title: In vivo delivery of FTY720 prevents radiation-induced ovarian failure and infertility in adult female nonhuman primates.
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.
  
  
  METHODS
  Research animal study.
  
  
  METHODS
  Research laboratory and teaching hospital.
  
  
  METHODS
  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.
  
  
  METHODS
  None.
  
  
  METHODS
  Ovarian histologic analysis, ovarian reserve measurements, and fertility in mating trials.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  S1P and its analogs hold clinical promise as therapeutic agents to preserve ovarian function and fertility in female cancer patients exposed to cytotoxic treatments.
authors.affiliation: Division of Reproductive Sciences, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon.
authors.forename: Mary B
authors.initials: MB
authors.lastname: Zelinski
authors.forename: Mark K
authors.initials: MK
authors.lastname: Murphy
authors.forename: Maralee S
authors.initials: MS
authors.lastname: Lawson
authors.forename: Andrea
authors.initials: A
authors.lastname: Jurisicova
authors.forename: K Y Francis
authors.initials: KY
authors.lastname: Pau
authors.forename: Natalia P
authors.initials: NP
authors.lastname: Toscano
authors.forename: Darla S
authors.initials: DS
authors.lastname: Jacob
authors.forename: John K
authors.initials: JK
authors.lastname: Fanton
authors.forename: Robert F
authors.initials: RF
authors.lastname: Casper
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Dertinger
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Tilly
mesh_terms: D000328:Adult; D000367:Age Factors; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007247:Infertility, Female / Q000473:pathology / Q000517:prevention & control*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D010049:Ovarian Diseases / Q000473:pathology / Q000517:prevention & control*; D010053:Ovary / Q000187:drug effects / Q000637:transplantation; D011247:Pregnancy; D011256:Pregnancy Outcome; D011409:Propylene Glycols / Q000008:administration & dosage*; D011833:Radiation Injuries, Experimental / Q000473:pathology / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D055815:Young Adult
chemical_list: D011409:Propylene Glycols; D011837:Radiation-Protective Agents; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine