Skip to main content
SpringerLink
Log in

The Dominant Mechanism of Cyclophosphamide-Induced Damage to Ovarian Reserve: Premature Activation or Apoptosis of Primordial Follicles?

  • Review
  • Published:
Reproductive Sciences Aims and scope Submit manuscript

Abstract

Cyclophosphamide (CPM), a part of most cancer treatment regimens, has demonstrated high gonadal toxicity in females. Initially, CPM is believed to damage the ovarian reserve by premature activation of primordial follicles, for the fact that facing CPM damage, primordial oocytes show the activation of PTEN/PI3K/AKT pathways, accompanied by accelerated activation of follicle developmental waves. Meanwhile, primordial follicles are dormant and not considered the target of CPM. However, many researchers have found DNA DSBs and apoptosis within primordial oocytes under CPM-induced ovarian damage instead of premature accelerated activation. A stricter surveillance system of DNA damage is also thought to be in primordial oocytes. So far, the apoptotic death mechanism is considered well-proved, but the premature activation theory is controversial and unacceptable. The connection between the upregulation of PTEN/PI3K/AKT pathways and DNA DSBs and apoptosis within primordial oocytes is also unclear. This review aims to highlight the flaw and/or support of the disputed premature activation theory and the apoptosis mechanism to identify the underlying mechanism of CPM’s injury on ovarian reserve, which is crucial to facilitate the discovery and development of effective ovarian protectants. Ultimately, this review finds no good evidence for follicle activation and strong consistent evidence for apoptosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin. 2019;69:7–34. https://doi.org/10.3322/caac.21551.

    Article  PubMed  Google Scholar 

  2. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, Jemal A, Siegel RL. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438–51. https://doi.org/10.3322/caac.21583.

    Article  PubMed  Google Scholar 

  3. Anderson RA, Brewster DH, Wood R, Nowell S, Fischbacher C, Kelsey TW, Wallace WHB. The impact of cancer on subsequent chance of pregnancy: a population-based analysis. Hum Reprod. 2018;33:1281–90. https://doi.org/10.1093/humrep/dey216.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Tschudin S, Bitzer J. Psychological aspects of fertility preservation in men and women affected by cancer and other life-threatening diseases. Hum Reprod Update. 2009;15:587–97. https://doi.org/10.1093/humupd/dmp015.

    Article  PubMed  Google Scholar 

  5. Anazodo A, Ataman-Millhouse L, Jayasinghe Y, Woodruff TK. Oncofertility-an emerging discipline rather than a special consideration. Pediatr Blood Cancer. 2018;65:e27297. https://doi.org/10.1002/pbc.27297.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Woodruff TK. The emergence of a new interdiscipline: oncofertility. In: Woodruff TK, Snyder KA (eds.) Oncofertility Fertility Preservation for Cancer Survivors. 2007;138:3–11. https://doi.org/10.1007/978-0-387-72293-1_1 .

  7. Xiong J, Xue L, Li Y, Tang W, Chen D, Zhang J, Dai J, Zhou S, Lu Z, Wu M, et al. THERAPY OF ENDOCRINE DISEASE: Novel protection and treatment strategies for chemotherapy-associated ovarian damage. Eur J Endocrinol. 2021;184:R177–92. https://doi.org/10.1530/EJE-20-1178.

    Article  CAS  PubMed  Google Scholar 

  8. Bedoschi G, Navarro PA, Oktay K. Chemotherapy-induced damage to ovary: mechanisms and clinical impact. Future Oncol. 2016;12:12.

    Article  Google Scholar 

  9. Hanel M, Kroger N, Sonnenberg S, Bornhauser M, Kruger W, Kroschinsky F, Hanel A, Metzner B, Birkmann J, Schmid B, et al. Busulfan, cyclophosphamide, and etoposide as high-dose conditioning regimen in patients with malignant lymphoma. Ann Hematol. 2002;81:96–102. https://doi.org/10.1007/s00277-001-0413-8.

    Article  CAS  PubMed  Google Scholar 

  10. Teske E, Straten G, van Noort R, Rutteman GR. Chemotherapy with cyclophosphamide, vincristine, and prednisolone (COP) in cats with malignant lymphoma: new results with an old protocol. J Vet Intern Med. 2002;16:8.

    Article  Google Scholar 

  11. Pennipede D, Mohyuddin GR, Hawkins R, Ganguly S, Shune L, Ahmed N, Mohan MA-O, Cui W, Mahmoudjafari Z, McGuirk J, et al. Carfilzomib, cyclophosphamide, and dexamethasone (KCd) for the treatment of triple-class relapsed/refractory multiple myeloma (RRMM). Eur J Haematol. 2021;107(6):602–8. https://doi.org/10.1111/ejh.13697.

  12. Yimer H, Melear J, Faber E, Bensinger WI, Burke JM, Narang M, Stevens D, Gunawardena S, Lutska Y, Qi K, et al. Daratumumab, bortezomib, cyclophosphamide and dexamethasone in newly diagnosed and relapsed multiple myeloma: LYRA study. Br J Haematol. 2019;185(3):492–502. https://doi.org/10.1111/bjh.15806.

  13. Nakatsukasa K, Koyama H, Oouchi Y, Imanishi S, Mizuta N, Sakaguchi K, Fujita Y, Fujiwara I, Kotani T, Matsuda T, et al. Docetaxel and cyclophosphamide as neoadjuvant chemotherapy in HER2-negative primary breast cancer. Breast Cancer. 2017;24:6. https://doi.org/10.1007/s12282-016-0666-7.

    Article  Google Scholar 

  14. Hayashi N, Yagata H, Tsugawa K, Kajiura Y, Yoshida A, Takei J, Yamauchi H, Nakamura S. Response and prognosis of docetaxel and cyclophosphamide as neoadjuvant chemotherapy in ER(+) HER2(-) breast cancer: a prospective phase II study. Clin Breast Cancer. 2020;20:4. https://doi.org/10.1016/j.clbc.2020.09.007.

    Article  CAS  Google Scholar 

  15. Madden JA, Keating AF. Ovarian xenobiotic biotransformation enzymes are altered during phosphoramide mustard-induced ovotoxicity. Toxicol Sci. 2014;141:441–52. https://doi.org/10.1093/toxsci/kfu146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chemaitilly W, Li Z, Krasin MJ, Brooke RJ, Wilson CL, Green DM, Klosky JL, Barnes N, Clark KL, Farr JB, et al. Premature ovarian insufficiency in childhood cancer survivors: a report from the St. Jude Lifetime Cohort. J Clin Endocrinol Metab. 2017;102:2242–50. https://doi.org/10.1210/jc.2016-3723.

    Article  PubMed  PubMed Central  Google Scholar 

  17. De Vos M, Smitz J, Woodruff TK. Fertility preservation in women with cancer. Lancet. 2014;384:1302–10. https://doi.org/10.1016/s0140-6736(14)60834-5.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Sonigo C, Beau I, Grynberg M, Binart N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice. FASEB J. 2019;33:1278–87. https://doi.org/10.1096/fj.201801089R.

    Article  CAS  PubMed  Google Scholar 

  19. Zhou L, Xie Y, Li S, Liang Y, Qiu Q, Lin H, Zhang Q. Rapamycin prevents cyclophosphamide-induced over-activation of primordial follicle pool through PI3K/Akt/mTOR signaling pathway in vivo. J Ovarian Res. 2017;10:56. https://doi.org/10.1186/s13048-017-0350-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kalich-Philosoph L, Roness H, Carmely A, Fishel-Bartal M, Ligumsky H, Paglin S, Wolf I, Kanety H, Sredni B, Meirow D. Cyclophosphamide triggers follicle activation and “burn-out”, AS101 prevents follicle loss and preserves fertility. Sci Transl Med. 2013;5:185ra162. https://doi.org/10.1126/scitranslmed.3005402.

    Article  CAS  Google Scholar 

  21. Goldman KN, Chenette D, Arju R, Duncan FE, Keefe DL, Grifo JA, Schneider RJ. mTORC1/2 inhibition preserves ovarian function and fertility during genotoxic chemotherapy. Proc Natl Acad Sci USA. 2017;114:3186–91. https://doi.org/10.1073/pnas.1617233114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chen X-Y, Xia H-X, Guan H-Y, Li B, Zhang W. Follicle loss and apoptosis in cyclophosphamide-treated mice: what’s the matter? Int J Mol Sci. 2016;17(6):836. https://doi.org/10.3390/ijms17060836.

  23. Tuppi M, Kehrloesser S, Coutandin DW, Rossi V, Luh LM, Strubel A, Hotte K, Hoffmeister M, Schafer B, De Oliveira T, et al. Oocyte DNA damage quality control requires consecutive interplay of CHK2 and CK1 to activate p63. Nat Struct Mol Biol. 2018;25:261–9. https://doi.org/10.1038/s41594-018-0035-7.

    Article  CAS  PubMed  Google Scholar 

  24. Gonfloni S, Di Tella L, Caldarola S, Cannata SM, Klinger FG, Di Bartolomeo C, Mattei M, Candi E, De Felici M, Melino G, et al. Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy-induced death. Nat Med. 2009;15:1179–85. https://doi.org/10.1038/nm.2033.

    Article  CAS  PubMed  Google Scholar 

  25. Bolcun-Filas E, Rinaldi VD, White ME, Schimenti JC. Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. Science. 2014;343:533–6. https://doi.org/10.1126/science.1247671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luan Y, Edmonds ME, Woodruff TK, Kim S-Y. Inhibitors of apoptosis protect the ovarian reserve from cyclophosphamide. J Endocrinol. 2019;240:243–56. https://doi.org/10.1530/joe-18-0370.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kano M, Sosulski AE, Zhang L, Saatcioglu HD, Wang D, Nagykery N, Sabatini ME, Gao G, Donahoe PK, Pepin D. AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. Proc Natl Acad Sci USA. 2017;114:E1688–97. https://doi.org/10.1073/pnas.1620729114.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Suh EK, Yang A, Kettenbach A, Bamberger C, Michaelis AH, Zhu Z, Elvin JA, Bronson RT, Crum CP, McKeon F. p63 protects the female germ line during meiotic arrest. Nature. 2006;444:624–8. https://doi.org/10.1038/nature05337.

    Article  CAS  PubMed  Google Scholar 

  29. Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem. 1998;273:5858–68. https://doi.org/10.1074/jbc.273.10.5858.

    Article  CAS  PubMed  Google Scholar 

  30. Nguyen Q-N, Zerafa N, Liew SH, Morgan FH, Strasser A, Scott CL, Findlay JK, Hickey M, Hutt KJ. Loss of PUMA protects the ovarian reserve during DNA-damaging chemotherapy and preserves fertility. Cell Death Dis. 2018;9:618. https://doi.org/10.1038/s41419-018-0633-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ganesan S, Keating AF. The ovarian DNA damage repair response is induced prior to phosphoramide mustard-induced follicle depletion, and ataxia telangiectasia mutated inhibition prevents PM-induced follicle depletion. Toxicol Appl Pharmacol. 2016;292:65–74. https://doi.org/10.1016/j.taap.2015.12.010.

    Article  CAS  PubMed  Google Scholar 

  32. Nguyen QN, Zerafa N, Liew SH, Findlay JK, Hickey M, Hutt KJ. Cisplatin- and cyclophosphamide-induced primordial follicle depletion is caused by direct damage to oocytes. Mol Hum Reprod. 2019;25:433–44. https://doi.org/10.1093/molehr/gaz020.

    Article  CAS  PubMed  Google Scholar 

  33. Li F, Turan V, Lierman S, Cuvelier C, De Sutter P, Oktay K. Sphingosine-1-phosphate prevents chemotherapy-induced human primordial follicle death. Hum Reprod. 2014;29:107–13. https://doi.org/10.1093/humrep/det391.

    Article  CAS  PubMed  Google Scholar 

  34. Meng Y, Xu Z, Wu F, Chen W, Xie S, Liu J, Huang X, Zhou Y. Sphingosine-1-phosphate suppresses cyclophosphamide induced follicle apoptosis in human fetal ovarian xenografts in nude mice. Fertil Steril. 2014;102:871–7 e873. https://doi.org/10.1016/j.fertnstert.2014.05.040.

    Article  CAS  PubMed  Google Scholar 

  35. Asadi Azarbaijani B, Sheikhi M, Oskam IC, Nurmio M, Laine T, Tinkanen H, Makinen S, Tanbo TG, Hovatta O, Jahnukainen K. Effect of previous chemotherapy on the quality of cryopreserved human ovarian tissue in vitro. PLoS One. 2015;10:e0133985. https://doi.org/10.1371/journal.pone.0133985.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Lande Y, Fisch B, Tsur A, Farhi J, Prag-Rosenberg R, Ben-Haroush A, Kessler-Icekson G, Zahalka MA, Ludeman SM, Abir R. Short-term exposure of human ovarian follicles to cyclophosphamide metabolites seems to promote follicular activation in vitro. Reprod BioMed Online. 2017;34:104–14. https://doi.org/10.1016/j.rbmo.2016.10.005.

    Article  CAS  PubMed  Google Scholar 

  37. Hao X, Anastácio A, Liu K, Rodriguez-Wallberg KA. Ovarian follicle depletion induced by chemotherapy and the investigational stages of potential fertility-protective treatments—a review. Int J Mol Sci. 2019;20:4720–4746. https://doi.org/10.3390/ijms20194720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, Du C, Tang W, Hämäläinen T, Peng SL, et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science. 2008;319:611–3. https://doi.org/10.1126/science.1152257.

  39. Adhikari D, Zheng W, Shen Y, Gorre N, Hamalainen T, Cooney AJ, Huhtaniemi I, Lan ZJ, Liu K. Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet. 2010;19:397–410. https://doi.org/10.1093/hmg/ddp483.

    Article  CAS  PubMed  Google Scholar 

  40. Adhikari D, Flohr G, Gorre N, Shen Y, Yang H, Lundin E, Lan Z, Gambello MJ, Liu K. Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles. Mol Hum Reprod. 2009;15:765–70. https://doi.org/10.1093/molehr/gap092.

    Article  CAS  PubMed  Google Scholar 

  41. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19. https://doi.org/10.1038/nrg1879.

    Article  CAS  PubMed  Google Scholar 

  42. Cantley LC. The phosphoinositide 3-kinase pathway. Science. 2002;296:1655–7. https://doi.org/10.1126/science.296.5573.1655.

    Article  CAS  PubMed  Google Scholar 

  43. Yang Q, Guan KL. Expanding mTOR signaling. Cell Res. 2007;17:666–81. https://doi.org/10.1038/cr.2007.64.

    Article  CAS  PubMed  Google Scholar 

  44. Maidarti M, Anderson RA, Telfer EE. Crosstalk between PTEN/PI3K/Akt signalling and DNA damage in the oocyte: implications for primordial follicle activation, oocyte quality and ageing. Cells. 2020;9. https://doi.org/10.3390/cells9010200.

  45. SEIICHI HIROBE, WEI-WU HE, MARY M. LEE, DONAHOE, P.K. Mullerian inhibiting substance messenger ribonucleic acid expression in granulosa and sertoli cells coincides with their mitotic activity*. Endocrinology. 1992;131:9.

    Google Scholar 

  46. Titus S, Szymanska KJ, Musul B, Turan V, Taylan E, Garcia-Milian R, Mehta S, Oktay K. Individual-oocyte transcriptomic analysis shows that genotoxic chemotherapy depletes human primordial follicle reserve in vivo by triggering pro-apoptotic pathways without growth activation. Sci Rep. 2021;11:407. https://doi.org/10.1038/s41598-020-79643-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kim SY, Nair DM, Romero M, Serna VA, Koleske AJ, Woodruff TK, Kurita T. Transient inhibition of p53 homologs protects ovarian function from two distinct apoptotic pathways triggered by anticancer therapies. Cell Death Differ. 2019;26:502–15. https://doi.org/10.1038/s41418-018-0151-2.

    Article  CAS  PubMed  Google Scholar 

  48. Dupont J, Scaramuzzi RJ. Insulin signalling and glucose transport in the ovary and ovarian function during the ovarian cycle. Biochem J. 2016;473:1483–501. https://doi.org/10.1042/bcj20160124.

    Article  CAS  PubMed  Google Scholar 

  49. Zheng W, Zhang H, Gorre N, Risal S, Shen Y, Liu K. Two classes of ovarian primordial follicles exhibit distinct developmental dynamics and physiological functions. Hum Mol Genet. 2014;23:920–8. https://doi.org/10.1093/hmg/ddt486.

    Article  CAS  PubMed  Google Scholar 

  50. Baskar R, Lee KA, Yeo R, Yeoh KW. Cancer and radiation therapy: current advances and future directions. Int J Med Sci. 2012;9(3):193–9. https://doi.org/10.7150/ijms.3635.

  51. Lisio MA, Fu L, Goyeneche A, Gao ZA-O, Telleria CA-O. High-grade serous ovarian cancer: basic sciences, clinical and therapeutic standpoints. Int J Mol Sci. 2019;20:952. https://doi.org/10.3390/ijms20040952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kerr JB, Hutt KJ, Michalak EM, Cook M, Vandenberg CJ, Liew SH, Bouillet P, Mills A, Scott CL, Findlay JK, et al. DNA damage-induced primordial follicle oocyte apoptosis and loss of fertility require TAp63-mediated induction of Puma and Noxa. Mol Cell. 2012;48:343–52. https://doi.org/10.1016/j.molcel.2012.08.017.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kerr JB, Hutt KJ, Cook M, Speed TP, Strasser A, Findlay JK, Scott CL. Cisplatin-induced primordial follicle oocyte killing and loss of fertility are not prevented by imatinib. Nat Med. 2012;18:1170–2, author reply 1172-1174. https://doi.org/10.1038/nm.2889.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Titus S, Li F, Stobezki R, Akula K, Unsal E, Jeong K, Dickler M, Robson M, Moy F, Goswami S, et al. Impairment of BRCA1-related DNA double-strand break repair leads to ovarian aging in mice and humans. Sci Transl Med. 2013;5:172ra121. https://doi.org/10.1126/scitranslmed.3004925.

    Article  CAS  Google Scholar 

  55. Tubbs A, Nussenzweig A. Endogenous DNA damage as a source of genomic instability in cancer. Cell. 2017;168:644–56. https://doi.org/10.1016/j.cell.2017.01.002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Liu JC, Xing CH, Xu Y, Pan ZN, Zhang HL, Zhang Y, Sun SC. DEHP exposure to lactating mice affects ovarian hormone production and antral follicle development of offspring. J Hazard Mater. 2021;416:125862. https://doi.org/10.1016/j.jhazmat.2021.125862.

    Article  CAS  PubMed  Google Scholar 

  57. An R, Wang X, Yang L, Zhang J, Wang N, Xu F, Hou Y, Zhang H, Zhang L. Polystyrene microplastics cause granulosa cells apoptosis and fibrosis in ovary through oxidative stress in rats. Toxicology. 2021;449:152665. https://doi.org/10.1016/j.tox.2020.152665.

  58. Khedr NF. Protective effect of mirtazapine and hesperidin on cyclophosphamide-induced oxidative damage and infertility in rat ovaries. Exp Biol Med (Maywood). 2015;240:1682–9. https://doi.org/10.1177/1535370215576304.

    Article  CAS  PubMed  Google Scholar 

  59. Jeelani R, Khan SN, Shaeib F, Kohan-Ghadr HR, Aldhaheri SR, Najafi T, Thakur M, Morris R, Abu-Soud HM. Cyclophosphamide and acrolein induced oxidative stress leading to deterioration of metaphase II mouse oocyte quality. Free Radic Biol Med. 2017;110:11–8. https://doi.org/10.1016/j.freeradbiomed.2017.05.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Chapman JR, Taylor MR, Boulton SJ. Playing the end game: DNA double-strand break repair pathway choice. Mol Cell. 2012;47:497–510. https://doi.org/10.1016/j.molcel.2012.07.029.

    Article  CAS  PubMed  Google Scholar 

  61. Whitaker AM, Schaich MA, Smith MS, Flynn TS, Freudenthal BD. Base excision repair of oxidative DNA damage: from mechanism to disease. Front Biosci (Landmark Ed). 2017;22:1493–1522. https://doi.org/10.2741/4555.

  62. Reyes GX, Schmidt TT, Kolodner RD, Hombauer H. New insights into the mechanism of DNA mismatch repair. Chromosoma. 2015;124:443–62. https://doi.org/10.1007/s00412-015-0514-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eker AP, Quayle C, Chaves I, van der Horst GT. DNA repair in mammalian cells: direct DNA damage reversal: elegant solutions for nasty problems. Cell Mol Life Sci. 2009;66:968–80. https://doi.org/10.1007/s00018-009-8735-0.

    Article  CAS  PubMed  Google Scholar 

  64. Stringer JM, Winship A, Zerafa N, Wakefield M, Hutt K. Oocytes can efficiently repair DNA double-strand breaks to restore genetic integrity and protect offspring health. Proc Natl Acad Sci. 2020;117:11513–22. https://doi.org/10.1073/pnas.2001124117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. So S, Davis AJ, Chen DJ. Autophosphorylation at serine 1981 stabilizes ATM at DNA damage sites. J Cell Biol. 2009;187:977–90. https://doi.org/10.1083/jcb.200906064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Jungmichel S, Stucki M. MDC1: The art of keeping things in focus. Chromosoma. 2010;119:337–49. https://doi.org/10.1007/s00412-010-0266-9.

    Article  CAS  PubMed  Google Scholar 

  67. Lukas J, Lukas C, Bartek J. More than just a focus: the chromatin response to DNA damage and its role in genome integrity maintenance. Nat Cell Biol. 2011;13:1161–9. https://doi.org/10.1038/ncb2344.

    Article  CAS  PubMed  Google Scholar 

  68. Nazarov IB, Smirnova AN, Krutilina RI, Svetlova MP, Solovjeva LV, Nikiforov AA, Oei S-L, Zalenskaya IA, Yau PM, Bradbury EM, et al. Dephosphorylation of histone γ-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A. Radiat Res. 2003;160:309–17. https://doi.org/10.1667/rr3043.

    Article  CAS  PubMed  Google Scholar 

  69. Tomilin NV, Solovjeva LV, Svetlova MP, Pleskach NM, Zalenskaya IA, Yau PM, Bradbury EM. Visualization of focal nuclear sites of DNA repair synthesis induced by bleomycin in human cells. Radiat Res. 2001;156:347–54. https://doi.org/10.1667/0033-7587(2001)156.

    Article  CAS  PubMed  Google Scholar 

  70. Roos WP, Kaina B. DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis. Cancer Lett. 2013;332:237–48. https://doi.org/10.1016/j.canlet.2012.01.007.

    Article  CAS  PubMed  Google Scholar 

  71. Kujjo LL, Ronningen R, Ross P, Pereira RJ, Rodriguez R, Beyhan Z, Goissis MD, Baumann T, Kagawa W, Camsari C, et al. RAD51 plays a crucial role in halting cell death program induced by ionizing radiation in bovine oocytes. Biol Reprod. 2012;86:76. https://doi.org/10.1095/biolreprod.111.092064.

    Article  CAS  PubMed  Google Scholar 

  72. Kujjo LL, Laine T, Pereira RJ, Kagawa W, Kurumizaka H, Yokoyama S, Perez GI. Enhancing survival of mouse oocytes following chemotherapy or aging by targeting Bax and Rad51. PLoS One. 2010;5:e9204. https://doi.org/10.1371/journal.pone.0009204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Collins JK, Jones KT. DNA damage responses in mammalian oocytes. Reproduction. 2016;152:R15–22. https://doi.org/10.1530/REP-16-0069.

    Article  CAS  PubMed  Google Scholar 

  74. Oktem O, Oktay K. A novel ovarian xenografting model to characterize the impact of chemotherapy agents on human primordial follicle reserve. Cancer Res. 2007;67:10159–62. https://doi.org/10.1158/0008-5472.CAN-07-2042.

    Article  CAS  PubMed  Google Scholar 

  75. Pampanini V, Wagner M, Asadi-Azarbaijani B, Oskam IC, Sheikhi M, Sjodin MOD, Lindberg J, Hovatta O, Sahlin L, Bjorvang RD, et al. Impact of first-line cancer treatment on the follicle quality in cryopreserved ovarian samples from girls and young women. Hum Reprod. 2019;34:1674–85. https://doi.org/10.1093/humrep/dez125.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Oktay KH, Bedoschi G, Goldfarb SB, Taylan E, Titus S, Palomaki GE, Cigler T, Robson M, Dickler MN. Increased chemotherapy-induced ovarian reserve loss in women with germline BRCA mutations due to oocyte deoxyribonucleic acid double strand break repair deficiency. Fertil Steril. 2020;113:1251–60 e1251. https://doi.org/10.1016/j.fertnstert.2020.01.033.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Bildik G, Akin N, Senbabaoglu F, Sahin GN, Karahuseyinoglu S, Ince U, Taskiran C, Selek U, Yakin K, Guzel Y, et al. GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro. Hum Reprod. 2015;30(12):2912–25. https://doi.org/10.1093/humrep/dev257.

  78. Amelio I, Grespi F, Annicchiarico-Petruzzelli M, Melino G. p63 the guardian of human reproduction. Cell Cycle. 2012;11:4545–51. https://doi.org/10.4161/cc.22819.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Levine AJ, Tomasini R, McKeon FD, Mak TW, Melino G. The p53 family: guardians of maternal reproduction. Nat Rev Mol Cell Biol. 2011;12:259–65. https://doi.org/10.1038/nrm3086.

    Article  CAS  PubMed  Google Scholar 

  80. de la Mata M, Grosshans H. TAp63 as a guardian of female germ line integrity. Nat Struct Mol Biol. 2018;25:195–7. https://doi.org/10.1038/s41594-018-0040-x.

    Article  CAS  PubMed  Google Scholar 

  81. Bursch W, Paffe S, Putz B, Barthel G, Schulte-Hermann R. Determination of the length off the histological stages off apoptosis in normal liver and in altered hepatic foci of rats. Carcinogenesis. 1990;11:847–53. https://doi.org/10.1093/carcin/11.5.847.

  82. Ji J, Zhang Y, Redon CE, Reinhold WC, Chen AP, Fogli LK, Holbeck SL, Parchment RE, Hollingshead M, Tomaszewski JE, et al. Phosphorylated fraction of H2AX as a measurement for DNA damage in cancer cells and potential applications of a novel assay. PLoS One. 2017;12:e0171582. https://doi.org/10.1371/journal.pone.0171582.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bellusci G, Mattiello L, Iannizzotto V, Ciccone S, Maiani E, Villani V, Diederich M, Gonfloni S. Kinase-independent inhibition of cyclophosphamide-induced pathways protects the ovarian reserve and prolongs fertility. Cell Death Dis. 2019;10:726. https://doi.org/10.1038/s41419-019-1961-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Yang J, Campobasso N, Biju MP, Fisher K, Pan XQ, Cottom J, Galbraith S, Ho T, Zhang H, Hong X, et al. Discovery and characterization of a cell-permeable, small-molecule c-Abl kinase activator that binds to the myristoyl binding site. Chem Biol. 2011;18:177–86. https://doi.org/10.1016/j.chembiol.2010.12.013.

    Article  CAS  PubMed  Google Scholar 

  85. Suzuki N, Yoshioka N, Takae S, Sugishita Y, Tamura M, Hashimoto S, Morimoto Y, Kawamura K. Successful fertility preservation following ovarian tissue vitrification in patients with primary ovarian insufficiency. Hum Reprod. 2015;30:608–15. https://doi.org/10.1093/humrep/deu353.

    Article  PubMed  Google Scholar 

  86. McLaughlin M, Kinnell HL, Anderson RA, Telfer EE. Inhibition of phosphatase and tensin homologue (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles. Mol Hum Reprod. 2014;20:736–44. https://doi.org/10.1093/molehr/gau037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Maidarti M, Clarkson YL, McLaughlin M, Anderson RA, Telfer EE. Inhibition of PTEN activates bovine non-growing follicles in vitro but increases DNA damage and reduces DNA repair response. Hum Reprod. 2019;34:297–307. https://doi.org/10.1093/humrep/dey354.

    Article  CAS  PubMed  Google Scholar 

  88. Astle MV, Hannan KM, Ng PY, Lee RS, George AJ, Hsu AK, Haupt Y, Hannan RD, Pearson RB. AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene. 2012;31:1949–62. https://doi.org/10.1038/onc.2011.394.

    Article  CAS  PubMed  Google Scholar 

  89. Xu N, Hegarat N, Black EJ, Scott MT, Hochegger H, Gillespie DA. Akt/PKB suppresses DNA damage processing and checkpoint activation in late G2. J Cell Biol. 2010;190:297–305. https://doi.org/10.1083/jcb.201003004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Karimian A, Mir SM, Parsian H, Refieyan S, Mirza-Aghazadeh-Attari M, Yousefi B, Majidinia M. Crosstalk between Phosphoinositide 3-kinase/Akt signaling pathway with DNA damage response and oxidative stress in cancer. J Cell Biochem. 2019;120:10248–72. https://doi.org/10.1002/jcb.28309.

    Article  CAS  PubMed  Google Scholar 

  91. Lai KP, Leong WF, Chau JF, Jia D, Zeng L, Liu H, He L, Hao A, Zhang H, Meek D, et al. S6K1 is a multifaceted regulator of Mdm2 that connects nutrient status and DNA damage response. EMBO J. 2010;29:2994–3006. https://doi.org/10.1038/emboj.2010.166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Qin Xie and Qiuyue Liao contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qin Xie, Qiuyue Liao, Lingjuan Wang, Yan Zhang, Jing Chen, Hualin Bai, Kezhen Li & Jihui Ai

  2. Department of Reproductive Medicine Center, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, No.136, Jingzhou Road, Xiangcheng District, Xiangyang, 441021, Hubei Province, People’s Republic of China

    Qin Xie

Authors
  1. Qin Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiuyue Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lingjuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hualin Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kezhen Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jihui Ai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, Qin Xie and Qiuyue Liao, writing—original draft preparation, Qin Xie and Qiuyue Liao, writing—review and editing, Qiuyue Liao, Lingjuan Wang, and Yan Zhang, visualization, Jing Chen and Hualin Bai, supervision, Jihui Ai and Kezhen Li.

Corresponding authors

Correspondence to Kezhen Li or Jihui Ai.

Ethics declarations

Ethics Approval

This is a comprehensive review. Ethics Committee of the TongJi Hospital has confirmed that no ethical approval is required.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xie, Q., Liao, Q., Wang, L. et al. The Dominant Mechanism of Cyclophosphamide-Induced Damage to Ovarian Reserve: Premature Activation or Apoptosis of Primordial Follicles?. Reprod. Sci. 31, 30–44 (2024). https://doi.org/10.1007/s43032-023-01294-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s43032-023-01294-w

Keywords

Search

Navigation