Innovations for Optimizing Fertility and Ovarian Functionality in Female Cancer Patients

Main Article Content

Ellen Cristina Rivas Leonel


The survival rates and quality of life of patients undergoing cancer treatments have significantly increased in recent years. However, these advanced treatments are known to exert a potentially gonadotoxic effect, impairing the female population of germ cells and, consequently, leading to ovarian failure through hormonal dysfunction and premature menopause. Nowadays, it is strongly recommended that oncologists discuss the risks of infertility and alternatives with each patient individually, recommending a consultation with a reproductive specialist as early as possible. In this context, remarkable progress has been made in assisted reproductive techniques aimed at fertility preservation for female patients. The main currently applied methods to avoid total loss of ovarian activity as a result of chemo or radiotherapy include oocyte, embryo, or ovarian tissue cryopreservation. This topic review summarizes the recent advances in these techniques, which have increased the chances of fertility preservation and family planning, as well as providing hope for cancer survivors. Oocyte cryopreservation followed by in vitro fertilization and embryo transfer are currently the recommended first-line fertility preservation approaches. However, for prepubertal individuals, the technique of ovarian tissue cryopreservation is advised; this is, moreover, the best method for efficient maintenance of the follicular reserve and allows future tissue transplantation, which not only restores fertility but also resumes natural ovarian hormonal activity. Recently, the discussion about the reestablishment of ovarian function in a defective tissue has raised compelling arguments, based on the theory about the presence of germ stem cells in the ovary. Despite the relevance of the results and the psychological benefits, the number of female patients diagnosed with cancer who are offered any method of fertility preservation is low. Multidisciplinary teams working jointly with oncologists and fertility specialists are essential for better outcomes regarding the wellness of patients who recover from cancer. Although further studies are needed to improve some of the available approaches, for now, comprehensive availability of oocyte/embryo or ovarian tissue freezing services is necessary worldwide to meet patient needs.

Article Details

How to Cite
LEONEL, Ellen Cristina Rivas. Innovations for Optimizing Fertility and Ovarian Functionality in Female Cancer Patients. Medical Research Archives, [S.l.], v. 10, n. 10, oct. 2022. ISSN 2375-1924. Available at: <>. Date accessed: 19 june 2024. doi:
Research Articles


1. Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64(1):9-29.
2. Bertuccio P, Alicandro G, Malvezzi M, et al. Childhood cancer mortality trends in Europe, 1990-2017, with focus on geographic differences. Cancer Epidemiol. 2020;67:101768.
3. Ward E, DeSantis C, Robbins A, Kohler B, Jemal A. Childhood and adolescent cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):83-103.
4. Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update. 2001;7(6):535-543.
5. Martin JA, Hamilton BE, Osterman MJK, Driscoll AK, Drake P. Births: final data for 2016. Published online 2018.
6. Logan S, Perz J, Ussher JM, Peate M, Anazodo A. Systematic review of fertility-related psychological distress in cancer patients: Informing on an improved model of care. Psychooncology. 2019;28(1):22-30. doi:
7. Muharam R, Setiawan MW, Ikhsan M, Rizkinya HE, Sumapraja K. Depression and its link to other symptoms in menopausal transition. Middle East Fertil Soc J. 2018;23(1):27-30.
8. Talaulikar V. Menopause transition: Physiology and symptoms. Best Pract Res Clin Obstet Gynaecol. Published online 2022.
9. Loren AW, Mangu PB, Beck LN, et al. Fertility Preservation for Patients With Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update. Journal of Clinical Oncology. 2013;31(19):2500-2510. doi:10.1200/JCO.2013.49.2678
10. Rives N, Courbière B, Almont T, et al. What should be done in terms of fertility preservation for patients with cancer? The French 2021 guidelines. Eur J Cancer. 2022;173:146-166. doi:10.1016/j.ejca.2022.05.013
11. Cosgrove CM, Salani R. Ovarian effects of radiation and cytotoxic chemotherapy damage. Best Pract Res Clin Obstet Gynaecol. 2019;55:37-48.
12. Li F, Turan V, Lierman S, Cuvelier C, de Sutter P, Oktay K. Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death. Human Reproduction. 2014;29(1):107-113.
13. Lande Y, Fisch B, Tsur A, et al. Short-term exposure of human ovarian follicles to cyclophosphamide metabolites seems to promote follicular activation in vitro. Reprod Biomed Online. 2017;34(1):104-114.
14. Melekoglu R, Ciftci O, Eraslan S, Cetin A, Basak N. Beneficial effects of curcumin and capsaicin on cyclophosphamide-induced premature ovarian failure in a rat model. J Ovarian Res. 2018;11(1):33. doi:10.1186/s13048-018-0409-9
15. Petrillo SK, Desmeules P, Truong TQ, Devine PJ. Detection of DNA damage in oocytes of small ovarian follicles following phosphoramide mustard exposures of cultured rodent ovaries in vitro. Toxicol Appl Pharmacol. 2011;253(2):94-102.
16. Piasecka-Srader J, Blanco FF, Delman DH, et al. Tamoxifen prevents apoptosis and follicle loss from cyclophosphamide in cultured rat ovaries. Biol Reprod. 2015;92(5):131-132.
17. Yuksel A, Bildik G, Senbabaoglu F, et al. The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells. Human reproduction. 2015;30(12):2926-2935.
18. Luo Q, Yin N, Zhang L, et al. Role of SDF-1/CXCR4 and cytokines in the development of ovary injury in chemotherapy drug induced premature ovarian failure mice. Life Sci. 2017;179:103-109.
19. di Emidio G, D’Aurora M, Placidi M, et al. Pre-conceptional maternal exposure to cyclophosphamide results in modifications of DNA methylation in F1 and F2 mouse oocytes: evidence for transgenerational effects. Epigenetics. 2019;14(11):1057-1064.
20. Wallace WHB, Thomson AB, Kelsey TW. The radiosensitivity of the human oocyte. Human Reproduction. 2003;18(1):117-121. doi:10.1093/humrep/deg016
21. Marci R, Mallozzi M, di Benedetto L, et al. Radiations and female fertility. Reproductive Biology and Endocrinology. 2018;16(1):1-12.
22. Mattiello L, Pucci G, Marchetti F, Diederich M, Gonfloni S. Asciminib mitigates DNA damage stress signaling induced by cyclophosphamide in the ovary. Int J Mol Sci. 2021;22(3):1395.
23. Iussig B, Maggiulli R, Fabozzi G, et al. A brief history of oocyte cryopreservation: Arguments and facts. Acta Obstet Gynecol Scand. 2019;98(5):550-558. doi:
24. Cobo A, Diaz C. Clinical application of oocyte vitrification: a systematic review and meta-analysis of randomized controlled trials. Fertil Steril. 2011;96(2):277-285. doi:10.1016/j.fertnstert.2011.06.030
25. Gala A, Ferrières- Hoa A, Loup-Cabaniols V, et al. Closed vitrification system and egg donation: Predictive factors of oocyte survival and pregnancy. J Gynecol Obstet Hum Reprod. 2020;49(3):101687. doi:
26. Galvão A, Segers I, Smitz J, Tournaye H, de Vos M. In vitro maturation (IVM) of oocytes in patients with resistant ovary syndrome and in patients with repeated deficient oocyte maturation. J Assist Reprod Genet. 2018;35(12):2161-2171. doi:10.1007/s10815-018-1317-z
27. Chen D, Bernardi LA, Pavone ME, Feinberg EC, Moravek MB. Oocyte cryopreservation among transmasculine youth: a case series. J Assist Reprod Genet. 2018;35(11):2057-2061. doi:10.1007/s10815-018-1292-4
28. Dinh T, Son WY, Demirtas E, Dahan MH. How long can oocytes be frozen with vitrification and still produce competent embryos? A series of six cases. Korean J Obstet Gynecol. 2022;0. doi:10.5468/ogs.20344
29. Cobo A, García-Velasco JA, Remohí J, Pellicer A. Oocyte vitrification for fertility preservation for both medical and nonmedical reasons. Fertil Steril. 2021;115(5):1091-1101. doi:
30. Rienzi L, Romano S, Albricci L, et al. Embryo development of fresh ‘versus’ vitrified metaphase II oocytes after ICSI: a prospective randomized sibling-oocyte study. Human reproduction. 2010;25(1):66-73.
31. Cobo A, Meseguer M, Remohí J, Pellicer A. Use of cryo-banked oocytes in an ovum donation programme: a prospective, randomized, controlled, clinical trial. Human reproduction. 2010;25(9):2239-2246.
32. Potdar N, Gelbaya TA, Nardo LG. Oocyte vitrification in the 21st century and post-warming fertility outcomes: a systematic review and meta-analysis. Reprod Biomed Online. 2014;29(2):159-176.
33. Talreja D, Gupta C, Pai H, Palshetkar N. Oocyte vitrification: A comparative analysis between fresh and cryopreserved oocytes in an oocyte donation program. Fertility & Reproduction. 2020;2(01):9-13.
34. Domingues TS, Aquino AP, Barros B, et al. Egg donation of vitrified oocytes bank produces similar pregnancy rates by blastocyst transfer when compared to fresh cycle. J Assist Reprod Genet. 2017;34(11):1553-1557.
35. Doyle JO, Richter KS, Lim J, Stillman RJ, Graham JR, Tucker MJ. Successful elective and medically indicated oocyte vitrification and warming for autologous in vitro fertilization, with predicted birth probabilities for fertility preservation according to number of cryopreserved oocytes and age at retrieval. Fertil Steril. 2016;105(2):459-466.
36. Peschansky C, Patel S, Amir J, et al. PICTURE PERFECT?: DETERMINING THE CLINICAL UTILIZATION OF ARTIFICIAL INTELLIGENCE IN OOCYTE CRYOPRESERVATION. Fertil Steril. 2021;116(3):e157. doi:10.1016/j.fertnstert.2021.07.424
37. Hajek J, Baron R, Sandi-Monroy N, et al. A randomised, multi-center, open trial comparing a semi-automated closed vitrification system with a manual open system in women undergoing IVF. Human Reproduction. 2021;36(8):2101-2110. doi:10.1093/humrep/deab140
38. Trounson A, Mohr L. Human pregnancy following cryopreservation, thawing and transfer of an eight-cell embryo. Nature. 1983;305(5936):707-709. doi:10.1038/305707a0
39. Cohen J, Simons R, Fehilly C, et al. BIRTH AFTER REPLACEMENT OF HATCHING BLASTOCYST CRYOPRESERVED AT EXPANDED BLASTOCYST STAGE. The Lancet. 1985;325(8429):647. doi:10.1016/S0140-6736(85)92194-4
40. Ramadan H, Pakrashi T, Thurman AR, Pomeroy KO, Celia G. Cryopreservation Does Not Affect the Clinical Pregnancy Rate of Blastocysts Derived from Vitrified Oocytes. Sci Rep. 2022;12(1):8970. doi:10.1038/s41598-022-12992-x
41. Andrabi SW, Arora PR, Mir J, Kaur S, Khan A, Albarki AS. Developmental Potential of embryos does not Impact Pregnancy Outcomes, but it Affects Live Birth Rates in Frozen Blastocyst Transfer Cycles. JBRA Assist Reprod. 2022;26(3):426.
42. Walls M, Junk S, Ryan JP, Hart R. IVF versus ICSI for the fertilization of in-vitro matured human oocytes. Reprod Biomed Online. 2012;25(6):603-607. doi:
43. van Landuyt L, de Vos A, Joris H, Verheyen G, Devroey P, van Steirteghem A. Blastocyst formation in in vitro fertilization versus intracytoplasmic sperm injection cycles: Influence of the fertilization procedure. Fertil Steril. 2005;83(5):1397-1403. doi:10.1016/j.fertnstert.2004.10.054
44. Kolibianakis EM, Zikopoulos K, Devroey P. Implantation Potential and Clinical Impact of Cryopreservation—A Review. Placenta. 2003;24:S27-S33. doi:
45. Sciorio R, Thong KJ, Pickering SJ. Single blastocyst transfer (SET) and pregnancy outcome of day 5 and day 6 human blastocysts vitrified using a closed device. Cryobiology. 2018;84:40-45. doi:
46. di Guardo F, Racca A, Coticchio G, et al. Impact of cell loss after warming of human vitrified day 3 embryos on obstetric outcome in single frozen embryo transfers. J Assist Reprod Genet. Published online 2022. doi:10.1007/s10815-022-02572-3
47. Rienzi L, Gracia C, Maggiulli R, et al. Oocyte, embryo and blastocyst cryopreservation in ART: systematic review and meta-analysis comparing slow-freezing versus vitrification to produce evidence for the development of global guidance. Hum Reprod Update. 2017;23(2):139-155.
48. Xu L, Gao S, Jiang J, Sun M, Sheng Y, Tang R. Outcomes of embryo vitrification at different developmental stages: Evaluation of 2412 warming cycles. Medicine. 2022;101(19):e29233-e29233.
49. Kim CH, Lee YJ, Lee KH, et al. The effect of luteal phase progesterone supplementation on natural frozen-thawed embryo transfer cycles. Obstet Gynecol Sci. 2014;57(4):291-296.
50. Schwartz E, Bernard L, Ohl J, et al. Luteal phase progesterone supplementation following induced natural cycle frozen embryo transfer: a retrospective cohort study. J Gynecol Obstet Hum Reprod. 2019;48(2):95-98.
51. Franco Jr JG, Martins A, Baruffi RLR, et al. Best site for embryo transfer: the upper or lower half of endometrial cavity? Human Reproduction. 2004;19(8):1785-1790.
52. Mains L, van Voorhis BJ. Optimizing the technique of embryo transfer. Fertil Steril. 2010;94(3):785-790. doi:
53. dos Anjos JF, Osorio EGP, Peñarrubia J, Vidal E, Gasol FF. Transmyometrial embryo transfer as a useful method to overcome difficult embryo transfers-a single-center retrospective study. JBRA Assist Reprod. 2018;22(2):134.
54. Dolmans MM, Hollanders de Ouderaen S, Demylle D, Pirard C. Utilization rates and results of long-term embryo cryopreservation before gonadotoxic treatment. J Assist Reprod Genet. 2015;32(8):1233-1237. doi:10.1007/s10815-015-0533-z
55. Okutsu-Horage Y, Iwahata H, Suzuki-Takahashi Y, Sugisita Y, Takae S, Suzuki N. Clinical outcome of embryo cryopreservation in Japanese breast cancer patients: pregnancy rates after transfer of thawed embryos. J Assist Reprod Genet. Published online 2022. doi:10.1007/s10815-022-02575-0
56. Kappy M, Lieman HJ, Pollack S, Buyuk E. Fertility preservation for cancer patients: treatment gaps and considerations in patients’ choices. Arch Gynecol Obstet. 2021;303(6):1617-1623. doi:10.1007/s00404-021-05985-0
57. Arapaki A, Christopoulos P, Kalampokas E, Triantafyllidou O, Matsas A, Vlahos NF. Ovarian Tissue Cryopreservation in Children and Adolescents. Children. 2022;9(8):1256.
58. Donnez J, Dolmans MM, Demylle D, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. The Lancet. 2004;364(9443):1405-1410. doi:10.1016/S0140-6736(04)17222-X
59. Dolmans MM, Falcone T, Patrizio P. Importance of patient selection to analyze in vitro fertilization outcome with transplanted cryopreserved ovarian tissue. Fertil Steril. 2020;114(2):279-280. doi:10.1016/j.fertnstert.2020.04.050
60. Mat Jin N, Ahmad SM, Mohd Faizal A, Abdul Karim AK bin, Abu MA. Ovarian tissue cryopreservation in Malaysia: a case series. Published online 2022. doi:doi:10.1515/hmbci-2021-0096
61. Corkum KS, Rhee DS, Wafford QE, et al. Fertility and hormone preservation and restoration for female children and adolescents receiving gonadotoxic cancer treatments: A systematic review. J Pediatr Surg. 2019;54(11):2200-2209. doi:10.1016/j.jpedsurg.2018.12.021
62. Oktay KH, Marin L, Petrikovsky B, Terrani M, Babayev SN. Prolonging Reproductive Life Span and Delaying Menopause: Prime Time for Elective Cryopreservation and Transplantation? Trends Mol Med. 2021;27(8):753.
63. Vuković P, Kasum M, Orešković D, et al. Importance of ovarian tissue cryopreservation in fertility preservation and anti-aging treatment. Gynecological Endocrinology. 2019;35(11):919-923. doi:10.1080/09513590.2019.1611763
64. Kolibianaki EE, Goulis DG, Kolibianakis EM. Ovarian tissue cryopreservation and transplantation to delay menopause: facts and fiction. Maturitas. 2020;142:64-67. doi:
65. Jadoul P, Donnez J, Dolmans MM, Squifflet J, Lengele B, Martinez-Madrid B. Laparoscopic ovariectomy for whole human ovary cryopreservation: technical aspects. Fertil Steril. 2007;87(4):971-975.
66. Westphal JR, Gerritse R, Braat DDM, Beerendonk C, Peek R. Complete protection against cryodamage of cryopreserved whole bovine and human ovaries using DMSO as a cryoprotectant. J Assist Reprod Genet. 2017;34(9):1217-1229.
67. Suzuki N, Yoshioka N, Takae S, et al. Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Human Reproduction. 2015;30(3):608-615. doi:10.1093/humrep/deu353
68. Hossay C, Camboni A, Cacciottola L, et al. Can frozen-thawed human ovary withstand refreezing-rethawing in the form of cortical strips? J Assist Reprod Genet. 2020;37(12):3077-3087. doi:10.1007/s10815-020-01960-x
69. Dolmans MM, Masciangelo R. Risk of transplanting malignant cells in cryopreserved ovarian tissue. Minerva Ginecol. 2018;70(4):436-443.
70. Díaz-García C, Herraiz S, Such E, et al. Dexamethasone does not prevent malignant cell reintroduction in leukemia patients undergoing ovarian transplant: risk assessment of leukemic cell transmission by a xenograft model. Human Reproduction. 2019;34(8):1485-1493. doi:10.1093/humrep/dez115
71. Masciangelo R, Bosisio C, Donnez J, Amorim CA, Dolmans MM. Safety of ovarian tissue transplantation in patients with borderline ovarian tumors. Human Reproduction. 2018;33(2):212-219. doi:10.1093/humrep/dex352
72. Bastings L, Beerendonk CCM, Westphal JR, et al. Autotransplantation of cryopreserved ovarian tissue in cancer survivors and the risk of reintroducing malignancy: a systematic review. Hum Reprod Update. 2013;19(5):483-506. doi:10.1093/humupd/dmt020
73. Peek R, Bastings L, Westphal JR, Massuger LFAG, Braat DDM, Beerendonk CCM. A preliminary study on a new model system to evaluate tumour-detection and tumour-purging protocols in ovarian cortex tissue intended for fertility preservation. Human Reproduction. 2015;30(4):870-876. doi:10.1093/humrep/dev013
74. Chiti MC, Dolmans MM, Hobeika M, Cernogoraz A, Donnez J, Amorim CA. A modified and tailored human follicle isolation procedure improves follicle recovery and survival. J Ovarian Res. 2017;10(1):1-9.
75. Leonel ECR, Lucci CM, Amorim CA. Cryopreservation of Preantral Follicles. In: Cryopreservation Biotechnology in Biomedical and Biological Sciences. IntechOpen; 2018.
76. Vanacker J, Luyckx V, Amorim C, et al. Should we isolate human preantral follicles before or after cryopreservation of ovarian tissue? Fertil Steril. 2013;99(5):1363-1368.e2. doi:10.1016/j.fertnstert.2012.12.016
77. Fan Y, Flanagan CL, Brunette MA, et al. Fresh and cryopreserved ovarian tissue from deceased young donors yields viable follicles. F S Sci. 2021;2(3):248-258.
78. Lierman S, Tilleman K, Cornelissen M, et al. Follicles of various maturation stages react differently to enzymatic isolation: a comparison of different isolation protocols. Reprod Biomed Online. 2015;30(2):181-190.
79. Carroll J, Whittingham DG, Wood MJ, Telfer E, Gosden RG. Extra-ovarian production of mature viable mouse oocytes from frozen primary follicles. Reproduction. 1990;90(1):321-327. doi:10.1530/jrf.0.0900321
80. Hao X, Anastácio A, Rodriguez-Wallberg KA. Feasibility of Secondary Follicle Isolation, Culture and Achievement of In-Vitro Oocyte Maturation from Superovulated Ovaries: An Experimental Proof-of-Concept Study Using Mice. J Clin Med. 2021;10(13):2757.
81. Beckmann MW, Dittrich R, Lotz L, et al. Fertility protection: complications of surgery and results of removal and transplantation of ovarian tissue. Reprod Biomed Online. 2018;36(2):188-196. doi:
82. Donnez J, Dolmans MM, Diaz C, Pellicer A. Ovarian cortex transplantation: time to move on from experimental studies to open clinical application. Fertil Steril. 2015;104(5):1097-1098.
83. Donnez J, Dolmans MM. Fertility preservation in women. Nat Rev Endocrinol. 2013;9:735.
84. Andersen CY, Rosendahl M, Byskov AG, et al. Two successful pregnancies following autotransplantation of frozen/thawed ovarian tissue. Human reproduction. 2008;23(10):2266-2272.
85. Donnez J, Dolmans MM. Ovarian cortex transplantation: 60 reported live births brings the success and worldwide expansion of the technique towards routine clinical practice. J Assist Reprod Genet. 2015;32(8):1167-1170. doi:10.1007/s10815-015-0544-9
86. Rosendahl M, Loft A, Byskov AG, et al. Biochemical pregnancy after fertilization of an oocyte aspirated from a heterotopic autotransplant of cryopreserved ovarian tissue: Case Report. Human Reproduction. 2006;21(8):2006-2009. doi:10.1093/humrep/del140
87. Gavish Z, Peer G, Hadassa R, Yoram C, Meirow D. Follicle activation and “burn-out” contribute to post-transplantation follicle loss in ovarian tissue grafts: The effect of graft thickness. Human Reproduction. 2014;29(5):989-996. doi:10.1093/humrep/deu015
88. Fabbri R, Sapone A, Paolini M, et al. Effects of N-acetylcysteine on human ovarian tissue preservation undergoing cryopreservation procedure. Published online 2015.
89. Kang BJ, Wang Y, Zhang L, Xiao Z, Li SW. bFGF and VEGF improve the quality of vitrified-thawed human ovarian tissues after xenotransplantation to SCID mice. J Assist Reprod Genet. 2016;33(2):281-289.
90. Donnez J, Dolmans MM. Fertility Preservation in Women. New England Journal of Medicine. 2017;377(17):1657-1665. doi:10.1056/NEJMra1614676
91. Shapira M, Dolmans MM, Silber S, Meirow D. Evaluation of ovarian tissue transplantation: results from three clinical centers. Fertil Steril. 2020;114(2):388-397.
92. Moghassemi S, Dadashzadeh A, de Azevedo RB, Amorim CA. Secure transplantation by tissue purging using photodynamic therapy to eradicate malignant cells. J Photochem Photobiol B. Published online 2022:112546.
93. Li J, Kawamura K, Cheng Y, et al. Activation of dormant ovarian follicles to generate mature eggs. Proceedings of the National Academy of Sciences. 2010;107(22):10280-10284. doi:10.1073/pnas.1001198107
94. Reddy P, Liu L, Adhikari D, et al. Oocyte-Specific Deletion of Pten Causes Premature Activation of the Primordial Follicle Pool. Science (1979). 2008;319(5863):611-613. doi:10.1126/science.1152257
95. Adhikari D, Liu K. mTOR signaling in the control of activation of primordial follicles. Cell Cycle. 2010;9(9):1673-1674. doi:10.4161/cc.9.9.11626
96. Eppig JJ, O’Brien MJ. Development in vitro of mouse oocytes from primordial follicles. Biol Reprod. 1996;54(1):197-207.
97. O’Brien MJ, Pendola JK, Eppig JJ. A revised protocol for in vitro development of mouse oocytes from primordial follicles dramatically improves their developmental competence. Biol Reprod. 2003;68(5):1682-1686.
98. McLaughlin M, Albertini DF, Wallace WHB, Anderson RA, Telfer EE. Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. MHR: Basic science of reproductive medicine. 2018;24(3):135-142.
99. Amorim CA, Shikanov A. The artificial ovary: current status and future perspectives. Future oncology. 2016;12(19):2323-2332.
100. Shaw JM, Oranratnachai A, Trounson AO. Fundamental cryobiology of mammalian oocytes and ovarian tissue. Theriogenology. 2000;53(1):59-72.
101. Pors SE, Ramløse M, Nikiforov D, et al. Initial steps in reconstruction of the human ovary: survival of pre-antral stage follicles in a decellularized human ovarian scaffold. Human Reproduction. 2019;34(8):1523-1535. doi:10.1093/humrep/dez077
102. Liu WY, Lin SG, Zhuo RY, et al. Xenogeneic decellularized scaffold: a novel platform for ovary regeneration. Tissue Eng Part C Methods. 2017;23(2):61-71.
103. Dath C, Dethy A, Langendonckt A van, et al. Endothelial cells are essential for ovarian stromal tissue restructuring after xenotransplantation of isolated ovarian stromal cells. Human Reproduction. 2011;26.
104. Soares M, Sahrari K, Amorim CA, Saussoy P, Donnez J, Dolmans MM. Evaluation of a human ovarian follicle isolation technique to obtain disease-free follicle suspensions before safely grafting to cancer patients. Fertil Steril. 104:672.e2-680.e2.
105. Mendez U, Zhou H, Shikanov A. Synthetic PEG hydrogel for engineering the environment of ovarian follicles. Methods in Molecular Biology. 2018;1758.
106. Paulini F, Vilela JM v, Chiti MC, et al. Survival and growth of human preantral follicles after cryopreservation of ovarian tissue, follicle isolation and short-term xenografting. Reprod Biomed Online. 2016;33(3):425-432.
107. Faulk DM, Johnson SA, Zhang L, Badylak SF. Role of the extracellular matrix in whole organ engineering. J Cell Physiol. 2014;229.
108. Kim J, Perez AS, Claflin J, David A, Zhou H, Shikanov A. Synthetic hydrogel supports the function and regeneration of artificial ovarian tissue in mice. NPJ Regen Med. 2016;1(1):1-8.
109. Yoon MD, Fisher JP. Natural and Synthetic Scaffolds. Natural and Synthetic Scaffolds. Published online 2009.
110. Rios PD, Kniazeva E, Lee HC, et al. Retrievable hydrogels for ovarian follicle transplantation and oocyte collection. Biotechnol Bioeng. 2018;115.
111. Kniazeva E, Hardy AN, Boukaidi SA, Woodruff TK, Jeruss JS, Shea LD. Primordial follicle transplantation within designer biomaterial grafts produce live births in a mouse infertility model. Sci Rep. 2015;5:17709.
112. Oktay K, Türkçüoğlu I, Rodriguez-Wallberg KA. Four spontaneous pregnancies and three live births following subcutaneous transplantation of frozen banked ovarian tissue: what is the explanation? Fertil Steril. 2011;95(2):804-e7.
113. Tartagni M, Cicinelli E, de Pergola G, de Salvia MA, Lavopa C, Loverro G. Effects of pretreatment with estrogens on ovarian stimulation with gonadotropins in women with premature ovarian failure: a randomized, placebo-controlled trial. Fertil Steril. 2007;87(4):858-861. doi:10.1016/j.fertnstert.2006.08.086
114. van Kasteren YM, Schoemaker J. Premature ovarian failure: a systematic review on therapeutic interventions to restore ovarian function and achieve pregnancy. Hum Reprod Update. 1999;5(5):483-492. doi:10.1093/humupd/5.5.483
115. Oktay K. Spontaneous conceptions and live birth after heterotopic ovarian transplantation: is there a germline stem cell connection? Human Reproduction. 2006;21(6):1345-1348. doi:10.1093/humrep/del007
116. Jurisicova A, Lee HJ, D’Estaing SG, Tilly J, Perez GI. Molecular requirements for doxorubicin-mediated death in murine oocytes. Cell Death Differ. 2006;13(9):1466-1474. doi:10.1038/sj.cdd.4401819
117. Liu J, Zhang H, Zhang Y, et al. Homing and restorative effects of bone marrow-derived mesenchymal stem cells on cisplatin injured ovaries in rats. Mol Cells. 2014;37(12):865.
118. Salooja N, Szydlo RM, Socie G, et al. Pregnancy outcomes after peripheral blood or bone marrow transplantation: a retrospective survey. The Lancet. 2001;358(9278):271-276. doi:10.1016/S0140-6736(01)05482-4
119. Herraiz S, Romeu M, Buigues A, et al. Autologous stem cell ovarian transplantation to increase reproductive potential in patients who are poor responders. Fertil Steril. 2018;110(3):496-505.e1. doi:10.1016/j.fertnstert.2018.04.025
120. Gupta S, Lodha P, Karthick MS, Tandulwadkar SR. Role of Autologous Bone Marrow-Derived Stem Cell Therapy for Follicular Recruitment in Premature Ovarian Insufficiency: Review of Literature and a Case Report of World’s First Baby with Ovarian Autologous Stem Cell Therapy in a Perimenopausal Woman of Age. J Hum Reprod Sci. 2018;11(2):125-130. doi:10.4103/jhrs.JHRS_57_18
121. Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ. Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature. 2006;441(7097):1109-1114. doi:10.1038/nature04929
122. Veitia RA, Gluckman E, Fellous M, Soulier J. Recovery of female fertility after chemotherapy, irradiation, and bone marrow allograft: further evidence against massive oocyte regeneration by bone marrow-derived germline stem cells. Stem Cells. 2007;25(5):1334-1335.
123. Neves J, Sousa-Victor P, Jasper H. Rejuvenating strategies for stem cell-based therapies in aging. Cell Stem Cell. 2017;20(2):161-175.
124. Price CA. Mechanisms of fibroblast growth factor signaling in the ovarian follicle. Journal of Endocrinology. 2016;228(2):R31-R43. doi:10.1530/JOE-15-0414
125. Bhartiya D, Patel H. Ovarian stem cells—resolving controversies. J Assist Reprod Genet. 2018;35(3):393-398.
126. Virant-Klun I, Skutella T, Hren M, et al. Isolation of small SSEA-4-positive putative stem cells from the ovarian surface epithelium of adult human ovaries by two different methods. Biomed Res Int. 2013;2013.
127. Virant-Klun I, Zech N, Rožman P, et al. Putative stem cells with an embryonic character isolated from the ovarian surface epithelium of women with no naturally present follicles and oocytes. Differentiation. 2008;76(8):843-856.
128. White YAR, Woods DC, Takai Y, Ishihara O, Seki H, Tilly JL. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Nat Med. 2012;18(3):413-421.
129. Zou K, Yuan Z, Yang Z, et al. Production of offspring from a germline stem cell line derived from neonatal ovaries. Nat Cell Biol. 2009;11(5):631-636.
130. Bukovsky A. Can ovarian infertility be treated with bone marrow-or ovary-derived germ cells? Reproductive Biology and Endocrinology. 2005;3(1):1-3.
131. Sharma D, Bhartiya D. Aged mice ovaries harbor stem cells and germ cell nests but fail to form follicles. J Ovarian Res. 2022;15(1):1-13.
132. Wagner M, Yoshihara M, Douagi I, et al. Single-cell analysis of human ovarian cortex identifies distinct cell populations but no oogonial stem cells. Nat Commun. 2020;11(1):1147. doi:10.1038/s41467-020-14936-3
133. Alberico H, Fleischmann Z, Bobbitt T, et al. Workflow Optimization for Identification of Female Germline or Oogonial Stem Cells in Human Ovarian Cortex Using Single-Cell RNA Sequence Analysis. Stem Cells. 2022;40(5):523-536. doi:10.1093/stmcls/sxac015