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Xenotransplantation of pre-pubertal ovarian cortex and prevention of follicle depletion with anti-Müllerian hormone (AMH)

  • Fertility Preservation
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Objective

To determine whether recombinant AMH (rAMH) could prevent post-transplant follicular depletion by acting on the stemness markers Oct-4, Sox2, and NANOG.

Materials and methods

This was an experimental study where 12 ovariectomized nude mice were xenotransplanted with vitrified/warmed ovarian cortex obtained from a pre-pubertal girl and Alzet pumps delivering rAMH, or placebo (control), were inserted intra-abdominally. Previously vitrified/warmed ovarian cortex fragments were transplanted after 7 days and then harvested after 14 days from pump placement. We performed real-time RT-PCR analyses, ELISA for AMH, FSH, and estradiol, histologic measurement of ovarian follicles, and immunohistochemistry for Ki67 and TUNEL. The main outcome measures were serum levels and tissue expression of the parameters under investigation and follicle count.

Results

Serum AMH, FSH, and estradiol reflected post-ovariectomy profiles and were mildly influenced by rAMH administration. Ovarian cortex expression of AMH, AMH-R2, VEGF, GDF9, Oct-4, and Sox2 was lower in rAMH mice than in controls, while NANOG was upregulated. There was a non-significant decrease in primordial follicles after vitrification-warming, and xenotransplantation further decreased this number. There were lower cell replication and depressed apoptosis in the rAMH group.

Conclusions

Administration of recombinant AMH in the peri-transplant period did not protect the initial follicular depletion but decreased apoptosis and cellular activation and regulated stem cell markers’ tissue expression. These results aid our understanding of the inhibitory effects of AMH on follicular development and show the benefit of administering exogenous AMH at the time of pre-pubertal ovarian cortex transplant to protect the follicles from pre-activation and premature depletion.

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References

  1. 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;104:1097–8. https://doi.org/10.1016/j.fertnstert.2015.08.005.

    Article  PubMed  Google Scholar 

  2. Jadoul P, Dolmans MM, Donnez J. Fertility preservation in girls during childhood: is it feasible, efficient and safe and to whom should it be proposed? Hum Reprod Update. 2010;16:617–30.

    Article  PubMed  Google Scholar 

  3. Childhood cancer survival statistics 1973–2014. http://seer.cancer.gov. Released 4/4/2017. Accessed August 1, 2017.

  4. Green DM, Kawashima T, Stovall M, Leisenring W, Sklar CA, Mertens AC, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2009;27:2677–85. https://doi.org/10.1200/JCO.2008.20.1541.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Corkum KS, Laronda MM, Rowell EE. A review of reported surgical techniques in fertility preservation for prepubertal and adolescent females facing a fertility threatening diagnosis or treatment. Am J Surg. 2017;214:695–700. https://doi.org/10.1016/j.amjsurg.2017.06.013.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Liu J, Van der Elst J, Van den Broecke R, Dhont M. Early massive follicle loss and apoptosis in heterotopically grafted newborn mouse ovaries. Hum Reprod. 2002;17:605–11.

    Article  PubMed  Google Scholar 

  7. Gook DA, Edgar DH. Cryopreservation of the human female gamete: current and future issues. Hum Reprod. 1999;14:2938–40.

    Article  CAS  PubMed  Google Scholar 

  8. Van Eyck AS, Bouzin C, Feron O, Romeu L, Van Langendonckt A, Donnez J, et al. Both host and graft vessels contribute to revascularization of xenografted human ovarian tissue in a murine model. Fertil Steril. 2010;93:1676–85.

    Article  PubMed  Google Scholar 

  9. 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. 2017 Nov 3;35:61–9. https://doi.org/10.1007/s10815-017-1079-z.

    Article  PubMed  Google Scholar 

  10. Gook DA, McCully BA, Edgar DH, McBain JC. Development of antral follicles in human cryopreserved ovarian tissue following xenografting. Hum Reprod. 2001;16:417–22.

    Article  CAS  PubMed  Google Scholar 

  11. Flaws JA, Abbud R, Mann RJ, Nilson JH, Hirshfield AN. Chronically elevated luteinizing hormone depletes primordial follicles in the mouse ovary. Biol Reprod. 1997;57:1233–7.

    Article  CAS  PubMed  Google Scholar 

  12. Maltaris T, Beckmann MW, Binder H, Mueller A, Hoffmann I, Koelbl H, et al. The effect of a GnRH agonist on cryopreserved human ovarian grafts in severe combined immunodeficient mice. Reproduction. 2007;133:503–9.

    Article  CAS  PubMed  Google Scholar 

  13. Oktem O, Oktay K. The role of extracellular matrix and activin-A in in vitro growth and survival of murine preantral follicles. Reprod Sci. 2007;14:358–66.

    Article  CAS  PubMed  Google Scholar 

  14. Soleimani R, Heytens E, Oktay K. Enhancement of neoangiogenesis and follicle survival by sphingosine-1-phosphate in human ovarian tissue xenotransplants. PLoS One. 2011;6:e19475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abir R, Fisch B, Jessel S, Felz C, Ben-Haroush A, Orvieto R. Improving posttransplantation survival of human ovarian tissue by treating the host and graft. Fertil Steril. 2011;95:1205–10.

    Article  PubMed  Google Scholar 

  16. Yu J, Yaba A, Kasiman C, Thomson T, Johnson J. mTOR controls ovarian follicle growth by regulating granulosa cell proliferation. PLoS One. 2011;6:e21415. https://doi.org/10.1371/journal.pone.0021415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhang J, Liu W, Sun X, Kong F, Zhu Y, Lei Y, et al. Inhibition of mTOR signaling pathway delays follicle formation in mice. J Cell Physiol. 2017;232:585–95. https://doi.org/10.1002/jcp.25456.

    Article  CAS  PubMed  Google Scholar 

  18. Detti L, Fletcher NM, Saed GM, Peregrin-Alvarez I, Uhlmann RA. Anti-Mullerian hormone (AMH) may stall ovarian cortex function by receptor downregulation. In Press, Reprod Scien. 2017.

  19. Detti L, Fletcher NM, Uhlmann RA, Saed GM. Recombinant anti-Mullerian hormone (AMH) regulates ovarian cortex’s stemness potential in fresh and vitrified/thawed ovarian cortex, Under revision. Syst Biol Reprod Med. 2017.

  20. Kano M, Sosulski AE, Zhang L, Saatcioglu HD, Wang D, Nagykery N, et al. AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy. Proc Natl Acad Sci U S A. 2017;28(114):E1688–97. https://doi.org/10.1073/pnas.1620729114.

    Article  CAS  Google Scholar 

  21. Parry RL, Chin TW, Epstein J, Hudson PL, Powell DM, Donahoe PK. Recombinant human mullerian inhibiting substance inhibits human ocular melanoma cell lines in vitro and in vivo. Cancer Res. 1992;52:1182–6.

    CAS  PubMed  Google Scholar 

  22. Bullwinkel J, Baron-Lühr B, Lüdemann A, Wohlenberg C, Gerdes J, Scholzen T. Ki-67 protein is associated with ribosomal RNA transcription in quiescent and proliferating cells. J Cell Physiol. 2006;206:624–35.

    Article  CAS  PubMed  Google Scholar 

  23. Detti L, Uhlmann RA, Lu M, Zhang J, Diamond MP, Saed GM, et al. Serum markers of ovarian reserve and ovarian histology in adult mice treated with cyclophosphamide in pre-pubertal age. J Assist Reprod Genet. 2013;30:1421–9.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Griesinger G, Dafopoulos K, Buendgen N, Cascorbi I, Georgoulias P, Zavos A, et al. Elimination half-life of anti-Müllerian hormone. J Clin Endocrinol Metab. 2012;97:2160–3. https://doi.org/10.1210/jc.2012-1070.

    Article  CAS  PubMed  Google Scholar 

  25. Naunton M, Al Hadithy AFY, Brouwers JRBJ, Archer DF. Estradiol gel. Menopause. 2006;13:517–27. https://doi.org/10.1097/01.gme.0000191881.52175.8c.

    Article  PubMed  Google Scholar 

  26. Pellatt L, Rice S, Dilaver N, Heshri A, Galea R, Brincat M, et al. Anti-Müllerian hormone reduces follicle sensitivity to follicle-stimulating hormone in human granulosa cells. Fertil Steril. 2011;96:1246–1251.e1.

    Article  CAS  PubMed  Google Scholar 

  27. Hayes E, Kushnir V, Mia X, Biswas A, Prizant H, Gleicher N, et al. Intracellular mechanism of anti-Mullerian hormone (AMH) in regulation of follicular development. Mol Cell Endocrinol. 2016;433:56–65.

    Article  CAS  PubMed  Google Scholar 

  28. Fisher TE, Molskness TA, Villeda A, Zelinski MB, Stouffer RL, Xu J. Vascular endothelial growth factor and angiopoietin production by primate follicles during culture is a function of growth rate, gonadotrophin exposure and oxygen milieu. Hum Reprod. 2013;28:3263–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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. https://doi.org/10.1177/1933719115594021.

    Article  CAS  PubMed  Google Scholar 

  30. Di Clemente N, Goxe B, Remy JJ, et al. Inhibitory effect of AMH upon aromatase activity and LH receptors of granulosa cells of rat and porcine immature ovaries. Endocrine. 1994;2:553–8.

    Google Scholar 

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Acknowledgements

This study was supported by an institutional grant from the University of Tennessee Health Science Center, Memphis, TN (E07-3225-001).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, University of Tennessee Health Science Center, Memphis, TN, USA

    Laura Detti & Irene Peregrin-Alvarez

  2. Department of Surgery, University of Texas Rio Grande Valley, Edinburg, TX, USA

    Laura Detti

  3. Division of Reproductive Endocrinology and Infertility, Rout Center, 853 Jefferson Ave, Rm E102, Memphis, TN, 38163, USA

    Laura Detti

  4. The C. S. Mott Center for Human Growth and Development, Wayne State University School of Medicine, Detroit, MI, USA

    Nicole M. Fletcher, Ghassan M. Saed & Rebecca A. Uhlmann

  5. Department of Pharmacology, University of Tennessee Health Science Center, Memphis, TN, USA

    Trevor W. Sweatman

  6. St. Jude Children’s Research Hospital, Memphis, TN, USA

    Alberto Pappo

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  1. Laura Detti
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  2. Nicole M. Fletcher
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Correspondence to Laura Detti.

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Detti, L., Fletcher, N.M., Saed, G.M. et al. Xenotransplantation of pre-pubertal ovarian cortex and prevention of follicle depletion with anti-Müllerian hormone (AMH). J Assist Reprod Genet 35, 1831–1841 (2018). https://doi.org/10.1007/s10815-018-1260-z

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  • DOI: https://doi.org/10.1007/s10815-018-1260-z

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