx.doi.org/10.3390/ ijms21134777.

25. Madden S.K., Itzhaki L.S. Structural and mechanistic insights into the Keap1‑Nrf2 system as a route to drug discovery. Biochim. Biophys. Acta Proteins Proteom. 2020; 1868(7): 140405. https://dx.doi.org/10.1016/ j.bbapap.2020.140405.

26. Jiang X., Xing X., Zhang Y., Zhang C., Wu Y., Chen Y. et al. Lead exposure activates the Nrf2/Keap1 pathway, aggravates oxidative stress, and induces reproductive damage in female mice. Ecotoxicol. Environ. Saf. 2021; 207: 111231. https://dx.doi.org/10.1016/j.ecoenv.2020.111231.

27. Zhang M., Yu X., Li D., Ma N., Wei Z., Ci X., Zhang S. Nrf2 signaling pathway mediates the protective effects of daphnetin against D‑Galactose induced‑premature ovarian failure. Front. Pharmacol. 2022; 13: 810524. https://dx.doi.org/10.3389/fphar.2022.810524.

28. Iljas J.D., Wei Z., Homer H.A. Sirt1 sustains female fertility by slowing age‑related decline in oocyte quality required for post‑fertilization embryo development. Aging Cell. 2020; 19(9): e13204. https://dx.doi.org/10.1111/acel.13204.

29. Guo L., Liu X., Chen H., Wang W., Gu C., Li B. Decrease in ovarian reserve through the inhibition of SIRT1‑mediated oxidative phosphorylation. Aging (Albany NY). 2022; 14(5): 2335‑47. https://dx.doi.org/10.18632/ aging.203942.

30. Nie X., Dai Y., Zheng Y., Bao D., Chen Q., Yin Y. et al. Establishment of a mouse model of premature ovarian failure using Consecutive Superovulation. Cell. Physiol. Biochem. 2018; 51(5): 2341‑58. https://dx.doi.org/10.1159/000495895.

31. Immediata V., Ronchetti C., Spadaro D., Cirillo F., Levi-Setti P.E. Oxidative stress and human ovarian response‑from somatic ovarian cells to oocytes damage: a clinical comprehensive narrative review. Antioxidants (Basel). 2022; 11(7): 1335. https://dx.doi.org/10.3390/antiox11071335.

32. Link W. Introduction to FOXO biology. Methods Mol. Biol. 2019; 1890: 1‑9. https://dx.doi.org/10.1007/978‑1‑4939‑8900‑3_1.

33. Murtaza G., Khan A.K., Rashid R., Muneer S., Hasan S.M.F., Chen J. FOXO transcriptional factors and long‑term living. Oxid. Med. Cell. longev. 2017; 2017: 3494289. https://dx.doi.org/10.1155/2017/3494289.

34. Shi F., LaPolt P.S. Relationship between FoxO1 protein levels and follicular development, atresia, and luteinization in the rat ovary. J. Endocrinol. 2003; 179(2): 195‑203. https://dx.doi.org/10.1677/joe.0.1790195.

35. Shen M., Lin F., Zhang J., Tang Y., Chen W.K., Liu H. Involvement of the up‑regulated FoxO1 expression in follicular granulosa cell apoptosis induced by oxidative stress. J. Biol. Chem. 2012; 287(31): 25727‑40. https://dx.doi.org/10.1074/jbc.M112.349902.

36. Thanatsis N., Kaponis A., Koika V., Georgopoulos N.A., Decavalas G.O. Reduced Foxo3a, FoxL2, and p27 mRNA expression in human ovarian tissue in premature ovarian insufficiency. Hormones (Athens). 2019; 18(4): 409‑15. https://dx.doi.org/10.1007/s42000‑019‑00134‑4. Erratum in: Hormones (Athens). 2020 Jan 7.

37. Gouveia B.B., Barberino R.S., Dos Santos Silva R.L., Lins T.L.B.G., da Silva Guimarães V., do Monte A.P.O. et al. Involvement of PTEN and FOXO3a proteins in the protective activity of protocatechuic acid against cisplatin‑induced ovarian toxicity in mice. Reprod. Sci. 2021; 28(3): 865‑76. https://dx.doi.org/10.1007/s43032‑020‑00305‑4.

38. Lins T.L.B.G., Gouveia B.B., Barberino R.S., Silva R.L.S., Monte A.P.O., Pinto J.G.C. et al. Rutin prevents cisplatin‑induced ovarian damage via antioxidant activity and regulation of PTEN and FOXO3a phosphorylation in mouse model. Reprod. Toxicol. 2020; 98: 209‑17. https://dx.doi.org/10.1016/ j.reprotox.2020.10.001.

39. Yue J., López J.M. Understanding MAPK signaling pathways in apoptosis. Int. J. Mol. Sci. 2020; 21(7): 2346. https://dx.doi.org/10.3390/ijms21072346.

40. Sun J., Guo Y., Fan Y., Wang Q., Zhang Q., Lai D. Decreased expression of IDH1 by chronic unpredictable stress suppresses proliferation and accelerates senescence of granulosa cells through ROS activated MAPK signaling pathways. Free Radic. Biol. Med. 2021; 169: 122‑36. https://dx.doi.org/10.1016/ j.freeradbiomed.2021.04.016.

41. He X., Li Y., Deng B., Lin A., Zhang G., Ma M. et al. The PI3K/AKT signalling pathway in inflammation, cell death and glial scar formation after traumatic spinal cord injury: Mechanisms and therapeutic opportunities. Cell Prolif. 2022; 55(9): e13275. https://dx.doi.org/10.1111/cpr.13275.

42. Yan J., Deng D., Wu Y., Wu K., Qu J., Li F. Catalpol protects rat ovarian granulosa cells against oxidative stress and apoptosis through modulating the PI3K/Akt/mTOR signaling pathway. Biosci. Rep. 2020; 40(4): BSR20194032. https://dx.doi.org/10.1042/BSR20194032.

43. Li X., Chen H., Zhang Z., Xu D., Duan J., Li X. et al. Isorhamnetin promotes estrogen biosynthesis and proliferation in porcine granulosa cells via the PI3K/Akt signaling pathway. J. Agric. Food Chem. 2021; 69(23): 6535‑42. https://dx.doi.org/10.1021/acs.jafc.1c01543.

44. De Geyter C., Calhaz-Jorge C., Kupka M.S., Wyns C., Mocanu E., Motrenko T. et al. ART in Europe, 2014: results generated from European registries by ESHRE: The European IVF‑monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Hum. Reprod. 2018; 33(9): 1586‑601. https://dx.doi.org/10.1093/humrep/dey242.

45. Moolhuijsen L.M.E., Visser J.A. Anti‑Müllerian hormone and ovarian reserve: update on assessing ovarian function. J. Clin. Endocrinol. Metab. 2020; 105(11): 3361‑73. https://dx.doi.org/10.1210/clinem/dgaa513.

46. Practice Committee of the American Society for Reproductive Medicine. Electronic address: asrm@asrm.org; Practice Committee of the American Society for Reproductive Medicine. Testing and interpreting measures of ovarian reserve: a committee opinion. Fertil. Steril. 2020; 114(6): 1151‑7. https://dx.doi.org/10.1016/j.fertnstert.2020.09.134.

47. Wu Y., Chen W., Zhou L., Gao X., Xi X. Single embryo transfer improve the perinatal outcome in singleton pregnancy. J. Matern. Fetal Neonatal Med. 2020; 33(19): 3266‑71. https://dx.doi.org/10.1080/14767058.2019.1571029.

48. De Geyter C. Single embryo transfer in all infertile couples treated with assisted reproduction produces excellent results and avoids multiple births. Swiss. Med. Wkly. 2021; 151: w20499. https://dx.doi.org/10.4414/ smw.2021.20499.

49. Петросян Я.А., Сыркашева А.Г., Романов А.Ю., Макарова Н.П., Калинина Е.А. Дифференцированный подход к ведению эмбриологического этапа у пациенток в программах вспомогательных репродуктивных технологий с переносом размороженного эмбриона. Акушерство и гинекология. 2020; 11: 107‑13. [Petrosyan Ya.A., Syrkasheva A.G., Romanov A.Yu., Makarova N.P., Kalinina E.A. Differentiated approach to the embryological stage in frozen‑thawed embryo transfer. Obstetrics and Gynecology. 2020; (11): 107‑13. (in Russian)]. https://dx.doi.org/10.18565/aig.2020.11.107‑113.

50. Pandian Z., McTavish A.R., Aucott L., Hamilton M.P., Bhattacharya S. Interventions for 'poor responders' to controlled ovarian hyper stimulation (COH) in in‑vitro fertilisation (IVF). Cochrane Database Syst. Rev. 2010; (1): CD004379. https://dx.doi.org/10.1002/14651858.CD004379.pub3.

51. Errázuriz J., Romito A., Drakopoulos P., Frederix B., Racca A., De Munck N. et al. Cumulative live birth rates following stimulation with corifollitropin Alfa compared with hp‑hMG in a GnRH antagonist protocol in poor ovarian responders. Front. Endocrinol. (Lausanne). 2019; 10: 175. https://dx.doi.org/10.3389/fendo.2019.00175.

52. Liu Y., Su R., Wu Y. Cumulative live birth rate and cost‑effectiveness analysis of gonadotropin releasing hormone‑antagonist protocol and multiple minimal ovarian stimulation in poor responders. Front. Endocrinol. (Lausanne). 2021; 11: 605939. https://dx.doi.org/10.3389/fendo.2020.605939.

53. Yang C., Dong N., Li F., Ji Y., Pan Y., She H. The cumulative live birth rate of recombinant follicle‑stimulating hormone alfa verse urinary human follicle‑stimulating hormone for ovarian stimulation in assisted reproductive technology cycles. J. Ovarian Res. 2022; 15(1): 74. https://dx.doi.org/10.1186/ s13048‑022‑01009‑w.

54. Kim S.J., Lee D., Kim S.K., Jee B.C., Kim S.H. Cumulative live birth rate after up to three consecutive embryo transfer cycles in women with poor ovarian response. Clin. Exp. Reprod. Med. 2020; 47(2): 135‑9. https://dx.doi.org/10.5653/cerm.2019.03349.

55. Zhang X., Feng T., Yang J., Hao Y., Li S., Zhang Y., Qian Y. A flexible short protocol in women with poor ovarian response over 40 years old. J. Ovarian Res. 2021; 14(1): 3. https://dx.doi.org/10.1186/s13048‑020‑00761‑1.

56. Wang T., Sun Z., Lim J.P., Yu Y. Comparison of luteal phase ovulation induction and ultra‑short gonadotropin‑releasing hormone agonist protocols in older patients undergoing in vitro fertilization. Libyan J. Med. 2019; 14(1): 1597327. https://dx.doi.org/10.1080/19932820.2019.1597327.

57. Løssl K., Freiesleben N.C., Wissing M.L., Birch Petersen K., Holt M.D., Mamsen L.S. Biological and cinical rationale for androgen priming in ovarian stimulation. Front. Endocrinol. (Lausanne). 2020; 11: 627. https://dx.doi.org/10.3389/ fendo.2020.00627.

58. Qin Y. Effects of using letrozole in combination with the GnRH antagonist protocol for patients with poor ovarian response: a meta‑analysis. J. Gynecol. Obstet. Hum. Reprod. 2021; 50(8): 102139. https://dx.doi.org/10.1016/ j.jogoh.2021.102139.

59. Bülow N.S., Dreyer Holt M., Skouby S.O., Birch Petersen K., Englund A.L.M., Pinborg A., Macklon N.S. Co‑treatment with letrozole during ovarian stimulation for IVF/ICSI: a systematic review and meta‑analysis. Reprod. Biomed. Online. 2022; 44(4): 717‑36. https://dx.doi.org/10.1016/j.rbmo.2021.12.006.

60. Leaver M., Wells D. Non‑invasive preimplantation genetic testing (niPGT): the next revolution in reproductive genetics? Hum. Reprod. Update. 2020; 26(1): 16‑42. https://dx.doi.org/10.1093/humupd/dmz033.

61. Huang L., Bogale B., Tang Y., Lu S., Xie X.S., Racowsky C. Noninvasive preimplantation genetic testing for aneuploidy in spent medium may be more reliable than trophectoderm biopsy. Proc. Natl. Acad. Sci. USA. 2019; 116(28): 14105‑12. https://dx.doi.org/10.1073/pnas.1907472116.

62. Freis A., Roesner S., Marshall A., Rehnitz J., von Horn K., Capp E. et al. Non‑invasive embryo assessment: altered individual protein profile in spent culture media from embryos transferred at Day 5. Reprod. Sci. 2021; 28(7): 1866‑73. https://dx.doi.org/10.1007/s43032‑020‑00362‑9.

63. Макарова Н.П., Лисицына О.И., Непша О.С., Красный А.М., Садекова А.А., Незлина А.Л., Долгушина Н.В., Зингеренко Б.В., Калинина Е.А. Особенности профиля экспрессии митохондриальной ДНК в среде культивирования эмбрионов в программах вспомогательных репродуктивных технологий. Акушерство и гинекология. 2022; 3: 89‑96. [Makarova N.P., Lisitsyna O.I., Nepsha O.S., Krasnyi A.M., Sadekova A.A., Nezlina A.L., Dolgushina N.V., Zingerenko B.V., Kalinina E.A. Mitochondrial DNA expression profile in embryo culture medium in assisted reproductive technology. Obstetrics and Gynecology. 2022; (3): 89‑96. (in Russian)]. https://dx.doi.org/10.18565/ aig.2022.3.89‑96.

Received 07.02.2023

Accepted 29.03.2023

About the Authors

Leah V. Khachatryan, postgraduate student of the Department of Obstetrics, Gynecology, Perinatology and Reproductology, Faculty of Postgraduate Professional Training of Physicians, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University), +7(963)977-88-94, leahkhachatryan@gmail.com, https://orcid.org/0000-0003-4867-500X, 119991, Russia, Moscow, Trubetskaya str., 8-2.
Natalya P. Makarova, PhD, Leading Researcher at the Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, np_makarova@oparina4.ru, https://orcid.org/0000-0003-8922-2878, 117997, Russia, Moscow, Ac. Oparin str., 4.
Andrey P. Kalinin, student of the Faculty of Medicine, Pirogov Russian National Research Medical University, Ministry of Health of Russia, +7(985)157-78-31, zoaza8@mail.ru, 117997, Russia, Moscow, Ostrovitianov str., 1.
Veronika Yu. Smolnikova, Dr. Med. Sci., Leading Researcher, Department of Assistive Technologies in Infertility Treatment, Academician V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, v_smolnikova@oparina4.ru, 117997, Russia, Moscow, Ac. Oparin str., 4.

Similar Articles

By continuing to use our site, you consent to the processing of cookies that ensure the proper functioning of the site.