[en] Cryopreservation and transplantation of ovarian tissue represent a promising fertility preservation technique for prepubertal patients or for patients requiring urgent oncological management. However, this technique has some limitations, including follicular loss directly after transplantation mainly due to ischaemic damage but also due to activation of primordial follicles (also known as follicular burnout), leading to follicular reserve loss in the graft and thereby potentially reducing its lifespan. In vitro and in vivo studies indicate that the phosphatidylinositol-3-kinase (PI3K)/phosphatase and tensin homologue (PTEN)/Akt, mammalian target of rapamycin (mTOR), c-Jun-N-terminal kinase (JNK), and Hippo signalling pathways are involved in primordial follicle activation. Here, we review the basic mechanisms linked to the follicle activation that occurs after cryopreservation and transplantation of ovarian tissue. A better understanding of the crosstalk between the different signalling pathways may lead to potential improvement of fertility restoration by extending graft lifespan through selective control of the activation of dormant follicles after transplantation of cryopreserved ovarian tissue.
Disciplines :
Médecine de la reproduction (Gynécologie, andrologie, obstétrique)
Meirow D, Biederman H, Anderson RA, Wallace WHW. Toxicity of chemotherapy and radiation on female reproduction. Clin Obstet Gynecol. 2010;53:727–39. Available from: https://doi.org/10.1097/GRF.0b013e3181f96b54.
Demeestere I, Moffa F, Peccatori F, Poirot C, Shalom-Paz E. Multiple approaches for individualized fertility protective therapy in cancer patients. Obstet Gynecol Int. 2012;2011:1–12.
Donnez J, Dolmans MM. Fertility preservation in women. N Engl J Med. 2017;377:1657–65. DOI: 10.1056/NEJMra1614676
Sheshpari S, Shahnazi M, Mobarak H, Ahmadian S, Bedate AM, Nariman-Saleh-Fam Z, et al. Ovarian function and reproductive outcome after ovarian tissue transplantation: a systematic review. J Transl Med. BioMed central; 2019;17:1–15. Available from: https://doi.org/10.1186/s12967-019-02149-2.
Van DerVen H, Liebenthron J, Beckmann M, Toth B, Korell M, Krüssel J, et al. Ninety-five orthotopic transplantations in 74 women of ovarian tissue after cytotoxic treatment in a fertility preservation network: tissue activity, pregnancy and delivery rates. Hum Reprod. 2016;31:2031–41. DOI: 10.1093/humrep/dew165
Marin L, Bedoschi G, Kawahara T, Oktay KH. History, evolution and current state of ovarian tissue auto-transplantation with cryopreserved tissue: a successful translational research journey from 1999 to 2020. Reprod Sci. 2020; Available from::955–62. https://doi.org/10.1007/s43032-019-00066-9.
American Society for Reproductive Medicine. Ovarian tissue cryopreservation: a committee opinion. Fertil Steril. American Society for Reproductive Medicine; 2014;101:1237–43. Available from: https://doi.org/10.1016/j.fertnstert.2014.02.052
Hancke K, Walker E, Strauch O, Göbel H, Hanjalic-Beck A, Denschlag D. Ovarian transplantation for fertility preservation in a sheep model: can follicle loss be prevented by antiapoptotic sphingosine-1-phosphate administration? Gynecol Endocrinol. 2009;25:839–43. DOI: 10.3109/09513590903159524
Baird DT. Long-term ovarian function in sheep after ovariectomy and transplantation of autografts stored at −196 C. Endocrinology. 1999;140:462–71. Available from:. 10.1210/en.140.1.462. DOI: 10.1210/en.140.1.462
Roness H, Gavish Z, Cohen Y, Meirow D. Ovarian follicle burnout: a universal phenomenon? Cell Cycle. 2013;12:3245–6. DOI: 10.4161/cc.26358
Van Eyck A-S, Jordan BF, Gallez B, Heilier J-F, Van Langendonckt A, Donnez J. Electron paramagnetic resonance as a tool to evaluate human ovarian tissue reoxygenation after xenografting. Fertil Steril. 2009;92:374–81. Available from: https://doi.org/10.1016/j.fertnstert.2008.05.012.
Rimon E, Cohen T, Dantes A, Hirsh L, Amit A, Lessing JB, et al. Apoptosis in cryopreserved human ovarian tissue obtained from cancer patients: a tool for evaluating cryopreservation utility. Int J Oncol. 2005;27:345–53.
Stroh C, Cassens U, Samraj AK, Sibrowski W, Schulze-Osthoff K, Los M. The role of caspases in cryoinjury: caspase inhibition strongly improves the recovery of cryopreserved hematopoietic and other cells. FASEB J. 2002;16:1651–3. DOI: 10.1096/fj.02-0034fje
Roness H, Meirow D. Follicle reserve loss in ovarian tissue transplantation. Reproduction. 2019;158:F35–44. DOI: 10.1530/REP-19-0097
Henry L, Fransolet M, Labied S, Blacher S, Masereel M-C, Foidart J-M, et al. Supplementation of transport and freezing media with anti-apoptotic drugs improves ovarian cortex survival. J Ovarian Res. 2016;9:4 Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4751643&tool=pmcentrez&rendertype=abstract.
Henry L, Labied S, Fransolet M, Kirschvink N, Blacher S, Noel A, et al. Isoform 165 of vascular endothelial growth factor in collagen matrix improves ovine cryopreserved ovarian tissue revascularisation after xenotransplantation in mice. Reprod Biol Endocrinol. 2015;13:12. Available from: https://doi.org/10.1186/s12958-015-0015-2.
Labied S, Delforge Y, Munaut C, Blacher S, Colige A, Delcombel R, et al. Isoform 111 of vascular endothelial growth factor (VEGF111) improves angiogenesis of ovarian tissue xenotransplantation. Transp J. 2013;95:426–33. Available from: https://doi.org/10.1097/TP.0b013e318279965c.
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;33:281–9. DOI: 10.1007/s10815-015-0628-6
Tavana S, Valojerdi MR, Azarnia M, Shahverdi A. Restoration of ovarian tissue function and estrous cycle in rat after autotransplantation using hyaluronic acid hydrogel scaffold containing VEGF and bFGF. Growth Factors. 2016;34:97–106. DOI: 10.1080/08977194.2016.1194835
Mahmoodi M, Mehranjani MS, Shariatzadeh SMA, Eimani H, Shahverdi A. Effects of erythropoietin on ischemia, follicular survival, and ovarian function in ovarian grafts. Reproduction. 2014;147:733–41. DOI: 10.1530/REP-13-0379
Mahmoodi M, Soleimani Mehranjani M, Shariatzadeh SMA, Eimani H, Shahverdi A. N-acetylcysteine improves function and follicular survival in mice ovarian grafts through inhibition of oxidative stress. Reprod BioMed Online. Reproductive healthcare ltd.; 2015;30:101–10. Available from: https://doi.org/10.1016/j.rbmo.2014.09.013.
Kolusari A, Okyay AG, Koçkaya EA. The effect of erythropoietin in preventing ischemia–reperfusion injury in ovarian tissue transplantation. Reprod Sci. 2018;25:406–13. DOI: 10.1177/1933719117715127
Dolmans M-M. Recent advances in fertility preservation and counseling for female cancer patients. Expert Rev Anticancer Ther. 2018;18:115–20. Available from:. 10.1080/14737140.2018.1415758. DOI: 10.1080/14737140.2018.1415758
Zhang H, Liu K. Cellular and molecular regulation of the activation of mammalian primordial follicles: somatic cells initiate follicle activation in adulthood. Hum Reprod Update. 2015;21:779–86. DOI: 10.1093/humupd/dmv037
Hsueh AJW, Kawamura K, Cheng Y, Fauser BCJM. Intraovarian control of early folliculogenesis. Endocr Rev. 2015;36:1–24. DOI: 10.1210/er.2014-1020
Kim JY. Control of ovarian primordial follicle activation. Clin Exp Reprod Med. 2012;39:10–4. DOI: 10.5653/cerm.2012.39.1.10
Adhikari D, Liu K. Molecular mechanisms underlying the activation of mammalian primordial follicles. Endocr Rev. 2009;30:438–64. DOI: 10.1210/er.2008-0048
Kawamura K, Kawamura N, Hsueh AJW. Activation of dormant follicles: a new treatment for premature ovarian failure? Curr Opin Obstet Gynecol. 2016;28:217–22. Available from: https://doi.org/10.1097/GCO.0000000000000268.
Kim S-Y, Kurita T. New insights into the role of Phosphoinositide 3-kinase activity in the physiology of immature oocytes: lessons from recent mouse model studies. Eur Med J Reprod Health. 2018;3:119–25.
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76. Available from: https://doi.org/10.1016/j.cell.2017.03.035.
Correia B, Sousa MI, Ramalho-Santos J. The mTOR pathway in reproduction: from gonadal function to developmental coordination. Reproduction. 2020;159:R173–88. DOI: 10.1530/REP-19-0057
Adhikari D, Flohr G, Gorre N, Shen Y, Yang H, Lundin E, et al. Disruption of Tsc2 in oocytes leads to overactivation of the entire pool of primordial follicles. Mol Hum Reprod. 2009;15:765–70.
Adhikari D, Zheng W, Shen Y, Gorre N, Hämäläinen T, Cooney AJ, et al. Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet. 2009;19:397–410. DOI: 10.1093/hmg/ddp483
Bertoldo MJ, Bernard J, Duffard N, Tsikis G, Alves S, Calais L, et al. Inhibitors of c-Jun phosphorylation impede ovine primordial follicle activation. Mol Hum Reprod. 2016;22:338–49.
Oktem O, Buyuk E, Oktay K. Preantral follicle growth is regulated by c-Jun-N-terminal kinase (JNK) pathway. Reprod Sci. SAGE Publications Inc. 2010;18:269–76. DOI: 10.1177/1933719110385709
Zhao HF, Wang J, To SST. The phosphatidylinositol 3-kinase/Akt and c-Jun N-terminal kinase signaling in cancer: alliance or contradiction? (review). Int J Oncol. 2015;47:429–36. DOI: 10.3892/ijo.2015.3052
Wada KI, Itoga K, Okano T, Yonemura S, Sasaki H. Hippo pathway regulation by cell morphology and stress fibers. Development. 2011;138:3907–14. DOI: 10.1242/dev.070987
Kawashima I, Kawamura K. Regulation of follicle growth through hormonal factors and mechanical cues mediated by hippo signaling pathway. Syst Biol Reprod Med. Taylor & Francis; 2018;64:3–11. Available from: https://doi.org/10.1080/19396368.2017.1411990.
Pan D. Hippo signaling in organ size control. Genes Dev. 2007;21:886–97. DOI: 10.1101/gad.1536007
Durlinger ALL, Gruijters MJG, Kramer P, Karels B, Ingraham HA, Nachtigal MW, et al. Anti-Müllerian hormone inhibits initiation of primordial follicle growth in the mouse ovary. Endocrinology. 2002;143:1076–84.
Yang MY, Cushman RA, Fortune JE. Anti-Müllerian hormone inhibits activation and growth of bovine ovarian follicles in vitro and is localized to growing follicles. Mol Hum Reprod. 2017;23:282–91. DOI: 10.1093/molehr/gax010
Carlsson IB, Scott JE, Visser JA, Ritvos O, Themmen APN, Hovatta O. Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Hum Reprod. 2006;21:2223–7. DOI: 10.1093/humrep/del165
Schmidt KLT, Kryger-Baggesen N, Byskov AG, Andersen CY. Anti-Müllerian hormone initiates growth of human primordial follicles in vitro. Mol Cell Endocrinol. 2005;234:87–93. DOI: 10.1016/j.mce.2004.12.010
Pangas SA. Regulation of the ovarian reserve by members of the transforming growth factor beta family. Mol Reprod Dev. 2012;79:666–79. DOI: 10.1002/mrd.22076
Dunlop CE, Anderson RA. The regulation and assessment of follicular growth. Scand J Clin Lab Invest. Taylor & Francis. 2014;74:13–7. DOI: 10.3109/00365513.2014.936674
Masciangelo R, Hossay C, Chiti MC, Manavella DD, Amorim CA, Donnez J, et al. Role of the PI3K and Hippo pathways in follicle activation after grafting of human ovarian tissue. J Assist Reprod Genet. 2019;10:6–13.
Gosden RG, Mullan J, Picton HM, Yin H, Tan SL. Current perspective on primordial follicle cryopreservation and culture for reproductive medicine. Hum Reprod Update. 2002;8:105–10. DOI: 10.1093/humupd/8.2.105
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. Hum Reprod. 2014;29:989–96. DOI: 10.1093/humrep/deu015
Ayuandari S, Winkler-Crepaz K, Paulitsch M, Wagner C, Zavadil C, Manzl C, et al. Follicular growth after xenotransplantation of cryopreserved/thawed human ovarian tissue in SCID mice: dynamics and molecular aspects. J Assist Reprod Genet. 2016;33:1585–93. Available from:. 10.1007/s10815-016-0769-2. DOI: 10.1007/s10815-016-0769-2
Silber SJ, DeRosa M, Goldsmith S, Fan Y, Castleman L, Melnick J. Cryopreservation and transplantation of ovarian tissue: results from one center in the USA. J Assist Reprod Genet. 2018;35:2205–13. Available from:. 10.1007/s10815-018-1315-1. DOI: 10.1007/s10815-018-1315-1
David A, Van Langendonckt A, Gilliaux S, Dolmans MM, Donnez J, Amorim CA. Effect of cryopreservation and transplantation on the expression of kit ligand and anti-Mllerian hormone in human ovarian tissue. Hum Reprod. 2012;27:1088–95. DOI: 10.1093/humrep/des013
Amorim CA, David A, Dolmans MM, Camboni A, Donnez J, Van Langendonckt A. Impact of freezing and thawing of human ovarian tissue on follicular growth after long-term xenotransplantation. J Assist Reprod Genet. 2011;28:1157–65. DOI: 10.1007/s10815-011-9672-z
Gavish Z, Spector I, Peer G, Schlatt S, Wistuba J, Roness H, et al. Follicle activation is a significant and immediate cause of follicle loss after ovarian tissue transplantation. J Assist Reprod Genet. 2018;35:61–9.
Dolmans MM, Martinez-Madrid B, Gadisseux E, Guiot Y, Yuan WY, Torre A, et al. Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice. Reproduction. 2007;134:253–62.
Salama M, Isachenko V, Isachenko E, Rahimi G, Mallmann P. Updates in preserving reproductive potential of prepubertal girls with cancer: systematic review. Crit Rev Oncol Hematol. Elsevier Ireland ltd; 2016;103:10–21. Available from: https://doi.org/10.1016/j.critrevonc.2016.04.002.
Hovatta O. Methods for cryopreservation of human ovarian tissue. Reprod BioMed Online. Reproductive healthcare ltd, duck end farm, dry Drayton, Cambridge CB23 8DB, UK; 2005;10:729–34. Available from: https://doi.org/10.1016/S1472-6483(10)61116-9.
Visser JA, de Jong FH, Laven JSE, Themmen APN. Anti-Müllerian hormone: a new marker for ovarian function. Reproduction. 2006;131:1–9. DOI: 10.1530/rep.1.00529
Celik S, Celikkan FT, Ozkavukcu S, Can A, Celik-Ozenci C. Expression of inhibitor proteins that control primordial follicle reserve decreases in cryopreserved ovaries after autotransplantation. J Assist Reprod Genet. 2018;35:615–26. DOI: 10.1007/s10815-018-1140-6
Masciangelo R, Hossay C, Donnez J, Dolmans MM. Does the Akt pathway play a role in follicle activation after grafting of human ovarian tissue? Reprod BioMed Online. Elsevier ltd; 2019;39:196–8. Available from: https://doi.org/10.1016/j.rbmo.2019.04.007.
Greve T, Schmidt KT, Kristensen SG, Ernst E, Andersen CY. Evaluation of the ovarian reserve in women transplanted with frozen and thawed ovarian cortical tissue. Fertil Steril. Elsevier Inc.; 2012;97:1394-1398.e1. Available from: https://doi.org/10.1016/j.fertnstert.2012.02.036.
Andersen ST, Pors SE, Poulsen L la C, Colmorn LB, Macklon KT, Ernst E, et al. Ovarian stimulation and assisted reproductive technology outcomes in women transplanted with cryopreserved ovarian tissue: a systematic review. Fertil Steril. Elsevier Inc.; 2019;112:908–21. Available from: https://doi.org/10.1016/j.fertnstert.2019.07.008.
Silber S. Unifying theory of adult resting follicle recruitment and fetal oocyte arrest. Reprod BioMed Online. Reproductive healthcare ltd.; 2015;31:472–5. Available from: https://doi.org/10.1016/j.rbmo.2015.06.022.
Silber S, Pineda J, Lenahan K, Derosa M, Melnick J. Fresh and cryopreserved ovary transplantation and resting follicle recruitment. Reprod BioMed Online. Reproductive healthcare ltd.; 2015;30:643–50. Available from: https://doi.org/10.1016/j.rbmo.2015.02.010.
Lass A, Paul M, Margara R, Winston RML. Women with one ovary have decreased response to GnRHa/HMG ovulation induction protocol in IVF but the same pregnancy rate as women with two ovaries. Hum Reprod. 1997;12:298–300. DOI: 10.1093/humrep/12.2.298
Shah JS, Sabouni R, Cayton Vaught KC, Owen CM, Albertini DF, Segars JH. Biomechanics and mechanical signaling in the ovary: a systematic review. J Assist Reprod Genet. 2018;35:1135–48. DOI: 10.1007/s10815-018-1180-y
Grosbois J, Demeestere I. Dynamics of PI3K and hippo signaling pathways during in vitro human follicle activation. Hum Reprod. 2018;33:1705–14. DOI: 10.1093/humrep/dey250
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. DOI: 10.1093/humrep/dey354
Adib S, Valojerdi MR, Alikhani M. Dose optimisation of PTEN inhibitor, bpV (HOpic), and SCF for the in-vitro activation of sheep primordial follicles. Growth Factors. Taylor & Francis; 2019;37:178–89. Available from: https://doi.org/10.1080/08977194.2019.1680661.
Cheng Y, Kim J, Li XX, Hsueh AJ. Promotion of ovarian follicle growth following mTOR activation: synergistic effects of AKT stimulators. Yan W, editor. PLoS One. 2015;10:e0117769. Available from: https://doi.org/10.1371/journal.pone.0117769
Reddy P, Liu L, Adhikari D, Jagarlamudi K, Rajareddy S, Shen Y, et al. Oocyte-specific deletion of Pten causes premature activation of the primordial follicle pool. Science. 2008;319:611–3. Available from:. 10.1126/science.1152257. DOI: 10.1126/science.1152257
Hu L-L, Su T, Luo R-C, Zheng Y-H, Huang J, Zhong Z-S, et al. Hippo pathway functions as a downstream effector of AKT signaling to regulate the activation of primordial follicles in mice. J Cell Physiol. 2018;234:1578–87. Available from:. https://doi.org/10.1002/jcp.27024.
Xie Y, Li S, Zhou L, Lin H, Jiao X, Qiu Q, et al. Rapamycin preserves the primordial follicle pool during cisplatin treatment in vitro and in vivo. Mol Reprod Dev. 2020;87:442–53. Available from:. https://doi.org/10.1002/mrd.23330.
Grosbois J, Vermeersch M, Devos M, Clarke HJ, Demeestere I. Ultrastructure and intercellular contact-mediated communication in cultured human early stage follicles exposed to mTORC1 inhibitor. Mol Hum Reprod. 2019;25:706–16. Available from: https://doi.org/10.1093/molehr/gaz053.
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. Proc Natl Acad Sci. 2013;110:17474–9. Available from: https://doi.org/10.1073/pnas.1312830110.
Devos M, Grosbois J, Demeestere I. Interaction between PI3K/AKT and hippo pathways during in vitro follicular activation and response to fragmentation and chemotherapy exposure using a mouse immature ovary model. Biol Reprod. 2019:1–37. Available from: https://doi.org/10.1093/biolre/ioz215.
Kong HS, Kim SK, Lee J, Youm HW, Lee JR, Suh CS, et al. Effect of exogenous anti-Müllerian hormone treatment on cryopreserved and transplanted mouse ovaries. Reprod Sci. 2016;23:51–60. Available from:. 10.1177/1933719115594021. DOI: 10.1177/1933719115594021
Detti L, Fletcher NM, Saed GM, Sweatman TW, Uhlmann RA, Pappo A, et al. Xenotransplantation of pre-pubertal ovarian cortex and prevention of follicle depletion with anti-Müllerian hormone (AMH). J Assist Reprod Genet. 2018;35:1831–41. Available from:. https://doi.org/10.1007/s10815-018-1260-z.
Man L, Park L, Bodine R, Ginsberg M, Zaninovic N, Man OA, et al. Engineered endothelium provides angiogenic and paracrine stimulus to grafted human ovarian tissue. Sci Rep. Springer US; 2017;7:1–11. Available from: https://doi.org/10.1038/s41598-017-08491-z.
Zhang X m, Li L, Xu J j, Wang N, Liu W j, Lin X h, et al. Rapamycin preserves the follicle pool reserve and prolongs the ovarian lifespan of female rats via modulating mTOR activation and sirtuin expression. Gene. 2013;523:82–7. DOI: 10.1016/j.gene.2013.03.039
Yorino Sato, Kawamura K. Rapamycin treatment maintains developmental potential of oocytes in mice and follicle reserve in human cortical fragments grafted into immune-deficient mice. Mol Cell Endocrinol. Elsevier; 2020;504:110694. Available from: https://doi.org/10.1016/j.mce.2019.110694.
Ciołczyk-Wierzbicka D, Gil D, Laidler P. Treatment of melanoma with selected inhibitors of signaling kinases effectively reduces proliferation and induces expression of cell cycle inhibitors. Med Oncol. Springer US; 2018;35:1–9. Available from: https://doi.org/10.1007/s12032-017-1069-0.
Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, et al. Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep. 2018;39:1523–31.
Liu Q, Zhou X, Li C, Zhang X, Li CL. Rapamycin promotes the anticancer action of dihydroartemisinin in breast cancer MDA-MB-231 cells by regulating expression of Atg7 and DAPK. Oncol Lett. 2018;15:5781–6.
Martelli AM, Chiarini F, Evangelisti C, Cappellini A, Buontempo F, Bressanin D, et al. Two hits are better than one: targeting both phosphatidylinositol 3-kinase and mammalian target of rapamycin as a therapeutic strategy for acute leukemia treatment. Oncotarget. 2012;3:371–94.
Steelman LS, Martelli AM, Cocco L, Libra M, Nicoletti F, Abrams SL, et al. The therapeutic potential of mTOR inhibitors in breast cancer. Br J Clin Pharmacol. 2016;82:1189–212.
