Although modern, aggressive treatments using ionizing radiotherapy and chemotherapy destroy cancers, they can have lasting side effects, including elimination of germline cells in the testes and ovary, and hence infertility. Unlike young men who have a clinically proven option, the methods for fertility preservation for young women and girls remain experimental. The long-term goal of this project is to validate options for restoring fertility in female cancer survivors by preventing ovarian exposure to the gametotoxic effects of therapy (by removing and preserving biopsies) and returning gametes or embryos for fertility after eradicating the cancer. Translational studies will be performed in nonhuman primates to:
(Aim 1) Bioengineer a scaffold that supports the three-dimensional (3-D) architecture of the primate follicle and permits coordinated development of the follicle wall and oocyte in vitro;
(Aim 2) Evaluate the role of gonadotropic hormones and growth factors in promoting follicle growth and oocyte quality during 3-D culture;
(Aim 3) Optimize conditions for autotransplantation of ovarian cortex for coordinated follicle growth and oocyte maturation in vivo;
and (Aim 4) Assess the fertilization and embryonic potential of oocytes derived from in vitro matured follicles and transplanted ovarian cortical follicles in vivo. Immature follicles will be isolated from rhesus macaque ovaries and added to a 3-D matrix of alginate hydrogel and endogenous ECM components, as successfully employed for rodent follicles and extrapolated to the primate to permit growth. Various endocrine and local factors will be added to determine the appropriate milieu for follicle growth (somatic celh proliferation, antrum formation, follicular diameter), and differentiation (thecal development, estrogen secretion), as well as maturation of its enclosed cumulus-oocyte complex. Ovarian cortical samples will be autotransplanted to readily accessible sites and the ability of pro-angiogenic factors to promote restoration of ovarian function, i.e., antral follicle growth and menstrual cyclicity, will be monitored. Finally, mature oocytes produced by follicles in vitro and cortical transplants in vivo will be collected and evaluated for reproductive potential by in vitro fertilization, embryo transfer into surrogate macaque mothers, pregnancy initiation and health of offspring. This project will be facilitated by interactions with Oncofertility Consortium and include Dr. L. Shea and the Biomaterials Core P30A at Northwestern University, and provide samples for parallel studies on cryopreservation of primate samples to Dr. J. Critser and RO1A at the University of Missouri. The expected advances in promoting primate follicle growth in vitro, and alternatively optimizing ovarian cortical transplantation and growth in vivo, will be transferred rapidly to clinical efforts directed by Dr. T. Woodruff and the Fertility Center sites in RO1C and the National Physcians Cooperative in P30B, to promote fertility restoration in female cancer survivors.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Linked Research project Grant (RL1)
Project #
5RL1HD058294-05
Application #
8097317
Study Section
Special Emphasis Panel (ZRR1-SRC (99))
Program Officer
Lamar, Charisee A
Project Start
2007-09-30
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$661,751
Indirect Cost
Name
Oregon Health and Science University
Department
Physiology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Xu, Jing; McGee, Whitney K; Bishop, Cecily V et al. (2015) Exposure of female macaques to Western-style diet with or without chronic T in vivo alters secondary follicle function during encapsulated 3-dimensional culture. Endocrinology 156:1133-42
Rodrigues, J K; Navarro, P A; Zelinski, M B et al. (2015) Direct actions of androgens on the survival, growth and secretion of steroids and anti-Müllerian hormone by individual macaque follicles during three-dimensional culture. Hum Reprod 30:664-74
Xu, Jing; Xu, Min; Bernuci, Marcelo P et al. (2013) Primate follicular development and oocyte maturation in vitro. Adv Exp Med Biol 761:43-67
Peluffo, Marina C; Hennebold, Jon D; Stouffer, Richard L et al. (2013) Oocyte maturation and in vitro hormone production in small antral follicles (SAFs) isolated from rhesus monkeys. J Assist Reprod Genet 30:353-9
Telfer, Evelyn E; Zelinski, Mary B (2013) Ovarian follicle culture: advances and challenges for human and nonhuman primates. Fertil Steril 99:1523-33
Woodruff, Teresa K (2013) From the bench to bedside to babies: translational medicine made possible by funding multidisciplinary team science. J Assist Reprod Genet 30:1249-53
Xu, J; Lawson, M S; Yeoman, R R et al. (2013) Fibrin promotes development and function of macaque primary follicles during encapsulated three-dimensional culture. Hum Reprod 28:2187-200
McDade, Thomas W; Woodruff, Teresa K; Huang, Yuan-yen et al. (2012) Quantification of anti-Mullerian hormone (AMH) in dried blood spots: validation of a minimally invasive method for assessing ovarian reserve. Hum Reprod 27:2503-8
Peluffo, Marina C; Ting, Alison Y; Zamah, Alberuni M et al. (2012) Amphiregulin promotes the maturation of oocytes isolated from the small antral follicles of the rhesus macaque. Hum Reprod 27:2430-7
Xu, J; Lawson, M S; Yeoman, R R et al. (2011) Secondary follicle growth and oocyte maturation during encapsulated three-dimensional culture in rhesus monkeys: effects of gonadotrophins, oxygen and fetuin. Hum Reprod 26:1061-72

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