In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates

Mary Zelinski, Mark K. Murphy, Maralee S. Lawson, Andrea Jurisicova, K. Y Francis Pau, Natalia P. Toscano, Darla S. Jacob, John K. Fanton, Robert F. Casper, Stephen D. Dertinger, Jonathan L. Tilly

    Research output: Contribution to journalArticle

    56 Citations (Scopus)

    Abstract

    Objective: To determine whether sphingosine-1-phosphate (S1P), or the S1P mimetic FTY720 shields ovaries of adult female rhesus monkeys from damage caused by 15 Gy of targeted radiotherapy, allowing for the retention of long-term fertility, and to evaluate whether S1P protects human ovarian tissue (xenografted into mice) from radiation-induced damage. Design: Research animal study. Setting: Research laboratory and teaching hospital. Patient(s): Adult female rhesus macaques (8-14 years of age; n = 21) and two women (24 and 27 years of age) undergoing gynecologic surgery for benign reasons, after informed consent and approval. Intervention(s): None. Main Outcome Measure(s): Ovarian histologic analysis, ovarian reserve measurements, and fertility in mating trials. Result(s): Rapid ovarian failure was induced in female macaques by ovarian application of 15 Gy of radiation. Females given S1P or FTY720 by direct intraovarian cannulation for 1 week before ovarian irradiation rapidly resumed menstrual cycles because of maintenance of follicles, with greater beneficial effects achieved using FTY720. Monkeys given the S1P mimetic before ovarian irradiation also became pregnant in mating trials. Offspring conceived and delivered by radioprotected females developed normally and showed no evidence of genomic instability, as measured by micronucleus frequency in reticulocytes. Adult human ovarian cortical tissue xenografted into mice also exhibited a reduction in radiation-induced primordial oocyte depletion when preexposed to S1P. Conclusion(s): S1P and its analogs hold clinical promise as therapeutic agents to preserve ovarian function and fertility in female cancer patients exposed to cytotoxic treatments.

    Original languageEnglish (US)
    JournalFertility and Sterility
    Volume95
    Issue number4
    DOIs
    StatePublished - Mar 15 2011

    Fingerprint

    Infertility
    Primates
    Radiation
    Fertility
    Macaca mulatta
    Radiation Dosage
    Gynecologic Surgical Procedures
    Genomic Instability
    Reticulocytes
    Macaca
    Menstrual Cycle
    sphingosine 1-phosphate
    Fingolimod Hydrochloride
    Informed Consent
    Teaching Hospitals
    Catheterization
    Oocytes
    Haplorhini
    Ovary
    Research Design

    Keywords

    • cancer
    • Fertility preservation
    • FTY720
    • human
    • monkey
    • oocyte
    • ovary
    • sphingosine-1-phosphate

    ASJC Scopus subject areas

    • Obstetrics and Gynecology
    • Reproductive Medicine

    Cite this

    In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates. / Zelinski, Mary; Murphy, Mark K.; Lawson, Maralee S.; Jurisicova, Andrea; Pau, K. Y Francis; Toscano, Natalia P.; Jacob, Darla S.; Fanton, John K.; Casper, Robert F.; Dertinger, Stephen D.; Tilly, Jonathan L.

    In: Fertility and Sterility, Vol. 95, No. 4, 15.03.2011.

    Research output: Contribution to journalArticle

    Zelinski, M, Murphy, MK, Lawson, MS, Jurisicova, A, Pau, KYF, Toscano, NP, Jacob, DS, Fanton, JK, Casper, RF, Dertinger, SD & Tilly, JL 2011, 'In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates', Fertility and Sterility, vol. 95, no. 4. https://doi.org/10.1016/j.fertnstert.2011.01.012
    Zelinski, Mary ; Murphy, Mark K. ; Lawson, Maralee S. ; Jurisicova, Andrea ; Pau, K. Y Francis ; Toscano, Natalia P. ; Jacob, Darla S. ; Fanton, John K. ; Casper, Robert F. ; Dertinger, Stephen D. ; Tilly, Jonathan L. / In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates. In: Fertility and Sterility. 2011 ; Vol. 95, No. 4.
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    AU - Jurisicova, Andrea

    AU - Pau, K. Y Francis

    AU - Toscano, Natalia P.

    AU - Jacob, Darla S.

    AU - Fanton, John K.

    AU - Casper, Robert F.

    AU - Dertinger, Stephen D.

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