Mary B. Zelinski
The follicle is the functional unit of the ovary that consists of the centrally located oocyte (egg) surrounded by somatic cells (granulosa cells and theca cells) whose purpose is to nourish the oocyte and produce hormones such as estradiol (needed for female characteristics as well as bone, brain and cardiac health) and progesterone (essential for establishing pregnancy). Follicles begin their journey of development as primordial follicles that either eventually grow and mature to become the single dominant follicle that ovulates an oocyte during the menstrual cycle making it available for fertilization, or they degenerate and die at many stages of their developmental continuum. Nonhuman primates, such as the female rhesus and cynomolgus monkey, have ovarian and menstrual cycles similar to women, thus they are the ideal model in which to study issues associated with women's reproductive health. Understanding how oocytes and follicles grow and function is integral to developing clinical therapies to alleviate infertility, a major side effect of cancer treatments, or to control fertility with new female contraceptives. Over the past three decades, Dr. Zelinski's studies encompass nonhuman primate models of reproductive physiology that includes both infertility and contraceptive research. She has also developed numerous outreach activities to engage students of all ages in learning about reproduction and the importance of animals in biomedical research.
The American Cancer Society estimated that 1 in 52 human females between birth and age 39 – that is, the pre-reproductive and reproductive years – are diagnosed with cancer per year. Currently, 1 in 250 people in the U.S. will be survivors of childhood cancer. Many patients will be treated with chemo- and/or radiation therapy. Premature ovarian failure and infertility are well-known side-effects of many cancer treatments. The ultimate goal of our work is to develop safe and effective methods for protecting female ovaries that contain follicles and their enclosed oocytes (eggs) from side-effect damage caused by anti-cancer therapies. With collaborators in Boston, we tested agents administered directly to the ovary to see if they can protect follicles and oocytes from X-irradiation, and also whether normal offspring can be born after ovarian protection prior to ovarian X-irradiation in the mothers. Future studies will test other promising ferto-protectants in the macaque model. With collaborators in the Oncofertility Consortium (http://oncofertility.northwestern.edu/) we have established a method for growing monkey follicles in a bioengineered alginate matrix that maintains the 3-dimensional architecture of the follicle, evaluating autotransplantation of ovarian cortex to readily accessible sites in primates, and optimizing vitrification, i.e. cryopreservation methods for preserving ovarian tissue for subsequent transplantation or for 3-dimensional follicle culture. Our ultimate goal is to demonstrate in nonhuman priamtes that each method will safely yield oocytes that can fertilize and lead to normal offspring, thus providing the basis for clinical options for fertility preservation when cancer survivors decide to become parents.
We developed a low dose treatment of a specific progesterone receptor modulator in female rhesus monkeys that permits normal ovarian and menstrual cycles, prevents pregnancy, and is reversible. These studies provided the basis for use of this female contraceptive in China. A Contraceptive Development Research Center was established in the Division of Reproductive & Developmental Sciences to further develop novel female contraceptives that act at specific sites in the ovary or reproductive tract. In the Nonhuman Primate Contraceptive Core, we conduct contraceptive and reversibility trials of the drugs developed for female contraception in each project in the Contraceptive Center. We are testing agents that 1) block oocyte meiosis thereby preventing fertilization; 2) prevent follicle rupture/ovulation such that there is no release of an oocyte for fertilization, and 3) inhibit oocyte/embryo transport or fertilization within the oviduct as well as sperm transport via the cervix, thereby providing multiple novel approaches to female contraception. We also collaborate with investigators developing novel male contraceptives by providing expertise in the nonhuman primate model for assessing the efficacy of these agents to block sperm production or competence for fertilization in a reversible manner.
Science Education Outreach
We recently launched the "ART of Reproductive Medicine" curriculum (http://www.ohsu.edu/xd/research/centers-institutes/onprc/public-outreach/oncofertility-curriculum.cfm). This curriculum was developed to attract, prepare and retain high school students in science majors and careers as part of the National Institutes of Health (NIH) Interdisciplinary Research Consortium grant which funded the Oncofertility National Science Education Network (ONSEN) and more recently, as part of the National Institutes of Health(NIH) National Centers for Translational Research in Reproduction and Infertility (NCTRI). The curriculum includes teacher background, slide shows and lab activities designed to enhance high school and junior college biology courses. The curriculum was originally designed around the theme of "oncofertility", but currently also focuses on biomedical aspects of alleviating many other causes of human infertility. The curriculum provides opportunities to teach not only topics of general biology (meiosis, mitosis, cancer, male and female reproductive physiology), but to tie them to "real-life" clinical applications and current research on infertility, fertility preservation, cryobiology, ethics of reproductive technologies and more.
Mary Zelinski is a Research Associate Professor in the Division of Reproductive & Developmental Sciences, Oregon National Primate Research Center, and an Associate Professor in the Department of Obstetrics & Gynecology, Oregon Health & Science University. She received her B.S. degree in Dairy Science from the University of Wisconsin in 1976, and both her M.S. in 1979 and a Ph.D. in 1986 in Animal Science-Reproductive Physiology from Oregon State University. Dr. Zelinski has also conducted reproductive research in the Department of Physiology at the University of California at Davis and then came to ONPRC in 1987 as a Lalor Foundation post-doctoral fellow.
Ting, A.Y., Mullen, S.F., Zelinski, M.B.(2016) Vitrification of ovarian tissue for fertility preservation. In: Gosiengfiao YC, Woodruff TK. Pediatric and Adolescent Oncofertility: Best Practices and Emerging Technologies. Springer, SPi Global, Chennai, India, in press.
Roti Roti, E., Salih, S., Zelinski, M.B. (2015) In vivo models of ovarian toxicity. In: Spears N and Anderson RA (eds.), Cancer treatment and the ovary: clinical and laboratory analysis of ovarian toxicity, Elsevier Academic Press, London, pp. 65-79.
Castle, M., Cleveland, C., Gordon, D., Jones, L., Zelinski, M.B., Winter, P., Chang, J., Senegar-Mitchell, E., Coutifaris, C., Shuda, J., Mainigi, M., Bartolomei, M., Woodruff, T.K. (2016) Reproductive science for high school students: a shared curriculum model to enhance student success. Biol Reprod July 2016 95 (1) 28, 1-4; published ahead of print June 22, 2016, doi:10.1095/biolreprod.116.139998