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Journal of Assisted Reproduction and Genetics

, Volume 34, Issue 11, pp 1427–1434 | Cite as

Subcutaneous ovarian tissue transplantation in nonhuman primates: duration of endocrine function and normalcy of subsequent offspring as demonstrated by reproductive competence, oocyte production, and telomere length

  • David M. LeeEmail author
  • Carrie M. Thomas
  • Fuhua Xu
  • Richard R. Yeoman
  • Jing Xu
  • Richard L. Stouffer
  • Don P. Wolf
  • Mary B. Zelinski
Fertility Preservation

Abstract

Purpose

The main purposes of the study were to investigate the endocrine function of ovarian tissue transplanted to heterotopic subcutaneous sites and the reproductive competence and telomere length of a nonhuman primate originating from transplanted tissue.

Methods

Ovarian cortex pieces were transplanted into the original rhesus macaques in the arm subcutaneously, in the abdomen next to muscles, or in the kidney. Serum estradiol (E2) and progesterone (P4) concentrations were measured weekly for up to 8 years following tissue transplantation. A monkey derived from an oocyte in transplanted ovarian tissue entered time-mated breeding and underwent controlled ovarian stimulation. Pregnancy and offspring were evaluated. Telomere lengths and oocytes obtained following controlled ovarian stimulation were assessed.

Results

Monkeys with transplants in the arm and abdomen had cyclic E2 of 100 pg/ml, while an animal with arm transplants had E2 of 50 pg/ml. One monkey with transplants in the abdomen and kidney had ovulatory cycles for 3 years. A monkey derived from an oocyte in transplanted tissue conceived and had a normal gestation until intrapartum fetal demise. She conceived again and delivered a healthy offspring at term. Controlled ovarian stimulations of this monkey yielded mature oocytes comparable to controls. Her telomere length was long relative to controls.

Conclusions

Heterotopic ovarian tissue transplants yielded long-term endocrine function in macaques. A monkey derived from an oocyte in transplanted tissue was reproductively competent. Her telomere length did not show epigenetically induced premature cellular aging. Ovarian tissue transplantation to heterotopic sites for fertility preservation should move forward cautiously, yet optimistically.

Keywords

Ovarian tissue transplantation Steroid hormone Fertility Telomere Primate 

Notes

Acknowledgements

We are grateful for the assistance provided by members of the Division of Comparative Medicine, the Endocrine Technology Support Core, the ART Support Core, and the Biostatistics and Bioinformatics Unit at ONPRC. We appreciate Drs. Theodore R. Hobbs, Dave L. Hess, and Byung S. Park for their valuable expertise.

Funding

This work was supported by the National Institutes of Health (NIH) Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) UL1 RR024926 (the Oncofertility Consortium: RL1 HD058293, HD058295, PL1 EB008542), NIH NICHD through cooperative agreement as part of the Specialized Cooperative Center Program in Reproduction and Infertility Research U54 HD18185, NIH Office of the Director P51OD011092 (Oregon National Primate Research Center), and the Bidwell Foundation.

Compliance with ethical standards

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10815_2017_1019_MOESM1_ESM.docx (15 kb)
ESM 1 (DOCX 14.8 kb)
10815_2017_1019_MOESM2_ESM.docx (16 kb)
ESM 2 (DOCX 15.8 kb)

References

  1. 1.
    Meirow D, Nugent D. The effects of radiotherapy and chemotherapy on female reproduction. Hum Reprod Update. 2001;7:535–43.CrossRefPubMedGoogle Scholar
  2. 2.
    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;32:1167–70.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Müller A, Keller K, Wacker J, Dittrich R, Keck G, Montag M, et al. Retransplantation of cryopreserved ovarian tissue: the first live birth in Germany. Dtsch Arztebl Int. 2012;109:8–13.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Dunlop CE, Brady BM, McLaughlin M, Telfer EE, White J, Cowie F, et al. Re-implantation of cryopreserved ovarian cortex resulting in restoration of ovarian function, natural conception and successful pregnancy after haematopoietic stem cell transplantation for Wilms tumour. J Assist Reprod Genet. 2016;33:1615–20.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Van der Ven H, Liebenthron J, Beckmann M, Toth B, Korell M, Krüssel J, et al., on behalf of the FertiPROTEKT network. 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;9:2031–41.Google Scholar
  6. 6.
    Kim SS. Assessment of long term endocrine function after transplantation of frozen-thawed human ovarian tissue to the heterotopic site: 10 year longitudinal follow-up study. J Assist Reprod Genet. 2012;29:489–93.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Kim SS. Revisiting the role of heterotopic ovarian transplantation: futility or fertility. J Asst Reprod Genet. 2014;28:141–5.Google Scholar
  8. 8.
    Donnez J, Dolmans MM, Demylle D, Jadoul P, Pirard C, Squifflet J, et al. Livebirth after orthotopic transplantation of cryopreserved ovarian tissue. Lancet. 2004;364:1405–10.CrossRefPubMedGoogle Scholar
  9. 9.
    Meirow D, Levron J, Eldar-Geva T, Hardan I, Fridman E, Zalel Y, et al. Pregnancy after transplantation of cryopreserved ovarian tissue in a patient with ovarian failure after chemotherapy. New Eng J Med. 2005;355:318–21.CrossRefGoogle Scholar
  10. 10.
    Jensen AK, Macklon KT, Fedder J, Ernst E, Humaidan P, Andersen CY. 86 successful births and 9 ongoing pregnancies worldwide in women transplanted with frozen-thawed ovarian tissue: focus on birth and perinatal outcome in 40 of these children. J Assist Reprod Genet. 2017;34:325–36.CrossRefPubMedGoogle Scholar
  11. 11.
    Lee DM, Yeoman R, Battaglia DE, Stouffer RL, Fanton JW, Wolf DP. Birth of a monkey after heterotopic transplantation of fresh ovarian tissue and assisted reproduction. Nature. 2004;428:137–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Eppig JJ, O’Brien M. Development in vitro of mouse oocytes from primordial follicles. J Biol Reprod. 1996;54:197–207.CrossRefGoogle Scholar
  13. 13.
    Eppig JJ, O'Brien MJ, Wigglesworth K, Nicholson A, Zhang W, King BA. Effect of in vitro maturation of mouse oocytes on the health and lifespan of adult offspring. Hum Reprod. 2009;24:922–8.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Dennis C. Synthetic sex cells. Nature. 2003;424:364–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Blasco MA. The epigenetic regulation of mammalian telomeres. Nat Rev Genet. 2007;8:299–309.CrossRefPubMedGoogle Scholar
  16. 16.
    Xu J, Bernuci MP, Lawson MS, Yeoman RR, Fisher TE, Zelinski MB, et al. Survival, growth, and maturation of secondary follicles from prepubertal, young, and older adult rhesus monkeys during encapsulated three-dimensional culture: effects of gonadotropins and insulin. Reproduction. 2010;140:685–97.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Duffy DM, Stouffer RL. Follicular administration of a cyclooxygenase inhibitor can prevent oocyte release without alteration of normal luteal function in rhesus monkeys. Hum Reprod. 2002;17:2825–31.CrossRefPubMedGoogle Scholar
  18. 18.
    Zelinski MB, Murphy MK, Lawson MS, Juirisicova A, Pau KYF, Toscano NP, et al. In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates. Fertil Steril. 2011;95:1440–5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ouhibi N, Zelinski-Wooten MB, Thomson JA, Wolf DP. Assisted fertilization and nuclear transfer in nonhuman primates. In: Wolf DP, Zelinski-Wooten MB, editors. Contemporary endocrinology™ assisted fertilization and nuclear transfer in mammals. Totowa: Humana Press, Inc.; 2001. p. 253–84.CrossRefGoogle Scholar
  20. 20.
    Cawthon RM. Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 2009;37:e21.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lan Q, Cawthon R, Gao Y, Hu W, Hosgood HD III, Barone-Adesi F, et al. Longer telomere length in peripheral white blood cells is associated with risk of lung cancer and the rs2736100 (CLPTM1L-TERT) polymorphism in a prospective cohort study among women in China. PLoS One. 2013;8:e59230.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Demeestere I, Simon P, Emiliani S, Delbaere A, Englert Y. Orthotopic and heterotopic ovarian tissue transplantation. Hum Reprod Update. 2009;15:649–65.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Oktay K, Buyuk E, Rosenwaks Z, Rucinski J. A technique for transplantation of ovarian cortical strips to the forearm. Fertil Steril. 2003;80:193–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Li M, Zhao Y, Zhao CH, Yan J, Yan YL, Rong L, et al. High FSH decreases the developmental potential of mouse oocytes and resulting fertilized embryos, but does not influence offspring physiology and behavior in vitro or in vivo. Hum Reprod. 2013;28:1309–23.CrossRefPubMedGoogle Scholar
  25. 25.
    Fernández-Gonzalez R, Moreira P, Bilbao A, Jiménez A, Pérez-Crespo M, Ramírez MA, et al. Long-term effect of in vitro culture of mouse embryos with serum on mRNA expression of imprinting genes, development, and behavior. Proc Natl Acad Sci U S A. 2004;101:5880–5.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Keefe DL, Liu L, Marquard K. Telomeres and aging-related meiotic dysfunction in women. Cell Molec Life Sci. 2007;64:139–43.CrossRefPubMedGoogle Scholar
  27. 27.
    Keefe DL. Telomeres, reproductive aging, and genomic instability during early development. Reprod Sci. 2016;23:1612–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Guan J-Z, Guan W-P, Maeda T, Makino N. Different levels of hypoxia regulate telomere length and telomerase activity. Aging Clin Exp Res. 2012;24:213–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Guan J-Z, Guan W-P, Maeda T, Makino N. Alteration of telomere length and subtelomeric methylation in human endothelial cell under different levels of hypoxia. Arch Med Res. 2012;43:15–20.CrossRefPubMedGoogle Scholar
  30. 30.
    Minamino T, Mitsialis SA, Kourembanas S. Hypoxia extends the life span of vascular smooth muscle cells through telomerase activation. Mol Cell Biol. 2001;21:3336–42.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Davy P, Allsopp R. Hypoxia: are stem cells in it for the long run? Cell Cycle. 2011;10:206–11.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • David M. Lee
    • 1
    • 2
    Email author
  • Carrie M. Thomas
    • 1
  • Fuhua Xu
    • 1
    • 2
  • Richard R. Yeoman
    • 1
  • Jing Xu
    • 1
    • 2
    • 3
  • Richard L. Stouffer
    • 1
    • 2
  • Don P. Wolf
    • 1
    • 3
  • Mary B. Zelinski
    • 1
    • 2
  1. 1.Division of Reproductive & Developmental Sciences, Oregon National Primate Research CenterOregon Health & Science UniversityBeavertonUSA
  2. 2.Department of Obstetrics & Gynecology, School of MedicineOregon Health & Science UniversityPortlandUSA
  3. 3.Center for Embryonic Cell and Gene TherapyOregon Health & Science UniversityPortlandUSA

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