AMH AS PREDICTOR OF FOLLICLE FUNCTION DURING ENCAPSULATED 3D CULTURE IN MACAQUES

Oregon Health & Science University, Portland OR

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Ovarian failure is a common side-effect of radiation or chemotherapy treatment in girls and young women. In view of increasing survival rates, especially in breast cancer patients, long-term consequences of cancer treatments with respect to fertility are important considerations for quality of life after cancer. Novel strategies for protecting the ovaries from adverse effects of cancer therapies are currently under development. For example, direct ovarian exposure to sphingosine-I-phosphate (SIP) prior to radio-or chemotherapy in mice maintains the health and function of follicles and their enclosed oocytes from damage such that fertilization and birth of live offspring are possible. These studies have been extended to nonhuman primates wherein intraovarian infusion of SIP or SIP agonist prior to X-irradiation protects a cohort of follicles that leads to normal ovarian/menstrual cyclicity, production of mature oocytes capable of preimplantation embryonic development and live offspring devoid of DNA damage. One mechanism whereby SIP agonists confer ovarian protection involves the prevention of oocyte death by interference in the cell death pathway induced by radiation. We are investigating whether other ovarian cell types, i.e. follicular cells surrounding the oocyte and/or the ovarian vasculature, are also spared from the toxic effects of radiation with SIP agonist treatment in macaques. Preantral follicles isolated from macaque ovaries and encapsulated for 3-dimensional culture secrete steroids and local nonsteroidal factors (anti-Mullerian hormone [AMH], vascular endothelial growth factor [VEGF]) depending on duration and growth rate in culture. Early antral development is associated with increased steroid and VEGF, but decreased AMH, secretion. AMH levels did not correlate with oocyte maturation or health. Thus, the pattern of follicle growth, but not oocyte maturation, can be determined from AMH levels during the first 2 weeks of culture. Efforts continue to optimize a follicle culture system in macaques that can be translated to clinical use for fertility preservation in female cancer patients.