Regenerative approaches in ovarian rejuvenation: hope for fertility restoration

Sona Puliyilaparambil Chandran; Greena Susan Manoj; Nandhana Snehavilla Hari; Barry Cooper Hynniewta

doi:10.18203/2320-1770.ijrcog20262592

Authors

Sona Puliyilaparambil Chandran Department of Clinical Embryology, Yenepoya School of Allied Health Sciences, Yenepoya (deemed to-be) University, Mangalore, Karnataka, India
Greena Susan Manoj Department of Clinical Embryology, Yenepoya School of Allied Health Sciences, Yenepoya (deemed to-be) University, Mangalore, Karnataka, India
Nandhana Snehavilla Hari Department of Clinical Embryology, Yenepoya School of Allied Health Sciences, Yenepoya (deemed to-be) University, Mangalore, Karnataka, India
Barry Cooper Hynniewta Department of Clinical Embryology, MOMSOON Fertility and IVF Centre, Bangalore, Karnataka, India

DOI:

https://doi.org/10.18203/2320-1770.ijrcog20262592

Keywords:

Ovarian rejuvenation, PRP therapy, Stem cell therapy, Diminished ovarian reserve, Ovarian tissue transplantation

Abstract

Ovarian aging is a progressive biological process marked by a decrease in the amount and quality of oocytes, resulting in decreased fertility, diminished ovarian reserve (DOR), premature ovarian insufficiency (POI), and menopause. Multiple molecular processes, including as oxidative stress, mitochondrial dysfunction, telomere shortening, DNA damage, apoptosis, and hormone imbalance, all contribute to poor ovarian function and follicular depletion. Conventional fertility therapies and assisted reproductive technologies focus on the effects of ovarian malfunction rather than improving ovarian activity itself, with little success in women with low ovarian reserve. Recently, ovarian rejuvenation has emerged as a viable regenerative method for enhancing the ovarian microenvironment, awakening dormant follicles, and restoring endocrine and reproductive function. This study looks at the biology of ovarian aging, the pathophysiology of ovarian dysfunction, and recent breakthroughs in ovarian rejuvenation treatments such as platelet-rich plasma (PRP) treatment, stem cell-based therapy, in vitro activation (IVA), and ovarian tissue transplantation (OTT). PRP therapy has the potential to improve ovarian reserve markers such as AMH, FSH, and AFC, whereas mesenchymal stem cell therapy may promote angiogenesis, reduce inflammation, and support follicular survival via paracrine mechanisms. IVA and OTT are also novel fertility preservation and restoration procedures for women with DOR and POI. Although first results are intriguing, existing evidence is limited due to small sample sizes, a lack of standardized techniques, and insufficient long-term safety data. More large-scale randomized clinical trials are needed to determine the efficacy, safety, and therapeutic application of ovarian rejuvenation therapy in reproductive medicine.

Metrics

Metrics Loading ...

References

Cox E, Takov V. Embryology, ovarian follicle development. InStatPearls. 2025. StatPearls Publishing.

Lew R. Natural history of ovarian function including assessment of ovarian reserve and premature ovarian failure. Best practice & research Clinical obstetrics & gynaecology. 2019;55:2-13. DOI: https://doi.org/10.1016/j.bpobgyn.2018.05.005

Zhu Z, Xu W, Liu L. Ovarian aging: mechanisms and intervention strategies. Medical Review. 2023;2(6):590-610. DOI: https://doi.org/10.1515/mr-2022-0031

Mu L, Wang G, Yang X, Liang J, Tong H, Li L, et al. Physiological premature aging of ovarian blood vessels leads to decline in fertility in middle-aged mice. Nature communications. 2025;16(1):72. DOI: https://doi.org/10.1038/s41467-024-55509-y

Houeis L, Donnez J, Dolmans MM. Premature Ovarian Insufficiency and Diminished Ovarian Reserve: From Diagnosis to Current Management and Treatment. Journal of clinical medicine. 2025;14(21):7473.. DOI: https://doi.org/10.3390/jcm14217473

Fàbregues F, Ferreri J, Méndez M, Calafell JM, Otero J, Farré R. In vitro follicular activation and stem cell therapy as a novel treatment strategies in diminished ovarian reserve and primary ovarian insufficiency. Frontiers in Endocrinology. 2021;11:617704. DOI: https://doi.org/10.3389/fendo.2020.617704

Evers JL. Female subfertility. The lancet. 2002;360(9327):151-9. DOI: https://doi.org/10.1016/S0140-6736(02)09417-5

Sadeghi MR. Ovarian rejuvenation: Turning dreams into reality. Journal of Reproduction & Infertility. 2024;25(1):1. DOI: https://doi.org/10.18502/jri.v25i1.15192

Ingole S, Khare K, Dwivedi V, Taksande B, Umekar M, Mangrulkar S. Decoding ovarian aging in women: Cellular damage, signaling networks, and treatment frontiers. Reproductive Biology. 2025 ;25(4):101075. DOI: https://doi.org/10.1016/j.repbio.2025.101075

Harrath AH. Mechanistic insights into aging and longevity: Implications for ovarian function and health. Tissue and Cell. 2026:103473. DOI: https://doi.org/10.1016/j.tice.2026.103473

Esencan E, Beroukhim G, Seifer DB. Age-related changes in Folliculogenesis and potential modifiers to improve fertility outcomes-A narrative review. Reproductive biology and endocrinology. 2022;20(1):156. DOI: https://doi.org/10.1186/s12958-022-01033-x

Kerr JB, Rodgers RJ. The human ovarian reserve: the narrative and the science. Human Reproduction Update. 2025:dmaf031. DOI: https://doi.org/10.1093/humupd/dmaf031

Rimon-Dahari N, Yerushalmi-Heinemann L, Alyagor L, Dekel N. Ovarian folliculogenesis. Molecular mechanisms of cell differentiation in gonad development. 2016:167-90. DOI: https://doi.org/10.1007/978-3-319-31973-5_7

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

Li CJ, Lin LT, Tsai HW, Chern CU, Wen ZH, Wang PH, et al. The molecular regulation in the pathophysiology in ovarian aging. Aging and disease. 2021;12(3):934. DOI: https://doi.org/10.14336/AD.2020.1113

Downs JL, Wise PM. The role of the brain in female reproductive aging. Molecular and Cellular Endocrinology. 2009 ;299(1):32-8. DOI: https://doi.org/10.1016/j.mce.2008.11.012

Copeland JL, Chu SY, Tremblay MS. Aging, physical activity, and hormones in women—a review. Journal of Aging and Physical Activity. 2004;12(1):101-16. DOI: https://doi.org/10.1123/japa.12.1.101

Hirano M, Onodera T, Takasaki K, Takahashi Y, Ichinose T, Nishida H, et al. Ovarian aging: Pathophysiology and recent developments in maintaining ovarian reserve. Frontiers in Endocrinology. 2025;16:1619516. DOI: https://doi.org/10.3389/fendo.2025.1619516

Kaplan JR, Manuck SB. Ovarian dysfunction, stress, and disease: a primate continuum. ILAR journal. 2004;45(2):89-115. DOI: https://doi.org/10.1093/ilar.45.2.89

Zhu Q, Li Y, Ma J, Ma H, Liang X. Potential factors result in diminished ovarian reserve: a comprehensive review. Journal of Ovarian Research. 2023;16(1):208.

Busnelli A, Somigliana E, Cirillo F, Levi-Setti PE. Is diminished ovarian reserve a risk factor for miscarriage? Results of a systematic review and meta-analysis. Human Reproduction Update. 2021;27(6):973-88. DOI: https://doi.org/10.1093/humupd/dmab018

Zhu Q, Li Y, Ma J, Ma H, Liang X. Potential factors result in diminished ovarian reserve: a comprehensive review. Journal of ovarian research. 2023;16(1):208. DOI: https://doi.org/10.1186/s13048-023-01296-x

Mutlu MF, Erdem A. Evaluation of ovarian reserve in infertile patients. Journal of the Turkish German Gynecological Association. 2012 Sep 1;13(3):196. DOI: https://doi.org/10.5152/jtgga.2012.28

Chon SJ, Umair Z, Yoon MS. Premature ovarian insufficiency: past, present, and future. Frontiers in Cell and Developmental Biology. 2021;9:672890. DOI: https://doi.org/10.3389/fcell.2021.672890

Torrealday S, Kodaman P, Pal L. Premature Ovarian Insufficiency-an update on recent advances in understanding and management. F1000Research. 2017;6:2069. DOI: https://doi.org/10.12688/f1000research.11948.1

Kapoor E. Premature ovarian insufficiency. Current opinion in endocrine and metabolic research. 2023;28:100435. DOI: https://doi.org/10.1016/j.coemr.2023.100435

Zhang Y, Chen X, Yu H, Zhang X, Hu S, Chen X. Investigation of the conversion mechanism of endogenous semicarbazide in shrimp on the amino acid level. Ecotoxicology and Environmental Safety. 2023;249:114393. DOI: https://doi.org/10.1016/j.ecoenv.2022.114393

An L, Huang Y, Wang Y, Shen S, Luo X, Liang X, Lu L, Tang C, Lin J, Su T, Zhan M. Assessment of ovarian dysfunction induced by environmental toxins: a systematic review. Frontiers in Public Health. 2025;13:1575418. DOI: https://doi.org/10.3389/fpubh.2025.1575418

Spath MA, Braat DD. Iatrogenic and non‐iatrogenic causes of female fertility loss that may indicate fertility preservation. Acta obstetricia et gynecologica Scandinavica. 2019;98(5):559-62. DOI: https://doi.org/10.1111/aogs.13594

Éliás M, Kónya M, Kekk Z, Turan C, das Virgens IP, Tóth R, Keszthelyi M, Hegyi P, Várbíró S, Sipos M. Platelet-rich plasma (PRP) treatment of the ovaries significantly improves fertility parameters and reproductive outcomes in diminished ovarian reserve patients: a systematic review and meta-analysis. Journal of Ovarian Research. 2024;17(1):104. DOI: https://doi.org/10.1186/s13048-024-01423-2

Broekmans FJ, Soules MR, Fauser BC. Ovarian aging: mechanisms and clinical consequences. Endocrine reviews. 2009 Aug 1;30(5):465-93. DOI: https://doi.org/10.1210/er.2009-0006

Hassan N, Hussein DM, Malak FA, Abdelaziz MA, Boushra MI, Shaalan W, et al. Mesenchymal stem cells: a therapeutic approach in fertility restoration in premature ovarian insufficiency. Stem Cell Reviews and Reports. 2025;21(7):2089-102. DOI: https://doi.org/10.1007/s12015-025-10944-2

Yoon SY. Mesenchymal stem cells for restoration of ovarian function. Clinical and experimental reproductive medicine. 2019;46(1):1. DOI: https://doi.org/10.5653/cerm.2019.46.1.1

Devenutto LM, Valzacchi GR, Ercolano M, Etchegoyen O. Intraovarian platelet-rich plasma injection in poor responders. JBRA assisted reproduction. 2024;28(3):450. DOI: https://doi.org/10.5935/1518-0557.20240031

Dhurat R, Sukesh M. Principles and methods of preparation of platelet-rich plasma: a review and author's perspective. Journal of Cutaneous and Aesthetic Surgery. 2014;7(4):189-97. DOI: https://doi.org/10.4103/0974-2077.150734

Messora MR, Nagata MJ, Furlaneto FA, Dornelles RC, Bomfim SR, Deliberador TM, et al. A standardized research protocol for platelet-rich plasma (PRP) preparation in rats. RSBO Revista Sul-Brasileira de Odontologia. 2011;8(3):299-304.

Alonso-Frías P, Francés-Herrero E, Bueno-Fernandez C, Gómez-Álvarez M, Agustina-Hernández M, Cervelló I, et al. Beneficial effects of infiltration of platelet-rich plasma in the endometrium. Biology. 2025;14(4):319. DOI: https://doi.org/10.3390/biology14040319

Moustakli E, Potiris A, Zikopoulos A, Zachariou A, Topis S, Panagopoulos P, et al. Platelet-rich plasma (PRP) in reproductive medicine: a critical review of PRP therapy in low-reserve and premature ovarian insufficiency. Biomedicines. 2025;13(5):1257. DOI: https://doi.org/10.3390/biomedicines13051257

Patel H, Pundkar A, Shrivastava S, Chandanwale R, Jaiswal AM. A comprehensive review on platelet-rich plasma activation: a key player in accelerating skin wound healing. Cureus. 2023;15(11). DOI: https://doi.org/10.7759/cureus.48943

Pantos K, Simopoulou M, Pantou A, Rapani A, Tsioulou P, Nitsos N, et al. A case series on natural conceptions resulting in ongoing pregnancies in menopausal and prematurely menopausal women following platelet-rich plasma treatment. Cell transplantation. 2019;28(9-10):1333-40 DOI: https://doi.org/10.1177/0963689719859539

Simavlı S, Caglayan EK, Kaygusuz I, Albayrak F, Caliskan E. Changes in ovarian functions following platelet-rich plasma (prp) injection and its impact on in vitro fertilisation (ivf) treatment: A pre-post research. Clinical and Experimental Obstetrics & Gynecology. 2025;52(2):26053. DOI: https://doi.org/10.31083/CEOG26053

Farimani M, Nazari A, Mohammadi S, Anvari Aliabad R. Evaluation of intra-ovarian platelet-rich plasma administration on oocytes-dependent variables in patients with poor ovarian response: A retrospective study according to the POSEIDON criteria. Reproductive Biology and Endocrinology. 2021;19(1):137. DOI: https://doi.org/10.1186/s12958-021-00826-w

Herraiz S, Buigues A, Díaz-García C, Romeu M, Martínez S, Gómez-Seguí I, et al. Fertility rescue and ovarian follicle growth promotion by bone marrow stem cell infusion. Fertility and Sterility. 2018;109(5):908-18. DOI: https://doi.org/10.1016/j.fertnstert.2018.01.004

Cacciottola L, Vitale F, Donnez J, Dolmans MM. Use of mesenchymal stem cells to enhance or restore fertility potential: a systematic review of available experimental strategies. Human Reproduction Open. 2023;2023(4):hoad040. DOI: https://doi.org/10.1093/hropen/hoad040

Galderisi U, Peluso G, Di Bernardo G. Clinical trials based on mesenchymal stromal cells are exponentially increasing: where are we in recent years?. Stem Cell Reviews and Reports. 2022;18(1):23-36 DOI: https://doi.org/10.1007/s12015-021-10231-w

Cui X, Jing X. Stem cell-based therapeutic potential in female ovarian aging and infertility. Journal of Ovarian Research. 2024;17(1):171. DOI: https://doi.org/10.1186/s13048-024-01492-3

Volarevic V, Markovic BS, Gazdic M, Volarevic A, Jovicic N, Arsenijevic N, et al. Ethical and safety issues of stem cell-based therapy. International Journal of Medical Sciences. 2018;15(1):36. DOI: https://doi.org/10.7150/ijms.21666

Zadereev ES, Lopatina TS. Extraction of info chemicals inducing the production of resting eggs in cladocerans. InDoklady. Biochemistry and Biophysics. 2015;461:127. DOI: https://doi.org/10.1134/S1607672915020192

Kawamura K, Cheng Y, Suzuki N, Deguchi M, Sato Y, Takae S, et al. Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment. Proceedings of the National Academy of Sciences. 2013;110(43):17474-9. DOI: https://doi.org/10.1073/pnas.1312830110

Ghezelayagh Z, Khoshdel-Rad N, Ebrahimi B. Human ovarian tissue in-vitro culture: primordial follicle activation as a new strategy for female fertility preservation. Cytotechnology. 2022;74(1):1-5. DOI: https://doi.org/10.1007/s10616-021-00510-2

Kawamura K, Ishizuka B, Hsueh AJ. Drug-free in-vitro activation of follicles for infertility treatment in poor ovarian response patients with decreased ovarian reserve. Reproductive biomedicine online. 2020;40(2):245-53. DOI: https://doi.org/10.1016/j.rbmo.2019.09.007

Vo KC, Kawamura K. In vitro activation early follicles: from the basic science to the clinical perspectives. International Journal of Molecular Sciences. 2021;22(7):3785. DOI: https://doi.org/10.3390/ijms22073785

Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, Martinez-Madrid B, Van Langendonckt A. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. The Lancet. 2004;364(9443):1405-10. DOI: https://doi.org/10.1016/S0140-6736(04)17222-X

Donnez J, Jadoul P, Squifflet J, Van Langendonckt A, Donnez O, Van Eyck AS, Marinescu C, Dolmans MM. Ovarian tissue cryopreservation and transplantation in cancer patients. Best practice & research Clinical Obstetrics & Gynaecology. 2010;24(1):87-100. DOI: https://doi.org/10.1016/j.bpobgyn.2009.09.003

Silber SJ, Lenahan KM, Levine DJ, Pineda JA, Gorman KS, Friez MJ, et al. Ovarian transplantation between monozygotic twins discordant for premature ovarian failure. New England Journal of Medicine. 2005;353(1):58-63. DOI: https://doi.org/10.1056/NEJMoa043157

Practice Committee of the American Society for Reproductive Medicine. Ovarian tissue cryopreservation: a committee opinion. Fertility and Sterility. 2014;101(5):1237-43. DOI: https://doi.org/10.1016/j.fertnstert.2014.02.052

Oktay K, Economos K, Kan M, Rucinski J, Veeck L, Rosenwaks Z. Endocrine function and oocyte retrieval after autologous transplantation of ovarian cortical strips to the forearm. JAMA. 2001;286(12):1490-3. DOI: https://doi.org/10.1001/jama.286.12.1490

Diaz AA, Kubo H, Handa N, Hanna M, Laronda MM. A systematic review of ovarian tissue transplantation outcomes by ovarian tissue processing size for cryopreservation. Frontiers in Endocrinology. 2022;13:918899. DOI: https://doi.org/10.3389/fendo.2022.918899

Practice Committee of the American Society for Reproductive Medicine. Fertility preservation in patients undergoing gonadotoxic therapy or gonadectomy: a committee opinion. Fertility and Sterility. 2019;112(6):1022-33. DOI: https://doi.org/10.1016/j.fertnstert.2019.09.013